A new conceptualization for Mikulicz's disease as an IgG4-related plasmacytic disease

Abstract

Mikulicz's disease (MD) has been included within the diagnosis of primary Sjögren's syndrome (SS), but it represents a unique condition involving persistent enlargement of the lacrimal and salivary glands characterized by few autoimmune reactions and good responsiveness to glucocorticoids, leading to the recovery of gland function. Mikulicz's disease was recently reported to be associated with elevated immunoglobulin G4 (IgG4) concentrations in the serum and prominent infiltration of plasmacytes expressing IgG4 into the lacrimal and salivary glands. The following features were used for diagnosis: (1) visual confirmation of symmetrical and persistent swelling in more than two lacrimal and major salivary glands; (2) prominent mononuclear cell infiltration of lacrimal and salivary glands; and (3) exclusion of other diseases that present with glandular swelling, such as sarcoidosis and lymphoproliferative disease. These features are not observed in most SS cases. The complications of MD include autoimmune pancreatitis, retroperitoneal fibrosis, tubulointerstitial nephritis, autoimmune hypophysitis, and Riedel's thyroiditis, all of which show IgG4 involvement in their pathogenesis. Mikulicz's disease thus differs from SS and may be a systemic IgG4-related plasmacytic disease.     

IgG4-related disease manifesting as an acute gastric-pericardial fistula

Ig G4-related disease is a recently recognized entity linked initially to autoimmune pancreatitis and has been subsequently described in nearly every organ system. Men over the age of 50 represent the most affected demographic group and a comprehensive set of diagnostic criteria has been developed to aid treating clinicians. Though elevated levels of Ig G4 in the serum are suggestive of the disease, definitive diagnosis is made on histopathology. Treatment is tailored to the clinical presentation with corticosteroid therapy known to have proven efficacy. Gastric manifestations of the Ig G4-related disease primarily come in two varieties, notably chronic ulceration or pseudotumor formation. Autoimmune pancreatitis conveys increased risk for Ig G4-related disease of the stomach, which is independent of Helicobacter pylori status. In this case report, we present an acute gastric-pericardial fistula secondary to Ig G4-related disease that required urgent operative management. To our knowledge, this is the first report in the medical literature describing this complication of Ig G4-related disease.     

Immunoglobulin G4-related autoimmune pancreatitis and sialadenitis: A case report

Immunoglobulin G4 (IgG4)-related disease is a rare systemic diseases. A 67-year-old male presented at our institution with mild upper abdominal pain and jaundice for 20 d. Laboratory results revealed high levels of IgG4 (15.4 g/L, range: 0.08-1.4 g/L). Computed tomography (CT) showed significant enlargement of the entire pancreas and a capsule-like low-density rim surrounding the whole pancreas. Positron emission tomography/CT revealed increased uneven metabolism of the entire pancreas. Both magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography showed stenosis of the distal common bile duct and proximal main pancreatic duct, and dilation of the proximal common bile duct and extra- and intra-hepatic bile ducts. He was diagnosed with IgG4-related autoimmune pancreatitis. The patient was treated with prednisone for 14 mo. The patient responded well to prednisone but upon cessation of the corticosteroid developed enlargement of the submandibular gland. The patient’s serum IgG4 was elevated at 23.9 g/L. It is important to maintain treatment, so the patient was again treated with prednisone and had a good response. Follow-up of IgG4-related disease is thus necessary.     

Retroperitoneal fibrosis associated with immunoglobulin G4-related disease

Retroperitoneal fibrosis is a rare disease characterized by the development of inflammation and fibrosis in the soft tissues of the retroperitoneum and other abdominal organs.Retroperitoneal fibrosis can be of 2 types:idiopathic and secondary.The recently advocated concept and diagnostic criteria of immunoglobulin G4(IgG4)-related disease,derived from research on autoimmune pancreatitis(AIP),has led to widespread recognition of retroperitoneal fibrosis as a condition caused by IgG4-related disease.We now know that previously diagnosed idiopathic retroperitoneal fibrosis includes IgG4-related disease;however,the actual prevalence is unclear.Conversely,some reports on AIP suggest that retroperitoneal fibrosis is concurrently found in about 10% of IgG4-related disease.Because retroperitoneal fibrosis has no specific symptoms,diagnosis is primarily based on diagnostic imaging(computed tomography and magnetic resonance imaging),which is also useful in evaluating the effect of therapy.Idiopathic retroperitoneal fibrosis can occur at different times with other lesions of IgG4-related disease including AIP.Thus,the IgG4 assay is recommended to diagnose idiopathic retroperitoneal fibrosis.High serum IgG4 levels should be treated and monitored as a symptom of IgG4-related disease.The first line of treatment for retroperitoneal fibrosis is steroid therapy regardless of its cause.For patients with concurrent AIP,i.e.,IgG4-related retroperitoneal fibrosis,the starting dose of steroid is usually 30-40 mg/d.The response to steroid therapy is generally favorable.In most cases,the pancreatic lesion and retroperitoneal fibrosis improve after the initial treatment.However,the epidemiology,treatment for recurring retroperitoneal fibrosis,and long-term prognosis are still largely unknown.Further analysis of such cases and research are necessary.     

The use of immunohistochemistry for IgG4 in the diagnosis of autoimmune pancreatitis: A systematic review and meta-analysis

BackgroundThe diagnosis of autoimmune pancreatitis (AIP) remains challenging, especially when serum IgG4 is normal or imaging features are indeterminate. We performed a systematic review and meta-analysis to evaluate the performance of IgG4 immunostaining of pancreatic, biliary, and ampullary tissues as a diagnostic aid for AIP.MethodsA comprehensive literature search of the PubMed, EMBASE, and Ovid MEDLINE databases was conducted until February 2020. The methodological quality of each study was assessed according to the Quality Assessment of Diagnostic Accuracy Studies checklist. A random-effects model was used to summarize the diagnostic odds ratio and other measures of accuracy.ResultsThe meta-analysis included 20 studies comprising 346 patients with AIP and 590 patients with other pancreatobiliary diseases, including 371 pancreatobiliary malignancies. The summary estimates for tissue IgG4 in discriminating AIP and controls were as follows: diagnostic odds ratio 38.86 (95% confidence interval (CI), 18.70–80.75); sensitivity 0.64 (95% CI, 0.59–0.69); specificity 0.93 (95% CI, 0.91–0.95). The area under the curve was 0.939 for tissue IgG4 in discriminating AIP and controls. Subgroup analysis revealed no significant difference in diagnostic accuracy according to control groups (pancreatobiliary cancer versus other chronic pancreatitis) and sampling site (pancreas versus bile duct/ampulla).ConclusionsCurrent data demonstrate that IgG4 immunostaining of pancreatic, biliary, and ampullary tissue has a high specificity but moderate sensitivity for diagnosing AIP. IgG4 immunostaining may be useful in supporting a diagnosis of AIP when AIP is clinically suspected, but a combination of imaging and serology does not provide a conclusive diagnosis.     

Progressive multi-organ expression of immunoglobulin G4-related disease: A case report

A 63-year-old Caucasian man presented with a cholestatic syndrome, renal failure and arthralgias. A laboratory examination revealed high immunoglobulin G (IgG) and IgG4 levels (5.95 g/L; normal range: 0.08-1.4 g/L), pointing to a diagnosis of systemic IgG4-related disease, with definite radiological evidence of biliary and pancreatic expression, and plausible renal, articular, salivary and lacrimal glands involvement. Due to the rarity of the condition, there are currently no random control trials to point to the optimal therapeutic approach. The patient has been on steroid therapy with the subsequent introduction of azathioprine, with a complete resolution of all symptoms, a rapid reduction to normalization of all blood tests, and a complete regression of the radiological picture. Our experience underlines the complexity of IgG4-related disease and its variable and sometimes progressive presentation, while pointing out the need for a careful and complete assessment for possible multi-organ involvement.     

IgG4-related sclerosing disease

Based on histological and immunohistochemical exami- nation of various organs of patients with autoimmune pancreatitis （AIP）, a novel clinicopathological entity of IgG4-related sclerosing disease has been proposed. This is a systemic disease that is characterized by extensive IgG4-positive plasma cells and T-lymphocyte infiltration of various organs. Clinical manifestations are apparent in the pancreas, bile duct, gallbladder, salivary gland, retroperitoneum, kidney, lung, and prosrate, in which tissue fibrosis with obliterative phlebitis is pathologically induced. AlP is not simply pancreatitis but, in fact, is a pancreatic disease indicative of IgG4- related sclerosing diseases. This disease includes AlP, sclerosing cholangitis, cholecystitis, sialadenitis, retro-peritoneal fibrosis, tubulointerstitial nephritis, interstitial pneumonia, prostatitis, inflammatory pseudotumor and lymphadenopathy, all IgG4-related. Most IgG4-related sclerosing diseases have been found to be associated with AlP, but also those without pancreatic involvement have been reported. In some cases, only one or two organs are clinically involved, while in others, three or four organs are affected. The disease occurs predominantly in older men and responds well to steroid therapy. Serum IgG4 levels and immunos-taining with anti-IgG4 antibody are useful in making the diagnosis. Since malignant tumors are frequently suspected on initial presentation, IgG4-related sclerosing disease should be considered in the differential diagnosis to avoid unnecessary surgery.     

A new clinicopathological entity of IgG4-related autoimmune disease

Background Autoimmune pancreatitis (AIP) is occasionally associated with other autoimmune diseases.Methods To investigate the pathophysiology of AIP, we immunohistochemically examined the pancreas and other organs in eight patients with AIP, and in controls, using anti-CD4-T and CD8-T cell subsets, as well as IgG4 antibodies.Results In AIP patients, severe or moderate infiltration of IgG4-positive plasma cells associated with CD4- or CD8-positive T lymphocytes was detected in the peripancreatic tissue (6/6), bile duct (8/8), gallbladder (8/8), portal area of the liver (3/3), gastric mucosa (5/7), colonic mucosa (2/2), salivary glands (1/2), lymph nodes (6/6), and bone marrow (2/2), as well as in the pancreas (8/8). There were few IgG4-positive plasma cells at the same sites in controls.Conclusions These results suggest that AIP is not simply pancreatitis but that it is a pancreatic lesion involved in IgG4-related systemic disease with extensive organ involvement. We propose a new clinicopathological entity, of a systemic IgG4-related autoimmune disease in which AIP and its associated diseases might be involved.     

First case of IgG4-related sclerosing cholangitis associated with autoimmune hemolytic anemia

To our knowledge, patients with immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) associated with autoimmune hemolytic anemia (AIHA) have not been reported previously. Many patients with IgG4-SC have autoimmune pancreatitis (AIP) and respond to steroid treatment. However, isolated cases of IgG4-SC are difficult to diagnose. We describe our experience with a patient who had IgG4-SC without AIP in whom the presence of AIHA led to diagnosis. The patient was a 73-year-old man who was being treated for dementia. Liver dysfunction was diagnosed on blood tests at another hospital. Imaging studies suggested the presence of carcinoma of the hepatic hilus and primary sclerosing cholangitis, but a rapidly progressing anemia developed simultaneously. After the diagnosis of AIHA, steroid treatment was begun, and the biliary stricture improved. IgG4-SC without AIP was thus diagnosed.     

Biomarkers in autoimmune pancreatitis and immunoglobulin G4-related disease

Solitary organ autoimmune disorders, formerly known as autoimmune pancreatitis (AIP), autoimmune sialadenitis, and autoimmune sclerosing cholangitis, are now considered organ-specific manifestations of systemic immunoglobulin G4-related disease (IgG4-RD). AIP and IgG4-RD are characterized by elevated serum concentration of IgG4 antibody (Ab), accumulation of IgG4-expressing plasmacytes in the affected organs, and involvement of multiple organs. It is well established that enhanced IgG4 Ab responses are a hallmark of AIP and IgG4-RD for diagnosis and monitoring disease activity. However, a significant fraction of patients with AIP and IgG4-RD who develop chronic fibroinflammatory responses have normal serum concentrations of this IgG subtype. In addition, disease flare-up is sometimes seen even in the presence of normalized serum concentrations of IgG4 Ab after successful induction of remission by prednisolone. Therefore, it is necessary to identify new biomarkers based on the understanding of the pathophysiology of AIP and IgG4-RD. Recently, we found that activation of plasmacytoid dendritic cells producing both interferon-α (IFN-α) and interleukin-33 (IL-33) mediate murine AIP and human IgG4-RD. More importantly, we provided evidence that serum concentrations of IFN-α and IL-33 could be useful biomarkers for the diagnosis and monitoring of AIP and IgG4-RD activity after induction of remission in these autoimmune disorders. In this Frontier article, we have summarized and discussed biomarkers of AIP and IgG4-RD, including Igs, autoAbs, and cytokines to provide useful information not only for clinicians but also for researchers.     

儿童IgG4相关自身免疫性肝炎临床与病理特征分析*

目的 探讨儿童免疫球蛋白G4相关自身免疫性肝炎(IgG4-AIH)患者临床和肝组织病理学特征。方法 2014年6月～2019年6月我科收治的AIH儿童38例,符合2008年国际AIH小组(IAIHG)制定的简化诊断积分系统或1999年IAIHG制定的AIH诊断评分系统。根据肝组织IgG4阳性浆细胞浸润≥10个/高倍镜视野(HPF)诊断IgG4-AIH。采用ELISA法检测血清IgG和IgG4。常规行肝穿刺,采用免疫组织化学染色检测肝组织IgG4阳性浆细胞。结果 在38例AIH患者中,诊断IgG4-AIH患者4例,AIH患者34例;IgG4-AIH患者血清IgG和IgG4水平分别为22.6(13.2, 29.8)mg/dL和226.5(105.8,424.6)mg/dL,与AIH患者的18.9(10.4,25.3)mg/dL和209.4(96.1,401.6)mg/dL比,差异无统计学意义(P>0.05);IgG4-AIH组肝组织IgG4阳性浆细胞计数/HPF为40.2(25.4,55.7),显著高于AIH组患者;IgG4-AIH组肝组织IgG4阳性浆细胞计数与炎性反应活动分级(r=0.48)和肝纤维化分期(r=0.37)呈正相关(P<0.05);IgG4-AIH患者血清ALT恢复正常所需要的时间为(3.5±0.8)w,显著短于AIH组,血清AST恢复时间为(3.6±0.6)w,显著短于AIH组,血清碱性磷酸酶恢复时间为(4.0±1.1)w,显著短于AIH组,血清谷氨酰转肽酶恢复时间为(4.2±1.5)w,显著短于AIH组,血清IgG水平恢复正常的时间为(7.6±2.8)w,显著短于AIH组。结论 IgG4-AIH儿童具有AIH的基本特征,血清IgG4水平并不比AIH患者更高,但肝组织IgG4阳性浆细胞浸润显著多于AIH患者。另外,IgG4-AIH儿童对皮质激素治疗具有良好的应答反应,血清学指标的恢复时间也相对较短,这些特征有助于临床诊断。本组IgG4-AIH儿童例数太少,其结论有待于验证。     

Efficacy and safety of rituximab for IgG4-related pancreato-biliary disease: A systematic review and meta-analysis

BackgroundType I autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-SC) belong to the IgG4-related disease (IgG4-RD) spectrum. Both entities respond to glucocorticoids, but iatrogenic toxicity associated with prolonged steroid therapy and relapse represent relevant clinical concerns in the long-term. Rituximab is increasingly used as an effective alternative strategy to induce remission but data regarding the safety and efficacy of B-cell depletion therapy for pancreato-biliary involvement of IgG4-RD are limited. We performed a systematic review and meta-analysis to estimate the rate of remission, flare, and adverse events (AEs) occurring in pancreato-biliary IgG4-RD following rituximab treatment.MethodsThe MEDLINE, SCOPUS, and EMBASE databases were searched from inception to December 2020 to identify studies reporting the outcomes of IgG4-related pancreato-biliary disease after treatment with rituximab. Studies involving ≥2 patients were selected. In case of duplicated studies, the most recent or the one with the biggest N were chosen. The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled effects were calculated using a random-effect model and expressed in terms of pooled remission, relapse, and AEs rates.ResultsSeven cohort studies met inclusion criteria and 101 patients were included. Reasons for rituximab administration were new disease onset (18.5%), disease flare after glucocorticoids (63.5%), and glucocorticoids intolerance (17.9%). The median follow-up time was 19 months. The pooled rate of complete response at 6 months was 88.9% (95%CI 80.5–93.9) with no heterogeneity (I² = 0%). The pooled estimate of relapse rate was 21% (95%CI 10.5–40.3) with moderate heterogeneity (I² = 51%). A higher rate of relapse (35.9%, 95%CI 17.3–60.1) was reported in studies including patients with multiorgan involvement (OOI). The median time to relapse was 10 months. The pooled estimate of rituximab-related AEs was 25% (95%CI 8.8–53) with substantial heterogeneity (I² = 73.6%). No publication bias was observed.ConclusionTreatment of IgG4-related pancreato-biliary disease with rituximab is associated with high remission rate, a higher relapse rate in the presence of OOI, and limited AEs. Randomized controlled trials with adequate power are needed to confirm these findings.     

血清IgG4检测在IgG4相关性疾病诊治中的作用

IgG4相关性疾病(IgG4-related disease,IgG4-RD)是一种新发现的以IgG4阳性淋巴细胞-浆细胞浸润为特点的累及多器官的系统性纤维炎症性病变.IgG4-RD受累器官广泛,临床表现多样,具有独特的病理学及血清学表现.但病理学检查存在诸多缺点:标本不易获取,尤其涉及到特定组织(如腹膜后组织、纵膈)、器官(如垂体、胰腺);为有创检查,患者不易接受等,使其在临床实施过程中受到一定限制.血清IgG4浓度升高作为IgG4-RD的诊断标准之一,其检测在临床应用方面有许多优点:方便、快捷、具有较高的敏感度和特异度,在疾病的诊治过程有一定的价值.     

Immunoglobulin G4-related gastrointestinal diseases,are they immunoglobulin G4-related diseases?

In immunoglobulin G4(IgG4)-related disease(RD),organ enlargement or nodular lesions consisting of abundant infiltration of lymphocytes and IgG4-positive plasma cells and fibrosis are seen in various organs.Although infiltration of many IgG4-positive plasma cells is detected in the gastric and colonic mucosa and major duodenal papilla of patients with autoimmune pancreatitis,it cannot be diagnosed as a gastrointestinal lesion involved in IgG4-RD,because none of the following is observed in these lesions:a mass-like formation;dense fibrosis;or obliterative phlebitis.Based on our review of the literature,there appear to be two types of IgG4-related gastrointestinal disease.One is a gastrointestinal lesion showing marked thickening of the wall of the esophagus and stomach,consisting of dense fibrosis with abundant infiltration of IgG4-positive plasma cells,which usually show submucosal spreading.The other is an IgG4-related pseudotumor occurring in gastrointestinal regions such as the stomach,colon,and major duodenal papilla,showing polypoid or mass-like lesions.Most solitary IgG4-related gastrointestinal lesions that are not associated with other IgG4-RD appear to be difficult to diagnose.It is of utmost importance to rule out malignancy.However,these lesions may respond to steroid therapy.To avoid unnecessary resection,IgG4-related gastrointestinal diseases should be considered in the differential diagnosis.     

IgG4相关性肺疾病二例并文献复习

目的 总结IgG4相关性肺疾病的临床特点及诊治经验,提高临床对该病的认识,减少误诊误治.方法 分析第二军医大学附属长海医院呼吸内科收治的两例IgG4相关性肺疾病的一般情况、临床表现、实验室检查、组织病理学、治疗及预后,并进行相关文献复习.结果 两例患者均为男性,血清IgG4水平均显著升高(2.25 g/L;10 g/L).1例肺部影像学呈实性结节型改变,并有回盲部受累,糖皮质激素治疗有效.另1例肺部影像学呈支气管血管束型改变,对糖皮质激素治疗依赖.文献复习69例IgG4相关性肺疾病,因呼吸道症状就诊者39例(56.5％),伴有肺外受累者41例(59.4％).48例检测了血清IgG4水平,均显著升高(307 ～ 52 500 mg/L).胸部影像学表现实性结节型35例(50.7％).31例(44.9％)患者接受了糖皮质激素治疗,预后良好.结论 IgG4相关性肺疾病是临床少见的免疫性疾病,临床表现缺乏特异性,临床诊断应综合分析其血清免疫学检查、影像学表现及组织病理学结果,糖皮质激素治疗效果良好.     

Significance of peripheral eosinophilia for diagnosis of IgG4-related disease in subjects with elevated serum IgG4 levels

ObjectivesIn this study, we aim to assess the diagnostic utility of elevated serum IgG4 (sIgG4) concentration alone and in combination with peripheral eosinophilia (PE) for IgG4-related disease (IgG4-RD).MethodsFrom the Mayo Clinic, Rochester electronic medical record database we identified 409 patients with above normal levels of sIgG4 (reference range 121–140 mg/dL) who had sIgG4 measured to differentiate IgG4-RD from another disease.ResultsAmong 409 patients with any elevation in sIgG4 levels, 129 (31.5%) had a definite diagnosis of IgG4-RD. The prevalence of PE increased with increasing sIgG4 levels and was more likely to be seen in subjects with IgG4-RD vs. non-IgG4-RD at ≥1X (n = 35/120, 29.2% vs. n = 23/258, 8.9%; p < 0.001), ≥2X (n = 23/64, 35.9% vs. n = 5/54,9.3%; p = 0.001) and ≥3X (n = 18/42, 42.9% vs. n = 0/9, 0%; p = 0.015) of sIgG4 upper limit of normal (ULN), respectively. After adjusting for gender and age, sIgG4 levels ≥ 2X ULN with PE as a predictor, had a higher positive predictive value in predicting IgG4-RD (72.2% vs. 65.9%) with an Area Under the Receiver Operatic Characteristic Curve (AUC) of 0.776, compared to sIgG4 ≥ 2X ULN without PE predictor (AUC = 0.74), p = 0.016. PE, sIgG4≥2X ULN, male gender, and age independently predicted the disease with odds ratio of 4.89 (95% CI:2.51–9.54), 3.78 (95% CI:2.27–6.28), 2.78 (95% CI:1.55–4.97), and 1.03 (95% CI:1.02–1.05), respectively.ConclusionEven in subjects in whom IgG4-RD is suspected, only a minority (∼30%) with elevated sIgG4 levels have IgG4-RD. sIgG4 by itself is more specific at higher levels, though never diagnostic. PE increases with increasing sIgG4 and adds diagnostic value at higher sIgG4 levels.     

Isolated intrapancreatic Ig G4-related sclerosing cholangitis

Immunoglobulin G4-related sclerosing cholangitis(Ig G4-SC) is frequently associated with type 1 autoimmune pancreatitis(AIP). Association with AIP can be utilized in the diagnosis of Ig G4-SC. However, some cases of Ig G4-SC are isolated from AIP, which complicates the diagnosis. Most of the reported cases of isolated Ig G4-SC displayed hilar biliary strictures, whereas isolated Ig G4-SC with intrapancreatic biliary stricture is very rare. Recently, we have encountered 5 isolated intrapancreatic Ig G4-SC cases that were not associated with AIP, three of which were pathologically investigated after surgical operation. They all were males with a mean age of 74.2 years. The pancreas was not enlarged in any of these cases. No irregular narrowing of the main pancreatic duct was found. Bile duct wall thickening in lesions without luminal stenosis was detected by abdominal computed tomography in all five cases, by endoscopic ultrasonography in two out of four cases and by intraductal ultrasonography in all three cases. In three cases, serum Ig G4 levels were within the normal limits. The mean serum Ig G4 level measured before surgery was 202.1 mg/d L(4 cases). Isolated intrapancreatic Ig G4-SC is difficult to diagnose, especially if the Ig G4 level remains normal. Thus, this type of Ig G4-SC should be suspected in addition to cholangiocarcinoma and pancreatic cancer if stenosis of intrapancreatic bile duct is present.     

Intraductal papillary mucinous neoplasm of the pancreas and IgG4-related disease: A coincidental association

Background/aimsCoexistence of autoimmune pancreatitis (AIP) and pancreatic cancer, elevation of serum IgG4 levels in pancreatic cancer patients, and infiltration of IgG4-positive plasma cells in peritumorous pancreatitis have been described in a few reports. This study examined the relationship between intraductal papillary mucinous neoplasm (IPMN) of the pancreas and peritumorous IgG4-positive lymphoplasmacytic infiltrates.MethodsSerum IgG4 levels were measured in 54 patients with IPMN (median 70 years, 26 males and 28 females; 13 main duct type and 41 branch duct type). Histological findings focusing on dense lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis were reviewed, and immunostaining with IgG4 and IgG was performed in 23 surgically resected IPMN cases (18 main duct type and 5 branch duct type). The presence of IgG4-positive plasma cells >10/hpf and an IgG4-positive/IgG-positive plasma cell ratio >40% were considered significant.ResultsSerum IgG4 levels were elevated in 2 (4%) IPMN patients. Significant infiltration of IgG4-positive plasma cells was detected in 4 IPMN cases (17%). The IgG4-positive/IgG-positive plasma cell ratio was >40% in all 4 cases. In one case with a markedly elevated serum IgG4 level (624 mg/dL), typical lymphoplasmacytic sclerosing pancreatitis (AIP type 1) lesions surrounded the whole IPMN. In the 3 other cases, infiltration of IgG4-positive plasma cells with fibrosis was focally detected mainly in the periductal area around the IPMN.ConclusionsIn a few patients with IPMNs, IgG4-positive plasma cell infiltration can occur in the peritumorous area. The association of an IPMN with AIP type 1-like changes seems to be exceptional and coincidental.     

IgG4-related disease: Advances in the diagnosis and treatment

IgG4-related disease is a rare immune-mediated systemic disease with the capability of involving essentially any organ. Although the presenting clinical features vary substantially according to the speciality to which patients present first, perhaps the most common clinical presentation is that of single or multiple organ enlargement, arousing suspicion of cancer. The disease is frequently diagnosed unexpectedly in pathological specimens or on imaging studies. The diagnostic approach is complex and includes not only IgG4-related tests (serum levels, circulating plasmablasts, and specific immunohistochemical studies), but also clinical, laboratory, and imaging tests as well as the typical histopathological features (lymphocytic infiltration, storiform fibrosis, eosinophilic infiltration, and obliterative phlebitis). IgG4-related tests should not be considered as diagnostic in the absence of an appropriate clinical scenario. Therapeutic approaches reported to date pertain primarily to glucocorticoids, but the use of these medications has not been studied in a controlled or prospective manner. The most current investigational treatment approaches have focused on targeting cells of the B-cell lineage, including B-cell-depleting agents (rituximab) and a non-depleting homodimer monoclonal antibody targeting CD19 and Fc-gamma RIIIb.