Recent Concepts of Autoimmune Pancreatitis and IgG4-Related Disease

Recent studies suggested the existence of two subtypes of autoimmune pancreatitis (AIP): type 1 related with IgG4 (lymphoplasmacytic sclerosing pancreatitis; LPSP) and type 2 related with a granulocytic epithelial lesion (idiopathic duct-centric chronic pancreatitis; IDCP). Apart from type 2 AIP, the pathological features of type 1 AIP with increased serum IgG4/IgE levels, abundant infiltration of IgG4+ plasmacytes and lymphocytes, fibrosis, and steroid responsiveness are suggestive of abnormal immunity such as allergy or autoimmunity. Moreover, the patients with type 1 AIP often have extrapancreatic lesions such as sclerosing cholangitis, sclerosing sialadenitis, or retroperitoneal fibrosis showing similar pathological features. Based on these findings, many synonyms have been proposed for these conditions, such as “multifocal idiopathic fibrosclerosis”, “IgG4-related autoimmune disease”, “IgG4-related sclerosing disease”, “IgG4-related plasmacytic disease”, and “IgG4-related multiorgan lymphoproliferative syndrome”, all of which may refer to the same conditions. Therefore, the Japanese Research Committee for “Systemic IgG4-related Sclerosing Disease” proposed a disease concept and clinical diagnostic criteria based on the concept of multifocal fibrosclerosis in 2009, in which the term “IgG4-related disease” was appointed as a minimal consensus on these conditions. Although the significance of IgG4 in the development of “IgG4-related disease” remains unclear, we have proposed a hypothesis for the development of type 1 AIP, one of the IgG4-related disease. The concept and diagnostic criteria of “IgG4-related disease” will be changed in accordance with future studies.     

Organ Correlation in IgG4-Related Diseases

IgG4-related disease (IgG4-RD) is a potentially multiorgan disorder. In this study, clinical and serological features from 132 IgG4-RD patients were compared about organ correlations. Underlying pathologies comprised autoimmune pancreatitis (AIP) in 85 cases, IgG4-related sclerosing cholangitis (IgG4-SC) in 12, IgG4-related sialadenitis (IgG4-SIA) in 56, IgG4-related dacryoadenitis (IgG4-DAC) in 38, IgG4-related lymphadenopathy (IgG4-LYM) in 20, IgG4-related retroperitoneal fibrosis (IgG4-RF) in 19, IgG4-related kidney disease (IgG4-KD) in 6, IgG4-related pseudotumor (IgG4-PT) in 3. Sixty-five patients (49%) had multiple IgG4-RD (two affected organs in 36 patients, three in 19, four in 8, five in 1, and six in 1). Serum IgG4 levels were significantly higher with multiple lesions than with a single lesion (P<0.001). The proportion of association with other IgG4-RD was 42% in AIP, the lowest of all IgG4-RDs. Serum IgG4 level was lower in AIP than in other IgG4-RDs. Frequently associated IgG4-RDs were SIA (25%) and DAC (12%) for AIP; AIP (75%) for IgG4-SC; DAC (57%), AIP (38%) and LYM (27%) for IgG4-SIA; AIP (26%) and LYM (26%) for IgG4-DAC; SIA (75%), DAC (50%) and AIP (45%) for IgG4-LYM; SIA (58%), AIP (42%) and LYM (32%) for IgG4-RF; AIP (100%) and SIA (67%) for IgG4-KID; and DAC (67%) and SIA (67%) for IgG4-PT. Most associated IgG4-RD lesions were diagnosed simultaneously, but IgG4-SIA and IgG4-DAC were sometimes identified before other lesions. About half of IgG4-RD patients had multiple IgG4-RD lesions, and some associations were seen between specific organs.

Graphical Abstract

相似文献   

Antineutrophil cytoplasmic antibody-associated vasculitides and IgG4-related disease: A new overlap syndrome

Objective

Atypical manifestations have been described in patients with ANCA-associated vasculitides (AAV), such as pachymeningitis, orbital mass or chronic periaortitis. Because these manifestations have been associated to the spectrum of IgG4-related disease (IgG4-RD), we hypothesized that both diseases could overlap.

Distinct clinicopathological entity 'autoimmune pancreatitis-associated sclerosing cholangitis'

Autoimmune pancreatitis (AIP) is a recently proposed disease entity, in which an elevated serum IgG4 is characteristic. This disease is sometimes associated with other inflammatory diseases: Sjögren's disease, or sclerosing cholangitis. The aim of the present paper was to examine the difference in pathophysiology between AIP‐associated sclerosing cholangitis (AIP‐SC) and primary sclerosing cholangitis (PSC). The clinicopathological findings and the immunohistochemical expressions of IgG subclasses (IgG1, IgG2, IgG3, and IgG4) were evaluated for the two aforementioned diseases (six patients with each disease). Radiologically, the extrahepatic bile duct was involved in AIP‐SC, whereas both extrahepatic and intrahepatic bile ducts were involved in PSC. Clinically, bile duct lesions in the former responded well to steroid therapy. Histologically, various degrees of mononuclear cell infiltration and fibrosis around bile ducts and portal tracts were found in all patients. Immunohistochemically, the IgG4‐positive plasma cell/mononuclear cell ratio was significantly higher in AIP‐SC than in PSC (P < 0.05). The IgG4‐positive plasma cell/mononuclear cell ratio is a useful index to help distinguish AIP‐SC from PSC. A mechanism similar to that involved in AIP may be involved in AIP‐SC. The latter is a distinct clinicopathological entity that should be distinguished from PSC because it responds well to steroid therapy.     

Therapeutic strategy for autoimmune pancreatitis

Autoimmune pancreatitis (AIP) is a particular type of pancreatitis that is thought to have an autoimmune etiology. Before therapy for AIP is begun, accurate diagnosis of AIP is necessary. It is important to distinguish AIP from pancreatic cancer. Since there is currently no diagnostic serological marker for AIP, AIP should be diagnosed on the basis of a combination of abnormalities unique to AIP. The Japanese "Diagnostic Criteria for Autoimmune Pancreatitis 2006" require the characteristic imaging findings of AIP and that at least one of the laboratory criteria or histopathological criteria have to be present. Unlike in patients with usual chronic pancreatitis, corticosteroid therapy is frequently effective in resolving the morphological findings and the symptoms of AIP patients. Therefore, administration of oral steroid therapy has become standard therapy for AIP. Indications for steroid therapy for AIP are thought to include obstructive jaundice due to stenosis of the bile duct, associated extrapancreatic sclerosing lesions, and diabetes mellitus coincidental with AIP. Oral prednisolone is usually started at 30 mg/day and tapered by 5 mg every 1-2 weeks. Serological and imaging tests are followed periodically after commencement of steroid therapy. Patients in whom complete radiological improvement is documented can stop their medication. To prevent relapses, continued maintenance therapy with prednisolone 2.5-5 mg/day is sometimes required. Patients who relapse should be re-treated with high-dose steroid therapy. A poor response to steroid therapy should raise the possibility of pancreatic cancer and the need for further examination, including laparotomy.     

Inflammatory thoracic aortic aneurysm (lymphoplasmacytic thoracic aortitis): a 13-year-experience at a German Heart Center with emphasis on possible role of IgG4

Background & aim: Aortic aneurysms represent one of the major causes of cardiovascular surgery. Their etiology varies greatly based on patient’s age and other clinicopathologic determinants. In addition to common atherosclerotic vascular diseases, an inflammatory etiology, in particular IgG4-related disease (IgG4-RD) has increasingly emerged as a cause of dissecting inflammatory aortic aneurysms (IAA). Methods: To assess the frequency and types of IAA, we reviewed all cases of aortic aneurysms resected at our Erlangen Heart Center during 2000-2013. Results: 376 patients underwent resection of aortic aneurysms in the study period. These are further categorized as ascending aortic aneurysms (45%), aortic arch aneurysm (2%), descending aortic aneurysm (3%), type A dissection (46%) and type B dissection (4%). Fifteen cases (4%) showed variable lymphoplasmacytic inflammation thus qualifying as IAA. Affected were 9 females and 6 males (female to male ratio = 1.5:1; age range: 52-80 yrs; mean: 70 yrs; median: 72 yrs). None was known to have IgG4-RD and serum IgG4 and/or IgG levels (known in 6 cases) were normal. Variable sclerosing lymphoplasmacytic inflammation was seen either confined to the adventitia (periaortitis; mainly in males) or extending through all layers (mainly in females). A wide range of IgG4 plasma cells (range: 3-182/HPF; mean: 51/HPF) and IgG4: IgG ratios (range: 0.02 to 0.91; mean: 0.37) were detected. All but one of the cases with at least focally transmural inflammation showed a higher IgG4: IgG ratios in excess of 0.3 (range, 0.32-0.91; median, 0.62). Lymphoid follicle and variable fibrosis were common but obliterative phlebitis was not seen. Conclusion: IgG4-rich sclerosing lymphoplasmacytic thoracic aortitis is a constant histological feature of thoracic IAA. Normal serum IgG4 in most patients, predilection for women and absence of other features of IgG4-RD all suggest a tissue-specific localized autoimmunological process and argue against a systemic disorder. The relationship (if any) of IgG4-rich lymphoplasmacytic thoracic aortitis in those patients with IAA lacking other organ manifestations or an elevated serum IgG4 level to systemic IgG4-RD remains unclear and merit further studies.     

Autoimmune pancreatitis and biliary intraepithelial neoplasia of the common bile duct: a case with diagnostically challenging but pathogenetically significant association

Autoimmune pancreatitis (AIP) (also called IgG4-related sclerosing pancreatitis (IgG4-SP)) and IgG4-related sclerosing cholangitis (IgG4-SC) are frequently associated with each other. It is generally believed that association of these diseases with pancreatobiliary malignancy is, however, rare. Here, we report on the case of a patient with AIP whose biliary cytology revealed severely atypical cells. Surgically resected specimens from this patient showed typical AIP with IgG4-SC, as well as a mildly elevated lesion in the common bile duct with varying degrees of cellular atypia. In addition, the atypical cells tested positive for the mucin-core protein, MUC5AC and p53 overexpression. These findings led us to diagnose the common bile duct lesion as biliary intraepithelial neoplasia (BilIN, mainly BilIN-1/2). Recently, associations between K-ras mutations and pancreatobiliary carcinoma have been reported in patients with AIP. This case, therefore, provides important new insight into the potential association of AIP and/or IgG4-SC with malignancy (or precursor lesions) of the pancreatobiliary system.     

The immunobiology and clinical characteristics of IgG4 related diseases

Having the characteristic features of elevated serum IgG4 levels and prominent infiltration of IgG4-positive plasma cells with fibrosis in lesions, Mikulicz's disease (MD) has been recognized as an IgG4-related disease (IgG4-RD). Although incidence of autoimmune pancreatitis (AIP), one of the organ characteristics of IgG4-RD, has been internationally reported, there are only a few such reports of IgG4-related MD. The limited number of reports might be attributable to the low recognition of IgG4-related MD as a clinical entity as well as its misdiagnosis as Sj?gren's syndrome (SS). Thus, we compared several clinical features of MD with SS to improve proper clinical diagnosis of MD in the clinical setting. A total of 70 SS and 70 MD cases evaluated at Sapporo Medical University Hospital were retrospectively analyzed. In SS patients, sicca symptoms were the most frequent (87%), followed by articular symptoms (23%), while lacrimal and salivary gland swelling were a rare (10%) and transient manifestation. In contrast, lacrimal or salivary gland swelling was observed in all patients with MD. Although nearly 60% of MD patients complained of sicca syndrome, skin rash and arthralgia were rare symptoms. Hypergammaglobulinemia was recognized in both SS and MD patients, but the occurrence of autoantibodies in patients with IgG4-related MD was low. Extraglandular organ involvement, often involving the retroperitoneum, pancreas, kidney and lung, was often discovered at the time of IgG4-related MD diagnosis. Although corticosteroid therapy tended to delay the hypofunction of salivary gland in SS patients, recovery of decreased function of salivary glands were observed in IgG4-related MD patients. These results suggest the beneficial effect of aggressive corticosteroid intervention in patients with IgG4-related MD. Although SS and MD are both chronic inflammatory diseases affecting the lacrimal and salivary glands, their clinical features and corticosteroid responsiveness are different. Thus, differential diagnosis of these conditions is warranted.     

Current challenges in the diagnosis of autoimmune pancreatitis

Autoimmune pancreatitis (AIP), an inflammatory disease of the pancreas first described in Japan, is characterized by a tumefactive lesion in the pancreas, thus clinically resembling pancreatic cancer. Currently, it is classified into two variants – type 1 AIP and type 2 AIP, each with distinct clinico-pathologic and epidemiologic features. Type 1 AIP is a part of IgG4 related disease, a generalized multi-systemic disease, and recapitulates its clinical and pathologic features. Type 2 AIP is an isolated pancreas-centric disease, and is not associated with elevated tissue or serum IgG4. Histologically, type 1 AIP is characterized by storiform-type fibrosis and obliterative phlebitis, while type 2 disease shows granulocytic epithelial lesions. Even when AIP is suspected, a diagnosis should seldom be made in isolation, but should be rendered only after collating clinical and radiologic data. Steroids remain the mainstay of treatment for both variants of AIP, although other immunosuppressive drugs like rituximab have proven successful. In this review, we summarize the current knowledge of this entity and discuss diagnostic challenges, with particular emphasis on the interpretation of needle biopsies. Recognition of AIP as a mimic of pancreatic cancer is imperative to reduce unnecessary morbidity and mortality associated with pancreatic surgery.     

Autoimmune pancreatitis-associated prostatitis: distinct clinicopathological entity

Autoimmune pancreatitis (AIP) has been recently proposed as a disease entity, and an elevated serum IgG4 level is a characteristic finding in it. This disease is sometimes associated with other inflammatory diseases, such as retroperitoneal fibrosis and sclerosing cholangitis. To elucidate the clinicopathological characteristics of AIP-associated prostatitis (AIP-P), the clinicopathological findings of AIP-P patients were evaluated, and the immunohistochemical expression of the IgG subclasses (IgG1, IgG2, IgG3, and IgG4) in six AIP-P patients was compared with that in 10 control patients who were clinically diagnosed as suspicious for carcinoma but who had focal inflammation without adenocarcinoma on histological examination of the prostate. All AIP-P patients had the characteristic findings of AIP, and their lower urinary tract symptoms (LUTS) improved after steroid therapy. In four of five AIP-P patients, digital rectal examination indicated prostate enlargement. Histologically, AIP-P had lymphoplasmacytic and scattered eosinophilic infiltration and obliterative phlebitis accompanying gland atrophy with dense fibrosis. Immunohistochemically, the IgG4-positive plasma cell/mononuclear cell ratio was significantly higher in the AIP-P group than in the control group ( P  = 0.0011). AIP-P is a distinct clinicopathological entity, and a mechanism similar to that implicated in AIP may be involved in it as well.     

Sialadenitis in a patient with ulcerative colitis and autoimmune pancreatitis type 2

Autoimmune pancreatitis (AIP) is a distinct form of chronic pancreatitis that has been increasingly recognised over the last decades and shows a good response to corticosteroid treatment. Two different forms of AIP have been characterized. Type 1 AIP is the pancreatic manifestation of IgG4-related disease and often affects multiple organ systems. In contrast, type 2 AIP is confined to the pancreas and involvement of extra-pancreatic organs has previously only very rarely been reported, except for an association with inflammatory bowel disease. The hallmark lesion of type 2 AIP is the granulocyte epithelial lesion (GEL), showing infiltration of neutrophilic granulocytes in the epithelium of pancreatic ducts and their accumulation in the duct lumen. We present a 61-year-old female patient who underwent pancreaticoduodenectomy with a postoperative histological diagnosis of type 2 AIP. Three months later, she underwent colectomy and was diagnosed with ulcerative colitis. One year later, she presented with swelling and pain of the right-sided submandibular salivary gland which was resected. Sialadenitis with lymphoplasmacytic inflammation, obliterative phlebitis, fibrosis and frequent accumulation of neutrophilic granulocytes in ducts, reminiscent of GELs, without IgG4-positivity or epitheloid cell granulomas, was found. Later, she presented with swelling and pain related to the left-sided submandibular gland, which resolved after steroid treatment. We describe the clinical, histological and immunohistochemical findings in this patient. It may be hypothesized that the sialadenitis may represent a rare extrapancreatic manifestation of, alternatively a rare association with, type 2 AIP or ulcerative colitis.     

IgG4-related inflammatory abdominal aortic aneurysm associated with autoimmune pancreatitis

An association between autoimmune pancreatitis (AIP) and inflammatory abdominal aortic aneurysm (AAA) has never been reported. Reported herein is a case of IgG4-related inflammatory AAA accompanying metachronous AIP. A 77-year-old man presented with malaise and intermittent lower abdominal pain. Radiological examination showed inflammatory AAA and right hydronephrosis caused by retroperitoneal fibrosis. Surgical correction of the AAA was performed, but high levels of systemic inflammatory markers persisted. Four months after surgery, the patient presented with epigastric pain, backache, and jaundice. His serum IgG4 concentration was high (571 mg/mL), and he was diagnosed with AIP, based on clinical and radiological findings. Corticosteroid therapy resulted in improvement of the clinical findings and lowered his serum IgG4 levels. Subsequent histological examination of a specimen from the aortic wall showed irregular proliferation of fibroblastic and myofibroblastic cells, severe lymphoplasmacytic infiltration, and obliterative phlebitis in the adventitia. Furthermore, on immunohistochemistry many plasma cells within the lesion were found to be positive for IgG4. These findings suggest that inflammatory AAA has a pathological process similar to that of AIP, and that some cases of inflammatory AAA and retroperitoneal fibrosis may be aortic and periaortic lesions of an IgG4-related sclerosing disease.     

Mediators of angiogenesis and fibrosis in IgG4-related disease

IgG4-related disease (IgG4-RD) is a rare fibro-inflammatory condition that can affect almost any organ, characterized by tumefactive lesions and often by eosinophilia and elevated serum IgG4 concentrations. The aim of the study is to analyze in IgG4-RD patients the serum levels of a group of cytokines and growth factors potentially involved in the regulation of fibrotic processes. In the sera of 12 patients affected by IgG4-RD and of 15 normal healthy subjects (NHS), pro-fibrogenic mediators (TGF-β1 and periostin) and pro- (VEGF and angiogenin-1) and anti- (endostatin and thrombospondin-1) angiogenic mediators were measured by sandwich enzyme immunoassay. Among mediators regulating fibrosis and angiogenesis, endostatin levels were significantly higher in IgG4-RD patients compared to NHS (p < 0.0001). No differences in the levels of TGF-β1, periostin, VEGF, angiogenin-1 and thrombospondin-1 were observed between groups. Our study suggests that among the mediators mainly involved in fibrosis and angiogenesis endostatin might play a role in the pathogenetic processes of IgG4-RD.     

Diagnostic guidelines for IgG4-related disease with a focus on histopathological criteria

IgG4-related disease (IgG4-RD) is an under recognized, protean, multiorgan fibro-inflammatory condition of unknown aetiology that is defined by its unique histopathological features, that are fairly similar regardless of the affected organ. Patients with IgG4-RD also share certain clinical features: a tendency for formation of mass lesion(s), frequent elevations in their serum IgG4 concentration, as well as an excellent response to glucocorticoid treatment. The 3 key histologic features of IgG4-RD are: 1) dense lymphoplasmacytic infiltrate, 2) fibrosis, arranged at least focally in a storiform pattern, and 3) obliterative phlebitis. The diagnosis of IgG4-RD requires both these characteristic histologic features as well as elevated numbers of IgG4 positive plasma cells. Neither elevations in serum IgG4 concentrations nor increased tissue IgG4-plasma cells are in themselves sufficient for the diagnosis, and histopathology remains the key to the accurate diagnosis of IgG4-RD.     

1型自身免疫性胰腺炎的流行病学及临床特点

目的总结自身免疫性胰腺炎(AIP)的流行病特征、临床表现和诊断经验,提高诊治水平。方法回顾性分析了北京协和医院自1998年1月至2016年12月所有确诊为AIP的临床资料。结果共纳入194例1型AIP。该病发病的男女比例为3.51/1,平均发病年龄为(57±15)岁。最常见的症状是黄疸和腹痛等。最常见的胰腺外受累疾病是硬化性胆管炎、涎腺炎和IgG4肾病。36.68%AIP患者合并糖尿病。IgG4、ANA、ESR、C反应蛋白和CA199均有助于疾病诊断和病情判断。病理、pet-CT和激素治疗反应均有助于AIP的诊断。结论作为一种系统性疾病的胰腺表现,1型AIP有特殊的临床特点和实验室检查特点。AIP的诊断可应用多种检测手段和方法。     

IgG4-related disease

IgG4-related disease (IgG4-RD) is considered a fibro-inflammatory condition with a marked propensity to form mass forming lesions, characterized by a dense lymphoplasmacytic infiltrate, the presence of abundant IgG4+ plasma cells, frequent elevation of serum IgG4 and a dramatic initial response to glucocorticoid. Nowadays, IgG4-RD has been described in almost every organ system: the pancreatobiliary tract, liver, salivary glands, nasopharynx, bone marrow, lacrimal gland, extra-ocular muscles and retrobulbar space, kidneys, lungs, lymph nodes, meninges, aorta and arteries, skin, breast, prostate, thyroid gland and pericardium. Although the common diagnostic features of all these regional involvements cannot be defined with certainty, and slight differences have been noted in different organs, many histopathological features are shared. Consensus has not yet been reached regarding criteria that have to be fulfilled for a new IgG4-RD. The proposed criteria include appropriate clinical and histopathological findings, presence of abundant tissue-infiltrating IgG4+ plasma cells, high serum IgG4 concentrations, response to steroid therapy, other autoimmune diseases or other organ involvement. The two hallmark features for diagnosis are histopathological characteristics and the presence of infiltrating IgG4+ plasma cells. In this review, we will focus on the histopathological features of IgG4-RD in specific organs and discuss the relationship with inflammatory pseudotumour and malignancy, IgG4 counting methods, and diagnosis using biopsy specimens. IgG4-related disease (IgG4-RD) is a multi-organ system disease that has been recognized in the last 10 years. IgG4-RD has a marked propensity to present as mass-forming lesions. The two hallmark features for diagnosis are histopathological characteristics and the presence of infiltrating IgG4+ plasma cells. Correct identification is crucial to avoid unnecessary major surgical procedures and initiate corticosteroid therapy.     

IgG4-related sclerosing mesenteritis: a rare mesenteric disease of unknown etiology

Sclerosing mesenteritis is a rare inflammatory and fibrosing disorder of unknown etiology, while IgG4-related disease (IgG4-RD) consists of mass-forming, fibroinflammatory lesions characterized by high serum IgG4 levels and tissue infiltration of many IgG4-positive plasma cells; obliterative phlebitis is common. This report describes a case of sclerosing mesenteritis that was considered a manifestation of IgG4-RD. A 53-year-old man underwent right hemicolectomy because of an ileocecal mass that did not improve with conservative therapy. The ill-defined fibroinflammatory lesion extended in the mesentery with storiform fibrosis, obliterative phlebitis, and infiltration of many IgG4-positive plasma cells. The ratio of IgG4-positive/IgG-positive cells was 64%, and the ratio of forkhead box protein 3 (FOXP3)-positive/CD4-positive cells was elevated (13%). It is likely that at least some cases of sclerosing mesenteritis are a manifestation of IgG4-RD. It is important to investigate this relationship because steroid therapy may benefit such cases.     

Enterocolic lymphocytic phlebitis of the cecal pole and appendix vermiformis with increase of IgG4-positive plasma cells

Here we describe the clinicopathological course of a 20-year-old female patient with enterocolic lymphocytic phlebitis (ELP) of the appendix vermiformis and cecal pole with increase of IgG4-positive plasma cells. The patient presented with acute abdomen, suspicious of acute appendicitis. Diagnostic laparoscopy showed tumefaction of the cecal pole and appendix vermiformis. Histologic examination revealed mural thickening and a dense lymphoplasmocytic, partly obliterative infiltrate of the veins with sparing of the arteries, diagnostic of ELP. In addition, we found an elevated number of IgG4-positive plasma cells blended in with the lymphocytes. The IgG4-to-IgG ratio accounted for >40 %. This case meets the histopathological criteria requested for IgG4-related disease (IgG4-RD) and thus opens the possibility that ELP might be part of the IgG4-RD spectrum.     

Idiopathic vs. secondary retroperitoneal fibrosis: a clinicopathological study of 12 cases, with emphasis to possible relationship to IgG4-related disease

Retroperitoneal fibrosis (RF) is a rare disease characterized by inflammation and fibrosis of retroperitoneal soft tissues. It is classified into two types: idiopathic (iRF) and secondary (sRF). The aim of the study was to investigate the relationship between iRF and IgG4-related disease (IgG4-RD) and to eventually extend the clinicopathological features of this condition by analysis of the sample comprising six iRF and six sRF patients. The iRF patients included four males and two females, aged 12–62 years (median 55 years). Two lesions were periaortic, one was periureteral, and three cases showed both periaortic and periureteral localization. Two patients had increased serum levels of IgG4. None of the patients developed any manifestation of IgG4-RD during the follow-up period ranging for 15–133 months (median 43 months). Microscopically, in two iRF cases, fibrosis was highly cellular encircling the vessels, nerves, and paraganglia. Phlebitis was found in all cases and being obliterative in four. Lymphocytic inflammation with formation of follicles and plasma cell infiltration were scored as severe in five iRF cases. The numbers of IgG-positive plasma cells ranged 0–373 per 1 HPF (high power field; median 132) and of IgG4-positive plasma cells 0–238 per 1 HPF (median 91). The IgG4/IgG ratio values ranged 0.38–0.74 (median 0.68). Two of the iRF cases were diagnosed as definite and three cases as probable IgG4-RD. To the contrary, none of the sRF cases met the diagnostic criteria for either definite, probable, or possible IgG4-related disease. Our results indicate that a substantial portion of iRF cases, including some of very rare pediatric cases, is a manifestation of IgG4-RD.     

IgG4-positive sclerosing cholangitis following autoimmune pancreatitis with deranged CA19.9

Sclerosing cholangitis is an autoimmune condition characterized by lymphocytic infiltration within the biliary epithelium leading to multifocal stricturing of the biliary tree. Primary sclerosing cholangitis (PSC) is the most common type encountered clinically. However, a similar process may occur in conjunction with autoimmune pancreatitis (AIP), known as AIP-associated sclerosing cholangitis (AIP-SC). This subtype is associated with an elevated IgG(4) level and the presence of a number of autoantibodies. AIP-SC shows good response to steroid treatment, distinguishing it clinically from PSC. The authors report a case of AIP-SC in a patient who had previously undergone a biliary bypass for AIP-induced chronic pancreatitis. The presentation of jaundice and grossly elevated tumor marker, CA19.9, raised the concern of malignancy. The uncertainty of the diagnosis was resolved when AIP-SC was confirmed on liver biopsy, with a concomitantly elevated serum IgG(4) level. The disease went into remission with steroid treatment.