Autoimmune pancreatitis (AIP) is a chronic fibroinflammatory

Review Article Autoimmune Pancreatitis More Than Just a Pancreatic Disease? A Contemporary Review of Its Pathology Vikram Deshpande, MD; Mari Mino-Kenudson, MD; William Brugge, MD; Gregory Y. Lauwers, MD Context. Autoimmune pancreatitis (AIP) is a chronic inflammatory condition of the pancreas constituting one quarter of Whipple resections performed for benign conditions in North America. Objective. We review the clinical, radiologic, and characteristic histopathologic patterns of this disease and discuss the extrapancreatic manifestations of AIP. Design. We searched the literature using MEDLINE and OVID, related conference abstracts, and bibliographies of selected studies. Results. Autoimmune pancreatitis predominantly affects elderly individuals, frequently presenting as obstructive jaundice and occasionally in association with other autoimmune diseases. The histology is characterized by a collar of periductal inflammation, obliterative phlebitis, and the absence of stigmata of alcoholic pancreatitis. A prepancreatectomy diagnosis can be rendered using a combination of clinical findings, radiologic features, elevated immunoglobulin G4 levels, endoscopic ultrasoundguided fine-needle aspiration biopsy, and response to steroids. The disease can involve the bile ducts (sclerosing cholangitis), gallbladder (lymphoplasmacytic sclerosing cholecystitis), and kidney (interstitial nephritis) and can form inflammatory masses in the lungs. Conclusions. Despite significant evolution in our understanding of AIP, a prepancreatectomy diagnosis remains a challenge in the North American and European population. (Arch Pathol Lab Med. 2005;129:1148 1154) Autoimmune pancreatitis (AIP) is a chronic fibroinflammatory condition primarily affecting the pancreas. 1,2 The publication of more than 40 articles on this entity in 2004 emphasizes both the current interest and the significant gain in our understanding of this disease. The original description is attributed to Sarles and colleagues, 3,4 who reported several cases of chronic pancreatitis in patients with hypergammaglobulinemia in the 1960s. Until recently, AIP was included in the larger and heterogenous group of chronic idiopathic pancreatitis. In recent Japanese series, the incidence of AIP (whether confirmed by biopsy or not) ranges between 1.86% and 6.6% of chronic pancreatitis cases. 5 7 In North America, surgical series report that AIP represents between 21% and 34% of Whipple resections performed for benign conditions. 8,9 In many of these patients, imaging studies led to the suspicion of pancreatic malignancy, giving us in return a unique opportunity to evaluate the surgical pathology of this benign pancreatic disease. In this article, we briefly review the clinical and radiologic features of AIP before describing the various char- Accepted for publication May 16, 2005. From the Departments of Pathology (Drs Deshpande, Mino-Kenudson, and Lauwers) and Medicine (Dr Brugge), Massachusetts General Hospital, Boston. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Vikram Deshpande, MD, Department of Pathology, Massachusetts General Hospital, 55 Fruit St, Warren 831B, Boston, MA 02114 (e-mail: vdeshpande@partners.org). acteristic histopathologic patterns associated with this condition. CLINICAL FEATURES Most cases of AIP reported to date have involved patients in late adulthood, with a mean age of 56 years. 10,11 The mean age in the Japanese series has been slightly older (68.5 years). 1 However, the disease affects a wide age range, with several documented cases in the second and third decade of life. 10 Surgical series have reported a male predominance, varying from 1.7:1 to 2.1:1. 10 12 An important feature of AIP, responsible for the current interest in this condition, is its propensity to mimic pancreatic carcinoma both clinically and radiologically (Table 1). 1,9,11,12 A potential clue to the correct diagnosis is its frequent association with other autoimmune diseases. The most commonly reported autoimmune diseases include Sjögren syndrome 10,13 and rheumatoid arthritis. 12 Additionally, an association with ulcerative colitis and Crohn colitis has been documented. 10 In our own experience, 13% of cases were associated with ulcerative colitis, while others have reported a lower percentage. 1,2 Common presenting symptoms include jaundice, weight loss, and abdominal pain. 1 Other clinical manifestations, such as typical episodes of acute pancreatitis, are unusual, and abdominal pain is typically mild. 11 Although the pathogenesis of AIP remains unknown, immunologic evaluation of the patients frequently reveals the elevation of immunoglobulin (Ig) G and/or -globulin. 7,14 Rheumatoid factors, perinuclear anti-neutrophil cytoplasmic antibody, anti smooth muscle antibody, anti- 1148 Arch Pathol Lab Med Vol 129, September 2005 Autoimmune Pancreatitis Deshpande et al

Table 1. Clinical Features of Autoimmune Pancreatitis Obstructive jaundice Vague abdominal pain, without acute pancreatitis-like pain Frequently associated with other autoimmune diseases On imaging, diffuse enlargement of pancreas (sausage sign) or focal enlargement (mass forming) On ERCP, diffusely irregular main pancreatic duct with strictures and strictures of the common bile duct* Clinical response to steroids * ERCP indicates endoscopic retrograde pancreatocholangiography. mitochondrial antibody, anti-nuclear antibody, antithyroglobin, and anti-microsome antibodies have been variably reported, although none are consistently positive. 5,7,14,15 Antibodies to carbonic anhydrase II antigens (positive in 30% 59% of cases) and lactoferrin (positive in 50% 76% of cases) can also be detected. These antigens, which are present on the ductal and acinar cells, respectively, might be responsible for the Th-2 type antibodymediated immune reaction and the ensuing lymphocytic infiltrate observed in AIP. 5,7,15 17 RADIOLOGIC FEATURES Imaging studies of patients with AIP show either a diffuse or focal swelling of the pancreas (Figure 1). 18 21 Endoscopic ultrasound findings can be deceptively similar to those of pancreatic cancer. In a series of 14 cases, irregular hypoechoic masses were identified in 6. 19 Endoscopic retrograde pancreatocholangiography findings have been reported to be characteristic, with segmental or more frequently diffuse irregular narrowing of the main pancreatic duct. Of note, these pancreatic duct changes are usually accompanied by a stricture of the distal common bile duct. 22 However, large series of pancreatectomy specimens reported in the North American and European literature are testimony to the significant overlap in the clinical and radiologic features of AIP with pancreatic cancer. 9,11,12 GROSS FEATURES As highlighted by imaging studies, AIP may be either diffuse, involving the entire gland, or preferentially affecting the head of the pancreas. 14,23 25 On gross inspection, the pancreas has an unremarkable external appearance, but it is usually firm on palpation. 26 Importantly, despite the tumefactive nature of this condition, no dominant mass or well-circumscribed nodules are found. Sections through the gland reveal a fibrotic parenchyma, although pancreatic lobulation is usually retained to some extent. 27 Pancreatic resections for AIP may be particularly challenging because of the peripancreatic inflammation. 9 MICROSCOPIC FEATURES In Japan, the diagnosis of AIP is frequently made on the basis of radiologic findings, clinical data, and response to steroid therapy, with or without histologic evaluation. 7,14,25 However, given the evolving consensus on the histopathologic features of AIP, we and others 28 believe that histologic and cytologic features should be included as a major diagnostic criterion for the diagnosis of AIP. The cardinal features of AIP include a dense lymphoplasmacytic infiltrate of the pancreatic parenchyma with secondary fibrosis and absence of changes associated with chronic alcoholic pancreatitis (Table 2). A collar of inflammation around both small and large interlobular ducts 10,27,29 is one of the key diagnostic features (Figure 2). Although lymphocytic exocytosis (ie, infiltration of lymphocytes into the ductal epithelium) is present, significant epithelial damage is not seen consistently. This periductal infiltrate is predominantly composed of lymphocytes, sometimes forming germinal centers. A dense plasma cell infiltrate is also typical of this condition, as are scattered eosinophils. The ductal involvement is frequently patchy, in a pattern similar to the bile duct damage seen in primary biliary cirrhosis. This patchy nature frequently hampers a definitive diagnosis on needle biopsy material. The inflammatory infiltrate with accompanying fibroblasts/ myofibroblasts occasionally spills into and involves the peripancreatic soft tissue. The lymphocyte population is predominantly composed of T lymphocytes, but B cells are consistently present. Most cells are positive for CD4 (55%), although others report a predominance of CD8-positive T cells. 5,6,29,30 It has been suggested that cytokines released by T lymphocytes up-regulate the aberrant expression of HLA class II molecules by the duct epithelial cells. 16,29,30 Intraductal neutrophilic infiltration (Figure 3) is not always observed, and when present, these granulocytic epithelial lesions have been linked to the concurrent presence or future development of ulcerative colitis. 10 Although in a subgroup of cases the inflammation is confined to a periductal and interlobular location, there is also frequent involvement of the lobules. In these, loss of acinar parenchyma is frequent, reflecting both ductal obstruction and primary lobular involvement. Occasionally, almost exclusive lobular involvement with only minimal periductal inflammation is seen (Figure 4). We propose designating the former group as predominantly ductal AIP (AIP-PD) and the latter as predominantly lobular AIP (AIP-PL). Periphlebitis and obliterative phlebitis are invariably present and are useful in establishing a diagnosis of AIP. 10 12,27 The use of elastic stain has been advocated to facilitate the identification of these lesions, although a routine hematoxylin-eosin stain in our experience is adequate (Figure 5, A and B). The involved pancreatic veins are frequently obscured by inflammation, and its presence is identified by locating its companion artery. Rarely, arteritis is also seen. Perineural inflammation, although nonspecific, is noted frequently. Epithelioid cell granulomas have been reported only rarely in association with AIP. 27,31 However, in our review of 19 pancreatectomy specimens we identified granulomas in 6 cases (32%). In 3 of these cases, granulomas were identified in almost every section examined. In all cases, the granulomas showed an exquisite ductocentric location (Figure 6). The lack of nodal involvement and the periductal distribution help exclude pancreatic sarcoidosis and other granulomatous pathologies, including mycobacterial infections. 32,33 Finally, an important criterion for the diagnosis of AIP is the absence of features usually associated with alcoholic chronic pancreatitis, such as duct dilation with mucoprotein plugs, pseudocysts, autodigestive necrosis, and calcifications. 11,27,29 These are not, however, absolute exclusionary criteria, in light of recent reports of pseudocyts 34 and duct stones 35 in AIP. HISTOLOGIC SUBTYPING OF AUTOIMMUNE PANCREATITIS It is becoming apparent that AIP is not a homogeneous disease. 10,36 However, attempts to substratify AIP have had Arch Pathol Lab Med Vol 129, September 2005 Autoimmune Pancreatitis Deshpande et al 1149

Figure 1. Endoscopic ultrasound. Mass lesion in the head of the pancreas in a 27-year-old woman. Resection confirmed the diagnosis of autoimmune pancreatitis. Figure 2. Characteristic periductal cuffing of autoimmune pancreatitis (hematoxylin-eosin, original magnification 70). Figure 3. Intraductal neutrophilic microabscesses from a case with associated ulcerative colitis (hematoxylin-eosin, original magnification 125). Figure 4. Predominantly lobular involvement in autoimmune pancreatitis (hematoxylin-eosin, original magnification 70). Figure 5. A, Phlebitis is a characteristic feature of autoimmune pancreatitis (hematoxylin-eosin, original magnification 125). B, An elastic stain highlights obliterative phlebitis (left) and arteritis (elastin, original magnification 125). 1150 Arch Pathol Lab Med Vol 129, September 2005 Autoimmune Pancreatitis Deshpande et al

Table 2. Autoimmune Pancreatitis: Characteristic Histological Features Almost always seen 1. Periductal inflammation 2. Obliterative phlebitis 3. Dense lymphoplasmacytic inflammation 4. Perineural inflammation (nonspecific) 5. Acinar atrophy Occasionally seen 1. Periductal granulomas 2. Inflammatory pseudotumor limited success. One of these efforts stratified AIP into lymphoplasmacytic sclerosing pancreatitis and idiopathic duct-centric pancreatitis. Apart from a slight increase in jaundice in lymphoplasmacytic sclerosing pancreatitis cases, no other significant clinical differences were noted between the 2 groups, and subsequent studies failed to replicate these results. 10,11 However, in our own experience, there are significantly higher numbers of IgG4-positive plasma cells in cases with predominant lobular involvement (AIP-PL) (roughly corresponding to lymphoplasmacytic sclerosing pancreatitis) compared with cases with prominent ductal involvement (AIP-PD) (roughly corresponding to idiopathic duct-centric pancreatitis). Interestingly, the cases with predominant lobular involvement had a significantly higher incidence of jaundice at presentation. In some patients, the glandular parenchyma is ultimately replaced by a dense cellular proliferation of spindle cells or myofibroblasts, collagen, and variable amounts of lymphoplasmacytic infiltrate. 8,37 39 These lesions, sometimes reported as pseudotumors, have been noted to arise either independently or more typically in the background of a more classic AIP (Figure 7). 8 It is likely that the majority of so-called pseudotumors of the pancreas represent a tumoral phase of AIP. DIAGNOSIS OF AIP ON FINE-NEEDLE ASPIRATION BIOPSY AND CORE BIOPSY Given that AIP is a steroid-responsive disease, it has become paramount to achieve a preoperative diagnosis to avoid surgery. A review of our 16 confirmed cases of AIP showed us that, contrary to what could be expected, a dense lymphoid infiltrate is seen infrequently. Instead, cellular stromal fragments infiltrated by mononuclear inflammatory cells are common and in the appropriate clinical context can help establish a preoperative diagnosis of AIP (Figure 8, A). The diagnosis of AIP on core needle biopsy remains challenging. In one series, diagnostically relevant features were identified in 3 of 4 needle biopsies. 10 However, some authors are less enthusiastic about the effectiveness of needle biopsies in the diagnosis of AIP. 12 In our own review of 5 pancreatic needle-core biopsies, the 2 histologic hallmarks of AIP (ie, a periductal collar of inflammation and venulitis) were identified in only 1 case. Nonetheless, all 5 cases demonstrated a diffuse lymphocytic infiltrate with pancreatic acinar loss and focal to diffuse fibrosis associated with a myofibroblastic proliferation (Figure 8, B). These latter changes, although not pathognomonic, can support a diagnosis of AIP. IgG4 IN AUTOIMMUNE PANCREATITIS Immunoglobulin G4 is the least common of the IgG subclasses and accounts for only 3% to 6% of total IgG in the serum of normal subjects. It is unique among the IgG subclasses in its inability to bind C1q complement, thereby activating the classic pathway of complement, and in its low affinity for target antigen. 40 In a landmark paper, Hamanoetal 41 found that patients with AIP had significantly higher levels of serum IgG4 than patients with pancreatic cancer. Following steroid therapy, there was a significant decrease in IgG4 levels. Unfortunately, the experience with IgG4 in North America and Europe is limited and confined to sporadic case reports. 42 These findings, however, do raise the possibility that a tissue IgG4 immunoperoxidase could be useful, particularly when evaluating limited biopsy material. In our own experience, we identified a significantly higher number of pancreatic IgG4-positive plasma cells in AIP than in pancreatic carcinoma and chronic pancreatitis (Figure 9). Whether these data could be viewed as a surrogate marker of serum IgG4 levels remains to be determined. Nevertheless, these results do suggest that IgG4 may be as relevant in the North American population as it is for Japanese patients. However, although 9 of 19 pancreatic adenocarcinoma control cases were negative for tissue IgG4 plasma cells, the other 10 cases showed a mild to marked increase in IgG4 plasma cells, albeit patchy. Thus, we suspect that an immunoperoxidase stain would have limited specificity in evaluating biopsy material. Notably, chronic pancreatitis cases that lack histologic features of AIP are either devoid of IgG4- positive cells or show rare and scattered positive plasma cells. 31,43 CLINICAL AND ANATOMIC SPECTRUM OF AIP Biliary Involvement in AIP It appears that a subset of sclerosing cholangitis cases belong to the spectrum of AIP (Table 3). In a series of 14 cases, 5 were associated with AIP. 31 In these 5 cases, the bile ducts were damaged by a dense transmural lymphoplasmacytic infiltrate, with many IgG4-positive plasma cells and obliterative phlebitis (Figure 10). 31 Notably, primary sclerosing cholangitis (PSC) a clinically important differential diagnosis shows less inflammation, which is predominantly localized beneath the epithelium. 31 Increased numbers of tissue IgG4-positive plasma cells could help support a diagnosis of AIP-associated sclerosing cholangitis. Hepatic Involvement in AIP Intrahepatic biliary involvement can show overlapping features with PSC, 6 and cases with ulcerative colitis and sclerosing cholangitis present an additional diagnostic challenge. Interestingly, the strictures respond to steroid therapy; hence, distinguishing AIP-associated changes from PSC has therapeutic relevance. 44,45 In retrospect, cases of AIP with sclerosing cholangitis have been originally reported as PSC. The reevaluation of the material from a published report of PSC with extensive pancreaticobiliary involvement represented instead an example of AIP with involvement of the biliary tree and gallbladder. 46 In most instances, as in 2 of our own cases, the intrahepatic biliary changes develop after the diagnosis of AIP. 6 Additionally, cholangiographic features may allow the discrimination of sclerosing cholangitis with AIP from PSC. 47 When liver Arch Pathol Lab Med Vol 129, September 2005 Autoimmune Pancreatitis Deshpande et al 1151

Figure 6. Figure 7. Autoimmune pancreatitis with periductal, noncaseating epithelioid cell granulomas (hematoxylin-eosin, original magnification 250). Pancreatic inflammatory pseudotumor associated with autoimmune pancreatitis (hematoxylin-eosin, original magnification 70). Figure 8. A, Cytology of autoimmune pancreatitis (AIP). Cellular fragments with myofibroblast-type cells and infiltrating mononuclear cells (hematoxylin-eosin, original magnification 500). B, Needle biopsy of AIP. Diffuse loss of pancreatic parenchyma with a lymphoid infiltrate. The characteristic features of AIP (ie, periductal inflammation and phlebitis) are only occasionally seen (hematoxylin-eosin, original magnification 70). Figure 9. Immunohistochemical stain for IgG4 demonstrating a diffuse infiltrate of IgG4-positive plasma cells (IgG4 immunohistochemistry, original magnification 250). Figure 10. Autoimmune pancreatitis with sclerosing cholangitis. Common bile duct with transmural mononuclear cell infiltrate and fibrosis (hematoxylin-eosin, original magnification 30). 1152 Arch Pathol Lab Med Vol 129, September 2005 Autoimmune Pancreatitis Deshpande et al

Table 3. Extrapancreatic Conditions Associated With Autoimmune Pancreatitis Sclerosing cholangitis Lymphoplasmacytic sclerosing cholecystitis Hepatic inflammatory pseudotumor Pulmonary inflammatory masses Interstitial nephritis biopsies are performed, they show a portal-based lymphoplasmacytic infiltrate, usually centered around portal veins, although the experience is limited (Figure 11). Occasionally, microscopic portal-based inflammatory pseudotumor like lesions are seen. 31 Hepatic inflammatory pseudotumors that show a dense polyclonal lymphoplasmacytic infiltration with myofibroblastic proliferation and fibrosis have been reported to arise in association with sclerosing cholangitis 31 and AIP. Similar lesions have also involved the common bile duct, 48 and these may conceivably belong to the spectrum of AIP. 49 However, follicular dendritic cell tumors and inflammatory myofibroblastic tumors require exclusion. 50 Gallbladder in AIP About 25% of resected gallbladders from AIP patients show a diffuse, acalculous lymphoplasmacytic cholecystitis. 51 Despite overlapping features with PSC and malignancy-associated biliary obstruction, 52 lymphoplasmacytic cholecystitis associated with AIP is characterized by a deep mural inflammation and, in our experience, by numerous IgG4-positive plasma cells (Figure 12). 52 Although our experience with this antibody is limited, it appears to be an exciting marker in distinguishing lymphoplasmacytic cholecystitis associated with AIP from PSC. This feature may prove diagnostically useful when a cholecystectomy specimen is the sole tissue available. Extrapancreaticohepatobiliary Involvement There is a growing body of literature in support of a systemic condition characterized by the infiltration of IgG4-positive plasma cells. 43 Inflammatory masses composed of numerous IgG4-positive plasma cells have been reported to involve the lung and breast. 53,54 We identified 2 cases of AIP with interstitial pneumonia, both of which included biopsies of a pulmonary mass. Both biopsies showed perivascular interstitial expansion by a lymphoplasmacytic infiltrate and demonstrated significant venulitis. In 1 of the 2 cases, a diffuse and marked increase in tissue IgG4-positive cells could be demonstrated. Interstitial nephritis has been reported in association with AIP. 55,56 RESPONSE TO STEROIDS Clinical response to steroid therapy, at least a partial response, has been widely reported. 6 Improvement of the pancreatic swelling, main pancreatic duct narrowing, bile duct strictures, and retroperitoneal fibrosis have all been seen. 6,35 Despite clinical and biologic evidence of the reversibility (at least partial) of exocrine insufficiency with steroid therapy, little is known of the modulation of the inflammation and glandular damage under treatment. 6,7,16 Although we have noted improvement of the inflammatory infiltrate following steroid therapy, effacement of fibrosis is less likely. CONCLUSION Since the original recognition of AIP by Sarles and colleagues, significant advances have been achieved in the clinical diagnosis, management, and understanding of the pathogenesis of this condition. Autoimmune pancreatitis is characterized by a triad of characteristic histologic features, including diffuse pancreatic inflammation, a periductal collar of inflammation, and phlebitis. More recently, the extrapancreatic nature of this disease is being recognized, with involvement of the biliary tree and liver being reported most frequently. An IgG4 immunohistochemical stain may provide useful diagnostic information when extrapancreatic biopsies are reviewed. However, in North America and Europe, a prepancreatectomy diagnosis remains challenging, and the relevance of serum IgG4 has not been adequately assessed. Figure 11. Autoimmune pancreatitis with liver involvement. Mild portal triaditis. Note the perivenular distribution of the infiltrate (hematoxylineosin, original magnification 70). Figure 12. Gallbladder. Autoimmune pancreatitis with lymphoplasmacytic sclerosing cholecystitis (hematoxylin-eosin, original magnification 30). Arch Pathol Lab Med Vol 129, September 2005 Autoimmune Pancreatitis Deshpande et al 1153

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Am J Surg Pathol. 2005;29:275 278. 54. Taniguchi T, Ko M, Seko S, et al. Interstitial pneumonia associated with autoimmune pancreatitis. Gut. 2004;53:770; author reply, 770 771. 55. Takeda S, Haratake J, Kasai T, Takaeda C, Takazakura E. IgG4-associated idiopathic tubulointerstitial nephritis complicating autoimmune pancreatitis. Nephrol Dial Transplant. 2004;19:474 476. 56. Uchiyama-Tanaka Y, Mori Y, Kimura T, et al. Acute tubulointerstitial nephritis associated with autoimmune-related pancreatitis. Am J Kidney Dis. 2004; 43:e18 e25. 1154 Arch Pathol Lab Med Vol 129, September 2005 Autoimmune Pancreatitis Deshpande et al