Pancreatic ductal adenocarcinoma with autoimmune pancreatitis-like histologic and immunohistochemical features

Summary

Autoimmune pancreatitis (AIP) often manifests as a mass lesion causing obstructive jaundice, clinically mimicking pancreatic carcinoma. A diagnosis of AIP may obviate the need for surgical resection, as most patients respond to steroid treatment. However, it is not clear whether these 2 conditions can coexist. In this study, 105 specimens resected for pancreatic ductal adenocarcinoma (PDAC) that also have changes of chronic pancreatitis were examined for features considered to be characteristic of AIP. Of 105 cases of PDAC with changes of chronic pancreatitis, 10 (9.5%) exhibited histologic features of AIP, including exuberant fibrosis, lymphoplasmacytic infiltration, obliterative phlebitis, or granulocytic epithelial lesions. Of these 10 cases, 7 had more than 20 immunoglobulin G4+ plasma cells per high-power field. Of these 7 cases, 5 were analyzed for Kirsten rat sarcoma viral oncogene mutation and SMAD4 expression. Three cases showed K-ras mutation and/or loss of SMAD4 expression in benign AIP-like areas. These findings suggest 2 possibilities: first, AIP-like lesions may occur in a small but significant portion of PDAC cases; second, some PDACs may arise in a background of AIP. Therefore, caution is necessary when making a diagnosis of AIP by needle biopsy of a mass lesion, and patients with a tentative AIP diagnosis should be closely followed up clinically.

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.