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Autoimmune pancreatitis (AIP) is classified into type 1 (IgG4-related) and type 2 (IgG4-unrelated) and the interpretation of pancreatic biopsy findings plays a crucial role in their diagnosis. Needle biopsy of type 1 AIP in the acute or subacute phase shows a diffuse lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, and the infiltration of many IgG4-positive plasma cells. In a later phase, changes become less inflammatory and more fibrotic, making interpretations more challenging. Confirmation of the lack of 'negative' findings that are unlikely to occur in type 1 AIP (e.g., neutrophilic infiltration, abscess) is important to avoid an overdiagnosis. The number of IgG4-positive plasma cells increases to >10 cells/high-power field (hpf), and the IgG4/IgG-positive plasma cell ratio exceeds 40 %. However, these are minimal criteria and typical cases show >30 positive cells/hpf and a ratio >70 % even in biopsy specimens. Therefore, cases with a borderline increase in this number or ratio need to be diagnosed with caution. In cases of ductal adenocarcinoma, the upstream pancreas rarely shows type 1 AIP-like changes; however, the ratio of IgG4/IgG-positive plasma cells is typically <40 %. Although the identification of a granulocytic epithelial lesion (GEL) is crucial for type 2 AIP, this finding needs to be interpreted in conjunction with a background dense lymphoplasmacytic infiltrate. An isolated neutrophilic duct injury can occur in peritumoral or obstructive pancreatitis. Drug-induced pancreatitis in patients with inflammatory bowel disease often mimics type 2 AIP clinically and pathologically. IL-8 and PD-L1 are potential ancillary immunohistochemical markers for type 2 AIP, requiring validation studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Autoimmune pancreatitis (AIP) has attracted much attention in the last two decades, and due to the diagnostic value of immunoglobulin G4 (IgG4), the number of cases diagnosed in clinical practice has markedly increased. However, in contrast to prototypic IgG4-related type 1 AIP, a minor subtype of AIP, referred to as type 2 AIP, is less widely known and has thus not yet been characterized in detail. Type 2 AIP is unrelated to IgG4 and is a completely distinct entity from type 1 AIP. One confusing factor is that the two types of AIP share patterns of clinical presentation (e.g., acute pancreatitis and painless jaundice) and imaging abnormalities (e.g., diffuse or segmental enlargement). Since there are currently no established serum markers, the diagnosis of type 2 AIP is highly challenging and requires the tissue confirmation of neutrophilic injury to the pancreatic ducts, a finding designated as a granulocytic epithelial lesion. Approximately one-third of cases are associated with inflammatory bowel disease, particularly ulcerative colitis; however, the pathological relationship between these two conditions has not yet been clarified. Unanswered questions relate to its pathophysiology, the potential development of a similar granulocytic injury in other organs, and the characteristics of pediatric cases. This review summarizes consensus and controversies surrounding type 2 AIP, with the aim of increasing awareness and highlighting the unmet needs of this underrecognized condition.

Advances in the past two decades have resulted in the recognition of several tumefactive pancreatic lesions that, on histologic evaluation, show a varying combination of inflammation and fibrosis. Autoimmune pancreatitis, the prototypic tumefactive pancreatic fibroinflammatory lesion, is composed of two distinct diseases, type 1 autoimmune pancreatitis and the less common type 2 autoimmune pancreatitis. Although designated as autoimmune pancreatitis, the two diseases show little morphologic or pathogenic overlap. In type 1 disease, subsets of T lymphocytes (type 2 helper T cells, regulatory T cells, and T follicular helper 2 cells) are hypothesized to drive the inflammatory reaction. The B-cell response is characterized by an oligoclonal expansion of plasmablasts, with dominant clones that vary among patients and distinct clones that emerge at the time of relapse. Although the precise role of IgG4 in this condition remains uncertain, recent studies suggest that other IgG subclasses (eg, IgG1) may mediate the immune reactions, whereas IgG4 represents a response to dampen excessive inflammation. A recent study of type 2 autoimmune pancreatitis highlights the role of CXCL8 (alias IL-8), with duct epithelium and infiltrating T lymphocytes expressing this chemokine; the latter may contribute to the distinct form of neutrophilic inflammation in this disease. The review also highlights other forms of mass-forming chronic pancreatitis: follicular pancreatitis, groove pancreatitis, and those associated with rheumatologic diseases., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

IgG4-related disease (IgG4-RD) is a chronic relapsing multi-organ fibro-inflammatory syndrome of presumed autoimmune etiology. It is characterized by increased serum levels of IgG4 and tissue infiltration by IgG4 + cells. Increased titers of autoantibodies against a spectrum of self-antigens and response to steroids have led to its characterization as an autoimmune disease. However, the pathognomonic antigens probably differ among manifestations, and different antigens or autoantibodies produce similar immune reactions in different organs. Little is known about the pathogenic effects, if any, of serum IgG4 or IgG4 + plasma cells in tissues. Despite several animal models of the disease, none truly recapitulates human IgG4-RD. Histologic analyses of tissues from patients with IgG4-RD reveal a dense lymphoplasmacytic infiltrate rich in IgG4 + plasma cells, storiform fibrosis, and obliterative phlebitis, although these features vary among organs. Typical presentation and imaging findings include mass-forming synchronous or metachronous lesions in almost any organ, but most commonly in the pancreas, bile duct, retroperitoneum, kidneys, lungs, salivary and lacrimal glands, orbit, and lymph nodes. In all organs, inflammation can be reduced by corticosteroids and drugs that deplete B cells, such as rituximab. Patients with IgG4-RD have relapses that respond to primary therapy. Intense fibrosis accompanies the inflammatory response, leading to permanent organ damage and insufficiency. Death from IgG4-RD is rare. IgG4-RD is a multi-organ disease with predominant pancreatico-biliary involvement. Despite its relapsing-remitting course, patients have an excellent prognosis., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Aims: The diagnosis of IgG4-related disease (IgG4-RD) requires a multidisciplinary approach, in which histology plays an important role. Although a diagnosis was previously established by the use of surgically resected specimens, there is increasing clinical demand to diagnose this systemic condition by the use of biopsies. The aim of the present study was to elucidate how useful transbronchial lung biopsies (TBLBs) are for this diagnostic purpose., Methods and Results: The study cohort consisted of 20 consecutive patients diagnosed with IgG4-RD in other organs who underwent TBLB for potential pulmonary involvement. One case showing multiple granulomas suggestive of other conditions was excluded. Seven of the remaining 19 cases (37%) showed apparently normal lung tissue, indicating a sampling error, and 12 (63%) had microscopic abnormalities. Nine cases (47%) with a dense lymphoplasmacytic infiltrate met the number and ratio criteria for IgG4-positive plasma cell infiltration (>20 cells/high-power field, and an IgG4/IgG-positive plasma cell ratio of >40%). Obliterative phlebitis and storiform fibrosis were observed in one case each. In 43 control cases of various inflammatory conditions, tissue IgG4 elevations appeared to be uncommon, with only two cases (5%) each meeting the number or ratio criterion, and one case (2%) fulfilling both. All control cases with tissue IgG4 elevations were of eosinophilic pneumonia., Conclusions: Transbronchial lung biopsies provided histological findings that were supportive for the diagnosis of IgG4-RD in 47% of cases, with 98% diagnostic specificity. Therefore, they have potential as a useful and acceptable diagnostic approach for IgG4-related lung disease., (© 2018 John Wiley & Sons Ltd.)

A referring hospital diagnosed a 57-year-old man with a pancreatic head mass. The initial endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) was inconclusive because of the small sample size. Endoscopic ultrasonography elastography (EUS-EG) and contrast-enhanced harmonic endoscopic ultrasonography (CE-EUS), conducted at our institute, raised the possibility of mass-forming pancreatitis or autoimmune pancreatitis (AIP). A repeat EUS-FNA revealed inflammatory changes, including a neutrophilic duct injury suggestive of type 2 AIP. The pancreatic lesion responded well to the steroid therapy. The present case suggests that EUS-EG and CE-EUS may be useful for diagnostic exclusion of pancreatic cancers, and the combined use of EUS-EG and CE-EUS, with EUS-FNA, may help characterize inflammatory pancreatic lesions.

Type 2 autoimmune pancreatitis (type 2 AIP) develops in isolation or sometimes in association with ulcerative colitis. Its diagnosis requires the histologic confirmation of granulocytic epithelial lesions (GELs) with no diagnostic biomarker currently available. This study aimed to elucidate the tissue expression of cytokines and their diagnostic value in this condition. In quantitative polymerase chain reaction for multiple cytokines using tissue-derived mRNA, the expression level of interleukin (IL)-8 was markedly higher in type 2 AIP than in type 1 AIP (P<0.001). In immunostaining, IL-8 expression was detected in the ductal/ductular epithelium (11/13; 85%) and infiltrating neutrophils or lymphocytes (12/12; 100%) in type 2 AIP, but was almost entirely negative in type 1 AIP (n=13; both, P<0.001). Although obstructive pancreatitis adjacent to pancreatic cancers (peritumoral pancreatitis) exhibited IL-8 expression in the epithelium (3/12; 25%) and inflammatory cells (10/12; 83%), expression levels were significantly lower than those in type 2 AIP (P<0.001 and 0.020, respectively). The presence of either GELs or IL-8-positive epithelium discriminated type 2 AIP from type 1 AIP or obstructive pancreatitis with 92% sensitivity and 92% to 100% specificity. Furthermore, CD3/IL-8-coexpressing lymphocytes were almost restricted to type 2 AIP. Interestingly, a similar pattern of IL-8 expression was also observed in colonic biopsies of ulcerative colitis. In conclusion, the overexpression of IL-8 may underlie the development of GELs in type 2 AIP, and IL-8 immunostaining or IL-8/CD3 double staining may become an ancillary method for its diagnosis. The similar expression pattern of IL-8 in ulcerative colitis also suggests a pathogenetic link between the 2 conditions.

Background: More than 2 years have passed since the proposal of the diagnostic criteria for IgG4-related kidney disease (IgG4-RKD). The aim of this study was to estimate the number of histological diagnosis for IgG4-RKD throughout Japan and to clarify the regional distribution of the development of this disease., Methods: A questionnaire was supplied to 140 research facilities registered in the Japan Renal Biopsy Registry (J-RBR). The items of the questionnaire were the total number of renal biopsies performed and the number of cases diagnosed as IgG4-RKD in 2012 and 2013 at each facility. Age, sex, and diagnosis category were also included for the IgG4-RKD cases. The geographic distribution of the disease development was evaluated using clinical case reports presented at the Eastern/Western regional meeting of the Japanese Society of Nephrology during the 15 years following 2001., Results: Forty-seven facilities completed the questionnaire, resulting in a collection rate of 34 %. The total numbers of renal biopsies in 2012 and 2013 were 3387 and 3591, respectively. Forty-seven of these cases (24 in 2012 and 23 in 2013) were diagnosed as IgG4-RKD. The frequency of development of IgG4-RKD per one million over 40-year-old individuals during these 15 years varied between 0.9 and 3.1, depending on Japanese geographic region of Japan., Conclusion: The results of the present survey indicate that the number of diagnosis for IgG4-RKD is approximately 130 cases per year throughout Japan, and no regional differences in disease frequency appear to exist., Competing Interests: The authors have declared that no conflict of interest exists.

Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis that is characterized clinically by frequent presentation with obstructive jaundice, histologically by a dense lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to corticosteroid therapy. Two distinct diseases, type 1 and type 2 AIP, share these features. However, these 2 diseases have unique pancreatic histopathologic patterns and differ significantly in their demographic profiles, clinical presentation, and natural history. Recognizing the popular and long-standing association of the term "AIP" with what is now called "type 1 AIP," we suggest using "AIP" solely for type 1 AIP and to acknowledge its own distinct disease status by using "idiopathic duct-centric chronic pancreatitis" (IDCP) for type 2 AIP. AIP is the pancreatic manifestation of immunoglobulin G4-related disease (IgG4-RD). The etiopathogenesis of AIP and IgG4-RD is largely unknown. However, the remarkable effectiveness of B-cell depletion therapy with rituximab in patients with AIP and IgG4-RD highlights the crucial role of B cells in its pathogenesis. IDCP is less commonly recognized, and little is known about its pathogenesis. IDCP has no biomarker but is associated with inflammatory bowel disease in ~25% of patients. Recently, the international consensus diagnostic criteria for AIP identified combinations of features that are diagnostic of both diseases. Both AIP and IDCP are corticosteroid responsive; however, relapses are common in AIP and rare in IDCP. Therefore, maintenance therapy with either an immunomodulator (eg, azathioprine, 6-mercaptopurine, or mycophenolate mofetil) or rituximab is often necessary for patients with AIP. Long-term survival is excellent for both patients with AIP and patients with IDCP., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Immunoglobulin G4-related disease (IgG4-RD) is a recently discovered systemic condition, in which various organ manifestations are linked by a similar histological appearance. Our knowledge of this condition is still fragmented, as most studies have examined only a few dozen patients or focused on a particular organ manifestation. This study was conducted to learn the demography and patient characteristics of IgG4-RD using a large cohort. A total of 235 consecutive patients with IgG4-RD, diagnosed in 8 general hospitals in the same medical district, were identified by searching the institutions' radiology database. Inclusion criteria were histology-proven IgG4-RD according to the Pathology Consensus Statement and/or definitive type 1 autoimmune pancreatitis meeting the International Consensus Diagnostic Criteria. Clinical notes and images of selected patients were retrospectively reviewed. All patients were adults (M/F = 4/1). The median age was 67 years (range 35-86). Nine tenths were diagnosed in their 50s to 70s. Among 486 manifestations identified in total, the most common was pancreatitis diagnosed in 142 patients (60%), followed by sialadenitis (34%), tubulointerstitial nephritis (23%), dacryoadenitis (23%), and periaortitis (20%). The majority of patients (95%) had at least 1 of the 5 most common manifestations. Male and female patients differed in their organ manifestations (periaortitis more common in males and sialodacryoadenitis more common in females). Serum IgG4 (normal ≤135 mg/dL) was elevated to >135 mg/dL in 208 patients (88%) and >270 mg/dL in 167 (71%). The IgG4 value was significantly higher in patients with multiorgan involvement than in those with a single manifestation (median 629 mg/dL vs 299 mg/dL, P < 0.01). Of 218 patients, for whom both IgG4 and IgG values were available, the IgG4/IgG ratio was raised to >10% in 194 (89%). Corticosteroids were effective, but the relapse rate was estimated to be 24% in the study period (median 37 months). During the follow-up, 15 malignant diseases were diagnosed in 13 patients (6%). This figure is similar to the incidence (12.9 cancers) expected from the Japanese nationwide study for cancer epidemiology (standardized incidence ratio 1.16). In conclusion, this reliable dataset could improve the characterization of IgG4-RD, particularly its unique demography and the frequency of each organ manifestation.

An 84-year-old man was diagnosed with IgG4-related autoimmune pancreatitis and sclerosing cholangitis with jaundice. Endoscopic nasobiliary drainage was performed, but hemorrhagic shock due to multiple duodenal ulcers occurred about a week later. After several endoscopic hemostasis, he was given corticosteroids. Histopathology of duodenal ulcer biopsies showed IgG4-positive plasma cell infiltration. Reports about duodenal ulcers with IgG4-related disease are very rare and we consider this case valuable.

IgG4-related autoimmune pancreatitis is frequently accompanied by relevant lesions in the genitourinary tract and retroperitoneal organs, which cause various clinical problems, ranging from non-specific back pain or bladder outlet obstruction to renal failure. The diagnosis of IgG4-related retroperitoneal fibrosis requires a multidisciplinary approach, including serological tests, histological examination, imaging analysis, and susceptibility to steroid therapy. Radiological examinations are helpful to diagnose this condition, but surgical resection is occasionally unavoidable to exclude malignancy, particularly for patients with isolated retroperitoneal involvement. Steroid therapy is the treatment of choice for this condition, the same as for other manifestations of IgG4-related disease. For patients with severe ureteral obstruction, additional ureteral stenting needs to be considered prior to steroid therapy to preserve the renal function. Some papers have suggested that IgG4-related disease can affect male reproductive organs including the prostate and testis. IgG4-related prostatitis usually causes lower urinary tract symptoms, such as dysuria and pollakisuria. Patients sometimes state that corticosteroids given for IgG4-related disease at other sites relieve their lower urinary tract symptoms, which leads us to suspect prostatic involvement in this condition. Because of the limited number of publications available, further studies are warranted to better characterize IgG4-related disease in male reproductive organs.

IgG4-related disease is a recently established systemic condition. Tubulointerstitial nephritis is the most common renal manifestation. Glomerular lesions, particularly membranous glomerulonephritis, can develop simultaneously. Some patients present with serological renal dysfunction associated with elevated IgG or IgE levels and hypocomplementemia, while others are incidentally found to have abnormalities in kidneys on imaging. A majority of patients with IgG4-related kidney disease have similar lesions at other anatomical sites, which help us to suspect this condition. Serum IgG4 elevation (>135 mg/dL) is the most, although not entirely, specific marker for the diagnosis. Imaging findings varies from small nodules to bilateral diffuse abnormalities. In addition to the renal parenchyma, the renal pelvis and perirenal adipose tissue can be affected. Histological features include dense lymphoplasmacytic infiltration, storiform or "bird's eye" fibrosis (highlighted by PAM stain), and IgG4-positive plasma cell infiltration (>10 cells/high-power field and IgG4/IgG-positive cell ratio >40%). Immune complex deposition is detectable in the tubular basement membrane by immunofluorescence and/or electron microscopy. Patients usually respond well to corticosteroids, but highly active diseases may require other immunosuppressive therapies. Further investigations will be required to fully understand pathophysiology underlying this emerging condition.

Objective: Autoimmune pancreatitis (AIP) is a treatable form of chronic pancreatitis that has been increasingly recognised over the last decade. We set out to better understand the current burden of AIP at several academic institutions diagnosed using the International Consensus Diagnostic Criteria, and to describe long-term outcomes, including organs involved, treatments, relapse frequency and long-term sequelae., Design: 23 institutions from 10 different countries participated in this multinational analysis. A total of 1064 patients meeting the International Consensus Diagnostic Criteria for type 1 (n=978) or type 2 (n=86) AIP were included. Data regarding treatments, relapses and sequelae were obtained., Results: The majority of patients with type 1 (99%) and type 2 (92%) AIP who were treated with steroids went into clinical remission. Most patients with jaundice required biliary stent placement (71% of type 1 and 77% of type 2 AIP). Relapses were more common in patients with type 1 (31%) versus type 2 AIP (9%, p<0.001), especially those with IgG4-related sclerosing cholangitis (56% vs 26%, p<0.001). Relapses typically occurred in the pancreas or biliary tree. Retreatment with steroids remained effective at inducing remission with or without alternative treatment, such as azathioprine. Pancreatic duct stones and cancer were uncommon sequelae in type 1 AIP and did not occur in type 2 AIP during the study period., Conclusions: AIP is a global disease which uniformly displays a high response to steroid treatment and tendency to relapse in the pancreas and biliary tree. Potential long-term sequelae include pancreatic duct stones and malignancy, however they were uncommon during the study period and require additional follow-up. Additional studies investigating prevention and treatment of disease relapses are needed.

Liver transplantation (LT) is an effective treatment for patients with end-stage autoimmune liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis. Indications for LT for these diseases do not differ substantially from those used for other acute or chronic liver diseases. Despite the good outcomes reported, the recurrence of autoimmune liver disease is relatively common in the allograft. In addition, it has become apparent that autoimmunity and autoimmune liver disease can arise de novo after transplantation for nonautoimmune liver disorders. An awareness of the existence of recurrent autoimmune liver diseases and de novo autoimmune hepatitis after LT has important clinical implications because their management differs from the standard antirejection treatment and is similar to the management of classic autoimmune liver diseases in the native liver., (Copyright © 2013 American Association for the Study of Liver Diseases.)

Retroperitoneal fibrosis is one of the prototypic manifestations of immunoglobulin G4 (IgG4)-related disease (IgG4-RD), but there is growing evidence that the aorta is also involved. These 2 conditions are closely linked, and based on the epicenter of the disease, the clinical manifestations can be classified as retroperitoneal fibrosis, inflammatory abdominal aortic aneurysm (including a combination of the 2), and thoracic aortitis. IgG4-RD is responsible for only a subset (∼50%) of cases of retroperitoneal fibrosis and inflammatory aortic aneurysms. Histological features include an extensive lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, fibrosis arranged in a storiform pattern, moderate tissue eosinophilia, and partially or completely obliterated veins. Among the 3 layers comprising the aorta, the adventitia is most susceptible to IgG4-related inflammation. The inflammatory process can also disrupt the lamellar elastic fibers in the media, which is seemingly a critical event leading to aneurysmal transformation. Steroid therapy is effective for both retroperitoneal and aortic lesions, as it is for the other manifestations of IgG4-RD. The risk of rupture appears to be low in patients with IgG4-related aortic aneurysms, but immunosuppressive therapy may trigger this critical complication by reducing the wall thickness., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Since immunoglobulin G4 (IgG4)-related sclerosing cholangitis was first described in 2004, this condition has been recognized as a distinct entity characterized by unique pathologic features. Affected bile ducts show diffuse wall thickening, which represents transmural sclerosing inflammation composed of a dense lymphoplasmacytic infiltrate and fibrosis arranged at least focally in a storiform pattern. A diffuse IgG4-positive plasma cell infiltrate is demonstrable by immunohistochemistry. More than 90% of patients with IgG4-related sclerosing cholangitis have type 1 autoimmune pancreatitis, the remaining presenting as isolated cholangitis. The diagnosis requires a multidisciplinary approach, in which pathologic examination has a critical role. Tissue diagnosis on biopsy specimens (ie, bile duct biopsy, liver needle biopsies) is important, particularly for patients with isolated cholangitis, given the fact that radiological findings of IgG4-cholangitis are not reliable enough for establishing the diagnosis. Furthermore, serum IgG4 levels can be, albeit mildly, elevated in other biliary disorders. Histologic mimics of IgG4-related sclerosing cholangitis include primary sclerosing cholangitis, follicular cholangitis, and sclerosing cholangitis with granulocytic epithelial lesion, the latter 2 being recently described entities., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The association between autoimmune pancreatitis and sclerosing cholangitis has attracted considerable attention. In contrast to type 1 (IgG4-related) autoimmune pancreatitis, bile duct involvement is uncommon in type 2 autoimmune pancreatitis, a more benign condition characterized histologically by granulocytic epithelial lesions (GELs). Following our recent report on a child with GEL-positive sclerosing cholangitis and excellent response to steroids, we retrospectively reviewed the liver histology of a large number of patients with sclerosing cholangitis to investigate the possible role of type 2 autoimmune pancreatitis in this pathology. Liver biopsies of 103 children with autoimmune sclerosing cholangitis and 142 adults with primary sclerosing cholangitis were reviewed for the presence of neutrophilic bile duct injury. Histologic findings were correlated with clinical features, response to treatment, and outcome. Neutrophilic bile duct lesions similar to GEL were identified in 5 cases (4 children and 1 adult; 4% of autoimmune sclerosing cholangitis and 0.7% of primary sclerosing cholangitis). GEL was more commonly seen in wedge biopsy specimens. One patient had concomitant pancreatitis. Cholangiograms showed diffuse stricturing of bile ducts in all cases. The number of liver tissue IgG4 plasma cells did not increase, and serum IgG4 levels were normal in 3 patients tested. All patients went into remission with prednisolone and/or ursodeoxycholic acid, and their liver function tests remained completely normal without relapses over a follow-up period of 6 to 16 years. Although rare, the diagnosis of sclerosing cholangitis with GEL is important in view of its excellent and apparently sustained response to immunosuppressive treatment.

IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; and-often but not always-elevated serum IgG4 concentrations. An international symposium on IgG4-related disease was held in Boston, MA, on 4-7 October 2011. The organizing committee comprising 35 IgG4-related disease experts from Japan, Korea, Hong Kong, the United Kingdom, Germany, Italy, Holland, Canada, and the United States, including the clinicians, pathologists, radiologists, and basic scientists. This group represents broad subspecialty expertise in pathology, rheumatology, gastroenterology, allergy, immunology, nephrology, pulmonary medicine, oncology, ophthalmology, and surgery. The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4⁺ plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum.

Before the concept of autoimmune pancreatitis (AIP) was established, this form of pancreatitis had been recognized as lymphoplasmacytic sclerosing pancreatitis or non-alcoholic duct destructive chronic pancreatitis based on unique histological features. With the discovery in 2001 that serum IgG4 concentrations are specifically elevated in AIP patients, this emerging entity has been more widely accepted. Classical cases of AIP are now called type 1 as another distinct subtype (type 2 AIP) has been identified. Type 1 AIP, which accounts for 2% of chronic pancreatitis cases, predominantly affects adult males. Patients usually present with obstructive jaundice due to enlargement of the pancreatic head or thickening of the lower bile duct wall. Pancreatic cancer is the leading differential diagnosis for which serological, imaging, and histological examinations need to be considered. Serologically, an elevated level of IgG4 is the most sensitive and specific finding. Imaging features include irregular narrowing of the pancreatic duct, diffuse or focal enlargement of the pancreas, a peri-pancreatic capsule-like rim, and enhancement at the late phase of contrast-enhanced images. Biopsy or surgical specimens show diffuse lymphoplasmacytic infiltration containing many IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis. A dramatic response to steroid therapy is another characteristic, and serological or radiological effects are normally identified within the first 2 or 3 weeks. Type 1 AIP is estimated as a pancreatic manifestation of systemic IgG4-related disease based on the fact that synchronous or metachronous lesions can develop in multiple organs (e.g. bile duct, salivary/lacrimal glands, retroperitoneum, artery, lung, and kidney) and those lesions are histologically identical irrespective of the organ of origin. Several potential autoantigens have been identified so far. A Th2-dominant immune reaction and the activation of regulatory T-cells are assumed to be involved in the underlying immune reaction. IgG4 antibodies have two unique biological functions, Fab-arm exchange and a rheumatoid factor-like activity, both of which may play immune-defensive roles. However, the exact role of IgG4 in this disease still remains to be clarified. It seems important to recognize this unique entity given that the disease is treatable with steroids.

Objectives: To develop and validate histologic diagnostic criteria for autoimmune pancreatitis (AIP) and its types., Methods: Thirteen pathologists participated in this 2-phase study to develop diagnostic criteria for AIP types 1 and 2 (phase 1) and validate them (phase 2). A virtual library of 40 resected pancreata with AIP and other forms of chronic pancreatitis (CP) was constructed. Readers reviewed the slides online and filled out a questionnaire for histopathologic findings and diagnosis., Results: Diagnostic criteria for AIP and its types were proposed according to the results from the top 5 reviewers in phase 1. The interobserver agreement was significantly improved in phase 2 by applying the proposed diagnostic criteria. Features distinguishing AIP from alcoholic and obstructive forms of CP were periductal lymphoplasmacytic infiltrate, inflamed cellular stroma with storiform fibrosis, obliterative phlebitis, and granulocytic epithelial lesions. Although there was overlap, 2 types of AIP were recognized. Type 1 had dense lymphoplasmacytic infiltrate with storiform fibrosis and obliterative phlebitis, whereas type 2 was distinguished from type 1 by the presence of granulocytic epithelial lesions., Conclusions: Autoimmune pancreatitis can be distinguished from other forms of CP with substantial interobserver agreement. The 2 types of AIP can be distinguished by the proposed consensus histopathologic diagnostic criteria.

Purpose of Review: To review studies that have examined underlying genetic and immunological aspects of IgG4-related disease., Recent Findings: Genetic studies have suggested that several human leukocyte antigen (HLA) and non-HLA haplotypes/genotypes are associated with susceptibility to IgG4-related disease or to disease relapse after steroid therapy. Among several autoantibodies identified so far, autoantibodies against lactoferrin and carbonic anhydrase II are most frequently detected in serum of IgG4-disease patients. However, it has not been well clarified whether or not those autoantibodies belong to an IgG4 subclass. Studies that have demonstrated molecular mimicry between Helicobacter pylori and constituents of pancreatic epithelial cells suggest that gastric H. pylori infection triggers autoimmune pancreatitis in genetically predisposed individuals through antibody cross-reactivity. Recently, T-helper 2 immune reaction has been suggested to be predominant in IgG4-related disease. Interestingly, regulatory immune reactions are activated in IgG4-related disease, and regulatory cytokines interleukin-10 and transforming growth factor-b have been suggested, respectively, to play important roles in IgG4 class switch and fibroplasia., Summary: Autoimmunity has been considered the most probable pathogenesis of IgG4-related disease, but has not been completely proved so far. A breakthrough study to detect a specific autoantigen, autoantibody, or pathogen is necessary.

IgG4-related disease has been identified in various organs, but whether or not there are organ-specific characteristics related to the etiologic factors is still unknown. Here, we carried out a cross-sectional study of 114 patients with IgG4-related disease. On the basis of the location of the lesions, the patients were classified into 5 groups: head and neck (n=23), thoracic (n=16), hepatic and pancreatobiliary (n=27), retroperitoneal (n=13), and systemic (n=35). All groups had similar clinicopathologic features in various aspects. However, there were some organ-specific features: for example, the proportion of the female patients was significantly higher in the head and neck group, serum IgG4 concentrations were significantly higher in the head/neck and systemic groups, and all kidney lesions were associated with extrarenal disease. Unique pathologic features were dense fibrosis in dacryoadenitis, numerous lymph follicles in sialadenitis and dacryoadenitis, and obliterative arteritis in lung lesions. In addition, an epithelioid granuloma and rheumatoid nodule were noted within IgG4-related lesions in 2 patients, 1 each with a history of tuberculosis and rheumatoid arthritis, respectively. Malignant tumors (2 lung cancers and 1 malignant lymphoma) were identified after the diagnosis of IgG4-related disease in 3 patients, all in the systemic group. In conclusion, this study showed organ-specific features of IgG4-related disease. Further study is necessary to conclude whether these features reflect different manifestations of a single disease entity or suggest different underlying etiologic factors.

Background and Aim: Autoimmune pancreatitis is commonly associated with immunoglobulin (Ig) G4-related sclerosing cholangitis (IgG4-SC). The discrimination between IgG4-SC and pancreatobiliary malignancies or primary sclerosing cholangitis (PSC) is now an important issue. The present study was carried out to examine the usefulness of endoscopic biopsies from Vater's ampulla and the bile duct to diagnose IgG4-SC., Methods: The present study included 29 IgG4-SC patients (26 with both pancreatitis and cholangitis, and 3 with cholangitis only), 6 PSC patients, and 27 pancreatobiliary carcinoma patients. All patients underwent endoscopic biopsies from Vater's ampulla and the common bile duct. Biopsied specimens were histologically examined using immunostaining for IgG4., Results: For the ampullary and bile duct biopsies, the IgG4-SC samples had a significantly greater number of IgG4-positive plasma cells than the PSC or pancreatobiliary carcinoma specimens. In addition, bile duct biopsies from five patients (17%) with IgG4-SC showed diffuse inflammatory cell infiltration with irregular fibrosis corresponding to the histological features of lymphoplasmacytic sclerosing pancreatocholangitis. Based on the threshold of 10 IgG4-positive plasma cells per high power field, the diagnostic rates of the ampullar and bile duct biopsies were both 52% (15/29 cases). Twenty-one patients (72%) had more than 10 IgG4-positive plasma cells in at least one biopsy. The bile duct biopsy was significantly valuable for IgG4-SC patients with swelling of the pancreatic head., Conclusion: The present study suggested that ampullar and bile duct biopsies are useful for diagnosing IgG4-SC., (© 2010 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Background and Aim: Recently, we reported that immunoglobulin subtype 4 (IgG4) is involved in autoimmune hepatobiliary diseases, such as autoimmune hepatitis, sclerosing cholangitis, and pancreatitis. However, the association of IgG4 with autoimmune hepatic disease after living donor liver transplantation (LDLT) has not been investigated., Methods: Of the 72 LDLT recipients, four patients (5.6%) were suspected of having autoimmune-related hepatic disease after LDLT. The diagnosis was made based on a histological diagnosis following an examination of a biopsy liver specimen in three cases, while in one case a pemphigoid appeared in the flank with liver fibrosis of unknown cause. Human leukocyte antigen (HLA) mismatches were 3, 2, 2, and 2, respectively. The serum level of IgG4 in the patients was measured, and IgG4 immunohistochemical staining in the liver biopsy specimens was also performed., Results: In all cases, steroid pulse therapy or recycle treatment and subsequent increased steroid dose as well as additional azathioprine or mycophenolate mofetil were effective. While a few positive-stained cells for IgG4 were observed in the liver of one case, negative staining for IgG4 was observed in the other cases. All serum subclasses of IgG4 were within normal limits., Conclusion: In our series of LDLT, IgG4-related immune disorder is unlikely to be involved in post-transplant, autoimmune-related liver disease.

Autoimmune pancreatitis (AIP) is characterized by high serum immunoglobin (Ig) G4 concentrations, lymphoplasmacytic inflammation, and a favorable response to corticosteroid treatment. Since liver dysfunction is frequently seen in AIP patients, we investigated hepatic histopathology and its clinical significance in patients with AIP. We examined the clinical features, histology, and immunoglobin G (IgG)4-bearing plasma cell infiltration of liver biopsies from 17 patients with AIP and 63 patients with either autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or chronic viral hepatitis and histological changes in the 7 of 17 livers before and after glucocorticoid therapy. The liver histology of AIP was classified into 5 patterns: evident portal inflammation with or without interface hepatitis (6 cases), large bile-duct obstructive features (8 cases), portal sclerosis (8 cases), lobular hepatitis (5 cases), and canalicular cholestasis (4 cases); some of the histological features coexisted in the same liver. The number of IgG4-bearing plasma cells was significantly higher in AIP patients than controls (P < 0.01), and was significantly correlated with serum IgG4 concentration (P = 0.0014, r = 0.709). Glucocorticoid therapy reduced IgG4-bearing plasma cell infiltration in the liver (P = 0.031) and ameliorated other histological findings. In conclusion, virtually all AIP liver biopsies showed evidence of various pathological changes and infiltration of IgG4-bearing plasma cells. These features were ameliorated by steroid therapy, suggesting that the liver is concurrently affected in AIP, and that liver biopsies can provide significant information in the clinical evaluation and diagnosis of AIP.

Unlabelled: Immunoglobin G (IgG) 4-related sclerosing pancreatitis and cholangitis (autoimmune pancreato-cholangitis [AIPC]) are recently recognized disease entities characterized by high serum IgG4 concentrations and sclerosing inflammation with numerous IgG4-positive plasma cells, although the underlining immune mechanism remains only speculative. In this study, the immunopathogenesis of AIPC was examined with respect to the production of cytokines in situ and the possible involvement of regulatory T cells (Tregs) using fresh (5 cases) and formalin-fixed (28 cases) specimens of AIPC and related extra-pancreatobiliary lesions. Quantitative real-time polymerase chain reaction revealed that AIPC and extra-pancreatobiliary lesions had significantly higher ratios of interleukin (IL)-4/interferon-gamma (IFN-gamma) (45.8-fold), IL-5/IFN-gamma (18.7-fold), IL-13/interferon (IFN)-gamma (20.7-fold), IL-10/CD4 (45.3-fold), and tumor growth factor (TGF)-beta/CD4 (39.4-fold) than did primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Lymphocytes with signals for IL-4 and IL-10 were frequently found in AIPC by in situ hybridization. The expression of Foxp3 messenger RNA, a transcription factor specific for naturally arising CD4(+)CD25(+) Tregs, was significantly increased in AIPC and extra-pancreatobiliary lesions in comparison to PSC and PBC (36.4-fold). Immunohistochemically, CD4(+)CD25(+)Foxp3(+) cells were frequently found in AIPC, while few were found in PSC and other disease controls. Taken together, AIPC could be characterized by the over-production of T helper (Th) 2 and regulatory cytokines. Tregs might be involved in the in situ production of IL-10 and TGF-beta, which could be followed by IgG4 class switching and fibroplasia., Conclusion: AIPC is a unique inflammatory disorder characterized by an immune reaction predominantly mediated by Th2 cells and Tregs.

Autoimmune pancreatitis (AIP) is radiologically characterized as diffuse swelling of the pancreatic parenchyma and irregular narrowing of the pancreatic ducts. We present a case of AIP with multiple small nodular lesions in the pancreas. This case suggests that AIP with only small nodular or localized lesions is more difficult to differentiate from pancreatic cancer than typical cases of AIP.

The article offers information on a research conducted on development of secondary anaplastic astrocytoma in young adult with autoimmune lymphoproliferative syndrome (ALPS). It mentions that ALPS is a rare apoptotic disorder and determinants of morbidity and mortality in ALPS are the severity of the autoimmune disease. It investigates a case of a young patient with ALPS type 1A manifesting a germ line FAS mutation.