Introduction

IgG4-related disease (IgG4-RD) is a chronic inflammatory process that involves many organ systems. Its exact cause is still not known, but it can be effectively treated with steroids. In 2003, Kamisawa et al. [1] reported on 21 pancreatitis patients whose disease was thought to be of autoimmune nature. These patients also had sclerosing cholangitis, retroperitoneal fibrosis, rheumatoid arthritis, and Sjögren’s syndrome [1]. Based on this observation, Kamisawa introduced the term “IgG4-related systemic disease,” hypothesizing that the various lesions may be organ manifestations of a systemic autoimmune disorder [1]. Since then, numerous reports have revealed that the disease can involve many more organs than was originally thought, notably the salivary glands, thyroid, lungs, liver, and kidney (Fig. 1) [2]. In 2011, a consensus meeting was held in Boston, which proposed the name “IgG4-RD” and highlighted three findings as histopathologic features: (1) lymphoplasmacytic infiltration containing abundant IgG4-positive plasma cells, (2) storiform fibrosis, and (3) obliterative phlebitis [3, 4].

Fig. 1
figure 1

Cartoon showing the main organ manifestations of IgG4-related disease (IgG4-RD)

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The recent definition of IgG4-RD as a systemic inflammatory disorder somehow hides the fact that a number of its organ manifestations were already described some decades ago [3,4,5,6]. This concerns particularly the manifestations of IgG4-RD in the pancreas and the extrahepatic bile duct system. Pancreatitis cases showing the histopathologic criteria of IgG4-RD were reported from 1950 onwards [7,8,9]. In 1991 and 1997 followed the reports of Kawaguchi et al. [9] and Ectors et al. [12], which laid the basis for the detailed histopathology of the disease and its clear distinction from other types of pancreatitis such as alcoholic pancreatitis. In 1995, Yoshida et al. named the disease autoimmune pancreatitis (AIP) [7]. In 2003 and 2004, Notohara et al. [10] and Zamboni et al. [11] showed in their studies that AIP is a heterogeneous disease including two types: type 1 AIP, also called “lymphoplasmacytic sclerosing pancreatitis,” and type 2 AIP, also called “idiopathic duct-centric pancreatitis” [9, 12]. Further analysis of the serological and clinical features of AIP patients soon revealed that type 1 AIP represents a manifestation of IgG4-RD, while type 2 AIP is unrelated to IgG4-RD [13,14,15,16,17].

Already in 1963, a special form of sclerosing cholangitis (SC) was described that, in retrospect, corresponds to a manifestation of IgG4-RD in the common bile duct. It was part of a multi-inflammatory syndrome encompassing also retroperitoneal fibrosis (RF) and Riedel’s thyroiditis [6]. SC was also part of a systemic disease described by Comings et al. [5] in 1967 as multifocal fibrosclerosis. Two patients, brothers with consanguineous parents, had, in addition to SC, orbital inflammatory pseudotumor, RF, mediastinal fibrosis, and Riedel’s thyroiditis [5]. In the ensuing decades, until the inclusion of lymphoplasmacytic SC into IgG4-RD as IgG4-related SC, it has become clear that IgG4-related SC involves the bile duct system in two ways. Most commonly, it affects the intrapancreatic section of the distal common bile duct in association with type 1 AIP. Rarely it diffusely affects the extrapancreatic biliary duct system or presents as solitary manifestation in the hilar bile ducts (with or without concomitant involvement of the intrahepatic bile ducts) or the gallbladder [13]. The term “IgG4-related hepatopathy” is used for portal liver changes in relation to IgG4-RD. Whether the recently described IgG4-positive subtype of autoimmune hepatitis (AIH) belongs to IgG4-RD has not yet been settled.

The serum half-life of IgG4 is around 23 days, and this marker can therefore be used to track response to treatment to some extent [18]. It can be roughly assumed that the sensitivity of serum IgG4 for type 1 AIP is around 66%, even though it varies between different regions and countries [14, 19,20,21]. Besides, the sensitivity and specificity are dependent on the cutoff value used. Using a cutoff of > 140 mg/dl, IgG4 had a sensitivity and specificity of 76 and 93%, respectively, but using a cutoff of > 280 mg/dl, these values were 53 and 99%, respectively [22]. For differentiating IgG4-related SC from primary sclerosing cholangitis (PSC) and primary biliary cholangitis, the sensitivity of serum IgG4 is reported to be high, around 90%, with a specificity of 85% [23].

In this review, we outline the general histopathologic features of IgG4-RD and focus then on the pathology of the IgG4-RD lesions in the pancreas and the bile ducts. Particular emphasis is put on the discussion of the biopsy-relevant histologic features of IgG4-RD in the pancreas and the bile ducts, since these lesions are clinically notoriously difficult to distinguish from neoplastic disease. However, as IgG4-RD is responsive to steroids, a correct preoperative diagnosis that often requires a biopsy is of utmost importance to avoid resection.

General histopathologic features of IgG4-RD

The Boston criteria encompass the three histologic key findings: lymphoplasmacytic infiltration affecting the tissue either diffusely or patchy and focusing on ducts (Fig. 2a), storiform fibrosis composed of thick collagen bundles which form a characteristic “swirling” and focally cartwheel-like (e.g., storiform) pattern (Fig. 2b), and obliterative phlebitis characterized in its early stage by a mainly lymphocytic perivascular infiltrate and in its later stages by an intravascular infiltration that finally leads to fibroinflammatory obliteration (Fig. 2c) and may only be recognized in Elastica-Van Gieson or Verhoeff staining (Fig. 2d). However, it is noteworthy that the three criteria are not observed in all organ manifestations of the disease. For instance, storiform fibrosis and obliterative phlebitis may be insignificant or even absent in the lacrimal glands, salivary glands, lymph nodes, lung, or kidney [3]. Infiltration by eosinophilic granulocytes is another histologic finding that may be observed in association with IgG4-RD [3, 24], but has insufficient diagnostic sensitivity and specificity in the absence of the major features to serve as a cardinal feature for the disease [3, 24]. Findings that are not compatible with the diagnosis of IgG4-RD are neutrophilic microabscesses, granulomas, necrosis, and multinucleated giant cells [2, 3, 25].

Fig. 2
figure 2

Key histologic features of IgG4-RD in type 1 AIP. a Diffuse infiltration of pancreatic tissue by lymphocytes and plasma cells with periductal accentuation and fibrosis (H&E staining). b Diffuse storiform fibrosis replacing pancreatic tissue (H&E staining). Obliterative phlebitis with H&E staining (c) and Verhoeff elastin staining (d), highlighting the wall of the vein

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The most important adjunct to the tissue diagnosis of IgG4-RD is immunostaining for IgG4-positive plasma cells [21]. It should be performed even in cases showing all three major histologic features—simply because it supports firmly the diagnosis [3]. Immunohistochemical IgG4 positivity means abundant tissue infiltration by IgG4-positive plasma cells (Fig. 3a) [26]. To avoid overdiagnosis of IgG4-RD, due to the fact that the mere infiltration with IgG4-positive cells can occur in many other diseases, especially diseases involving mucosal surfaces as in plasma cell mucositis, Crohn’s disease and ulcerative colitis, or diseases such as multicentric Castleman disease and granulomatosis with polyangiitis, it is important to apply both a cutoff for the number of infiltrating IgG4-positive cells and a ratio of IgG4- over IgG-positive cells (Fig. 3) [27,28,29]. These ratios vary and are dependent on the affected organ and the focality of the disease [3]. However, a cutoff of 10 IgG4-positive cells/high-power field (HPF) in biopsy specimens and 50 IgG4-positive cells/HPF in resection specimens, both with an IgG4/IgG ratio of more than 40%, may be recommended as a general rule [3, 30, 31]. For special IgG4-RD manifestations such as the salivary glands or lymph nodes, organ-specific cutoff values for IgG4-positive cell infiltration and IgG4/IgG ratios have been recommended to avoid overdiagnosis [3].

Fig. 3
figure 3

IgG4-related type 1 AIP showing increased numbers of immunostained a IgG4- and b IgG-positive cells surrounding a vein and its corresponding artery. IgG4-positive cells are outnumbered by IgG-positive cells by a ratio of 0.48

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Tissue diagnosis of IgG4-RD in the pancreas

IgG4-RD in the pancreas, called type 1 AIP, grossly imitates pancreatic ductal adenocarcinoma (PDAC), because it commonly forms a firm tumor-like mass in the pancreatic head, narrowing the intrapancreatic common bile duct and the main pancreatic duct [32,33,34,35]. In a surgical series of European AIP patients, the disease affected the pancreatic head region in 76% of the patients, while it rarely occurred in the body (6%) or tail (14%) or occupied the entire pancreas (3%) [13]. The striking focality of AIP, noted in this study but also in other studies based on pancreatic resection specimens, may be, however, overestimated, since if not only surgical patients but also conservatively treated patients are considered, about 40% of type 1 AIP patients appear to have whole-organ involvement [36]. Pseudocysts or calculi, features of early and late alcoholic chronic pancreatitis, are usually not seen in type 1 AIP [10,11,12].

Histologically, the lymphoplasmacytic infiltration and the storiform and swirling fibrosis (Fig. 2b) are often diffuse but change in intensity in the involved area. In addition, most medium-sized ducts are typically surrounded and often narrowed by a collar-like lymphoplasmacytic infiltrate (Fig. 2a). Obliterative phlebitis affects particularly medium-sized veins next to arteries and may be so pronounced that it obscures the involved vessel (Fig. 2c, d). Immunostaining of the infiltrating inflammatory cells reveals abundant CD3- and CD4-positive lymphocytes and, to a lesser extent, CD8-positive lymphocytes [37]. Next in frequency are plasma cells (including IgG4-positive cells), CD68-positive macrophages, and myofibroblasts [11, 37, 38]. Rarely the infiltrate contains significant numbers of eosinophils as the dominating inflammatory cell type, giving a reason to the diagnosis of eosinophilic pancreatitis [39].

In a few cases of type 1 AIP, the inflammatory process presents as an IgG4-related inflammatory pseudotumor (IgG4-related IPT) [40]. These IgG4-related IPTs that are rare in the pancreas and more often seen in the liver, lung, orbit, or kidney are histologically dominated by storiform cellular fibrosis with increased numbers of IgG4-positive cells [40].

After steroid therapy, the pancreas normalizes in size or may even shrink [41, 42]. Data regarding the histologic changes in post-steroid pancreatic tissue are sparse. Two papers describing three AIP patients (probably type 1 AIP, as granulocytic epithelial lesions (GELs) were lacking) in whom biopsies were taken before and after steroid therapy noted that the degree of lymphoplasmacytic infiltration and fibrosis appeared to be decreased after therapy [41, 42]. However, it has also been reported that the pancreas still may show fibrosis with some degree of inflammation, even though the patient clinically may show signs of good response [43].

Type 1 AIP has to be distinguished from type 2 AIP because of the biologic diversity of the two diseases, although both respond equally well to steroid treatment. Clinically, type 1 AIP is commonly (20–50% of the cases) associated with other manifestations of IgG4-RD, is more prevalent in men (75%) than in women, and has its peak incidence between 60 and 70 years [13,14,15,16,17]. Type 2 AIP, in contrast, is associated with inflammatory bowel disease, with frequencies between 10 and 48%, and affects both genders equally and typically in their 40s [11, 13, 15, 36]. Macroscopically, both types of AIP look alike. Histologically, however, type 2 AIP is distinguished from type 1 AIP by a finding called GEL (Fig. 4). GELs are characterized by neutrophilic granulocyte penetration through the duct epithelium, resulting in rupture of the epithelium and luminal microabscesses [11]. GELs may be rare or may occur in many large and small ducts and even in acini [11, 44]. In addition, there are lymphoplasmacytic infiltrates, swirling perilobular fibrosis, and obliterative phlebitis, but usually to a lesser extent and more patchy than in type 1 AIP. Particularly, the lymphoplasmacytic infiltration may sometimes be scarce and concentrated to the periductal (ductocentric) regions.

Fig. 4
figure 4

Type 2 AIP. Small duct with a granulocytic epithelial lesion (GEL). Destruction of the duct epithelium and intraductal accumulation of neutrophilic granulocytes (H&E staining)

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Biopsy diagnosis of IgG4-RD in the pancreas

The main indications for a biopsy of the pancreas in a patient with suspected AIP is the histologic proof of the disease, the exclusion of a carcinoma, and the distinction of type 1 AIP from type 2 AIP. For the diagnosis of AIP in core needle biopsy specimens, all the key features of IgG4-RD in the pancreas (see above) are relevant. However, due to the limited sample size in core needle biopsies, difficulties in establishing the diagnosis may be encountered. If at least two of the three key features such as lymphoplasmacytic infiltration and storiform fibrosis are present (Fig. 2a, b) and a significant increase in IgG4-positive cells (Fig. 3a) and an increased IgG4/IgG ratio (Fig. 3) are demonstrated, the diagnosis of IgG4-RD is highly suggestive (Table 1). If not all of these criteria are met, the diagnosis of IgG4-RD is probable but needs additional evidence such as increased serum IgG4 levels, imaging findings, and/or involvement of other organs [45]. Recently, it was reported that also increased numbers of circulating plasmablasts can support the diagnosis of IgG4-RD, independent of the serum IgG4 value [46].

Table 1 Histologic features relevant for the biopsy diagnosis and differential diagnosis in patients with suspected type 1 (IgG4-related) autoimmune pancreatitis (AIP)
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The distinction of AIP from PDAC may be easy or difficult. It is easy if either all criteria of AIP are present or if neoplastic duct structures are unequivocally recognized (Fig. 5a). Difficulties arise in biopsy specimens that show an unspecific type of chronic pancreatitis that could be caused by a PDAC in the near vicinity that obstructs the draining ducts (see the obstructive chronic pancreatitis in Table 1 and Fig. 5b, c). In such biopsies, there is no conclusive diagnosis possible, as neither AIP can be demonstrated nor a tumor can safely be excluded [47, 48]. The likelihood that a patient with AIP has also, or develops, a PDAC is small. There are, to date, only few case reports on PDACs that were found synchronously or developed metachronously together with AIP. Moreover, there are controversial data on the question whether there is an increased incidence in the total number of malignancies in patients with IgG4-RD compared to the general population [13, 20, 49, 50].

Fig. 5
figure 5

Pancreatic core needle biopsy (CNB) and EUS-guided fine needle biopsy (FNB) in pancreatic ductal adenocarcinoma (a) and peritumoral pancreatitis (b, c). a CNB with neoplastic duct-like glands of variable size embedded in dense fibrotic tissue (H&E staining). b EUS-guided FNB showing peritumoral pancreatitis with ductular complexes surrounded by lymphocytes (H&E staining). c Most lymphocytes stain for CD3 (CD3 immunostaining)

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The distinction of type 1 from type 2 AIP is easy in resection specimens but can be difficult in core needle or histological fine needle biopsies, which are needed in patients in whom typical features of type 1 AIP such as diffuse “sausage-like” enlargement of the pancreas at imaging, extrapancreatic organ involvement, or an elevated serum IgG4 are lacking. In a study including 26 patients with AIP, it was possible to distinguish type 1 AIP from type 2 AIP by using the abovementioned criteria. Forty-five percent of the patients showed GELs indicative of type 2 AIP (Fig. 4), while 38% of the patients had infiltration with IgG4-positive cells indicative of type 1 AIP [24].

Follicular pancreatitis is a rare type of chronic pancreatitis that shares lymphoplasmacytic infiltration with AIP. However, in contrast to AIP, follicular pancreatitis shows numerous lymphoid follicles, often with activated germinal centers, as the dominating feature and lacks storiform fibrosis, obliterative phlebitis, and intense infiltration by IgG4-positive cells [24]. Other types of pancreatitis such as alcoholic chronic pancreatitis do usually play no role in the differential diagnosis of AIP, since alcoholic chronic pancreatitis is mostly already recognized by imaging, revealing pseudocystic and necrotic changes and/or calculi in distorted ducts and dense but patchy fibrosis [51, 52].

While ultrasound-guided core needle (trucut) biopsies mostly provide satisfactory results for the histodiagnosis of AIP and allow a distinction of type 2 from type 1 AIP, fine needle aspiration (FNA) cytology usually lacks the specificity necessary for a diagnosis of AIP [20, 24, 26, 53, 54]. Only if the FNA material, as was observed in some endoscopic ultrasound (EUS)-guided FNA biopsies, contained small tissue fragments enabling the search for the histological features typical for IgG4-RD, satisfactory results were reported [55, 56]. Therefore, new types of EUS-guided needles such as the ProCore or SharkCore needle have been developed. So far, published data on the use of ProCore or SharkCore fine needle biopsies (FNBs) in AIP patients are limited to small series and case reports [20, 57,58,59]. However, in our institution, the increased use of EUS-guided FNB obtained with the SharkCore needle (Fig. 6) has resulted in a low rate of inconclusive diagnoses [60]. In the work up of a biopsy, we cut 13 serial sections upfront from the tissue block. Sections 1 and 13 are stained with hematoxylin and eosin and section 2 with alcian blue periodic acid-Schiff. The remaining sections are initially left unstained and only used if supplementary stains are needed for establishing the diagnosis. Stains that may aid in the diagnosis of IgG4-RD, particularly when the EUS-guided FNB specimen (Fig. 6) is small or shows crush artifacts, are Verhoeff elastin, IgG4 (Fig. 6c), IgG, CD3, and CD38. If malignancy is suspected, also tumor markers are applied such as carcinoembryonic antigen (CEA), maspin, MUC5AC, or SMAD4.

Fig. 6
figure 6

EUS-guided fine needle biopsy (FNB) in type 1 AIP. Diffuse (a) and periductal (b) lymphoplasmacytic infiltration, fibrosis, and c IgG4-positive plasma cells

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Tissue diagnosis of IgG4-related SC

Type 1 AIP is usually located in the pancreatic head and therefore also involves the distal common bile duct. If this is considered as IgG4-related SC, it is the most frequent extrapancreatic manifestation of IgG4-RD [13, 15]. However, if only the isolated extrapancreatic involvement of the large bile ducts is recognized as IgG4-related SC, it is rare and was only the sixth most common manifestation of IgG4-RD in a consecutive series of 235 IgG4-RD patients [61]. Isolated distal (intrapancreatic) IgG4-related SC is extremely uncommon [43].

Grossly, IgG4-related SC presents in most cases as a tumorous thickening of the wall of the common hepatic duct at the hilar region, resulting in a bile duct stricture. It may also manifest as a mass-forming, tumor-like lesion at the liver hilus (Fig. 7a). The extrahepatic changes can be associated with involvement of the intrahepatic bile ducts, leading to various patterns of strictures and dilatations that are best recognized and classified in cholangiograms [62]. Histologically, it shows the characteristic features of IgG4-RD, even though storiform fibrosis and obliterative phlebitis may not be as prominent as in type 1 AIP (Table 2) [63]. In typical cases, a transmural lymphoplasmacytic infiltrate (Fig. 7b, c) rich in IgG4-positive plasma cells (> 50 cells per HPF in resection specimens and > 10 cells per HPF in biopsies), often also containing eosinophilic granulocytes, leads to diffuse and circumferential thickening of the duct wall. The mucosa is intact, and granulomas, abscesses, multinucleated giant cells, and excess of neutrophils are usually not seen [64]. Mucosal erosion and infiltration by neutrophils are usually due to stenting of the narrowed bile duct.

Fig. 7
figure 7

IgG4-related sclerosing cholangitis (IgG4-related SC). a Cut section through the liver hilus showing a tumor-like thickening of the wall of the right prestenotic hepatic bile duct (courtesy of Dr. Dankoweit-Timpe, Hannover, Germany). b Bile duct wall showing fibroinflammatory thickening (H&E staining). c Immunostaining for CD38 reveals high numbers of plasma cells

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Table 2 Histologic features relevant for the biopsy diagnosis and differential diagnosis in patients with suspected IgG4-related sclerosing cholangitis (IgG4-related SC)
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Liver changes in IgG4-RD, characterized by inflammatory portal tract infiltrates containing increased numbers of IgG4-positive plasma cells, have been termed IgG4-related hepatopathy. An IgG4-positive subtype of AIH has also been described, but when using the strict criteria put forward by Umemura et al. including elevated serum IgG4 levels, fulfillment of diagnostic criteria for classical AIH, and detection of at least 10 IgG4-positive cells per HPF in portal tracts on liver biopsy, only three unequivocal cases are identified in the recent literature [65, 66].

Isolated tumorous manifestations of IgG4-RD in the liver were reported as IgG4-related IPT [4, 67]. They have to be distinguished from fibrohistiocytic IPTs, which, in contrast to IgG4-related IPTs, occur more often in the liver periphery than in the hilar region [68]. Even though obliterative phlebitis and venous occlusion may occasionally be seen, this type of IPT seems not to be related to IgG4-RD [68].

In the differential diagnosis of IgG4-related SC from PSC, the following histological findings are important. PSC usually involves the luminal part of the bile ducts, particularly the mucosa, where ulceration and xanthogranulomatous inflammation and/or sclerosis may be observed and the key findings of IgG4-related SC are missing [43]. Other features that contribute very much to the separation of PSC from IgG4-related SC are imaging and clinical data. PSC affects often patients below the age of 40 and sometimes even children, and these patients have commonly associated inflammatory bowel disease and p-ANCA antibodies [69]. Only those PSC patients may be difficult to separate from IgG4-related SC patients, in whom the sclerosis particularly involves the extrahepatic bile ducts and/or is associated with elevated serum IgG4 levels, which, however, often are below two times of the upper normal limit.

Recently, Zen et al. described a sclerosing cholangitis with GELs, mainly in liver core needle biopsies from children who otherwise had features of PSC [70]. This may be a possible biliary counterpart to type 2 AIP. Apart from GELs, the other histological findings in these cases were similar to PSC, including onion-skin periductal sclerosis. It remains to be elucidated if a similar GEL-positive, IgG4-negative type of large-duct SC exists.

Another, though very rare, type of chronic cholangitis that has to be distinguished from IgG4-related SC is follicular cholangitis. Like follicular pancreatitis, it shows numerous lymphoid follicles and dense infiltration with lymphocytes and plasma cells [71]. Obliterative phlebitis and a storiform type of fibrosis as well as IgG4 positivity in the tissue are not observed.

Biopsy diagnosis of IgG4-related SC

Good cytological brushings and biopsies from extrahepatic biliary strictures are notoriously difficult to obtain. If bile duct brushings contain epithelial cells, they often have an atypical appearance. Such cells have to be interpreted with great caution, particularly if they are observed on a background of inflammation, as they are most likely reactive and unspecific in nature. Therefore, these brushings are usually unable to safely exclude a hilar carcinoma. Moreover, they fail to establish the diagnosis of IgG4-related SC or its differential diagnosis, PSC (Table 2) [69, 72,73,74]. If histologic biopsy material is available, the diagnosis can be straightforward, in case adenocarcinoma cells are identified without any doubt (Fig. 8a). To support a diagnosis of low-grade adenocarcinoma of the bile duct over reactive changes, immunohistochemistry showing overexpression of maspin (Fig. 8b) and CEA or loss of SMAD4 can be helpful.

Fig. 8
figure 8

Endoscopic bile duct biopsy. a Neoplastic duct-like glands with angular and irregular contours, indicative of bile duct adenocarcinoma (H&E staining). b The neoplastic glands show immunohistochemical overexpression of maspin

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However, in many cases, the diagnosis is hampered by the fact that stenting (which often precedes the biopsy because of a bile duct stenosis) usually leads to reactive epithelial changes that may mimic neoplastic alterations and could result in the wrong diagnosis of adenocarcinoma. Also, the proper diagnosis of IgG4-related SC is severely limited. The tiny subepithelial connective tissue that is usually found in the biopsies is not sufficient enough to reveal key findings of IgG4-related SC, such as obliterative phlebitis and storiform fibrosis. If the subepithelial tissue contains small lymphoplasmacytic infiltrates showing some IgG4 positivity, these findings have also to be interpreted with caution, since they are unfortunately also frequently encountered in bile duct carcinomas [75, 76]. The diagnostic value of an additional liver core needle biopsy is often limited, since in most instances, only secondary obstructive changes are found. Only in 26% of IgG4-related SC patients, particularly in those with intrahepatic cholangiographic strictures, the disease was found to extend along the portal tracts and involve the intrahepatic small bile ducts [77]. In these instances, an inflammatory fibrosis (so-called “inflammatory nodule”) expanding the portal tracts (Fig. 9a) and showing a lymphoplasmacytic infiltrate with high numbers of IgG4-positive cells (Fig. 9b) and sometimes also eosinophils may be found, and is then highly suggestive of IgG4-related SC [64]. The neutrophilic infiltration, which may also be observed in these biopsies, accompanies reactive bile ductules around the portal tracts and is an unspecific finding [43]. It is important to note that, at present, isolated intrahepatic small-duct IgG4-related SC has not been reported [77].

Fig. 9
figure 9

Liver core needle biopsy showing a fibroinflammatory expansion of a portal tract, a so-called “inflammatory nodule,” and b infiltration by IgG4-positive cells

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Because of the diagnostic difficulties so often encountered in bile duct biopsies, biopsies from the ampulla of Vater have been recommended. They may show increased IgG4-positive cells and IgG4/IgG ratios [72, 78]. However, in our experience and in the experience of others, the sensitivity and specificity of this approach is often low and only rarely useful in the diagnosis of IgG4-related SC [79]. Ampullary biopsies are of greatest value in patients with suspected AIP and showing a pathologically enlarged papilla.

Conclusion

Among the various organ manifestations of IgG4-RD, the pancreas and the common bile duct represent some of the most important sites because of the disease’s difficult distinction from pancreatic and bile duct carcinoma, respectively. The histologic features of IgG4-RD in the pancreas and the bile duct are easily recognized in resection specimens. In biopsies, however, changes representative of the disease may be difficult to identify. Therefore, it is important to correlate the biopsy findings with clinical, imaging, and serological data, in close collaboration with the gastroenterologist, radiologist, and surgeon. Future prospective studies are needed to evaluate whether new histologic biopsy needles guided by endoscopic ultrasound (pancreas) or cholangioscopy (bile ducts) can improve the tissue yield and the diagnostic sensitivity and specificity.