Available online at www.annclinlabsci.org Annals of Clinical & Laboratory Science, vol. 39, no. 2, 2009 167 Autoimmune Pancreatitis: Case Series and Review of the Literature.

Rada Shakov,1 Joseph R. DePasquale,1 Hossam Elfarra,2 and Robert S. Spira1 1Division of Gastroenterology, St. Michael’s Medical Center, Newark, New Jersey 2Division of Gastroenterology, St. Joseph’s Regional Medical Center, Paterson, New Jersey

Abstract. Autoimmune pancreatitis (AuP) is a chronic pancreatic inflammation secondary to an underlying autoimmune mechanism. After early reports of a particular type of pancreatitis associated with hypergammaglobulinemia, others asserted that there is an autoimmune mechanism involved in some patients with chronic pancreatitis. In 1995 AuP was first described as a distinct clinical entity. Since then, there have been many documented cases of AuP in Japan, and now, perhaps due to increased awareness, more cases are being reported in Europe and the United States. Herein we present our experience with 3 cases of AuP and we review the relevant literature. These 3 cases demonstrate the difficulties that exist in making the diagnosis of AuP and the impact that the diagnosis can have on patient management.

Keywords: autoimmune pancreatitis, lymphoplasmacytic pancreatitis, IgG4

Introduction AuP in Japan, and now, due to increased awareness, more cases are being reported [7,11-13]. The clinical entity that is now referred to as AuP Herein we describe 3 cases of AuP and we has been described by a variety of terms over the review the pertinent clinical and pathological last 4 decades. These include nonalcoholic duct- features of AuP. destructive chronic pancreatitis, lymphoplasmacytic sclerosing pancreatitis with cholangitis, chronic Case Series sclerosing pancreatitis, pseudotumorous pancrea- titis, duct-narrowing chronic pancreatitis, idio- Case 1. A 50-year-old Hispanic female presented with 5 days pathic duct destructive pancreatitis, primary of scleral icterus, pruritus, dark urine, clay colored stool, malaise, and fatigue. She denied nausea, vomiting, weight inflammatory pancreatitis, and, recently, idiopathic loss, or abdominal pain. Vital signs were stable and physical tumefactive chronic pancreatitis [1-8]. exam was benign. There was no history of alcohol abuse nor AuP is a chronic pancreatic inflammation did the patient have any medical conditions such as diabetes, secondary to an underlying autoimmune hypertension, or thyroid problems. mechanism. The initial recognition that pancreatitis Serum analytes revealed an elevated total bilirubin 8.1 mg/dl (reference range 0.2-1.3 mg/dl), direct bilirubin 5.9 can result from immune dysregulation was a report mg/dl (reference range 0.1-0.5 mg/dl), alkaline phosphatase in 1961 of a case of pancreatitis accompanied by (ALP) 562 IU/L (reference range 20-125 IU/L), aspartate hypergammaglobulinemia [9]. In 1995 the term aminotransferase (AST) 264 IU/L (reference range 3-35 IU/ “autoimmune pancreatitis” was used by Yoshida et L), alanine aminotransferase (ALT) 427 IU/L (reference range 3-40 IU/L), amylase 46 u/L (reference range 0-99 u/L), al [10], stating that it was a distinct disease. Since lipase 18 u/L (reference range 0-59 u/L), and prothrombin then there have been many documented cases of time (INR) of 1 (reference range 0.9-1.1). Autoimmune serologic tests, including anti-neutrophil antibody (ANA), Address correspondence to Rada Shakov, M.D., St. Michael’s perinuclear anti-neutrophil cytoplasmic antibody (pANCA), Medical Center, 268 Martin Luther King Boulevard, Newark, and anti-smooth muscle antibody (ASMA) were all negative. NJ 07102, USA; tel 718 915 2706; fax 973 877 2984; e-mail Ultrasound examination showed an enlarged, heterogeneous [email protected]. pancreas and a common bile duct (CBD) 1 cm in diameter, 0091-7370/09/0200-0167. $2.70. © 2009 by the Association of Clinical Scientists, Inc. 168 Annals of Clinical & Laboratory Science, vol. 39, no. 2, 2009

Fig. 1. CT of the abdomen demonstrating pancreatic Fig. 3. Pancreatic biopsy in case 1 shows fragments of prominence in case 1. fibroadipose tissue with lymphoplasma cells and few eosinophils (H&E stain, 30x).

Fig. 2. ERCP demonstrating proximal CBD dilatation along with a 4-cm distal stricture in case 1. without evidence of intrahepatic biliary dilatation. Cat scan Fig. 4. ERCP demonstrating apple-core appearance in the (CT) of the abdomen demonstrated a “prominent pancreas” distal biliary tree in case 2. (Fig. 1) and magnetic resonance imaging (MRI) showed a diffusely enlarged pancreas with heterogeneous enhancement. A pancreatic biopsy was obtained and pathologic Obstruction of the CBD at the pancreatic head was noted, as examination revealed fragments of fibroadipose tissue with well as splenic vein thrombosis. Endoscopic retrograde lymphoplasma cells and few eosinophils, without histologic cholangiopancreatography (ERCP) demonstrated a 4 cm evidence of lymphoma (Fig. 3). The patient was scheduled for distal stricture in the CBD along with proximal dilatation a Whipple’s procedure, but antecedent to that a trial of (Fig. 2). Sphincterotomy and placement of a plastic biliary prednisone (40 mg daily po) was started, since the diagnosis stent into the CBD were performed and antibiotic therapy of AuP was considered. Within weeks there was remarkable was initiated. improvement in the patient’s symptoms and normalization of Autoimmune pancreatitis 169 her liver function tests (LFT). On repeat MRI and ERCP, the Case 3. A 62-yr-old Caucasian male presented with abdominal pancreas and CBD had both returned to normal appearance. and epigastric pain with concomitant 12 lb weight loss. The patient also noticed yellowing of his skin and eyes. There was Case 2. A 57-yr-old Asian (South Indian) female presented a history of chronic alcohol abuse, although the extent and with weakness, unintentional 20 lb weight loss, dark urine, quantity were unclear. Medical history was significant for pruritus, and jaundice of several mo duration. There was no hypercholesterolemia and hypertriglyceridemia. Initial serum history of alcohol or illicit drug use and the medical history analyses showed total bilirubin 2.0 mg/dl, AST 23 IU/L, was significant only for hypertension. On physical exam she ALT 32 IU/L, albumin 4 g/dl, amylase 515 u/L, and lipase was a normotensive, afebrile, thin, female with obvious scleral 648 u/L. CT exam of the abdomen displayed fullness of the icterus. The abdominal exam was benign without evidence of pancreatic head without evidence of a discrete mass. A portion hepatomegaly or splenomegaly. of the pancreatic duct near the junction of the neck and body Initial serum analytes yielded a total bilirubin of 0.81 revealed moderate dilatation. mg/dl, ALP 342 IU/L, AST 41 IU/L, ALT 95 IU/L, amylase Approximately 1 mo later, the tests were repeated and 63 u/L, and lipase 35 u/L. On CT exam, the gallbladder was revealed a total bilirubin of 18.6 mg/dl, AST 354 u/l, ALP moderately distended with wall enhancement, but without 388 u/L, ALT 778 IU/L, direct bilirubin 12.3 mg/dl, positive gallstones or pericholecystic fluid. The pancreas was without ANA, and IgG subclass 4 of 113 mg/dl (reference range 1-115 focal or diffuse enlargement. On ultrasound exam, the CBD mg/dl). A mass (4.0 x 2.5 x 2 cm) at the pancreatic head was was dilated to 9 mm without evidence of intrahepatic biliary observed on abdominal ultrasound. The CBD was 1.18 cm dilatation. The LFT were repeated and autoimmune serologic with some intrahepatic prominence. Subsequent ERCP tests were obtained. The ALP was IU/L, AST 169 IU/L, and demonstrated a CBD stricture requiring stent placement. The ALT 224 IU/L. The ANA, ASMA, and anti-mitochondrial body of the pancreatic duct displayed beading with distortion antibody (AMA) tests were all negative; IgG, however, was of the secondary radicles. Following ERCP the patient under- elevated, 2,644 mg/dl (reference range 694-1,618 mg/dl). went endoscopic ultrasound (EUS) with fine needle aspiration MRI exam showed dilatation of the central intrahepatic and (FNA). Although there was no evidence of cancer, there were extrahepatic biliary ductal system with dilatation of the insufficient cells for sampling and a definitive diagnosis could gallbladder without calculi, a 1.4 cm CBD, and normal not be made. A few weeks later the patient was hospitalized pancreatic duct (PD). The pancreatic head was without signal with symptoms of cholangitis, which lead to replacement of abnormalities on T1 or T2 weighted sequences. ERCP the original stent. Due to the patient’s history of alcohol abuse demonstrated firm bulbous swelling of the major papilla and and radiologic findings, the differential diagnoses included tissue biopsies were obtained to rule out cholangiocarcinoma chronic pancreatitis and pancreatic malignancy. Surgery was or ampullary cancer. There was an area of irregular filling recommended based on the inconclusive findings. with an apple-core appearance in the distal biliary tree (Fig. The patient underwent a successful Whipple’s procedure 4). Brush cytology samples were obtained with subsequent and pathological findings were consistent with AuP. Following placement of a 7 cm straight plastic stent across the lesion.The surgery the patient had complete resolution of his symptoms ampullary biopsy revealed acute and chronic inflammation, although he was never treated with corticosteroids. marked reactive changes, and prominent lymphoid aggregates with extensive crush artifact and focal ill-defined epitheloid Clinical Features of AuP cell clusters. No evidence of carcinoma was identified. Because of the appearance of the distal biliary tree, specifically the apple-core lesion, the patient underwent a Patients with AuP may be completely asymptomatic successful Whipple’s procedure. After the surgery the patient or have mild abdominal discomfort without attacks was noted still to have jaundice, and laboratory analyses were of pancreatitis [14]. The most common clinical repeated. The total bilirubin and ALP were elevated, 5 mg/dl and 739 u/L, respectively. The cause of these elevations was presentation is painless obstructive jaundice, which unknown and an MRI was performed. There was no evidence is also a common presentation of pancreatic cancer. of intra- or extrahepatic biliary ductal dilatation nor any The biliary obstruction is secondary to autoimmune evidence of a filling defect. sclerosing cholangitis involving the bile duct [15]. Surgical pathological examinations of biopsies There appears to be an association with type 2 subsequently revealed multiple nodular lymphoplasmacytic infiltrates with acinar destruction in the pancreas, again diabetes, caused by T-cell mediated mechanisms without evidence of carcinoma. The ampulla, hepatic duct, mainly involving islet beta cells and pancreatic duct cystic duct, CBD, and pancreas all had severe diffuse lympho- cells [15]. Unlike most autoimmune processes plasmacytic eosinophilic infiltrates associated with fibrosis where there is female preponderance, the most and destruction of pancreatic acini, consistent with AuP. The patient was started on daily prednisone therapy with common form of AuP occurs more frequently in improvement in symptoms and normalization of the serum males, particularly elderly males, with an overall transaminases and total bilirubin. ratio of approximately 2:1 for all males [16]. AuP patients can be subdivided into clinico- pathologically distinct groups. The first and most Table 1. Diagnostic criteria for AuP. 170

2002 Japan Pancreas Society Criteria [37]* 2006 Intractable Pancreatic Diseases Res. Asan Medical Center Criteria [35] * Mayo Clinic Criteria [26] 2009 39, 2, no. vol. Science, &Laboratory of Clinical Annals Team, Ministry of Health, Labor &Welfare and Japan Pancreatic Society Criteria [38] *

Diffuse narrowing of the main PD with Pancreatic imaging studies show narrowing CT: Diffuse enlargement (swelling of the Group A: Diagnostic pancreatic histology irregular wall (>1/3 length of the entire of the main PD and pancreatic enlargement. pancreas). (one or both must be present): pancreas) and pancreatic enlargement. 1. Resection specimen or core biopsy shows full spectrum of LPSP. 2. >10 IgG4 positive cells/HPF on IgG4 immunostaining of pancreatic tissue.

Elevated levels of serum gamma globulin Presence of serum autoantibodies or elevated ERCP: diffuse or segmental irregular Group B: Typical imaging and serology and/or IgG or presence of autoantibodies. levels of gamma globulin, IgG, or IgG4. narrowing of the main PD. (all must be present): 1. CT or MRI shows diffusely enlarged pancreas with delayed & rim enhancement. 2. Pancreatogram has diffusely irregular PD. 3. Elevated serum IgG4.

Marked lymphoplasmacytic infiltration Histopathology of pancreas shows fibrosis Elevated levels of IgG and/or IgG4 or Group C: Response to steroids (all must & dense fibrosis. and pronounced infiltration of cells, mainly detected autoantibodies. be present): lymphocytes and plasmacytes. 1. Unexplained pancreatic disease after negative workup for known etiologies including cancer. 2. Elevated serum IgG4 or other organ involvement confirmed by presence of abundant IgG4 positive cells. 3. Resolution or marked improvement of pancreatic or extrapancreatic manifestations with steroid therapy.

*The diagnosis is fulfilled when the first *Diagnosis is confirmed when criterion 1 Fibrosis and lymphoplasmacytic infiltration. criterion is present in association with is present along with either criterion 2 or 3. either the second or third criterion. It is also necessary to exclude malignant diseases such as pancreatic or biliary cancer. Response to steroid.

*The diagnosis of AuP is definitive when the first criterion is present in conjunction with any of the remaining criteria. Autoimmune pancreatitis 171 common group is seen in older males, mainly in epithelium with lymphocytes [15]. The lumen may their 60s, and is associated with Sjogren’s syndrome have a star-like appearance because the infiltrates and bile-duct stenosis. Histologically these cases encompass the ducts and narrow their lumens by tend to display the lymphoplasmacytic sclerotic infolding the epithelium [23]. In later stages pattern of AuP [14]. The second form is seen in periductal fibrosis thickens the duct wall. In younger patients, mainly in their 40s, exhibiting contrast to other forms of chronic pancreatitis such an equal male to female ratio and more frequently as alcoholic, tropical, or hereditary, no distinct found in patients with inflammatory bowel disease. ductal dilatations, pseudocysts, or calculi (intra- Histologically these cases resemble neutrophilic ductal calcifications) are found in AuP [23]. ductitis [16]. The biliary tree can also be involved. The In addition to the sclerotic process and ductal common bile duct demonstrates marked thickening changes, vascular changes can be found. The small of the wall due to a diffuse lymphoplasmacytic veins are more commonly involved. Obliterative infiltrate combined with fibrosis [23]. Intrahepatic arteritis is less common [18]. In some cases (earlier biliary involvement can also be present. When this lesions) inflammation is more peri-vascular (“peri- occurs there may be overlapping features with phlebitis”), while in more advanced lesions, venulitis primary sclerosing cholangitis. The gallbladder can obscure the involved vessel (“obliterative phleb- may also be affected and 25% of resected gallbladder itis”) making the vessel recognizable only by its specimens from AuP patients show diffuse contours or the remaining lumen that looks like a acalculous lymphoplasmacytic cholecystitis [27]. defect in the center of an inflammatory focus [16]. This type of cholecystitis associated with AuP is AuP may in fact be a systemic autoimmune characterized by deep mural inflammation and a disorder with various extrapancreatic manifest- significant number of IgG4 positive plasma cells. ations. Biliary lesions, sialadenitis, retroperitoneal fibrosis, enlarged celiac and hilar lymph nodes, Pathophysiology of AuP chronic thyroiditis, intersititial nephritis, and inter- sititial pneumonia have been described [19,20]. The pathogenesis of AuP remains a mystery. The A new classification system for chronic occasional coexistence of AuP with other auto- pancreatitis (TIGAR-O) has been proposed. immune diseases suggests that there may be According to this system, chronic pancreatitis is common target antigens in the pancreas and the categorized as idiopathic, genetic, toxic-metabolic, other exocrine organs, such as the salivary glands, autoimmune, recurrent and severe acute pancreatitis, biliary tract, and renal tubules [28]. A number of or obstructive, with AuP classified as an isolated autoantibodies such as rheumatoid factor (RF), p- and syndromic type [14,17]. ANCA, ANA, ASMA, AMA, antithyroglobulin, and anti-microsomal antibodies have been reported General Pathological Observations in AuP [29]. Other autoantibodies such as antilactoferrin antibody (ALF) and anticarbonic anhydrase II Grossly, the inflammation in AuP is commonly (CA-II) have also been reported. CA-II and ALF found in the head of the pancreas and can mimic are distributed in cells of several exocrine glands carcinoma [21]. Less frequently, AuP is seen in the and the high prevalence of these antibodies suggests body or tail of the pancreas [18,22,23]. A gray to that they might be target antigens in AuP [28]. yellow-white induration of the affected tissue occurs with loss of normal lobular shape because of Histopathology and Clinical Pathology of AuP the inflammation. The histologic hallmark in the pancreas is an intense inflammatory cell infiltrate Microscopic findings in AuP show lymphoplasma- around medium and large sized interlobular ducts cytic sclerosing pancreatitis with diffuse lympho- [24,25]. In advanced cases involvement of smaller plasmacytic infiltration and pronounced acinar ducts may occur [23,24]. This infiltrate may be atrophy [30]. The contiguous soft tissue and the mainly subepithelial with rare infiltration of the entire pancreas may display fibrosis that is similar 172 Annals of Clinical & Laboratory Science, vol. 39, no. 2, 2009 to the findings in retroperitoneal fibrosis. ERCP frequently reveals diffuse segmental Obliterative phlebitis in and around the pancreas irregular narrowing of the main PD [33]. This can involve the portal vein. finding parallels the pathologic findings of the Some AuP patients have abnormally high pancreatic duct lumen, which is compressed by serum amylase and lipase levels, but these are not lymphoplasmacytic infiltration and fibrosis. The specific features. In 94% of patients with AuP, terms “diffuse” and “segmental” are used to describe serum levels of IgG4 are elevated [21]. Elevated the narrowing; the former indicates that the entire IgG4 levels in the presence of radiologic findings main PD is narrowed whereas the latter describes may warrant initiation of steroid therapy. strictures involving multiple parts of the pancreas Immunohistochemical staining shows mainly with other parts appearing normally. CD3 positive T-lymphocytes in the periductal MRCP can be used in place of ERCP, but is infiltrate, which includes a combination of CD4 limited in that AuP is a narrow-duct disease [27]. and CD8 cells [31]. CD20 positive B-lymphocytes No exogenous contrast is used in MRCP and the and macrophages that label CD68 are also present resolution is inferior to that of ERCP, so the [30]. The CD4 and CD8 cells contain HLA-DR. pathology of the main PD is not clearly defined. The HLA-DR antigens are expressed on pancreatic EUS with core biopsy can be diagnostic for duct cells and CD4 positive T cells, which suggests AuP. Immunostaining of tissue for IgG4 is that an autoimmune process is involved in the imperative [34]. Unfortunately, core biopsies are inflammation [28]. The CD4 cells are divided into done in a limited number of institutions and as of Th1 and Th2 type cells based on cytokine yet the evidence in support of EUS with FNA alone production. The Th1 cells predominate over Th2 in diagnosing AuP is lacking. [22]. Even when the cells in some cases of AuP. They may be essential in CT findings are normal, EUS can show diffuse the induction or maintenance of AuP whereas Th2 gland enlargement and is a sensitive tool for cytokines may be involved in disease progression, alterations in echotexture. If one suspects AuP and especially local B cell activation [28]. a diagnosis of pancreatic cancer must be ruled out, then the use of EUS with FNA or EUS with core Imaging Findings in AuP biopsies should be considered.

The first diagnostic test in AuP patients is often an Diagnostic Criteria for AuP abdominal ultrasound. A hypoechoic diffuse swelling in the pancreas (sausage-like appearance) In 2002 the Japan Pancreas Society published the or focal swelling of the pancreas mimicking a first diagnostic criteria for AuP [35-37]. These neoplastic lesion may be observed [32]. Dilatation criteria set an initial standard regarding diagnosis. of the CBD due to inflammation of intrapancreatic In 2006, the Intractable Pancreatic Diseases portion may be seen as well. The irregular focal or research team funded by the Ministry of Health, diffuse narrowing of the main PD or the Labor and Welfare and the Japan Pancreatic Society intrapancreatic bile duct, which are often present, expanded the diagnostic criteria [19,38]. Response may not be seen by ultrasound. to steroids was added by the Asan Medical Center The most common finding on CT is a diffusely [35,36]. Kim et al [33,36] and Pearson et al [39] enlarged pancreas without peripancreatic fat incorporated histology and cytology, an association infiltration, phlegmon, or pseudocysts. A “sausage- with other probable autoimmune diseases, and the like” appearance of the pancreas can be observed. response to steroids in their proposed criteria. Most The pancreas appears hypodense as compared to recently, new diagnostic criteria were published the spleen on arterial enhanced phase whereas in from the Mayo Clinic [26]. These criteria take into the delayed phase the attenuation increases [33]. A account all aspects of imaging, pathology, laboratory capsule-like low-density rim around the pancreas values, and the response to steroids. Table 1 presents in early and delayed images can be seen in some a comparison of various formulations of diagnostic patients who show delayed enhancement. criteria for AuP. Autoimmune pancreatitis 173

Therapeutic Approaches in AuP imaging studies. Biopsies of the ampulla of Vater and brushings of the bile duct were negative. In Steroids are a well-known efficacious treatment in short, none of clinical parameters were typical for AuP, leading to regression of the inflammatory AuP. As a result the diagnosis was not considered. infiltration and pancreatic fibrosis [5,40,41]. An IgG4 test was never ordered. No steroids were Prednisolone is usually started po at 30-40 mg/day given. A diagnosis of cholangiocarcinoma was with a taper of 5-10 mg/day to the lowest effective suspected. The patient was sent for surgical dose at 1-2 week intervals [17,22,35,36,41]. There evaluation at a university center. At that time are second line agents that have also been used, but surgery was deemed the best option. Only when the outcomes are less clear. These include proton the pathological finding were reported was AuP pump inhibitors and histamine 2-receptor antag- diagnosed and the patient was started on steroids. onists (at their regular doses), atropine sulfate (1.5 In case 3, the patient presented with jaundice, mg/day po in divided doses), and scopolamine unexplained weight loss, and abnormal imaging hydrobromide (1.2-2.4 mg/day) [17,42]. Gabexate studies. In addition, he had a history of chronic mesilate, a protease inhibitor, has also been alcohol abuse. ERCP showed evidence of distortion administered iv at dosages of 100-300 mg/day [17, of the main pancreatic duct. In addition, distortion 42]. Morphologic improvement is indicated by of secondary radicles, suggestive of chronic alcoholic normalization of imaging and normalization of pancreatitis, was also seen. Serological tests were IgG4 levels. These are also indices that favor the performed. The ANA was positive but the IgG4 discontinuation of treatment [43]. result was normal. Finally, EUS was done but was not diagnostic. Even though a diagnosis of AuP Discussion was seriously considered the findings were deemed inconclusive. As a result, the team referred the AuP is a major clinical problem because it can be patient to a university facility that specialized in readily mistaken for pancreatic cancer. Our 3 cases pancreatic diseases for a second opinion. Surgery illustrate the need for greater awareness of AuP and was recommended. The patient had a successful the difficulties in making a definitive diagnosis. Whipple’s procedure performed. His symptoms In case 1, a diagnosis of AuP was not initially revolved completely following surgery. Steroids entertained. A biopsy of the pancreas was performed were never started and he remains symptom free. to rule out pancreatic cancer or lymphoma. The Physicians in the USA are becoming more histology showed evidence of lymphoplasma cells aware of AuP as a distinct clinical entity due to the and few eosinophils; there was no histologic growing number of reported cases in Japan and evidence of lymphoma. No staining for IgG4 was Europe. AuP should be considered in any patient requested. Fortunately, the treating physicians were who presents with pancreatitis, including chronic aware of AuP as a clinical entity and entertained alcoholics and patients who have only radiologic the diagnosis. In the hope of avoiding unnecessary findings or laboratory results that suggest AuP. In surgery a trial of steroids was initiated. There was patients with episodes of recurrent pancreatitis or remarkable improvement in the patient’s symptoms unexplained pancreatitis, AuP is now routinely and LFT within weeks. The jaundice, malaise, and considered in the differential diagnosis. Based on fatigue resolved and the LFT ultimately normalized. our experience, we believe that timely diagnosis of On repeat MRI and ERCP, the pancreas and CBD AuP requires keen awareness of the disease and an both returned to normal appearance. appropriate index of suspicion. This awareness In case 2, an “apple-core” lesion was found on coupled with imaging studies, laboratory tests, ERCP. The patient was female, presented without and, ultimately, tissue biopsy, will be necessary to abdominal pain, and had an unexplained 20 lb make the timely diagnosis. weight loss. The findings appeared most consistent Our case presentations underscore the varied with bile duct or pancreatic malignancy. clinical presentations of AuP. Not all patients are Parenthetically, the pancreas was normal on middle-aged men who present with abdominal 174 Annals of Clinical & Laboratory Science, vol. 39, no. 2, 2009 pain, jaundice, elevated serum IgG4 level, and Bibliography enlargement of the pancreas. In fact, the clinical presentation, lab results, and imaging studies may 1. Kawaguchi K, Koike M, Tsuruta K, Okamoto A, Tabata not be diagnostic. In case 3 all of the appropriate I, Fujita N. Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing tests including EUS with FNA were performed and cholangitis extensively involving pancreas. Hum Pathol the diagnosis was still uncertain. If a trial of steroids 1991;22:387-395. had been included in the diagnostic criteria, surgery 2. Ectors N, Maillet B, Aerts R, Geboes K, Donner A, might have been avoided. Ultimately, tissue Borchard F, Lankisch P, Stolte M, Lüttges J, Kremer B, Klöppel G. Non-alcoholic duct destructive chronic diagnosis with immunohistochemical assays is the pancreatitis. Gut 1997;41:263-268. gold standard for diagnosis. 3. Sood S, Fossard DP, Shorrock K. Chronic sclerosing New criteria for diagnosing AuP have been pancreatitis in Sjogren’s syndrome: a case report. developed by various institutions and it is essential Pancreas 1995;10:419-421. for physicians to be cognizant of the updates. 4. Kodama T, Abe M, Sato H, Imamura Y, Koshitani T, Kato K, Uehira H, Yamane Y, Horii Y, Yamagishi M, Initially, the use of radiology, pathology, and lab Yamagishi H. A case of pseudotumorous pancreatitis values were the key factors in diagnosis. Now the that presented unique pancreatoscopic findings with the response to steroids has an important role as well. peroral electronic pancreatoscope. J Gastroenterol Questions may arise regarding the use of steroids in Hepatol 2003;18:108-111. 5. Wakabayashi T, Kawaura Y, Satomura Y, Watanabe H, patients without a definitive diagnosis in an attempt Motoo Y, Sawabu N. Long-term prognosis of duct- to avoid surgery. A consensus should be established narrowing chronic pancreatitis: strategy for steroid regarding the diagnostic criteria in an effort to aid treatment. Pancreas 2005;30:31-39. physicians in evaluating and treating patients 6. Yadav D, Notahara K, Smyrk TC, Clain JE, Pearson appropriately. Although there are a number of RK, Farnell MB, Chari ST. Idiopathic tumefactive chronic pancreatitis: clinical profile, histology, and criteria available, we believe that the Mayo Clinic natural history after resection. Clin Gastroenterol criteria [26] are the most comprehensive. Hepatol 2003;1:29-35. Patients can fit into 1 of 3 groups in which 7. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, histology, imaging, serum IgG4 values, and Akamatsu T, Fukushima M, Nikaido T, Nakayama K, Usuda N, Kiyosawa K. High serum IgG4 concentrations response to steroids are taken into account. The in patients with sclerosing pancreatitis. NEJM 2001;344: inclusion of response to steroids as a diagnostic 732-738. criterion differentiates the Mayo criteria from the 8. Wakabayashi T, Kawaura Y, Satomura Y, Fujii T, Motoo Japanese criteria. This inclusion provides physicians Y, Okai T, Sawabu N. Clinical study of chronic with the broadest scope and best possibility for pancreatitis with focal irregular narrowing of the main pancreatic duct and mass formation: comparison with making the diagnosis of AuP before surgery. chronic pancreatitis showing diffuse irregular narrowing In conclusion, AuP should be considered in of the main pancreatic duct. Pancreas 2002;25:283- any patient presenting with elevated pancreatic 289. enzymes, mild abdominal pain, enlargement of the 9. Sarles H, Sarles JC, Muratore R, Guien C. Chronic inflammatory sclerosis of the pancreas: an autoimmune pancreatic head, and/or hypergammaglobulinemia. pancreatic disease? Am J Dig Dis 1961;6:688-698. A complete evaluation based on established 10. Yoshida K, Toki F, Takeuchi T, Watanabe S, Shiratori diagnostic criteria should follow. Tissue biopsy K, Hayashi N. Chronic pancreatitis caused by an with immunohistochemical assays remain the gold autoimmune abnormality. Proposal of the concept of standard for diagnosis. A trial of steroids is autoimmune pancreatitis. Dig Dis Sci 1995;40:1561- 1568. reasonable if the diagnosis is uncertain after a 11. Ohana M, Okazaki K, Hajiro K, Kobashi Y. Multiple careful evaluation. This may help avoid unnecessary pancreatic masses associated with autoimmunity. Am J surgery. Unfortunately, even when AuP is suspected, Gastroenterol 1996;93:99-102. the diagnosis may not be established until surgical 12. Horiuchi A, Kawa S, Akamatsu T, Aoki Y, Mukawa K, Furuya N, Ochi Y, Kiyosawa K. Characteristic pancreatic pathology results are available. duct appearance in autoimmune chronic pancreatitis: a case report and review of the Japanese literature. Am J Gastroenterol 1998;93:260-263. Autoimmune pancreatitis 175

13. Ito T, Nakano I, Koyanagi S, Miyahara T, Migita Y, 29. Mino-Kenudson M, Lauwers GY. Histopathology of Ogoshi K, Sakai H, Matsunaga S, Yasuda O, Sumii T, autoimmune pancreatitis: recognized features and Nawata H. Autoimmune pancreatitis as a new clinical unsolved Issues. J Gastrointest Surg 2005;9:6-10. entity. Three cases of autoimmune pancreatitis with 30. Okazaki K. Autoimmune pancreatitis: etiology, patho- effective steroid therapy. Dig Dis Sci 1997;42:1458- genesis, clinical findings and treatment. The Japanese 1468. experience. J Pancreas 2005;6(1 Suppl):89-96. 14. Okazaki K, Uchida K, Matsushita M, Takaoka M. 31. Klimstra DS, Adsay NV. Lymphoplasmacytic sclerosing Autoimmune Pancreatitis. Intern Med 2005;44:1215- (autoimmune) pancreatitis. Semin Diagn Pathol 2004; 1223. 21:237-246. 15. Kamisawa T, Okamoto A. Autoimmune pancreatitis: 32. Morana G, Tapparelli M, Faccioli N, D’Onofrio M, proposal of IgG4-related sclerosing disease. J Gastro- Mucelli RP. Autoimmune pancreatitis: instrumental enterol 2006; 41:613-625. diagnosis. J Pancreas 2005;6(1 Suppl):102-107. 16. Adsay NV, Basturk O, Thirabanjasak D. Diagnostic 33. Kim KP, Kim MH, Song MH, Lee SS, Seo DW, Lee SK. features and differential diagnosis of autoimmune Autoimmune chronic pancreatits. Amer J Gastroenterol pancreatitis. Semin Diag Pathol 2005;22:309-317. 2004;99:1605-1616. 17. Etemab B, Whitcomb DC. Chronic pancreatitis: 34. Zhang L, Notohara K, Levy MJ, Chari ST, Smyrk TC. diagnosis, classification, and new genetic developments. IgG4-positive plasma cell infiltration in the diagnosis of Gastroenterology 2001;120:682-707. autoimmune pancreatitis. Mod Pathol 2007;20:23-28. 18. Kloppel G, Luttges J, Sipos B, Capelli P, Zamboni G. 35. Kim KP, Kim MH, Kim JC, Lee SS, Seo DW, Lee SK. Autoimmune pancreatitis: pathological findings. J Diagnostic criteria for autoimmune chronic pancreatitis Pancreas 2005;61(1 Suppl):97-101. revisited. World J Gastroenterol 2006;12:2487-2496. 19. Okazaki K, Uchida K, Matsushita M, Takaoka M. How 36. Choi EK, Kim MH, Kim JC, Han J, Seo DW, Lee SS, to diagnose autoimmune pancreatitis by the revised Lee SK. The Japanese diagnostic criteria for autoimmune Japanese clinical criteria. J Gastroenterol 2007;42(Suppl chronic pancreatitis: is it completely satisfactory? 18):32-38. Pancreas 2006;33:13-19. 20. Kawa S, Hamano H. Clinical features of autoimmune 37. Criteria Committee for Autoimmune Pancreatitis of the pancreatitis. J Gastroenterol 2007;42(Suppl 18):9-14. Japan Pancreas Society. Diagnostic criteria for auto- 21. Kamisawa T, Egawa N, Nakajima H, Tsuruta K, immune pancreatitis. J Jpn Pancreas Soc 2002;17:585- Okamato A, Kamata N. Clinical difficulties in the 587. differentiation of autoimmune pancreatitis and 38. Okazaki K, Kawa S, Kamisawa T, Naruse S, Tanaka S, pancreatic carcinoma. Amer J Gastroenterol 2003;98: Nishimori I, Ohara H, Ito T, Kiriyama S, Inui K, 2694-2699. Shimosegawa T, Koizumi M, Suda K, Shiratori K, 22. Pickartz T, Mayerle J, Lerch MM. Autoimmune Yamaguchi K, Yamaguchi T, Sugiyama M, Otsuki M; pancreatitis. Nature Clin Pract Gastroenterol Hepatol Research Committee of Intractable Diseases of the 2007;4:314-323. Pancreas. Clinical diagnostic criteria of autoimmune 23. Kloppel G, Luttges J, Lohr M, Zamboni G, Longnecker pancreatitis: revised proposal. J Gastroenterol 2006;41: D. Autoimmune pancreatitis: pathological, clinical, and 626-631. immunological features. Pancreas 2003;27:14-19. 39. Pearson RK, Longnecker DS, Chari ST, Smyrk TC, 24. Kloppel G, Sipos B, Zamboni G, Kojima M, Morohoshi Okazaki K, Frulloni L, Cavallini G. Controversies in T. Autoimmune pancreatitis: histo- and immunopathol- clinical pancreatology: autoimmune pancreatitis: does it ogical features. J Gastroenterol 2007;42(Suppl 18):28- exist? Pancreas 2003;27:1-13. 31. 40. Pezzilli R. New insights into the pathology and treatment 25. Krasinkas AM, Raina A, Khalid A, Tublin M, Yadav D. of autoimmune pancreatitis. J Pancreas 2005;6:197-199. Autoimmune pancreatitis. Gastroenterol Clin N Amer 41. Song MH, Kim MH, Lee SK, Seo DW, Lee SS, Han J, 2007;36:239-257. Kim KP, Min YI, Song DE, Yu E, Jang SJ. Regression of 26. Chari ST, Smyrk TC, Levy MJ, Topazian MD, pancreatic fibrosis after steroid therapy in patients with Takahashi N, Zhang L, Clain JE, Pearson RK, Petersen autoimmune chronic pancreatitis. Pancreas 2005;30:83- BT, Vege SS, Farnell MB. Diagnosis of autoimmune 86. pancreatitis: the Mayo Clinic experience. Clin Gastro- 42. Okazaki K. Autoimmune-related pancreatitis. Curr enterol Hepatol 2006;4:1010-1016. Treat Options Gastroenterol 2001;4:369-375. 27. Deshpande V, Mino-Kenudson M, Brugge W, Lauwers 43. Kamisawa T, Egawa N, Nakajima H, Tsuruta K, G Y. Autoimmune pancreatitis more than just a Okamoto A. Morphological changes after steroid pancreatic disease? A contermporary review of its therapy in autoimmune pancreatitis. Scand J Gastro- pathology. Arch Pathol Lab Med 2005;129:1148-1154. enterol 2004;39:1154-1158. 28. Okazaki K, Chiba T. Autoimmune related pancreatitis. Gut 2002;51:1-4.