Original contributionPancreatic ductal adenocarcinoma with autoimmune pancreatitis-like histologic and immunohistochemical features☆,☆☆
Introduction
As a distinct type of idiopathic chronic pancreatitis, autoimmune pancreatitis (AIP) is associated with characteristic clinical, radiologic, and pathologic features [1]. Currently, it is believed that AIP accounts for approximately 6% of idiopathic chronic pancreatitis cases [2]. The disease usually leads to diffuse or focal enlargement of the pancreas, forming a mass lesion and causing obstructive symptoms and jaundice [3], [4]. Radiographically, the diffuse enlargement of the pancreas gives rise to hypoechoic diffuse swelling of the pancreas (sausage-like appearance) in ultrasound examination, and endoscopic retrograde cholangiopancreatography may show diffuse irregular narrowing of the main pancreatic duct or focal narrowing. Most of these patients respond to steroid therapy [5].
AIP may be misdiagnosed as pancreatic ductal adenocarcinoma (PDAC), due to jaundice and mass lesions at presentation in many cases. In fact, in the original series described by Yoshida et al [6], most patients underwent surgical resections. Although the original histologic descriptions of AIP focused on the presence of fibrosis and mild mononuclear cell infiltration [6], [7] with acinar atrophy [8], it later became clear that diagnostic histologic features of AIP also included periductal lymphoplasmacytic infiltration with periductal fibrosis, coupled with the lack of typical histologic features of alcoholic pancreatitis, such as ductal dilatation or irregularity, calculi, and pseudocysts. In 2001, elevation of the serum immunoglobulin G4 (IgG4) level was identified as a crucial diagnostic feature of AIP [9]. Subsequently, tissue infiltration by an increased number of IgG4+ plasma cells in patients with AIP was also recognized [10]. The utility of IgG4 as a diagnostic marker for AIP thus allowed for the recognition of many additional cases and provided a context for understanding the pathogenesis of the disorder.
Several sets of diagnostic criteria and classification schemes have been proposed, often with different cutoffs for tissue IgG4+ plasma cells [11], [12], [13], [14]. Two types of AIP have been proposed to include cases that do not fit the description of the original case series in the International Consensus Diagnostic Criteria for Autoimmune Pancreatitis [14]. These roughly correspond to the so-called lymphoplasmacytic sclerosing pancreatitis (LPSP) and idiopathic duct-centric pancreatitis types. Histologically, LPSP is characterized by dense periductal infiltration of lymphoplasmacytic cells, storiform fibrosis, obliterative venulitis, and abundant (>10 cells per high-power field [HPF]) IgG4-positive plasma cells; idiopathic duct-centric pancreatitis is characterized by granulocytic epithelial lesions (GELs), which are defined as granulocytic infiltration of duct epithelium. Of the 2, cases of type 1 AIP predominantly present as a mass lesion with painless obstructive jaundice and more likely mimic pancreatic carcinoma.
Despite the refinement of diagnostic criteria, the specificity of the histologic and immunohistochemical (IHC) features accepted for diagnosing AIP has not been fully scrutinized. It must be pointed out that due to poor case definition or lack of strict objective criteria in selection of study cases in some of the published studies, conclusions drawn by different studies have not been consistent. This is partly reflected by the need for multiple revisions and “updates” by “expert panels” [15], [16].
Furthermore, the question as to whether PDAC and AIP can coexist has not been adequately examined, although several recent studies and case reports have demonstrated increased cancer risk in various organs in patients with AIP [17], [18]. One multicenter study identified pancreatic carcinoma in 5 of 978 patients with type 1 AIP in follow-up [17]. Molecular studies have suggested that AIP may be a risk factor for pancreatic carcinoma, as KRAS mutations are frequently detected in the pancreatic tissue of patients with AIP [19]. Moreover, the transforming growth factor β (TGF-β) signaling pathway, which is deregulated in many pancreatic carcinomas, is also involved in the pathogenesis of AIP [20], [21].
While examining Whipple resections performed for PDAC, we encountered cases in which there were areas in the specimen showing features thought to be characteristic of AIP, including dense periductal or lobular storiform fibrosis and heavy lymphoplasmacytic infiltration. This prompted us to conduct a more systematic study to see if some of these cases indeed contained histologic features indistinguishable from those of AIP. The main aim of this study was thus to determine the frequency of AIP-like pancreatitis in PDAC with chronic pancreatitis. Among 105 cases reviewed, 6.7% had changes that fulfill the histologic diagnostic criteria for AIP. In addition, KRAS mutation and/or loss of SMAD4 expression were noted in AIP-like areas in 3 of 5 studied cases. The results suggest that PDAC may coexist with AIP-like pancreatitis, which may pose diagnostic difficulties in needle biopsies.
Section snippets
Case selection
With institutional review board approval, the surgical pathology archives of the University of Chicago and Cleveland Clinic were searched from 1990 to 2010 for pancreatectomy specimens with a diagnosis of PDAC with concurrent chronic pancreatitis. Consultation cases were excluded, and 105 consecutive cases were retrieved, which were reviewed for histologic features characteristic of AIP. The 4 characteristic histologic features described in the international consensus statement [14] were used.
Histologic features of PDAC with AIP features
Of the 105 cases of PDAC with chronic pancreatitis reviewed, 10 (9.5%) were found to have histologic features of AIP in the parenchyma away from the tumor, using the criteria as described in the “Methods” section. These constitute the study group (n = 10). Demographic data of these cases are summarized in Table 1. Of the remaining 95 cases without AIP features, detailed demographic information was retrieved for 52 (all from the University of Chicago; Table 1). These 52 cases were used for
Discussion
The first description of what was later labeled “autoimmune pancreatitis (AIP)” may be credited to Sarles et al [25], but the term autoimmune pancreatitis was first proposed in 1995 [6]. Since then, with better awareness of this clinical entity among surgeons, gastroenterologists, and pathologists, more cases have been diagnosed. The most important feature of AIP is its close similarity to pancreatic carcinoma in terms of clinical presentation and radiologic imaging. Moreover, AIP and
Acknowledgments
The authors thank Dr Elizabeth Hyjek, Terri Li, Can Gong, and Poluru Reddy for their technical assistance.
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2024, Seminars in Diagnostic PathologyDevelopment of efficient on-bead protein elution process coupled to ultra-high performance liquid chromatography–tandem mass spectrometry to determine immunoglobulin G subclass and glycosylation for discovery of bio-signatures in pancreatic disease
2020, Journal of Chromatography ACitation Excerpt :In this study, we aimed to develop an analytical workflow that could accurately determine IgG subclass and Fc-glycopeptides for clinical serum samples. Another issue is that patients with AIP might have similar clinical symptoms or imaging performances to pancreatic ductal adenocarcinoma (PDAC) which causes difficulty in differential diagnosis [27]. We also included serum samples from patients with PDAC in the application to evaluate if there is profile difference of IgG between patients.
Prognostic significance of IgG4+ plasma cell infiltrates following neoadjuvant chemoradiation therapy for esophageal adenocarcinoma
2017, Human PathologyCitation Excerpt :The distribution and frequency of IgG4+ plasma cells in EAC post–neoadjuvant CRT were different than those of EAC in the surgery-only group in this study and from tumors in other sites described in previous studies. In pancreatic ductal adenocarcinoma, moderate to marked numbers of IgG4+ plasma cells were noted in 12% of cases [14], and IgG4+ plasma cell counts were >50/HPF in 4.8% of cases [16], whereas in another study, none of the cases showed >50 IgG4+ plasma cells [15]. In a study of non–small cell lung cancers, 2% of cases revealed >50 IgG4+ plasma cells per HPF [18].
Association of IgG4 response and autoimmune pancreatitis with intraductal papillary-mucinous neoplasms
2017, PancreatologyCitation Excerpt :The finding by Dhall et al. of varying numbers of IgG4-positive plasma cells in the vicinity of pancreatic ductal adenocarcinomas suggests that these carcinomas may also produce an epitope that elicits an IgG4 response [6]. There are also reports of coincidental occurrence of AIP and pancreatic ductal adenocarcinomas (PDAC) [9–11], and a report of a patient with a mucinous cystic neoplasm and stigmata of AIP [12]. The latter authors speculated that their case reflected “an anti-inflammatory antitumor response driven by Th2 cytokines” rather than a typical type 1 AIP (IgG4-related disease).
Endoscopic ultrasound-guided fine-needle aspiration biopsy of autoimmune pancreatitis: Diagnostic clues and pitfalls
2015, Journal of the American Society of CytopathologyCitation Excerpt :Pancreatic adenocarcinoma has been shown to have significant IgG4-positive plasma cell infiltration,23,24 suggesting that IgG4-positive plasma cells may have limited value in rendering a definite diagnosis of AIP. Recently there has been a report of pancreatic ductal adenocarcinoma with AIP-like histologic and immunohistochemical features.25 Thereby, the presence of AIP-like features does not exclude malignancy.
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Disclosure: The authors declare no conflict of interest.
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Results from a part of this study were presented at the 2010 USCAP Annual Meeting in Washington, DC.