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Diagnostic features and differential diagnosis of autoimmune pancreatitis
Seminars in Diagnostic Pathology (2005) 22, 309-317
Diagnostic features and differential diagnosis of autoimmune pancreatitis N. Volkan Adsay, MD, Olca Basturk, MD, Duangpen Thirabanjasak, MD From the Department of Pathology, The Karmanos Cancer Institute and Wayne State University School of Medicine, Detroit, Michigan.
KEYWORDS Pancreas; Pancreatitis; Autoimmune; Pseudotumor
A clinically and pathologically distinct form of chronic pancreatitis is now widely recognized and has been designated variably as lymphoplasmacytic sclerosing pancreatitis, duct-destructive (duct-centric) pancreatitis or autoimmune pancreatitis. This entity is currently defined by a constellation of clinical and pathologic findings, including the lack of both conventional risk factors for pancreatitis, such as alcohol use and gallstones, and their hallmark pattern of injury, including calcifications and pseudocysts. Histologically, it is characterized by lymphoplasmacytic inflammation with abundant IgG4positive plasma cells that exhibit an affinity for ducts as well as venules (“peri-venulitis,” with or without frank vasculitis). Inflammation is often associated with sclerosis and expansion of periductal tissue. In some cases, fibroblastic activity is prominent and resembles “inflammatory pseudotumor” or is even misdiagnosed as “inflammatory myofibroblastic tumor.” In what appears to be a distinct subset of this entity, intraepithelial granulocytic infiltrates may be seen. Well-developed examples are readily recognized; however, lesser ones may be difficult to distinguish from other forms of pancreatitis based on morphology alone. This type of pancreatitis is considered an autoimmune process. In about 15% to 20% of patients, the clinical stigmata of autoimmune conditions are present at the time of diagnosis, and in many others, discovered subsequently. The usual “lymphoplasmacytic sclerotic” type tends to be associated with Sjogren, whereas the “granulocytic” subset, with inflammatory bowel disease. Most patients present with a pancreatic head mass, often with an accompanying stricture of the distal common bile duct, which thus radiologically resembles “pancreas cancer.” In fact, this entity accounts for more than a third of the cases of pseudotumoral pancreatitis (mass-forming inflammatory lesions that resemble carcinoma). Elevated serum IgG4 levels are characteristic and may be very helpful in the differential diagnosis from tumors and tumor-like lesions of the pancreas which seldom result in levels above 135 mg/dL. The mean age of the patients with this condition is in the mid-50s; the subset with granulocytic intraepithelial lesions seem to be younger (mid 40s). Despite the autoimmune association, males are afflicted as commonly as (if not more than) females. Following resection, emergence of new fibro-inflammatory lesions in the remaining pancreaticobiliary tree has been noted in some cases; however, the process typically responds to steroids. It is important to recognize the distinctive clinicopathologic features of this entity, so that it can be diagnosed accurately and managed appropriately. © 2005 Elsevier Inc. All rights reserved.
Address reprint requests and correspondence: N. Volkan Adsay, MD, Department of Pathology, Harper University Hospital, 3990 John R, Detroit, MI 48201. E-mail address: [email protected].
0740-2570/$ -see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.semdp.2006.04.008
Autoimmune pancreatitis, also known as lymphoplasmacytic sclerosing1-7 or duct-centric (duct-destructive) pancreatitis,8-10 had fallen under the generic heading of “idiopathic chronic pancreatitis” until it began to be recognized as a special type of pancreatic injury in the 1990s. It is now widely accepted as a distinct entity. Each term proposed for this entity in the 1990s high-
310 lights a different facet of this process, but may not reflect other aspects. The name lymphoplasmacytic sclerosing pancreatitis (LPSP)1-5 is a morphology-based, descriptive term that embraces the two main features of this lesion, the participation of plasma cells, and presence of sclerosis. However, there is a subset of this entity recognized recently that is characterized by granulocytic epithelial lesions and may lack the prominent plasma cell infiltration or sclerosis. The pancreatitis in AIP is believed to be autoimmune based, and there is mounting evidence to support this notion; however, the majority of the patients lack the clinical and serologic stigmata of autoimmune disorders, and thus the association may not be as strong as the term “autoimmune” implies.4,7,11 Also, it is not clear whether the subtle changes identified in the pancreata of patients with autoimmune conditions such as incidental, microscopic foci of vasculitis without gross alterations ought to be regarded as a manifestation of this entity or not. Our bias is to take a purist’s approach and reserve the diagnosis of AIP only for the cases that show substantial pancreatic injury, the features of which are described below. Another important issue that somewhat blurs the definition of AIP is its relationship to other types of pseudotumoral pancreatitis. In most studies concerning AIP, the cases were identified among patients that had undergone pancreatectomy for a pancreatic mass, typically with the clinical diagnosis of carcinoma. We now know that many, but not all, of these cases are in fact AIP. There are, however, other clinicopathologic entities that cause pseudotumor formation in the pancreas, and some of these appear to have been included into the category of AIP due to lack of recognition and proper criteria until recently. It is our opinion that AIP ought to be defined by the combination of specific clinical and pathologic criteria established recently. It is acknowledged that this purist’s approach may disregard, perhaps inaccurately, the lesser or evolving examples of this entity; however, the opposite (the inclusive approach) leads to misdiagnosis of alcoholic, gallstone-related, and paraduodenal types of pancreatitis as AIP. Therefore, we believe that, until the nature of these gray-zone cases is better elucidated, the criteria established recently ought to be applied rather strictly. AIP has also been referred as nonalcoholic duct-destructive pancreatitis.8,10,12 Currently, almost by definition, the diagnosis of AIP is reserved only for nonalcoholic patients. The problem with this criterion is that this history is often not available for the pathologists. Moreover, in some cases, even the clinicians may not possess this information. Furthermore, the amount of alcohol required to cause alcoholic pancreatitis is not as straightforward as it may seem; despite the international guidelines and consensus definitions, the biologic significance of the figures proposed are not clear. Also, this criterion
Seminars in Diagnostic Pathology, Vol 22, No 4 dictates that alcoholic patients are invincible to autoimmune type injury in the pancreas, which may not be necessarily true. Nevertheless, for practical purposes, it is important to rule out alcoholic injury before the diagnosis of AIP can be rendered.
Clinical features AIP is slightly more common in males (M/F ⫽ 2/1) despite the well known propensity of autoimmune conditions to occur in females. The patients seem to cluster into two clinico-pathologically distinct subsets.13 One type occurs predominantly in older men (mean age, mid60s), is often associated with Sjögren syndrome, bileduct stenosis, and morphologically exhibits the classical lymphoplasmacytic sclerotic pattern of “AIP.” The second is seen in younger patients (mean age, early 40s), show an almost equal male–female ratio, relatively higher incidence of inflammatory bowel disease, and demonstrate what we call “neutrophilic ductitis” on microscopic examination.5,13 Jaundice, presumably due to the sclerotic changes involving the bile duct is the most common presentation finding of AIP, seen in ⬎70% of the cases. Approximately 25% of patients present with abdominal pain or discomfort without jaundice.11,14,15 In about 80% of the cases, the lesion is located in the head of the organ,1,5,9,12,16,17 and also involves the bile-duct.18,19 Radiologically, the sclerotic process in the pancreatic head is very difficult, if not impossible, to distinguish from adenocarcinoma.20-24 For this reason, especially before sophisticated radiologic methods have become widely applicable, most patients of AIP had undergone resection with the clinical diagnosis of carcinoma. In fact, AIP used to be one of the most common causes of “pseudotumor” formation in the pancreas. This potential of AIP to mimic neoplasia is not limited to the radiologic level; the lesion can be so exuberant that in some cases it has been classified as inflammatory pseudotumor or inflammatory myofibroblastic tumor (discussed below). Owing to the recent advances in radiologic methods, along with the awareness of the existence of this entity, AIP can now be diagnosed preoperatively; however, it is still very difficult in some cases. The discovery of the fairly specific and sensitive association of AIP with increased serum IgG4 levels has been instrumental in the preoperative evaluation of these patients. Levels above 135 mg/dL are seldom seen in any pancreatic massforming lesion other than AIP.25 Autoimmune diseases are identified in approximately 15% to 20% of the patients.5,9,16 In many, the disease is known to the clinicians at the time of presentation, and in some, it is detected after the diagnosis of AIP is rendered. Sjögren syndrome and inflammatory bowel disease are the most common,2,7,26-38 and as mentioned previously, seem to have different sets of demographic and pathologic associations.
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Microscopic characteristics
Figure 1 Gross appearance of AIP. The lesion produces a sclerotic mass replacing the pancreatic carcinoma and often mimics pancreas cancer.
Some cases of AIP are associated with a group of disorders also known as idiopathic inflammatory fibrosclerosis.39-47 This conceptual category encompasses retroperitoneal fibrosis, orbital pseudotumor, and Riedel struma, which are also thought to be autoimmune.
Pathologic characteristics AIP is characterized by fibrosis and inflammation of pancreatic tissue, which typically manifests as enlargement of the pancreatic head, and constriction of the common bile duct. In a small percentage of cases, the lesion occurs in the tail, may involve the peripancreatic adipose tissue and cause adhesions to the surrounding organs including the colon or spleen. Diffuse involvement of pancreas may also occur but is uncommon.5,9
In the “usual” examples, AIP is characterized (and partially defined) by a lymphoplasmacytic infiltration associated with sclerosis, involving and replacing the pancreatic parenchyma. Plasma cells are often prominent. Inflammation is typically condensed around the ducts (thus, the name “ductcentric” pancreatitis), which leads to the formation of a band-like periductal zone, and the ducts appear thickened.1,5,9,12,13,16,17,47-49 Medium sized and larger ducts are more involved, and the common bile duct is also often affected.1,9,18,50 The distribution of inflammation and sclerosis around the ducts may vary; in more typical examples, inflammatory cells are lying in a collagenous, sclerotic matrix, arranged in cords and single cells separated by wavy collagen fibers (Figure 2). Less commonly, there is a band of paucicellular homogenous sclerosis around the ducts, with a separate layer of inflammation (Figure 3). In a few others, lymphoplasmacytic infiltrate may be more dense or localized, with no visible fibrous strands between the inflammatory cells that surround the ducts, although more typical foci would be present elsewhere. Compared with the degree of inflammation in the periductal tissue, intraepithelial lymphoplasmacytic infiltration is fairly minimal, though identifiable by careful inspection in most cases (Figure 4). In some cases, lymphoplasmacytic infiltrates are perilobular: atrophic lobules are surrounded by a cuff of lymphoid infiltrate, creating a fairly specific low-power appearance (Figure 5). In these cases, the intervening stroma can be paucicellular, and densely fibrotic. Lymphoid infiltrates may form germinal centers, but this is more typical for the inflammation that spills to the peripancreatic adipose tissue, and rarely evident in the periductal or perilobular compo-
Macroscopic features Macroscopically, AIP result in firm, sclerotic, tumorlike transformation of the pancreatic parenchyma. Some cases have more homogenous, milky-white, and smooth cut surfaces (Figure 1) in contrast with the more shiny, gray-green discoloration that desmoplastic stroma imparts many adenocarcinomas. Also, unlike carcinomas, AIP may transform the entire pancreatic head to a firm mass (clinically described as “swollen” pancreas) which is somewhat delineated from the surrounding tissues.1,5,9,12,16,17 In contrast, adenocarcinomas that infiltrate the entire head also typically send irregular projections to the surrounding tissue with puckering of adipose tissue in these areas. Those AIP cases with abundant inflammatory infiltrates tend to have slightly more beige color but are still firm due to the underlying sclerosis in the stroma.
Figure 2 Characteristic “band-like” periductal inflammation, with a dense rim of inflammatory cells (including numerous lymphocytes and plasma cells) and concentric wavy collagen fibers surrounding the pancreatic duct. (Color version of figure is available online at http:// journals.elsevierhealth.com/periodicals/ysdia.)
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Figure 3 Less commonly, there is a band of paucicellular homogenous sclerosis around the ducts separating the ductal epithelium from the inflammatory cells. (Color version of figure is available online at http://journals.elsevierhealth.com/periodicals/ ysdia.)
Figure 5 Another highly characteristic histologic finding is atrophic lobules surrounded by a cuff of lymphoplasmacytic infiltration accentuating the lobular architecture of the pancreas on lowpower. (Color version of figure is available online at http:// journals.elsevierhealth.com/periodicals/ysdia.)
nents. Peripancreatic lymph nodes are often enlarged and show prominent follicles. Vascular involvement by the inflammatory process is also characteristic. Arteries are mostly spared; however, venous lesions are invariably and readily apparent. In some areas (presumably in the earlier lesions), inflammation is more peri-vascular (“peri-phelibits”; Figure 6A). In more advanced lesions, venulitis may obscure the involved vessel; the vessel may become recognizable only by its contours or the remainder of the lumen that appears like a defect in the middle of an inflammatory focus (“obliterative phlebitis”51; Figure 6B). In fact, in
some areas, all there is left to be identified is a distinct zone of inflammation adjacent to an artery. The fibrosis in most cases, appears as thick wavy collagen fibers interspersed with lymphoplasmacytic infiltrates is also prominent, especially around the ducts16,52 (Figures 2 and 3). In some cases, however, there is an interstitial fibroblastic proliferation with a distinctive storiform pattern,16 admixed with interspersed inflammatory cells (Figure 7) (predominantly lymphocytes and plasma cells, and occasionally macrophages, eosinophils, or mast cells), and the overall picture resembles that of the “plasma cell granuloma of the lungs,” leading to the misdiagnosis of “inflammatory pseudotumor.”41,42,47,51,53-61 In rare AIP cases occurring in the tail, there is a peculiar sclerosis around the adipocytes we refer to as nested stromal angiosis (Figure 8), in which small, compressed capillaries are surrounded by edema, few inflammatory cells including eosinophils, and an outer zone of sclerosis. Cases demonstrating prominent neutrophilic inflammation with a propensity to involve the ductal epithelium (granulocytic epithelial lesions, GELs) appear to represent a distinct subset of AIP.5,13 In this group, neutrophils show an affinity for relatively smaller ducts, and typically involve and destroy the duct epithelium (Figure 9). Neutrophils may be present in the intralobar ducts and acini as well.
Figure 4 High-power examination of ductal epithelium often reveals extension of lymphoplasmacytic infiltration into epithelial layer, with destruction of the ductal cells; however, this is not a prominent feature and may be difficult to appreciate in low-power examination. (Color version of figure is available online at http:// journals.elsevierhealth.com/periodicals/ysdia.)
Additional studies Simple histochemical stains may help confirm the vascular involvement by the inflammatory process. Special stains that highlight the components of the vessels such
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Figure 6 Vascular involvement is typical. (A) In some areas there are lymphoid aggregates clustering around the vessels (peri-phlebitis). Involvement of arterial wall (left) is much less common. (B) In the most typical lesions, the inflammatory cells undermine the endothelium and produce fibrous obliteration of the veins. The remainder of the lumen appears like a defect in the middle of an inflammatory focus (obliterative phlebitis). (Color version of figure is available online at http://journals.elsevierhealth.com/periodicals/ysdia.)
as EVG or movat pentichrome,62 or in some cases, muscular or endothelial markers, may help confirm the presence of periphlebitis. Immunohistochemical stain for IgG4 is becoming a very helpful adjunct for the diagnosis of AIP, not only in resection specimens, but also in biopsies.44,63-65 Recent studies indicate that in many patients with AIP of the “usual” type (LPSP), there are more than 50 IgG4-positive plasma cells per high-power field; this number is fairly specific for AIP and is seldom seen (if at all) in other forms of pancreatitis. It also correlates well with serum IgG4 levels of ⬎135mg/dL which appear to be the
Figure 7 Some cases have a much more profound expansion of the fibroinflammatory process, with a complete replacement of the pancreatic parenchyma. Notice the storiform stroma admixed with interspersed inflammatory cells and abundant collagen deposition. (Color version of figure is available online at http://journals. elsevierhealth.com/periodicals/ysdia.)
levels that identifies AIP more specifically.25 In fact, immunohistochemical stains may even detect some cases with lower serum levels.65 On the other hand, although this finding is highly sensitive in identifying patients with the usual type of AIP, it is not a feature of the “granulocytic” type65 in which the lymphoplasmacytic infiltrates are less prominent, and the process is characterized instead by granulocytic epithelial lesions (GELs). Also, this increment of IgG4-positive plasma cells in the pancreas of even “usual” type AIP does not seem to apply to the duodenum; the number of IgG4 positive cells has been found to be not too different than in other diseases in duodenum.64 Not surprisingly, the lymphocytic infiltrates in AIP are composed of T-cells, which can be verified by T-cell
Figure 8 Stromal angiosis is a very rare finding, in which small, compressed capillaries are surrounded by edema, inflammatory cells, and an outer zone of peculiar sclerosis. (Color version of figure is available online at http://journals.elsevierhealth.com/ periodicals/ysdia.)
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Figure 9 In some cases, there is neutrophilic infiltration of the relatively smaller ducts, with ductal epithelial involvement, termed “granulocytic epithelial lesions (GELs)”. These cases appear to represent a separate subset of AIP. (Color version of figure is available online at http://journals.elsevierhealth.com/periodicals/ ysdia.)
markers.5,66 In some recent reports, oligoclonal T-cell peaks in T-cell gamma receptor gene rearrangement have been found to have diagnostic value as a useful adjunctive assay for AIP53; however, more data are needed to determine the practical applicability and specificity of this assay.
Differential diagnosis It is important to distinguish AIP from the other types of pancreatitis, in particular, alcoholic, because the management and prognosis are vastly different. This differential is challenging both at the clinical and pathologic levels, and the correlation of clinical and pathologic findings may be necessary. As discussed previously, lack of alcohol history has been advocated as one of the defining criteria for AIP. The morphologic findings are also helpful in this distinction. Ductal dilation, intraluminal proteinaceous concretions and pancreatolithiasis which characterize alcoholic pancreatitis are not features of AIP. Alcoholic pancreatitis cases also often show evidence of ongoing active disease including peripancreatic fat necrosis and pseudocyst formation. These are not common features of AIP unless there is a history of biopsy or instrumentation. In contrast, dispersion of inflammatory cells, particularly plasma cells, in individual cells or cords, separated by wavy, collagenous matrix is more characteristic of AIP.9 Lymphoid infiltration may be seen in other forms of chronic pancreatitis, often forming discrete clusters or zones, but these are typically devoid of any significant plasma cell participation, and the pattern of inflammation
Seminars in Diagnostic Pathology, Vol 22, No 4 with sclerosis or storiform-like fibrosis are lacking. The expansion of the periductal zone by a sclero-inflammatory process is also not a common feature of alcoholic pancreatitis.67-69 In alcoholic pancreatitis, neutrophilic infiltrates are typically condensed around the fat necrosis occurring in the peripancreatic or perilobular tissue. It is highly unusual to see neutrophils within the epithelium except for “type 2” or “type 3” necrosis, which are rare subsets of acute pancreatitis.70 Naturally, if there is a history of instrumentation, acute inflammation may also be seen in the epithelium, but is typically confined to peri-ampullary ductal units. Therefore, the presence of neutrophils within the epithelium of the pancreas proper should raise the possibility of AIP of the neutrophilic type. Similar to AIP, paraduodenal pancreatitis also often presents as a pseudotumor in the pancreas or duodenal wall. In paraduodenal pancreatitis, the pathologic process is less cellular and is typically centered in the accessory duct or duodenal wall, or involves the groove (the area between the CBD, duodenum and pancreatic head). Usually the stromal proliferation is more myoid than fibroblastic or inflammatory.71-76 In patients with florid fibroblastic proliferation, in particular when there is storiform architecture, the stromal elements of AIP gives the impression of a spindle cell neoplasm, and may be misdiagnosed as “inflammatory myofibroblastic tumor.”41,42,51,53-59 Expression of ALK-1, p53 and high Ki-67 levels, which are common in IMTs, are not features of AIP.77 Clinically, the main differential diagnosis of AIP is with pancreatic adenocarcinoma.13,16,48,78 Experienced clinicians are able to appreciate the subtle findings on CT scans including the more diffuse nature of AIP versus the focality of carcinoma; however, the distinction can be impossible in some cases. Lymph node enlargement, which is very common in AIP, further complicates this differential diagnosis.22,79 Serum IgG4 levels may be most helpful. For the microscopic differential diagnosis of benign reactive changes (including AIP) from carcinoma, the readers are referred to a recent publication that has focused on this issue.80 It should be mentioned here though, that peritumoral pancreatitis associated with carcinoma may mimic AIP,5 every solid lesion in the pancreas should be investigated thoroughly before the diagnosis of adenocarcinoma can be excluded. Accordingly, a resection specimen should be sampled extensively (if not entirely) to rule out this possibility.
Fine needle aspiration biopsy Patients with AIP often undergo fine-needle aspiration biopsy with the preoperative diagnosis of carcinoma. The presence of stromal fragments with lymphocytes greater than 30 per 60⫻ has been found to be in favor of AIP,81
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although it is by no means specific. Also, the stromal fragments are significantly more cellular in AIP cases.5,81-84 If these findings are evaluated in conjunction with the clinical and radiologic findings, they may help achieve the correct diagnosis, or at least prompt the clinicians to perform serum IgG4 levels.
Management and outcome Until recently, most AIPs have been resected due to the preoperative misdiagnosis of adenocarcinoma. This is still true for most patients. Following surgery, some patients experienced emergence of new foci of strictures or pseudotumors.16,47,48 There is overwhelming evidence in the literature that AIP is highly responsive to steroid therapy.25,85-91 It is expected that as the clinical and pathologic criteria for the diagnosis of AIP are better defined it will become increasingly feasible to avoid unnecessary operations, and the patients will be managed medically with steroid therapy.
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316 38. Barthet M, Hastier P, Bernard JP, et al: Chronic pancreatitis and inflammatory bowel disease: true or coincidental association? Am J Gastroenterol 94:2141-2148, 1999 39. Hastier P, Buckley MJ, Le Gall P, et al: First report of association of chronic pancreatitis, primary biliary cirrhosis, and systemic sclerosis. Dig Dis Sci 43:2426-2428, 1998 40. Bartholomew LG, Cain JC, Woolner LB, et al: Sclerosing cholangitis: its possible association with Riedel’s struma and fibrous retroperitonitis. Report of two cases. N Engl J Med 269:8-12, 1963 41. Chutaputti A, Burrell MI, Boyer JL: Pseudotumor of the pancreas associated with retroperitoneal fibrosis: a dramatic response to corticosteroid therapy. Am J Gastroenterol 90:1155-1158, 1995 42. Clark A, Zeman RK, Choyke PL, et al: Pancreatic pseudotumors associated with multifocal idiopathic fibrosclerosis. Gastrointestinal Radiol 13:30-32, 1988 43. Comings DE, Skubi KB, Van Eyes J, et al: Familial multifocal fibrosclerosis findings suggesting that retroperitoneal fibrosis, mediastinal fibrosis, sclerosing cholangitis, Riedel’s thyroiditis, and pseudotumor of the orbit may be different manifestations of a single disease. Ann Intern Med 66:884-892, 1967 44. Kamisawa T, Funata N, Hayashi Y, et al: Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis. Gut 52:683687, 2003 45. Kamisawa T, Matsukawa M, Ohkawa M: Autoimmune pancreatitis associated with retroperitoneal fibrosis. Jop 6:260-263, 2005 46. Levey JM, Mathai J: Diffuse pancreatic fibrosis: an uncommon feature of multifocal idiopathic fibrosclerosis. Am J Gastroenterol 93:640642, 1998 47. Klimstra DS, Conlon KC, Adsay NV: Lymphoplasmacytic sclerosing pancreatitis with pseudotumor formation. Pathol Case Rev 6:94-99, 2001 48. Hardacre JM, Iacobuzio-Donahue CA, Sohn TA, et al: Results of pancreaticoduodenectomy for lymphoplasmacytic sclerosing pancreatitis. Ann Surg 237:853-858, 2003 49. Youssef N, Petitjean B, Bonte H, et al: Non-alcoholic duct destructive chronic pancreatitis: a histological, immunohistochemical and in-situ apoptosis study of 18 cases. Histopathology 44:453-461, 2004 50. Scully RE, Mark EJ, McNeely BU: Weekly clinico-pathological exercises: case 6. N Engl J Med 306:349-358, 1982 51. Wreesmann V, van Eijck CH, Naus DC, et al: Inflammatory pseudotumour (inflammatory myofibroblastic tumour) of the pancreas: a report of six cases associated with obliterative phlebitis. Histopathology 38:105-110, 2001 52. Klöppel G, Detlefsen S, Feyerabend B: Fibrosis of the pancreas: the initial tissue damage and the resulting pattern. Virchows Arch 445:1-8, 2004 53. Esposito I, Bergmann F, Penzel R, et al: Oligoclonal T-cell populations in an inflammatory pseudotumor of the pancreas possibly related to autoimmune pancreatitis: an immunohistochemical and molecular analysis. Virchows Arch 444:119-126, 2004 54. Fukushima N, Suzuki M, Abe T, et al: A case of inflammatory pseudotumour of the common bile duct. Virchows Archiv 431:219224, 1997 55. Nonomura A, Minato H, Shimizu K, et al: Hepatic hilar inflammatory pseudotumor mimicking cholangiocarcinoma with cholangitis and phlebitis–a variant of primary sclerosing cholangitis? Pathol Res Pract 193: 519-525, 1997 56. Palazzo JP, Chang CD: Inflammatory pseudotumour of the pancreas. Histopathology 23:475-477, 1993 57. Renner IG, Ponto GC, Savage WT 3rd, et al: Idiopathic retroperitoneal fibrosis producing common bile duct and pancreatic duct obstruction. Gastroenterology 79:348-351, 1980 58. Uchida K, Okazaki K, Asada M, et al: Case of chronic pancreatitis involving an autoimmune mechanism that extended to retroperitoneal fibrosis. Pancreas 26:92-94, 2003 59. Walsh SV, Evangelista F, Khettry U: Inflammatory myofibroblastic tumor of the pancreaticobiliary region: morphologic and immunocytochemical study of three cases. Am J Surg Pathol 22:412-418, 1998
Seminars in Diagnostic Pathology, Vol 22, No 4 60. Petter LM, Martin JK Jr, Menke DM: Localized lymphoplasmacellular pancreatitis forming a pancreatic inflammatory pseudotumor. Mayo Clinic Proceedings 73:447-450, 1998 61. Taniguchi T, Seko S, Azuma K, et al: Autoimmune pancreatitis detected as a mass in the tail of the pancreas. J Gastroenterol Hepatol 15:461-464, 2000 62. Papouchado B, Lane Z, Bronner MP: The role of movat pentichrome stain in the diagnosis of lymphoplasmocytic sclerosing pancreatitis (Abstract). Mod Pathol 19:279A, 2006 63. Kamisawa T: IgG4-positive plasma cells specifically infiltrate various organs in autoimmune pancreatitis. Pancreas 29:167-168, 2004 64. Zhang H, Levy M, Chari S, et al: IgG4 stain for the diagnosis of autoimmune pancreatitis: helpful in pancreatic biopsies, but not in the duodenum. Mod Pathol 19:283A, 2006 65. Dhall D, Suriawinata A, Shia J, et al: Immunohistochemical detection of IgG4-positive plasma cells helps distinguish lymphoplasmacytic sclerosing pancreatitis (LPSP) from pancreatitis associated with carcinoma or other conditions (Abstract). Mod Pathol 19:273A, 2006 66. Kamisawa T, Funata N, Hayashi Y, et al: A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 38:982-984, 2003 67. Sarles H: Definitions and classifications of pancreatitis. Pancreas 6:470-474, 1991 68. De Angelis C, Valente G, Spaccapietra M, et al: Histological study of alcoholic, nonalcoholic, and obstructive chronic pancreatitis. Pancreas 7:193-196, 1992 69. Klöppel G: Pathology of chronic pancreatitis and pancreatic pain. Acta Chir Scand 156:261-265, 1990 70. Klöppel G: Acute pancreatitis. Semin Diagn Pathol 21:221-226, 2004 71. Bogina G, Scarpa A, Mombello A: Cystic dystrophy of the duodenal wall is a pancreatitis of the intraduodenal pancreas caused by the obstruction o papilla minor. Am J Surg Pathol 2005, in press 72. Holstege A, Barner S, Brambs HJ, et al: Relapsing pancreatitis associated with duodenal wall cysts: diagnostic approach and treatment. Gastroenterology 88:814-819, 1985 73. Procacci C, Graziani R, Zamboni G, et al: Cystic dystrophy of the duodenal wall: radiologic findings. Radiology 205:741-747, 1997 74. Shudo R, Yazaki Y, Sakurai S, et al: Groove pancreatitis: report of a case and review of the clinical and radiologic features of groove pancreatitis reported in Japan. Intern Med 41:537-542, 2002 75. Adsay N, Zamboni G: Paraduodenal pancreatitis: a clinico-pathologically distinct entity unifying “cystic dystrophy of heterotopic pancreas,” “para-duodenal wall cyst” and “groove pancreatitis”. Semin Diag Pathol 21:247-254, 2004 76. Flejou JF, Potet F, Molas G, et al: Cystic dystrophy of the gastric and duodenal wall developing in heterotopic pancreas: an unrecognised entity. Gut 34:343-347, 1993 77. Mizukami H, Yajima N, Wada R, et al: Pancreatic malignant fibrous histiocytoma, inflammatory myofibroblastic tumor, and inflammatory pseudotumor related to autoimmune pancreatitis: characterization and differential diagnosis. Virchows Arch 2006, in press 78. Abraham SC, Wilentz RE, Yeo CJ, et al: Pancreaticoduodenectomy (Whipple resections) in patients without malignancy: are they all ‘chronic pancreatitis’? Am J Surg Pathol 27:110-120, 2003 79. Procacci C, Carbognin G, Biasiutti C, et al: Autoimmune pancreatitis: possibilities of CT characterization. Pancreatology 1:246-253, 2001 80. Klimstra D, Adsay NV: Lymphoplasmacytic sclerosing (autoimmune) pancreatitis. Semin Diagn Pathol 21:237-246, 2004 81. Deshpande V, Mino-Kenudson M, Brugge WR, et al: Endoscopic ultrasound guided fine needle aspiration biopsy of autoimmune pancreatitis: diagnostic criteria and pitfalls. Am J Surg Pathol 29:14641471, 2005 82. Fritscher-Ravens A, Brand L, Knofel WT, et al: Comparison of endoscopic ultrasound-guided fine needle aspiration for focal pancreatic lesions in patients with normal parenchyma and chronic pancreatitis. Am J Gastroenterol 97:2768-2775, 2002
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83. Hollerbach S, Klamann A, Topalidis T, et al: Endoscopic ultrasonography (EUS) and fine-needle aspiration (FNA) cytology for diagnosis of chronic pancreatitis. Endoscopy 33:824-831, 2001 84. Stelow EB, Bardales RH, Lai R, et al: The cytological spectrum of chronic pancreatitis. Diagn Cytopathol 32:65-69, 2005 85. Kazumori H, Ashizawa N, Moriyama N, et al: Primary sclerosing pancreatitis and cholangitis. Int J Pancreatol 24:123-127, 1998 86. Horiuchi A, Kawa S, Hamano H, et al: ERCP features in 27 patients with autoimmune pancreatitis. Gastrointest Endosc 55:494-499, 2002 87. Kojima E, Kimura K, Noda Y, et al: Autoimmune pancreatitis and
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multiple bile duct strictures treated effectively with steroid. J Gastroenterol 38:603-607, 2003 Saito T, Tanaka S, Yoshida H: A case of autoimmune pancreatitis responding to steroid theraphy:evidence of histologic recovery. Pancreatology 2002:550-556, 2002 Okazaki K, Chiba T: Autoimmune related pancreatitis. Gut 51:1-4, 2002 Erkelens G, Vleggaar FP, Lesterhuis W: Sclerosing pancreatocholangitis responsive to steroid theraphy. Lancet 354:43-44, 1999 Hong SP, Park SW, Chung JP, et al: Autoimmune pancreatitis with effective steroid therapy. Yonsei Med J 44:534-538, 2003
Diagnostic features and differential diagnosis of autoimmune pancreatitis N. Volkan Adsay, MD, Olca Basturk, MD, Duangpen Thirabanjasak, MD From the Department of Pathology, The Karmanos Cancer Institute and Wayne State University School of Medicine, Detroit, Michigan.
KEYWORDS Pancreas; Pancreatitis; Autoimmune; Pseudotumor
A clinically and pathologically distinct form of chronic pancreatitis is now widely recognized and has been designated variably as lymphoplasmacytic sclerosing pancreatitis, duct-destructive (duct-centric) pancreatitis or autoimmune pancreatitis. This entity is currently defined by a constellation of clinical and pathologic findings, including the lack of both conventional risk factors for pancreatitis, such as alcohol use and gallstones, and their hallmark pattern of injury, including calcifications and pseudocysts. Histologically, it is characterized by lymphoplasmacytic inflammation with abundant IgG4positive plasma cells that exhibit an affinity for ducts as well as venules (“peri-venulitis,” with or without frank vasculitis). Inflammation is often associated with sclerosis and expansion of periductal tissue. In some cases, fibroblastic activity is prominent and resembles “inflammatory pseudotumor” or is even misdiagnosed as “inflammatory myofibroblastic tumor.” In what appears to be a distinct subset of this entity, intraepithelial granulocytic infiltrates may be seen. Well-developed examples are readily recognized; however, lesser ones may be difficult to distinguish from other forms of pancreatitis based on morphology alone. This type of pancreatitis is considered an autoimmune process. In about 15% to 20% of patients, the clinical stigmata of autoimmune conditions are present at the time of diagnosis, and in many others, discovered subsequently. The usual “lymphoplasmacytic sclerotic” type tends to be associated with Sjogren, whereas the “granulocytic” subset, with inflammatory bowel disease. Most patients present with a pancreatic head mass, often with an accompanying stricture of the distal common bile duct, which thus radiologically resembles “pancreas cancer.” In fact, this entity accounts for more than a third of the cases of pseudotumoral pancreatitis (mass-forming inflammatory lesions that resemble carcinoma). Elevated serum IgG4 levels are characteristic and may be very helpful in the differential diagnosis from tumors and tumor-like lesions of the pancreas which seldom result in levels above 135 mg/dL. The mean age of the patients with this condition is in the mid-50s; the subset with granulocytic intraepithelial lesions seem to be younger (mid 40s). Despite the autoimmune association, males are afflicted as commonly as (if not more than) females. Following resection, emergence of new fibro-inflammatory lesions in the remaining pancreaticobiliary tree has been noted in some cases; however, the process typically responds to steroids. It is important to recognize the distinctive clinicopathologic features of this entity, so that it can be diagnosed accurately and managed appropriately. © 2005 Elsevier Inc. All rights reserved.
Address reprint requests and correspondence: N. Volkan Adsay, MD, Department of Pathology, Harper University Hospital, 3990 John R, Detroit, MI 48201. E-mail address: [email protected].
0740-2570/$ -see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.semdp.2006.04.008
Autoimmune pancreatitis, also known as lymphoplasmacytic sclerosing1-7 or duct-centric (duct-destructive) pancreatitis,8-10 had fallen under the generic heading of “idiopathic chronic pancreatitis” until it began to be recognized as a special type of pancreatic injury in the 1990s. It is now widely accepted as a distinct entity. Each term proposed for this entity in the 1990s high-
310 lights a different facet of this process, but may not reflect other aspects. The name lymphoplasmacytic sclerosing pancreatitis (LPSP)1-5 is a morphology-based, descriptive term that embraces the two main features of this lesion, the participation of plasma cells, and presence of sclerosis. However, there is a subset of this entity recognized recently that is characterized by granulocytic epithelial lesions and may lack the prominent plasma cell infiltration or sclerosis. The pancreatitis in AIP is believed to be autoimmune based, and there is mounting evidence to support this notion; however, the majority of the patients lack the clinical and serologic stigmata of autoimmune disorders, and thus the association may not be as strong as the term “autoimmune” implies.4,7,11 Also, it is not clear whether the subtle changes identified in the pancreata of patients with autoimmune conditions such as incidental, microscopic foci of vasculitis without gross alterations ought to be regarded as a manifestation of this entity or not. Our bias is to take a purist’s approach and reserve the diagnosis of AIP only for the cases that show substantial pancreatic injury, the features of which are described below. Another important issue that somewhat blurs the definition of AIP is its relationship to other types of pseudotumoral pancreatitis. In most studies concerning AIP, the cases were identified among patients that had undergone pancreatectomy for a pancreatic mass, typically with the clinical diagnosis of carcinoma. We now know that many, but not all, of these cases are in fact AIP. There are, however, other clinicopathologic entities that cause pseudotumor formation in the pancreas, and some of these appear to have been included into the category of AIP due to lack of recognition and proper criteria until recently. It is our opinion that AIP ought to be defined by the combination of specific clinical and pathologic criteria established recently. It is acknowledged that this purist’s approach may disregard, perhaps inaccurately, the lesser or evolving examples of this entity; however, the opposite (the inclusive approach) leads to misdiagnosis of alcoholic, gallstone-related, and paraduodenal types of pancreatitis as AIP. Therefore, we believe that, until the nature of these gray-zone cases is better elucidated, the criteria established recently ought to be applied rather strictly. AIP has also been referred as nonalcoholic duct-destructive pancreatitis.8,10,12 Currently, almost by definition, the diagnosis of AIP is reserved only for nonalcoholic patients. The problem with this criterion is that this history is often not available for the pathologists. Moreover, in some cases, even the clinicians may not possess this information. Furthermore, the amount of alcohol required to cause alcoholic pancreatitis is not as straightforward as it may seem; despite the international guidelines and consensus definitions, the biologic significance of the figures proposed are not clear. Also, this criterion
Seminars in Diagnostic Pathology, Vol 22, No 4 dictates that alcoholic patients are invincible to autoimmune type injury in the pancreas, which may not be necessarily true. Nevertheless, for practical purposes, it is important to rule out alcoholic injury before the diagnosis of AIP can be rendered.
Clinical features AIP is slightly more common in males (M/F ⫽ 2/1) despite the well known propensity of autoimmune conditions to occur in females. The patients seem to cluster into two clinico-pathologically distinct subsets.13 One type occurs predominantly in older men (mean age, mid60s), is often associated with Sjögren syndrome, bileduct stenosis, and morphologically exhibits the classical lymphoplasmacytic sclerotic pattern of “AIP.” The second is seen in younger patients (mean age, early 40s), show an almost equal male–female ratio, relatively higher incidence of inflammatory bowel disease, and demonstrate what we call “neutrophilic ductitis” on microscopic examination.5,13 Jaundice, presumably due to the sclerotic changes involving the bile duct is the most common presentation finding of AIP, seen in ⬎70% of the cases. Approximately 25% of patients present with abdominal pain or discomfort without jaundice.11,14,15 In about 80% of the cases, the lesion is located in the head of the organ,1,5,9,12,16,17 and also involves the bile-duct.18,19 Radiologically, the sclerotic process in the pancreatic head is very difficult, if not impossible, to distinguish from adenocarcinoma.20-24 For this reason, especially before sophisticated radiologic methods have become widely applicable, most patients of AIP had undergone resection with the clinical diagnosis of carcinoma. In fact, AIP used to be one of the most common causes of “pseudotumor” formation in the pancreas. This potential of AIP to mimic neoplasia is not limited to the radiologic level; the lesion can be so exuberant that in some cases it has been classified as inflammatory pseudotumor or inflammatory myofibroblastic tumor (discussed below). Owing to the recent advances in radiologic methods, along with the awareness of the existence of this entity, AIP can now be diagnosed preoperatively; however, it is still very difficult in some cases. The discovery of the fairly specific and sensitive association of AIP with increased serum IgG4 levels has been instrumental in the preoperative evaluation of these patients. Levels above 135 mg/dL are seldom seen in any pancreatic massforming lesion other than AIP.25 Autoimmune diseases are identified in approximately 15% to 20% of the patients.5,9,16 In many, the disease is known to the clinicians at the time of presentation, and in some, it is detected after the diagnosis of AIP is rendered. Sjögren syndrome and inflammatory bowel disease are the most common,2,7,26-38 and as mentioned previously, seem to have different sets of demographic and pathologic associations.
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Microscopic characteristics
Figure 1 Gross appearance of AIP. The lesion produces a sclerotic mass replacing the pancreatic carcinoma and often mimics pancreas cancer.
Some cases of AIP are associated with a group of disorders also known as idiopathic inflammatory fibrosclerosis.39-47 This conceptual category encompasses retroperitoneal fibrosis, orbital pseudotumor, and Riedel struma, which are also thought to be autoimmune.
Pathologic characteristics AIP is characterized by fibrosis and inflammation of pancreatic tissue, which typically manifests as enlargement of the pancreatic head, and constriction of the common bile duct. In a small percentage of cases, the lesion occurs in the tail, may involve the peripancreatic adipose tissue and cause adhesions to the surrounding organs including the colon or spleen. Diffuse involvement of pancreas may also occur but is uncommon.5,9
In the “usual” examples, AIP is characterized (and partially defined) by a lymphoplasmacytic infiltration associated with sclerosis, involving and replacing the pancreatic parenchyma. Plasma cells are often prominent. Inflammation is typically condensed around the ducts (thus, the name “ductcentric” pancreatitis), which leads to the formation of a band-like periductal zone, and the ducts appear thickened.1,5,9,12,13,16,17,47-49 Medium sized and larger ducts are more involved, and the common bile duct is also often affected.1,9,18,50 The distribution of inflammation and sclerosis around the ducts may vary; in more typical examples, inflammatory cells are lying in a collagenous, sclerotic matrix, arranged in cords and single cells separated by wavy collagen fibers (Figure 2). Less commonly, there is a band of paucicellular homogenous sclerosis around the ducts, with a separate layer of inflammation (Figure 3). In a few others, lymphoplasmacytic infiltrate may be more dense or localized, with no visible fibrous strands between the inflammatory cells that surround the ducts, although more typical foci would be present elsewhere. Compared with the degree of inflammation in the periductal tissue, intraepithelial lymphoplasmacytic infiltration is fairly minimal, though identifiable by careful inspection in most cases (Figure 4). In some cases, lymphoplasmacytic infiltrates are perilobular: atrophic lobules are surrounded by a cuff of lymphoid infiltrate, creating a fairly specific low-power appearance (Figure 5). In these cases, the intervening stroma can be paucicellular, and densely fibrotic. Lymphoid infiltrates may form germinal centers, but this is more typical for the inflammation that spills to the peripancreatic adipose tissue, and rarely evident in the periductal or perilobular compo-
Macroscopic features Macroscopically, AIP result in firm, sclerotic, tumorlike transformation of the pancreatic parenchyma. Some cases have more homogenous, milky-white, and smooth cut surfaces (Figure 1) in contrast with the more shiny, gray-green discoloration that desmoplastic stroma imparts many adenocarcinomas. Also, unlike carcinomas, AIP may transform the entire pancreatic head to a firm mass (clinically described as “swollen” pancreas) which is somewhat delineated from the surrounding tissues.1,5,9,12,16,17 In contrast, adenocarcinomas that infiltrate the entire head also typically send irregular projections to the surrounding tissue with puckering of adipose tissue in these areas. Those AIP cases with abundant inflammatory infiltrates tend to have slightly more beige color but are still firm due to the underlying sclerosis in the stroma.
Figure 2 Characteristic “band-like” periductal inflammation, with a dense rim of inflammatory cells (including numerous lymphocytes and plasma cells) and concentric wavy collagen fibers surrounding the pancreatic duct. (Color version of figure is available online at http:// journals.elsevierhealth.com/periodicals/ysdia.)
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Figure 3 Less commonly, there is a band of paucicellular homogenous sclerosis around the ducts separating the ductal epithelium from the inflammatory cells. (Color version of figure is available online at http://journals.elsevierhealth.com/periodicals/ ysdia.)
Figure 5 Another highly characteristic histologic finding is atrophic lobules surrounded by a cuff of lymphoplasmacytic infiltration accentuating the lobular architecture of the pancreas on lowpower. (Color version of figure is available online at http:// journals.elsevierhealth.com/periodicals/ysdia.)
nents. Peripancreatic lymph nodes are often enlarged and show prominent follicles. Vascular involvement by the inflammatory process is also characteristic. Arteries are mostly spared; however, venous lesions are invariably and readily apparent. In some areas (presumably in the earlier lesions), inflammation is more peri-vascular (“peri-phelibits”; Figure 6A). In more advanced lesions, venulitis may obscure the involved vessel; the vessel may become recognizable only by its contours or the remainder of the lumen that appears like a defect in the middle of an inflammatory focus (“obliterative phlebitis”51; Figure 6B). In fact, in
some areas, all there is left to be identified is a distinct zone of inflammation adjacent to an artery. The fibrosis in most cases, appears as thick wavy collagen fibers interspersed with lymphoplasmacytic infiltrates is also prominent, especially around the ducts16,52 (Figures 2 and 3). In some cases, however, there is an interstitial fibroblastic proliferation with a distinctive storiform pattern,16 admixed with interspersed inflammatory cells (Figure 7) (predominantly lymphocytes and plasma cells, and occasionally macrophages, eosinophils, or mast cells), and the overall picture resembles that of the “plasma cell granuloma of the lungs,” leading to the misdiagnosis of “inflammatory pseudotumor.”41,42,47,51,53-61 In rare AIP cases occurring in the tail, there is a peculiar sclerosis around the adipocytes we refer to as nested stromal angiosis (Figure 8), in which small, compressed capillaries are surrounded by edema, few inflammatory cells including eosinophils, and an outer zone of sclerosis. Cases demonstrating prominent neutrophilic inflammation with a propensity to involve the ductal epithelium (granulocytic epithelial lesions, GELs) appear to represent a distinct subset of AIP.5,13 In this group, neutrophils show an affinity for relatively smaller ducts, and typically involve and destroy the duct epithelium (Figure 9). Neutrophils may be present in the intralobar ducts and acini as well.
Figure 4 High-power examination of ductal epithelium often reveals extension of lymphoplasmacytic infiltration into epithelial layer, with destruction of the ductal cells; however, this is not a prominent feature and may be difficult to appreciate in low-power examination. (Color version of figure is available online at http:// journals.elsevierhealth.com/periodicals/ysdia.)
Additional studies Simple histochemical stains may help confirm the vascular involvement by the inflammatory process. Special stains that highlight the components of the vessels such
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Figure 6 Vascular involvement is typical. (A) In some areas there are lymphoid aggregates clustering around the vessels (peri-phlebitis). Involvement of arterial wall (left) is much less common. (B) In the most typical lesions, the inflammatory cells undermine the endothelium and produce fibrous obliteration of the veins. The remainder of the lumen appears like a defect in the middle of an inflammatory focus (obliterative phlebitis). (Color version of figure is available online at http://journals.elsevierhealth.com/periodicals/ysdia.)
as EVG or movat pentichrome,62 or in some cases, muscular or endothelial markers, may help confirm the presence of periphlebitis. Immunohistochemical stain for IgG4 is becoming a very helpful adjunct for the diagnosis of AIP, not only in resection specimens, but also in biopsies.44,63-65 Recent studies indicate that in many patients with AIP of the “usual” type (LPSP), there are more than 50 IgG4-positive plasma cells per high-power field; this number is fairly specific for AIP and is seldom seen (if at all) in other forms of pancreatitis. It also correlates well with serum IgG4 levels of ⬎135mg/dL which appear to be the
Figure 7 Some cases have a much more profound expansion of the fibroinflammatory process, with a complete replacement of the pancreatic parenchyma. Notice the storiform stroma admixed with interspersed inflammatory cells and abundant collagen deposition. (Color version of figure is available online at http://journals. elsevierhealth.com/periodicals/ysdia.)
levels that identifies AIP more specifically.25 In fact, immunohistochemical stains may even detect some cases with lower serum levels.65 On the other hand, although this finding is highly sensitive in identifying patients with the usual type of AIP, it is not a feature of the “granulocytic” type65 in which the lymphoplasmacytic infiltrates are less prominent, and the process is characterized instead by granulocytic epithelial lesions (GELs). Also, this increment of IgG4-positive plasma cells in the pancreas of even “usual” type AIP does not seem to apply to the duodenum; the number of IgG4 positive cells has been found to be not too different than in other diseases in duodenum.64 Not surprisingly, the lymphocytic infiltrates in AIP are composed of T-cells, which can be verified by T-cell
Figure 8 Stromal angiosis is a very rare finding, in which small, compressed capillaries are surrounded by edema, inflammatory cells, and an outer zone of peculiar sclerosis. (Color version of figure is available online at http://journals.elsevierhealth.com/ periodicals/ysdia.)
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Figure 9 In some cases, there is neutrophilic infiltration of the relatively smaller ducts, with ductal epithelial involvement, termed “granulocytic epithelial lesions (GELs)”. These cases appear to represent a separate subset of AIP. (Color version of figure is available online at http://journals.elsevierhealth.com/periodicals/ ysdia.)
markers.5,66 In some recent reports, oligoclonal T-cell peaks in T-cell gamma receptor gene rearrangement have been found to have diagnostic value as a useful adjunctive assay for AIP53; however, more data are needed to determine the practical applicability and specificity of this assay.
Differential diagnosis It is important to distinguish AIP from the other types of pancreatitis, in particular, alcoholic, because the management and prognosis are vastly different. This differential is challenging both at the clinical and pathologic levels, and the correlation of clinical and pathologic findings may be necessary. As discussed previously, lack of alcohol history has been advocated as one of the defining criteria for AIP. The morphologic findings are also helpful in this distinction. Ductal dilation, intraluminal proteinaceous concretions and pancreatolithiasis which characterize alcoholic pancreatitis are not features of AIP. Alcoholic pancreatitis cases also often show evidence of ongoing active disease including peripancreatic fat necrosis and pseudocyst formation. These are not common features of AIP unless there is a history of biopsy or instrumentation. In contrast, dispersion of inflammatory cells, particularly plasma cells, in individual cells or cords, separated by wavy, collagenous matrix is more characteristic of AIP.9 Lymphoid infiltration may be seen in other forms of chronic pancreatitis, often forming discrete clusters or zones, but these are typically devoid of any significant plasma cell participation, and the pattern of inflammation
Seminars in Diagnostic Pathology, Vol 22, No 4 with sclerosis or storiform-like fibrosis are lacking. The expansion of the periductal zone by a sclero-inflammatory process is also not a common feature of alcoholic pancreatitis.67-69 In alcoholic pancreatitis, neutrophilic infiltrates are typically condensed around the fat necrosis occurring in the peripancreatic or perilobular tissue. It is highly unusual to see neutrophils within the epithelium except for “type 2” or “type 3” necrosis, which are rare subsets of acute pancreatitis.70 Naturally, if there is a history of instrumentation, acute inflammation may also be seen in the epithelium, but is typically confined to peri-ampullary ductal units. Therefore, the presence of neutrophils within the epithelium of the pancreas proper should raise the possibility of AIP of the neutrophilic type. Similar to AIP, paraduodenal pancreatitis also often presents as a pseudotumor in the pancreas or duodenal wall. In paraduodenal pancreatitis, the pathologic process is less cellular and is typically centered in the accessory duct or duodenal wall, or involves the groove (the area between the CBD, duodenum and pancreatic head). Usually the stromal proliferation is more myoid than fibroblastic or inflammatory.71-76 In patients with florid fibroblastic proliferation, in particular when there is storiform architecture, the stromal elements of AIP gives the impression of a spindle cell neoplasm, and may be misdiagnosed as “inflammatory myofibroblastic tumor.”41,42,51,53-59 Expression of ALK-1, p53 and high Ki-67 levels, which are common in IMTs, are not features of AIP.77 Clinically, the main differential diagnosis of AIP is with pancreatic adenocarcinoma.13,16,48,78 Experienced clinicians are able to appreciate the subtle findings on CT scans including the more diffuse nature of AIP versus the focality of carcinoma; however, the distinction can be impossible in some cases. Lymph node enlargement, which is very common in AIP, further complicates this differential diagnosis.22,79 Serum IgG4 levels may be most helpful. For the microscopic differential diagnosis of benign reactive changes (including AIP) from carcinoma, the readers are referred to a recent publication that has focused on this issue.80 It should be mentioned here though, that peritumoral pancreatitis associated with carcinoma may mimic AIP,5 every solid lesion in the pancreas should be investigated thoroughly before the diagnosis of adenocarcinoma can be excluded. Accordingly, a resection specimen should be sampled extensively (if not entirely) to rule out this possibility.
Fine needle aspiration biopsy Patients with AIP often undergo fine-needle aspiration biopsy with the preoperative diagnosis of carcinoma. The presence of stromal fragments with lymphocytes greater than 30 per 60⫻ has been found to be in favor of AIP,81
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although it is by no means specific. Also, the stromal fragments are significantly more cellular in AIP cases.5,81-84 If these findings are evaluated in conjunction with the clinical and radiologic findings, they may help achieve the correct diagnosis, or at least prompt the clinicians to perform serum IgG4 levels.
Management and outcome Until recently, most AIPs have been resected due to the preoperative misdiagnosis of adenocarcinoma. This is still true for most patients. Following surgery, some patients experienced emergence of new foci of strictures or pseudotumors.16,47,48 There is overwhelming evidence in the literature that AIP is highly responsive to steroid therapy.25,85-91 It is expected that as the clinical and pathologic criteria for the diagnosis of AIP are better defined it will become increasingly feasible to avoid unnecessary operations, and the patients will be managed medically with steroid therapy.
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