Lymphoplasmacytic sclerosing (autoimmune) pancreatitis

Seminars in Diagnostic Pathology (2004) 21, 237-246

Lymphoplasmacytic sclerosing (autoimmune) pancreatitis David S. Klimstra, MD,a N. Volkan Adsay, MDb a

From the Memorial Sloan-Kettering Cancer Center, New York, New York; and the Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.

b

KEYWORDS Lymphoplasmacytic; Pancreatitis; Autoimmune; IgG4

Lymphoplasmacytic sclerosing pancreatitis (LPSP), also known as autoimmune pancreatitis or nonalcoholic, duct destructive chronic pancreatitis, has been increasingly recognized in the past decade as a histologically distinctive type of pancreatitis that affects middle-aged patients who lack the typical risk factors for chronic pancreatitis (alcohol abuse in particular). LPSP is sometimes associated with other autoimmune diseases or fibroinflammatory lesions, although in some patients, pancreatic and biliary involvement represent the only known disease process. Many patients present with pancreatic masses clinically and radiographically simulating pancreatic carcinoma, and associated bile duct strictures enhance the resemblance. Elevated serum IgG4 levels have been described in patients with LPSP and have been used to distinguish LPSP from pancreatic carcinoma preoperatively. Although there is some heterogeneity of pathologic findings, resected cases of LPSP typically demonstrate dense periductal lymphoplasmacytic inflammation, periductal and parenchymal fibrosis, and obliterative venulitis; neutrophilic infiltration of the ductal epithelium (“granulocytic epithelial lesions”) may also occur. Large tumor-like masses of fibroinflammatory tissue (“reactive fibroinflammatory pseudotumors”) may develop and extend beyond the pancreas. Following surgical resection, a few patients suffer recurrence of fibroinflammatory lesions in the pancreatobiliary tree, or they may develop other manifestations of autoimmune disease elsewhere in the body. However, the overall prognosis is excellent. Response to steroid therapy has been noted. Current studies are focusing on identifying additional preoperative diagnostic tests and on characterizing possible variants of LPSP. This review presents the defining clinical and pathologic features of LPSP and discusses the ongoing efforts to understand the pathogenesis of this disease. © 2005 Elsevier Inc. All rights reserved.

Most patients with clinically apparent chronic pancreatitis have an obvious predisposition to pancreatic inflammatory disease, such as alcohol abuse, biliary stone disease, or congenital malformations in the region. However, it has long been recognized that some patients develop idiopathic chronic pancreatitis, and although there have been a number of known diseases associated with idiopathic chronic pancreatitis (such as sclerosing cholangitis and chronic inflammatory bowel disease), the specific etiopathologic features of these cases were not well described before the mid-

Address reprint requests and correspondence: David S. Klimstra, MD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. E-mail address: [email protected].

0740-2570/$ -see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.semdp.2005.07.004

1990s. An interesting subset of these patients has come to pathologic attention because the clinical features of the chronic pancreatitis sufficiently resembled pancreatic carcinoma that the patients were treated by pancreatectomy. Histologic examination of these “tumoral pancreatitis” cases revealed certain shared features, and exploration of the clinical histories uncovered a variety of associated diseases, many of which have known or presumed autoimmune etiologies. Different terms have been used for this condition, including the descriptive “nonalcoholic, duct-destructive chronic pancreatitis”1-3 and “lymphoplasmacytic sclerosing pancreatitis” as well as the more etiologically suggestive “autoimmune pancreatitis,”4-7 and although the described clinical and pathologic features of these entities may not be entirely superimposable, it is clear that there is

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a reasonably discrete disease entity that needs to be distinguished from other types of chronic pancreatitis and, importantly, from pancreatic cancer. Lymphoplasmacytic sclerosing (autoimmune) pancreatitis (LPSP) can be defined as a specific type of chronic pancreatitis characterized by a mixed inflammatory cell infiltrate centered around the pancreatic ducts, associated with tumor-like regions of fibrosis and obliterative venulitis, affecting patients without a history of alcohol abuse, biliary stone disease, significant duodenal wall inflammation, prior bouts of acute pancreatitis, or pancreatic neoplasms.

Clinical findings LPSP affects adults, and although the disease has been reported from the teens to the 80s, most patients are 40 to 60 years old (mean ⫽ 56).3,7-9 It has been suggested that a somewhat different histologic pattern is seen in younger patients; specifically, those patients having a more pronounced neutrophilic inflammatory cell infiltrate (“granulocytic epithelial lesions,” see below) are usually in their mid-40s.7,8 The gender ratio also varies with the histologic pattern: the younger group with neutrophilic inflammation contains equal numbers of men and woman, whereas the older group lacking neutrophils is predominantly male (male:female ⫽ 3.3:1).7,8 The prevalence of the disease is difficult to estimate, since the denominator used to identify the reported cases varies from pancreata resected with a diagnosis of carcinoma to all cases of chronic pancreatitis to all patients with a pancreatic mass. Relative to chronic pancreatitis of other etiologies, LPSP appears to be rare. However, cases are commonly found among patients operated on with a presumptive clinical diagnosis of a pancreatic tumor (but no preoperative diagnosis) who had no neoplastic disease identified in the resected specimen.9 Zamboni and coworkers7 found LPSP in 26.5% of 200 patients undergoing surgery for chronic pancreatitis. If cases are excluded that show features linked to other types of pancreatitis (such as pseudocyst formation, necrotizing pancreatitis, lithiasis, pancreas divisum, duodenal wall inflammation, and a clinical history of alcohol abuse), a high proportion of the remaining pancreatitis cases will have features of LPSP.7,9,10 Clinical symptoms include abdominal pain, anorexia, and, for patients with involvement of the head of the pancreas, jaundice. The last symptom occurs in about 75% of cases and is typically due to direct involvement of the bile duct by the fibroinflammatory process, rather than simple compression by the mass. Almost by definition, patients with LPSP lack a significant history of alcohol use, prior pancreatic or biliary surgery, or stone disease. A wide array of associated diseases has been described, most falling generally into two categories. Autoimmune-associated diseases may occur, including sclerosing cholangitis,11-17 pri-

mary biliary cirrhosis,18 ulcerative colitis, and Sjogren’s syndrome.13-15,19-21 The other group of disorders reported in patients with LPSP is the family of tumor-like lesions known as multifocal idiopathic fibrosclerosis,18,22-28 including mediastinal and retroperitoneal fibrosis, Riedel’s thyroiditis, and inflammatory pseudotumor of the orbit. Some of these conditions appear to be more common in one of the two clinical subgroups of patients. Sjogren’s syndrome, for example, is more often reported in older male patients without neutrophilic inflammation, whereas chronic inflammatory bowel disease more often occurs in the younger LPSP patients who have neutrophilic inflammatory infiltrates.7,8 Based on these various associated conditions, it is easy to see why the term autoimmune pancreatitis has been used for LPSP. However, it should be noted that only approximately 35% of patients with LPSP have another autoimmune-associated disease.3,7,9 It could be possible that the other two-thirds of patients have autoimmune disease limited to the pancreas, but it remains to be determined whether all cases with the histologic features of LPSP share the same etiology. The possibility of an autoimmune etiology is supported by serologic findings. Patients with LPSP may have detectable autoantibodies such as antinuclear, antilactoferrin, antismooth muscle, and anticarbonic anhydrase II antibodies.4,29-32 Also reported are elevations in rheumatoid factor and hypergammaglobulinemia.4,30 More recently it has been observed that serum total IgG and more specifically IgG4 levels are commonly elevated in LPSP patients, a finding that has preoperative diagnostic utility. In one study, patients with LPSP had a mean serum IgG4 level of 663 mg/dL, compared with 51 mg/dL in normal individuals.33 Evaluation of pancreatic cancer patients has revealed that none had IgG4 levels above 150 mg/dL, and the finding of a level above 135 mg/dL in a patient with a pancreatic mass suggests that the diagnosis of LPSP should be considered.33 It must be noted, however, that not all patients with the histologic finding of LPSP have serum IgG4 elevations above 135 mg/dL,34 but the sensitivity of this finding is reportedly 95%.33 Not only are IgG4 levels low in pancreatic carcinoma and chronic pancreatitis of alcoholic or obstructive etiology, but patients with primary biliary cirrhosis, sclerosing cholangitis, or Sjogren’s syndrome unassociated with LPSP have low levels as well.33 IgG4 elevations have been used to correctly classify patients with pancreatic masses who could not be diagnosed based on initial diagnostic testing.35 The involvement of the pancreas by LPSP often is not diffuse, and the localized mass-like deposition of fibrous tissue often simulates a neoplasm radiographically. Radiographic features36-38 based on CT and MRI scanning include a diffusely or segmentally enlarged pancreas with obliteration or stenosis of the main pancreatic duct. Bile duct strictures also occur when the disease affects the head of the gland. The peripancreatic fat is not obscured. Ultrasound may show a diffusely swollen and hypoechoic pan-

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Figure 1 Gross appearance of LPSP. The lesion produces a mass of fibrous tissue that replaces the pancreatic parenchyma.

creas39,40 with what has been referred to as a “sausage-like” appearance.

Pathologic findings The gross examination of resected specimens generally reveals a localized region of fibrosis, most commonly in the

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head of the gland.3,7,9,41-43 The fibrotic areas are ill-defined and produce mass-like enlargement of the region, similar to the appearance of infiltrating ductal adenocarcinomas (Figure 1). Within the involved area, the major pancreatic ducts are usually stenotic and narrowed, and sometimes the walls of the ducts appear thickened. The pancreatic ducts distal to the area of involvement may be dilated, but stones are not typically found except in rare cases of long standing or recurrent LPSP.44 In cases with involvement of the head of the pancreas, there is usually (over 90% of cases) thickening and stenosis of the adjacent common bile duct,45 with proximal dilation. Some cases of LPSP have more pronounced tumor-like qualities, with large reactive fibroinflammatory pseudotumors extending into the peripancreatic tissues.32,46-49 Finally, there may be more diffuse involvement of the gland in which the normal lobulated parenchyma is replaced to firm, fibrous tissue without a discrete mass, and the duct is diffusely narrowed. The histologic hallmark of LPSP is dense inflammation and fibrosis in a periductal distribution3,7,9,41-43 (Figure 2A and B). The presence of “duct-centric” inflammation is probably the most important feature to separate LPSP and related inflammatory lesions of the bile ducts and gallblad-

Figure 2 Characteristic periductal inflammation, with a dense rim of inflammatory cells surrounding the narrowed pancreatic duct. The periductal inflammation extends into regions of the pancreas not showing advances fibrosis (A). Elsewhere (B) there are concentric bands of periductal fibrous tissue accompanying the inflammation.

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Seminars in Diagnostic Pathology, Vol 21, No 4, November 2004 Another highly characteristic histologic finding is venulitis. Inflammatory cell aggregates surround small and medium-sized veins, a feature also termed periphlebitis (Figure 6). In the most typical lesions, the inflammatory cells undermine the endothelium and ultimately produce fibrous obliteration of the veins (obliterative venulitis). The extent of the venulitis varies by case, and in some instances a thorough search of multiple sections may be required to identify it. Elastin stains are helpful to identify obliterated veins in areas of dense stromal fibrosis and inflammation (Figure 6C). Much less commonly there is also fibrous obliteration of medium sized arteries, but true necrotizing vasculitis is not present. Inflammatory cells also commonly surround peripheral nerve branches,3 although this finding is not specific for LPSP. Examination of the ductal epithelium often reveals extension of lymphocytes into the epithelial layer, with destruction of the ductal cells. In a subset of cases there is also neutrophilic inflammation within the ducts, sometimes extending into the smaller intralobular ducts and acini (Figure 7). Again, ductal epithelial destruction is noted, and these foci have been termed “granulocytic epithelial lesions.”7 Granulocytic epithelial lesions are found in 37% to 45% of

Figure 3 The inflammatory infiltrate contains numerous lymphocytes and plasma cells.

der from other conditions. The medium sized and larger ducts are most involved, although not every duct within the lesion shows periductal inflammation. Conversely, the inflammatory infiltrate around the ducts may extend beyond the areas of fibrosis into otherwise uninvolved parenchyma.9 In some cases, the periductal tissues show only dense inflammation rich in lymphocytes and plasma cells (Figure 3), also commonly containing eosinophils and histocytes. The histiocytes are usually scattered, and although vague granuloma-like aggregates have been described, wellformed granulomas are not typically present. In some cases, there is lymphoid follicle formation, including germinal centers (Figure 4). Other ducts show concentric fibrosis with a more sparse band of inflammatory cells separating the ductal epithelium from the bands of collagen (Figure 2B). Accompanying the duct-centric inflammation there is extensive fibrosis that replaces much of the parenchyma. In contrast to the paucicellular fibrosis of alcoholic chronic pancreatitis, the fibrosis of LPSP retains a significant inflammatory cell component, including the same cell types that more densely surround the ducts (Figure 5). In addition, the collagen contains fibroblasts and myofibroblasts and may exhibit a storiform pattern.9

Figure 4 In some regions, germinal centers are found within the inflammatory infiltrate.

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Figure 5 The most extensively involved regions demonstrate interstitial fibrosis surrounding the inflamed ducts that replaces much of the acinar parenchyma (A). Interlobular fibrosis results in bands of collagen accentuating the lobular architecture of the atrophic pancreas (B).

LPSP cases,7,8 and it has been suggested that those ductcentric pancreatitis cases with prominent neutrophilic infiltration and extensive inflammation of the lobules may be distinct from LPSP.8 It appears that there are differences in age at presentation, gender predilection, frequency, and type of associated extrapancreatic autoimmune diseases, and frequency of serum IgG4 elevations between classic LPSP and cases with abundant neutrophilic inflammation7,8 (see above). However, the relationship between these two potential subgroups remains to be fully defined, and the possibility that the neutrophil-rich pattern is simply an earlier phase in the evolution of the disease could be considered. Similar fibroinflammatory processes involve the common bile duct (Figure 8), sometimes with extension to the hepatic hilum, and gallbladder involvement has been described.41,50 It is common for the inflammation to extend out of the pancreas into adjacent adipose tissue. In addition, some cases of LPSP have a much more profound expansion of the fibroinflammatory process, with complete replacement of the pancreatic parenchyma by a large tumor-like mass (“reactive fibroinflammatory pseudotumor”), sometimes reaching up to 10 cm.46,49,51-53 Although the central regions are

hyalinized (Figure 9), the periphery displays more intense inflammation and retains the more cellular storiform pattern described above. Lymphoid aggregates are commonly found in the surrounding tissues. These lesions have been reported as “inflammatory pseudotumors”; however, it is not clear that they represent the same entity now designated inflammatory myofibroblastic tumor (IMT) in the lung and other sites that is believed to be truly neoplastic.54 In most instances, the bulk of the reactive fibroinflammatory pseudotumors is heavily collagenized, without the myofibroblastic cellularity of true IMTs, and immunohistochemical staining for ALK is negative. Immunohistochemical staining demonstrates predominantly CD3 positive T-lymphocytes in the periductal infiltrates, including a mixture of CD4 and CD8 cell types.7,55 Also present are CD20 positive B-lymphocytes and macrophages that label for CD68. If germinal centers are present, they consist mainly of B-lymphocytes. The plasma cells are polyclonal and stain for both ␬ and ␭. Antibodies to IgG4 label many plasma cells,56 although this marker has not been shown to be specific for LPSP, and comparative studies with other types of pancreatitis (including the pancreatitis that accompanies carcinoma) have yet to be performed.

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Figure 6 Venulitis is typical, including small veins with aggregates of lymphoid cells in the wall and undermining the endothelium (A). Some of the veins are completely obliterated and replaced by lymphoid aggregates (B) and are recognized by their proximity to uninvolved arteries or by elastin stains (C).

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Figure 7 In some cases, there is neutrophilic infiltration of the ducts, with ductal epithelial destruction, termed “granulocytic epithelial lesions.”

Differential diagnosis The differential diagnosis at the clinical level is very different from the histologic differential diagnosis. Whereas the pathologic features of LPSP must be distinguished from other types of pancreatitis,3,7 clinically and radiographically the disease most commonly mimics pancreatic carcinoma.8-10,57 The finding of a mass like lesion (especially in those cases with reactive fibroinflammatory pseudotumors) in a patient without a predisposition for alcoholic or other known etiologies of pancreatitis, along with the potential for obstruction of the common bile duct, results in common clinical confusion for carcinoma. If the mass is resected, however, it is generally not difficult to recognize that no epithelial malignancy is present. In rare cases, the density of the lymphoid infiltrate has raised suspicions about malignant lymphoma,58 but the histologic differential diagnosis of LPSP predominantly includes pancreatitis of other types. Much of the early work of this entity focused on the distinguishing features of LPSP and alcoholic chronic pancreatitis. Some of these differences are apparent grossly. In alcoholic chronic pancreatitis (or in pancreatitis of obstructive etiology) the ducts are usually dilated and tortuous rather than stenonic. Calculi may be found within the ducts. Diffuse fibrosis of the gland may occur, although segmental chronic pancreatitis, particularly from localized ductal obstruction, may produce a localized fibrotic mass, as seen in LPSP. Pseudocyst formation and areas of fat necrosis are also much more characteristic of alcoholic or obstructive pancreatitis. Microscopically, alcoholic chronic pancreatitis lacks the dense inflammatory cell infiltrate of LPSP, and there is no concentration of inflammatory cells around the pancreatic ducts.59-61 The fibrosis is more diffuse, without a periductal distribution, and the storiform fibroinflammatory stroma of LPSP is not encountered. The obliterative venulitis of LPSP is also not present, although occasionally aggregates of lymphocytes may be found near small vessels. Finally, the common bile duct is rarely involved in alcoholic or obstructive pancreatitis.

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Another type of pancreatitis that is becoming better characterized is so-called “groove pancreatitis” also known as periampullary duodenal wall cyst or cystic dystrophy of the duodenal wall.62-66 The name we employ for this entity is paraduodenal pancreatitis. Paraduodenal pancreatitis generally develops in the region of the pancreas between the intrapancreatic bile duct and the duodenum proximal to the ampulla of Vater. Although there is inflammation and fibrosis in this portion of the pancreas, there is generally also inflammation in the duodenal wall associated with cystic structures. Current theories suggest that these cysts represent remnants of the minor papilla and associated submucosal pancreatic parenchyma that have become obstructed and inflamed. Some of the cysts demonstrate a partial epithelial lining, supporting their origin from preexisting ductal structures. Inspissated enzymatic secretions are also found within the cysts. The surrounding tissues often show dense inflammatory cell infiltrates and a pronounced myofibroblastic proliferation that includes apparent smooth muscle cells as well. This inflammatory and spindle cell process is often even more cellular than the storiform fibroinflammatory stroma of LPSP. The presence of cysts in the duodenal wall and the specific location of paraduodenal (groove) pancreatitis allow distinction from LPSP, and autoimmune conditions have not been associated with paraduodenal pancreatitis. Although the histologic distinction of well developed cases of LPSP from these other types of pancreatitis is generally not problematic, some authors have described in patients who lack predispositions for alcoholic or obstructive pancreatitis cases of pseudotumoral pancreatitis that do not demonstrate fully developed histologic features of LPSP. Such cases may show only focal periductal inflammation or poorly developed venulitis, and it has been difficult to determine whether these are incompletely developed examples of LPSP or rather other types of chronic pancreatitis. Since some studies addressing this issue were preformed before the association of LPSP with elevated serum levels of IgG4,9 it is not known whether additional

Figure 8 Involvement of the common bile duct. The wall is diffusely infiltrated by dense inflammatory infiltrates, and there is extensive fibrosis.

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Figure 9 Reactive fibroinflammatory pseudotumor formation, with extension of the fibroinflammatory process into the adjacent peripancreatic tissues, forming a large mass lesion (A). At higher power (B), the storiform fibroinflammatory stroma is evident, with abundant collagen deposition.

serological studies may have provided more accurate determination of etiology. It should be recognized, however, that if one evaluates all fibrotic and inflammatory lesions resected surgically as possible pancreatic neoplasms, there will be a group of cases for which specific subclassification based on the histologic findings is difficult. Although considerable attention has been focused on the histologic distinction of LPSP from other types of pancreatitis, it remains relevant to consider the potential histologic similarity of LPSP to the pancreatitis seen adjacent to neoplasms (“peritumoral pancreatitis”). Especially in the setting of biopsy diagnosis of a patient with a pancreatic mass possibly representing a carcinoma (see below), the findings of relatively dense inflammation and cellular fibrosis are not sufficient to distinguish peritumoral pancreatitis from LPSP.7 Furthermore, we have encountered foci of periductal inflammation and even focal venulitis adjacent to invasive carcinomas. Thus, in a patient who lacks any of the associated autoimmune or fibroinflammatory lesions and for whom serum IgG4 levels are not significantly elevated (or are unknown), peritumoral pancreatitis may be very difficult to distinguish from LPSP on the basis of a limited specimen.

Preoperative diagnosis With the recognition of LPSP and the potential for nonoperative treatment (see below), emphasis is being placed on accurate preoperative diagnosis. Because of the close clinical resemblance of LPSP to invasive ductal adenocarcinoma along with the surgical willingness to resect pancreatic masses without a tissue diagnosis, LPSP has commonly been treated surgically based on a presumptive diagnosis of carcinoma. In a relatively young patient (less than 50-55) with a history of other autoimmune diseases, the finding of a pancreatic mass should raise sufficient suspicions about LPSP for the diagnosis to be considered. In such a patient, a significant serum elevation in IgG4 may be sufficient to

strongly suggest a diagnosis of LPSP, with the potential for nonoperative treatment. In less suggestive cases, however, biopsies or fine needle aspiration cytology specimens may be obtained in an effort to confirm the diagnosis. If a core biopsy of the pancreas contains a duct with dense periductal inflammation or fibrosis or a vein with obliterative venulitis, the diagnosis can be suggested, but when a specimen only shows dense inflammation and cellular fibrosis, the possibility that there exists a carcinoma not sampled by the biopsy is hard to exclude. In one study, nine patients with LPSP were initially biopsied, six of whom had prior autoimmune or other fibroinflammatory diseases; five of these biopsies were suggestive or diagnostic of LPSP.7 However, it is unclear how many of the numerous other reported patients with LPSP treated by pancreatectomy had nondiagnostic preoperative biopsies, and the accuracy of biopsy in this setting is unknown. The cytological features of LPSP on fine needle aspiration have yet to be reported in detail. In general, smears of both LPSP and chronic pancreatitis of other etiologies show mixed inflammatory cells, fibrosis, and atrophic pancreatic parenchymal elements67-69; however, numerous background lymphocytes and cellular stromal fragments suggest the diagnosis of LPSP over chronic pancreatitis and help to distinguish it from adenocarcinoma.7,70 Correlation of these findings with the clinical and radiological data may indicate the need for serologic testing and other clinical investigations. However, in a patient with a clinical suspicion of pancreatic carcinoma, the findings on cytology may not be sufficiently specific to exclude a malignant neoplasm not sampled by the fine needle aspiration biopsy.

Outcome and treatment Surgical resection has been performed for many of the reported cases of LPSP, since most were not recognized preoperatively. Following surgery, some patients suffer re-

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currence of strictures or mass lesions in the biliary tree or elsewhere in the pancreas, and some develop additional extrapancreatic manifestations of autoimmune disease or multifocal fibrosclerosis.9,46,57 Interestingly, it appears that recurrence of the disease in the pancreas or biliary tree is more common in the clinical subgroup of LPSP that occurs in older patients who lack neutrophilic infiltrates histologically.7 In patients with LPSP recognized preoperatively, favorable responses to steroid treatment have been reported,33,71 emphasizing the need for accurate preoperative diagnosis. It has been suggested that patients with a clinical presentation suggestive of LPSP who have serum IgG4 elevations should be offered a trial of steroid therapy as first line treatment.

Conclusions Thus, it is clear that LPSP is a distinctive type of pancreatitis at the clinical, radiographic, histologic, and serologic levels. Increasing recognition of the disease and the availability of serologic testing are making the preoperative distinction of LPSP from pancreatic carcinoma a realistic possibility. However, cases exist of idiopathic tumoral pancreatitis that have yet to be clearly classified and may or may not represent related entities with autoiommune associations. Whether there exist clinically relevant subgroups of LPSP also remains an actively investigated question.

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