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Year : 2021  |  Volume : 64  |  Issue : 5  |  Page : 149-159
Autoimmune pancreatitis: Current perspectives

Department of Pathology, GIPMER, New Delhi, India

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Date of Submission20-Jan-2021
Date of Decision22-Mar-2021
Date of Acceptance04-Apr-2021
Date of Web Publication7-Jun-2021


Over the last two decades, our knowledge and understanding regarding the pathogenesis and biology of autoimmune pancreatitis (AIP) have improved tremendously. Type 1 AIP or IgG4-related pancreatitis (IgG4-RP) is now believed to be the prototype of the multisystemic IgG4-related disease. In view of clinical features like obstructive jaundice and mass-forming lesions in the pancreas in elderly men, type 1 AIP often mimics pancreatic cancer. IgG4-related sclerosing cholangitis concomitantly involving the extrahepatic and intrahepatic biliary tree is the most common extrapancreatic involvement seen in up to 80% of these patients, which needs to distinguish from cholangiocarcinoma. Histology is characterised by lymphoplasmacytic inflammation, abundant IgG4 positive plasma cell infiltration, storiform fibrosis and obliterative phlebitis. Apart from histology, high serum IgG4 levels, pancreatic parenchymal and duct imaging findings and other organ involvement aid in diagnosis especially in cases where definitive histology is not evident. Also, these parameters lay the foundation of various diagnostic criteria proposed over last few years. On the contrary, histology alone is the mainstay for establishing diagnosis of idiopathic duct-centric pancreatitis (IDCP) as it lacks any specific serological marker or imaging. Since both types of AIP respond dramatically to corticosteroid treatment, a biopsy is crucial to establish the preoperative diagnosis and to exclude malignancy so as to avoid unnecessary surgery. This review discusses the morphologic spectrum, treatment and prognosis of IgG4-RP and IDCP with an emphasis on approach to diagnosis with relevant histologic features, differential diagnoses and the challenges faced during biopsy interpretation.

Keywords: Autoimmune pancreatitis, histology, idiopathic duct-centric pancreatitis, IgG4-related disease, IgG4-related sclerosing cholangitis, IgG4-related inflammatory pseudotumor, lymphoplasmacytic pancreatitis

How to cite this article:
Goyal S, Sakhuja P. Autoimmune pancreatitis: Current perspectives. Indian J Pathol Microbiol 2021;64, Suppl S1:149-59

How to cite this URL:
Goyal S, Sakhuja P. Autoimmune pancreatitis: Current perspectives. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Oct 16];64, Suppl S1:149-59. Available from: https://www.ijpmonline.org/text.asp?2021/64/5/149/317915

   Introduction Top

Autoimmune pancreatitis (AIP) or IgG4-related pancreatitis is a chronic fibroinflammatory disease, which currently represents both a localised disease as well as a manifestation of the systemic IgG4-related disease (IgG4-RD) spectrum. AIP used to be a rare diagnosis till a decade ago; however, with the tremendous work in this field, in the recent years, our knowledge and understanding regarding the pathogenesis and biological behaviour of this entity have exponentially increased. The disease has myriad distinct multiorgan manifestations and is steroid responsive. Strong clinicoradiological and serological correlation and histological confirmation are required for establishing the diagnosis in majority of the cases. In this review article, we have tried to summarise the clinicopathological features and the most accepted diagnostic criteria, treatment and outcome of this multifaceted disease entity with an emphasis on diagnostic approach and problems encountered during biopsy interpretation.

   History and Classification Top

The reports of AIP were described first more than 50 years ago, when Sarles et al.[1] reported a case of sclerosing pancreatitis with hypergammaglobulinemia in 1961. Subsequently, few researchers diagnosed and reported patients of chronic pancreatitis with coexisting primary sclerosing cholangitis (PSC), Reidel thyroiditis or retroperitoneal fibrosis. Many of these cases were associated with autoimmune disorders like inflammatory bowel disease (IBD), Sjogren syndrome and systemic lupus erythematosus and had a complete histologic response to corticosteroids. The authors proposed that a single underlying pathophysiological mechanism might underly these distinct unrelated manifestations.[2] Kawaguchi et al.[3] described 'a variant of PSC extensively involving pancreas' and coined the term lymphoplasmacytic sclerosing pancreatitis (LPSP), which is the sine qua non for diagnosing AIP. Shortly after that Yoshida et al.[4] in 1995 proposed the concept of AIP in 11 patients of chronic pancreatitis with diffuse narrowing of the main pancreatic duct (MPD) on the basis of increased serum IgG levels, lymphoplasmacytic infiltration and prompt response to corticosteroid therapy. In 2001, Hamano et al.[5] published their landmark discovery of elevated IgG4 antibodies in patients with AIP that correlated with disease activity and represented a practical serological diagnostic biomarker. Soon after Kamisawa et al.[6] described tissue infiltration with IgG4 positive plasma cells in multiple extrapancreatic tissues including bile ducts, salivary glands, kidney and retroperitoneum in AIP patients and concluded that various lesions including LPSP are actually a part of multiorgan autoimmune disorder called IgG4-RD. This multisystemic form of AIP, which is associated with elevated IgG4 levels and histologically characterised by LPSP and storiform fibrosis, is called type 1 AIP.[7]

Simultaneously, researchers from Europe described a subset of patients very distinct from alcoholic pancreatitis, which were younger (mean age: 42 years), had severe abdominal pain, normal serum IgG4 levels and a close association with IBD.[8],[9] Notohara et al.[10] in 2003 described 35 patients of idiopathic chronic pancreatitis with lymphoplasmacytic infiltration, of which 22 had features of AIP type 1, whereas the remaining 13 patients were younger with no gender bias and were histologically characterised by neutrophilic infiltration into bile duct causing duct destruction and obliteration. This distinct form of AIP was termed as idiopathic duct-centric pancreatitis (IDCP)/type 2 AIP; the neutrophilic lesion was coined as granulocyte epithelial lesion (GEL), which is the histologic hallmark of IDCP. In 2011, International Consensus Diagnostic Criteria (ICDC) for AIP were established to achieve global uniformity in the terminology, and to establish standard criteria for the diagnosis of AIP.[11]

   IgG4-RD/Lymphoplasmacytic Sclerosing Pancreatitis (LPSP)/Type 1 AIP Top

Type 1 AIP, previously called LPSP, is a prototypic manifestation of IgG4-RD.[3] In an international multicentric analysis conducted on 1064 AIP patients, type 1 AIP was the predominant type seen in 978 (92%) patients with a mean patient age of 61.4 years at the time of diagnosis.[12]

Clinical features

The usual symptomatology is painless obstructive jaundice in elderly males (mean age 60–70 years). Significant pain is unusual and should suggest the possibility of malignancy. Imaging shows diffuse or focal pancreatic enlargement; sometimes appearing like a mass and pancreatic ductal strictures.[13] The most common extrapancreatic manifestation of IgG4-RD is IgG4-associated sclerosing cholangitis (IgG4-SC), seen in up to 80% patients with LPSP.[14] In a study from Mayo Clinic, it was found that 92% of 53 patients with IgG4-SC had concomitant type 1 AIP, whereas only 8% had isolated cholangitis.[15] In more than 90% patients, there are extrapancreatic manifestations in the form of sialadenitis (48%), pulmonary interstitial fibrosis (54%), mediastinal or retroperitoneal fibrosis (20%), peripancreatic lymphadenopathy (56%), tubulointerstitial nephritis (14%) and orbital pseudotumor.[16],[17] Although multisystem involvement is common, the absence of extrapancreatic manifestations does not rule out LPSP. Also, since AIP is rare compared to pancreatic cancer, malignancy should always be excluded.[7],[18]

Serological features

70%–80% of patients have a cholestatic pattern on liver function tests along with mild to moderate elevations of pancreatic enzymes. CA19–9 may be elevated in up to 50% of patients due to cholestasis. On serum electrophoresis, AIP patients display a polyclonal band in the rapidly migrating fraction representing the characteristic β_γ globulin bridging. Elevated IgG4 levels (>2 times the upper limit of normal) are seen in 90% of patients and are a 'Level 1' ICDC criteria for the diagnosis of LPSP.[11],[19] IgG4 levels with a cutoff >140 mg/dl had a sensitivity and specificity of 76% and 93%, respectively, which improved to a specificity of 99% and sensitivity of 53% if the cutoff values were raised to >280 mg/dl.[20] IgG4 can rarely be elevated in pancreatic cancer (10% cases), primary biliary cirrhosis (PBC), PSC and Sjögren's syndrome.[5] 1% of pancreatic cancer patients have IgG levels >2 times the upper normal limit.[5],[20] IgG4 gets elevated before clinically evident recurrence, thereby making it a useful marker for predicting flareups.[21] Furthermore, highly elevated IgG4 values indicate disease activity and shows association with multiple extrapancreatic lesions, significantly higher fluorodeoxyglucose (FDG) uptake in pancreatic lesions and requirement of long-term maintenance therapy.[5],[22] Normal IgG4 levels post-treatment represent an inactive disease and might indicate the cessation of maintenance therapy.[21] It is noteworthy that rarely type 1 also can be seronegative and without other organ involvement.


CECT shows diffuse enlargement of the pancreas (sausage-shaped pancreas) with delayed homogeneous enhancement (level 1 diagnostic criterion).[23] There is loss of normal fibrillary margin of the pancreas and a low-attenuation rim-like capsule representing surrounding dense fibrosis may be seen in 30%–40% patients.[23] Rarely, it can present as an enhancing focal mass lesion in the pancreas closely resembling pancreatic cancer, for which patients undergo surgery.[24] Positron emission tomography is not required for diagnosis, but if done shows intense, diffuse and heterogenous fluorine-18 FDG uptake, which resolves with steroids. On the contrary, solitary homogenous uptake in the pancreas suggests pancreatic cancer.[25] Concomitant FDG uptake by extrapancreatic organs also support the diagnosis of AIP.

MRCP and endoscopic retrograde cholangiopancreatography (ERCP) reveal characteristic diffuse narrowing of the MPD with long (>1/3rd of the pancreatic duct) or multifocal strictures, with lack of significant upstream dilatation and branching from the stenotic segment [Figure 1]. CBD strictures may also be seen due to concomitant IgG4-SC and thus need to be differentiated from SC and cholangiocarcinoma.[26]
Figure 1: (a) Axial contrast-enhanced MRI image shows diffuse enlargement of the pancreas with heterogeneous enhancement and hypointense sleeve of soft tissue around the bulky pancreas (arrowheads). (b) Coronal T2 weighted fat-suppressed image depicts diffusely bulky pancreas with mildly prominent pancreatic duct (arrow) in the body, suggesting long segment stricture in the head region

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Pancreatic ductal adenocarcinoma is usually a differential because AIP presents as tumor-like mass in the pancreatic head with multifocal pancreato-biliary strictures presenting with obstructive jaundice in elderly males.[27] Pancreatic head region has been reported to be most commonly involved (76% patients).[28] Although IgG4 serology, painless jaundice, lack of cachexia and imaging features are helpful in distinguishing AIP from pancreatic cancer, histopathology is required to establish a conclusive diagnosis in most of the cases.

Patients with LPSP have a characteristic triad of histologic features comprising diffuse lymphoplasmacytic infiltration, storiform fibrosis and obliterative phlebitis.[29],[30] Typical histology is duct narrowing and periductal collar-like polyclonal lymphoplasmacytic infiltrate [Figure 2]. Storiform fibrosis is composed of thick collagen bundles arranged in a characteristic swirling pattern reminiscent of cartwheel spokes [Figure 3]. Obliterative phlebitis is characterised by near-complete obliteration of small to medium veins. In the early stage, there is a lymphocytic dominant perivascular infiltrate causing vasculitis and resulting in fibroinflammatory obliteration [Figure 4]. The obliterated veins may only be recognized in elastic Van Gieson or Verhoeff staining.[31] It is important to mention that the three histologic criteria may not be consistently observed in all the sites. Storiform fibrosis and obliterative phlebitis may be absent at the extrapancreatic sites like salivary glands, lymph nodes, lung, or kidney. Infiltration by eosinophils can be a prominent histologic finding but is not pathognomonic. Findings that argue against the diagnosis of IgG4-RD are neutrophilic microabscesses, granulomas, necrosis, multinucleated giant cells and necrotising vasculitis.[18],[32] In the resected pancreatectomy specimens, interlobular sclerosis is more pronounced, whereas inflammatory infiltration is more prominent within the lobules leading to acinar destruction. Fat necrosis, pseudocyst formation, calcification and calculi in distorted ducts are features in favour of chronic alcoholic pancreatitis and rule out AIP.
Figure 2: (a) Photomicrograph from pancreas with classical features of AIP type 1 shows typical duct narrowing and periductal collar-like dense lymphoplasmacytic infiltrate (H and E ×100). (b) Higher magnification shows dense inflammatory infiltrate comprising numerous plasma cells in the pancreas with acinar atrophy and perilobular cellular fibrosis, and the inflammation is prominent around the ducts (H and E ×200)

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Figure 3: (a) Pancreas is diffusely involved by fibroinflammatory process comprising characteristic cellular fibrosis in a stroriform and undulating pattern. (b) There is a prominent infiltration by eosinophilic granulocytes that can be seen in few cases (H and E ×100)

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Figure 4: (a and b) Characteristic obliterative phlebitis seen in IgG4-RP comprising a lymphocytic predominant perivascular and intravascular infiltration of the vein, leading to partial or complete fibroinflammatory obliteration (H and E ×200)

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The hallmark of diagnosing IgG4-RD is tissue infiltration by IgG4+ plasma cells [Figure 5]. But latter is non-specific and can occur in many diseases like Crohn's disease, ulcerative colitis and multicentric Castleman disease. Thus, it is imperative to use a site-specific cutoff for the number of infiltrating IgG4+ cells and IgG4+/IgG ratio to avoid overdiagnosis.[30] A standard cutoff of 10 IgG4+ cells/high-power field (hpf) for biopsy specimens and 50 IgG4+ cells/hpf for resection specimens with an IgG4/IgG ratio of more than 40% in pancreatobiliary system has been recommended.[30],[33],[34] For extrapancreatic sites, such as salivary glands, the proposed cutoff value is 100 cells/hpf to avoid overdiagnosis.[30],[35]
Figure 5: The diagnostic hallmark of IgG4-RD—On immunohistochemistry, numerous IgG4 positive plasma cells are seen in the inflammatory infiltrate diffusely involving the pancreas (IgG4 ×200). Proposed cutoff values are >10 IgG4 + plasma cells/hpf for biopsies and >50 IgG4 + plasma cells/hpf in pancreatobiliary resection specimens

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After steroid therapy, the pancreas rapidly shrinks in size within initial few weeks. There is limited literature regarding the histologic changes after steroid therapy in AIP. However, one study has reported regression of fibrosis as well as inflammation after a course of steroids in some patients, while others still have persistent inflammation despite clinical remission.[36],[37] Larger prospective studies are required to evaluate on-treatment biopsies, which might aid in determining the complete withdrawal of maintenance therapy in these patients.

Diagnostic criteria

Since 2002, many diagnostic criteria for AIP based on characteristic imaging and ERCP findings, IgG4 serology and histopathology have been proposed from Japan, Korea, the United States and Europe. Modified HISORt (Histology, Imaging, Serology, Other organ involvement, and Response to therapy) criteria were proposed from Mayo Clinic in 2006 in which other organ involvement and response to therapy were the newly introduced parameters.[38]After thorough review of the existing criteria and to achieve uniformity across the world, ICDC were proposed in 2011 based on the following five chief features: 1) imaging of pancreatic parenchyma and ducts; 2) serology; 3) extrapancreatic involvement; 4) histology; and 5) treatment response.[11] Each feature was categorized as a level 1 or 2 depending on the diagnostic reliability. Based on these features, diagnosis is either definitive or probable, and not otherwise specified in some equivocal cases.[11] The major advantage of ICDC over other systems is the non-dependence on diagnostic invasive ERCP for ductal imaging, which is not routinely performed in the Western countries. A comparative study revealed that the ICDC possessed the highest diagnostic ability in terms of accuracy (95.0%), followed by Japanese Pancreatic Society-2011 (92.9%) and Korean (92.2%), and then HISORt (88.7%).[39],[40] [Table 1] shows the comparison of various scoring systems in terms of their cardinal criteria, accuracy, sensitivity and specificity used across the world to diagnose AIP.[11],[19],[39],[40] It is clear from the ICDC that type 1 AIP can be diagnosed without histology in the presence of collateral evidence, but histology is mandatory in IDCP for a definitive diagnosis.
Table 1: Comparison of various diagnostic criteria used for AIP

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   Type 2 AIP/Idiopathic Duct Centric Pancreatitis (IDCP) Top

Type 2 AIP/IDCP is clinically and biologically distinct from type 1 AIP and is ten times rarer than the latter. It has a striking association with IBD in 10%–48% cases and no correlation with IgG4 serology. It usually affect middle aged persons and both the genders equally.[28] In an international survey on 1064 AIP patients, type 2 AIP was found only in 86 patients (8%) with a mean age of 39.9 years at the time of diagnosis. Hart et al.[12] reported a lower proportion of this subtype in Asian countries (3.7%) compared to Europe (12.9%) and North America (13.7%). Serum IgG4 levels are normal or slightly elevated (≈200 mg/dl) in up to 25% of patients.[9] Patients usually present with recurrent acute pancreatitis, and less commonly as painless obstructive jaundice or pancreatic mass. Kawa et al.[41] found a lower prevalence of jaundice compared to type 1 AIP due to lower incidence of pancreatic head swelling and Common bile duct (CBD) stenosis. Both types of AIP look alike grossly and radiologically. The histological hallmark of type 2 AIP is granulocytic epithelial lesions (GELs), characterised by infiltration of duct epithelium by neutrophils resulting in rupture of the epithelium and luminal microabscesses [Figure 6].[9],[42] Lobular neutrophilic infiltration is a specific but uncommon finding [Figure 6]. Lymphoplasmacytic infiltrates, storiform fibrosis and obliterative phlebitis can be seen but usually is focal and much lesser as compared to type 1 AIP. IgG4 positive plasma cells may occasionally be present, but are lower than the cutoff values.[31]
Figure 6: Type 2 AIP. (a) Lymphoplasmacytic inflammation along with a prominent neutrophilic component within the pancreatic lobules and ducts (H and E ×400). (b) Cellular perilobular undulating fibrosis along with a lymphoplasmacytic inflammatory infiltrate admixed with numerous granulocytes (H and E ×200). (c) Neutrophilic infiltration into the acini with formation of microabscess, a less common but specific feature of type 2 AIP (H and E ×400). (d) Characteristic granulocytic epithelial lesion within a small duct characterised by neutrophilic infiltration into the duct epithelium resulting in rupture and formation of luminal microabscesses (H and E ×400)

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Since there is no serological marker or specific imaging for type 2 AIP, the histological confirmation by GELs or neutrophilic lobular inflammation is mandatory.[18]

   Biopsy Diagnosis Challenges and Approach Top

Obtaining sufficient pancreatic tissue is very crucial for patient management. The indications for a pancreatic biopsy in a patient with suspected AIP are for histologic confirmation of the disease, exclusion of a carcinoma and the distinction of type 1 from type 2.[31] Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) from pancreatic head although safe and easier than core biopsy has a very limited diagnostic role in routine practice. Few investigators have tried FNA using 22 G needle or larger needles and yielded conflicting results.[43] Many have reported poor diagnostic tissue yield resulting in low sensitivity, thereby proving FNA as an ineffective diagnostic modality in AIP.[44],[45] On the contrary, EUS-guided core biopsy and/or surgical biopsy provides larger tissue to assess architecture and immunostaining that allows a histologic diagnosis of AIP.[46] Although procurement of adequate core biopsy requires considerable expertise, it is a reliable and preferred diagnostic modality for AIP.[46],[47] Diagnosis on biopsy samples remains a challenge for the pathologist because key features like obliterative phlebitis and storiform fibrosis might not be evident in small biopsies.[18] Furthermore, strong background staining in IgG staining is a commonly encountered problem. Therefore, histological interpretation needs to be more dependent on >10 IgG4 positive cells/hpf and IgG4/IgG ratio. Even if obliterative phlebitis is not apparent on H and E-stained sections, elastic staining is suggested to detect completely obliterated veins embedded next to an artery.[18] Histological diagnosis is definitive only if at least two of the three key histologic features along with increased IgG4/IgG ratio >0.4 are present.[31],[48] A recent study has reported the role of increased numbers of circulating plasmablasts independent of the IgG4 serology in the diagnosis of IgG4-RD.[49] Diagnostic utility of biopsy cannot be overemphasized since it is conclusive in more than 70% cases of AIP and in more than 80% cases with pancreatic cancer. It is important to mention the negative findings in the biopsy report as the presence of certain features like necrosis, abscess or discrete granuloma in biopsy specimens can help in excluding the possibility of IgG4-RD.[18] Diagnosis of type 2 AIP is easier and straightforward with the identification of GELs and neutrophilic infiltration into pancreatic acini. Biopsy was able to diagnose AIP in 76% cases using six criteria namely GELs, >10 IgG4-positive plasma cells/hpf, >10 eosinophils/hpf, fibrosis, lymphoplasmacytic infiltration and venulitis. Also, 45% of the cases showed GELs indicating IDCP, while 38% of the type 1 AIP patients were diagnosed using these criteria.[50] [Table 2] enlists the various differential diagnoses of AIP commonly encountered in routine practice with their salient histopathologic features.[31]
Table 2: List of differential diagnosis with salient histological features in patients with suspected type 1 autoimmune pancreatitis (AIP)/IgG4-related AIP

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   IgG4-Related Sclerosing Cholangitis (IgG4-SC) Top

Since IgG4-related AIP is usually located in the pancreatic head, intrapancreatic segment of distal common bile duct is concomitantly affected in most of these patients. In fact, IgG4-SC is the most frequent extrapancreatic manifestation of IgG4-RD. Cholangiopathy may be the dominant manifestation at the time of relapse in type 1 AIP. Rarely, it involves only the extrapancreatic CBD or presents as isolated manifestation in the perihilar bile ducts or the gallbladder.[51],[52] Ghazale et al.[15] evaluated 53 patients with IgG4- SC and found that 92% of these patients had concomitant type 1 AIP, whereas only 8% presented with isolated cholangitis.

Large duct cholangiopathy

Grossly, the affected common bile duct resembles a pipestem with diffuse and circumferential wall thickening and multiple strictures.[53],[54] In contrast to cholangiocarcinoma, the mucosal surface is relatively smooth. Histologically, IgG4-SC is characterised by a transmural fibroinflammatory process comprising massive lymphoplasmacytic infiltration and occasional eosinophils leading to diffuse and circumferential thickening of the duct wall [Figure 7]. Storiform fibrosis and obliterative phlebitis are focal and not prominent. Characteristically, the lining epithelial of the bile duct is well preserved with periglandular concentric fibrosis, which explains the lower risk of dysplasia and epithelial malignancy in IgG4 [Figure 7]. Mucosal erosion and neutrophilic infiltration are exceptionally seen unless there is injury by stenting.[53] PSC and cholangiocarcinoma are the main differentials, which need to be excluded on histologic examination. A younger age (< 40 years), history of IBD, presence of pANCA antibodies and serum IgG4 levels below two times the upper normal limit favor PSC over IgG4-SC. PSC is characterised by a pronounced inflammation on the luminal side with ulceration and xanthogranulomatous inflammation. Obliterative phlebitis and storiform fibrosis are not features of PSC. The fibrous obliteration of the bile duct is almost pathognomonic for PSC.[18],[53],[54] IgG4 immunostaining needs to be interpreted cautiously as the bile ducts in PSC may be infiltrated by a significant number of IgG4 + plasma cells, but there is only focal aggregation, and the IgG4+/IgG cell ratio is typically less than 40%.[55]
Figure 7: Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC). (a) There is a prominent transmural lymphoplasmacytic inflammatory infiltrate with fibrosis. Peribiliary glands are entrapped within the fibroinflammatory process (H and E ×200). (b) Higher magnification confirms the same, the lining epithelium of this small duct is well preserved (H and E ×400). (c) On immunohistochemistry, numerous IgG4 positive plasma cells are seen around the duct (IgG4 ×200)

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Small duct cholangiopathy

This entity includes IgG4-RD affecting intrahepatic septal and interlobular bile ducts, which is almost always associated with inflammatory extension from the large bile ducts. Unlike small-duct PSC, IgG4-SC restricted to only small intrahepatic bile ducts has not yet been documented. Grossly, it appears as a whitish periductal lesion in resected specimens. On microscopy, portal tracts are enlarged with “an inflammatory nodule” comprising marked lymphoplasmacytic inflammatory infiltrates centred around small bile ducts [Figure 8].[54] The lining epithelia of bile ducts is preserved. IgG4 + plasma cells (>10 cells/hpf) with IgG4/IgG cell ratio >40% in the affected portal tracts is specific for IgG4-SC.[56] The pathologists need to determine on liver biopsy whether cholangiopathy is due to PSC or IgG4-SC. Portal inflammation, a bile ductular reaction with neutrophils, and copper-associated protein deposition in periportal hepatocytes are non-specific, therefore not helpful. Fibro-obliterative changes such as periductal concentric fibrosis and ductopenia favour PSC over IgG4-SC. Portal inflammatory nodule, although rarely seen in liver biopsies, is highly specific for this condition.[54] Involvement of portal tracts and intrahepatic small ducts was found only in 26% of IgG4- SC patients in a study.[56]
Figure 8: Liver biopsy in a case of IgG4-SC (small duct type). (a) Portal tract is significantly expanded with dense inflammatory infiltrate and fibrosis forming an 'inflammatory nodule', which is rarely seen, but a highly specific feature (H and E ×100). (b) Higher magnification shows dense inflammatory infiltrate in the portal area comprising numerous lymphocytes and plasma cells and fibrosis with interface activity and ductular reaction (H and E ×200). (c) IgG4 immunostaining reveals > 10 IgG4-positive plasma cells/hpf, diagnostic for IgG4-SC (IgG4 ×400)

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Whether IgG4-related cholangitis progresses to liver cirrhosis is controversial. In a study by Ghazale et al.,[15] 4 out of 53 patients of IgG4-SC developed cirrhosis within 5 years.

Biopsies from extrahepatic biliary strictures are seldom feasible and are required to exclude cholangiocarcinoma, which might be challenging to distinguish from chronic reactive changes induced by in situ stent. The tiny subepithelial connective tissue obtained in the biopsies is not sufficient enough to reveal obliterative phlebitis and storiform fibrosis.[57] Furthermore, IgG4+ plasma cells can be frequently seen in cholangiocarcinoma as well.[58] Few researchers have recommended biopsies from the ampulla of Vater to overcome the difficulties in obtaining bile duct biopsy and have demonstrated increased IgG4+ cells and IgG4/IgG ratios,[59] while others disagree and have questioned the usefulness of ampullary biopsy in diagnosis of IgG4-SC. Ampullary biopsy is diagnostically useful in those patients with suspected AIP who show a pathologically enlarged papilla.[60]

Another very rare, type of chronic cholangitis typically affecting perihilar large bile ducts that needs to be considered in the differentials is follicular cholangitis. This condition is characterised by numerous lymphoid follicles around the bile ducts and the typical findings of IgG4 RD are absent. Patients generally present with a hilar duct stricture or a periductal plaque like mass.[61]

   Sclerosing Cholangitis with Granulocytic Epithelial Lesion (SC with GEL) Top

Recently, Zen et al.[62] proposed a new entity of SC with GEL in liver biopsies of 5 out of 254 patients (2%) with PSC, which was characterised by neutrophilic small bile duct injury. Apart from GELs in these cases, tissue IgG4 + plasma cells and serum IgG4 levels were not increased. These patients went into remission with prednisolone and/or ursodeoxycholic acid. More evidence is required to prove whether it is GEL-positive, IgG4-negative type of large duct SC, which is probably a biliary counterpart of type 2 AIP exists.

   IgG4-Related Inflammatory Pseudotumors in the Liver (IgG4-IPT) Top

IgG4-SC occasionally manifests as solid whitish mass lesion usually in men typically involving perihilar large bile ducts, termed as inflammatory pseudotumors, which is best explained by pseudotumorous proliferation of SC.[63] Due to radiological features mimicking hilar cholangiocarcinoma, many patients often undergo unnecessary surgical resections. It is important to distinguish fibrohistiocytic IPTs, which is in contrast to IgG4-related IPTs, comprising extensive xanthogranulomatous inflammation and occur more often in the liver periphery than in the hilar region. Unlike cholangiocarcinoma, in IgG4-SC, the inflammatory process is restricted to hilar plate with no direct infiltration into the adjacent liver parenchyma. Microscopically, bile ducts and peribiliary glands are entrapped within the lymphoplasmacytic inflammatory process, with foci of storiform fibrosis and obliterative phlebitis of portal vein radicles.[53],[63]

   Pathogenesis Top

The likely pathogenesis of IgG4-RP is immune mediated with disease developing in genetically susceptible individuals with a particular HLA haplotype-DRB1*0405-DQB1*0401 when exposed to environmental factors. The abundance of plasma cells in the tissue, the presence of autoantibodies against lactoferrin and carbonic anhydrase II, increased levels of IgG4 and dramatic response to steroids suggest an autoimmune mechanism.[64] Typing of the CD4+ inflammatory duct-associated cells has revealed a predominance of Th2 cells over Th1 cells in few recent studies. Furthermore, infiltration of tissues by FoxP3 CD4+ CD25+ T regulatory cells (Tregs) has been documented, which is not the expected finding in autoimmune diseases like PBC and PSC.[64],[65] These Tregs produce a regulatory cytokine IL-10, which along with IL-4 react with B cells to induce IgG4 class switch. Therefore, combined activation of Th2 and Tregs may lead to the selective induction of IgG4. Also, Tregs overexpress a fibrogenic cytokine transforming growth factor beta (TGF-β), which plays a crucial role in fibroinflammatory process.[64],[65] There has been a upregulation in the expression and interaction of chemotactic factors like CCR8 in Th2 lymphocytes and FOXP3 Tregs and CCL1 in the ductal cells and endothelial cells.[66]

   Treatment Top

It is noteworthy that rarely pancreatic adenocarcinoma and AIP can coxist; thus, it is imperative to rule out malignancy before starting steroids.[7],[13] The clinical symptoms, imaging and pathological findings of AIP dramatically respond to corticosteroid therapy within initial 3–4 weeks. Thus, lack of response to steroids should raise the possibility of an alternative disease.[67] According to the Japanese Consensus Guidelines for Management of AIP, steroids in maintenance dose of 2.5–5 mg/d for 1–3 years is recommended to prevent recurrence.[68] Azathioprine (2 mg/kg daily) or mycophenolate mofetil (750 mg twice daily) can be used as a steroid-free regimen to maintain remission.[7] Rituximab may be preferred in patients at a high risk of relapse, such as those with proximal CBD involvement, young age, higher IgG4-Responder Index score after induction therapy and high alkaline phosphatase levels (at initial presentation).[69],[70]

   Prognosis Top

Timely diagnosis of LPSP is imperative in avoiding a delay in treatment and prevention of resultant complications. Amongst complications, pancreatic atrophy in the form of exocrine pancreatic insufficiency or diabetes mellitus can be seen in up to 35% of patients. AIP can progress to chronic calcific pancreatitis with severe atrophy in up to 22% of patients.[71] Patients of AIP type 1 with concurrent Ig4-SC can progress to secondary biliary cirrhosis if left untreated.

There is a high likelihood of relapses seen in up to 60%–90% of IgG4-RP patients, mostly within three years from the start of steroid treatment, which can be managed with a repeat course of prednisone or rituximab.[12],[21],[72] Kawa et al.[21] in a study on 51 AIP patients proposed that pancreatic stone formation is associated with recurrence and the immune complex level with a cutoff value of 10 microgram/dL can be a reliable predictor of recurrence.[12],[73]

Long-term immunosuppressive maintenance therapy is not recommended in IDCP because of lower risk of relapse (<10%).[7]

High incidence of extrapancreatic cancers diagnosed within 1 year of diagnosing AIP might point towards the underlying paraneoplastic phenomenon.[74] In cases of AIP complicated with pancreatic cancer, latter can be found simultaneously, or maybe detected 3–5 years later. Previous studies have reported conflicting results regarding the association of IgG4-RP or IDCP with the increased risk of pancreatic malignancy.[75],[76]

   Future Directions Top

The precise antigen responsible for triggering the inflammation in IgG4 RD remains unknown, resulting in lacunae of promising molecular markers for diagnosis and prognostication. Also, the reason why patients with AIP do not experience pain despite intense inflammation remains obscure (compared to acute and chronic pancreatitis that are very painful). More studies are needed to better define the emerging role of rituximab in induction and relapses in terms of duration.[7] Prospective studies are required to evaluate the regression of histological and imaging features with corticosteroids so as to identify prognostic biomarkers. New techniques for improving the diagnostic yield of guided endoscopic biopsies and FNAC might be useful in routine practice.

   Conclusion Top

To conclude, the term AIP comprises two clinically and histopathologically distinct forms of steroid responsive chronic pancreatitis namely IgG4-RP and IDCP. Apart from various extrapancreatic sites, IgG4-RP commonly involves bile duct (IgG4-SC), both of which need to be differentiated from malignancy to avoid unnecessary surgical intervention. Although histopathology remains gold standard for diagnosis in routine practice, it is important to correlate with clinicoradiological and serological data, along with a close multidisciplinary collaboration as the representative features may be difficult to identify in biopsy specimens. Future studies are required for better understanding the pathogenesis of the disease which may provide newer diagnostic and prognostic markers and treatment options.

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Conflicts of interest

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Correspondence Address:
Puja Sakhuja
Director Professor and Head, Department of Pathology, GIPMER, New Delhi - 110 002
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_59_21

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