Clinicopathological features of immunoglobulin G4-related constrictive pericarditis.

AIM: Constrictive pericarditis (CP) is characterised by scarring fibrosis and a loss of pericardial elasticity, which causes heart failure. IgG4 (immunoglobulin G4)-related disease (IgG4-RD) is a systemic fibro-inflammatory disease characterised by the infiltration of IgG4-immunopositive plasmacytes and high serum IgG4 levels that frequently shape tumorous lesions. Although pericardial involvement of IgG4-RD is rare, with indications of CP, pericardial effusion and irregular masses, the clinical and pathological features remain unclear. In this study, we examined the relationship between CP and IgG4-RD. METHODS: Among 35 thick-walled CP cases (histologically pericardial thickening ≥2 mm), eight cases were aetiology identified. Using the diagnostic criteria for IgG4-RD, 11 cases were classified as IgG4-CP, whereas the remainder were considered true idiopathic CP (16 cases) and the clinical pathological features were evaluated. RESULTS: Compared with the other groups, the IgG4-CP group was more common in men and associated with low-grade fever and massive pericardial effusion with frequent recurrence. Deaths resulting from heart failure occurred in a few cases of the IgG4-CP group, but not in other groups. An increase in C-reactive protein and a high positivity rate of anti-nuclear antibodies frequently occurred in the IgG4-CP group. Histologically, the IgG4-CP group included lymphoid follicle, eosinophil infiltration and few calcifications. CONCLUSIONS: Pericardial IgG4-RD occurs not only as nodular lesions, but also as thick-walled CP, and accounts for approximately 40% of thick-walled CP cases of unknown cause. The predominant clinical characteristic was refractory and recurrent pericardial effusion. Recognising IgG4-RD as a cause of CP is important to initiate appropriate therapy.

Validation of the Diagnostic Criteria for IgG4-Related Periaortitis/Periarteritis and Retroperitoneal Fibrosis (IgG4PA/RPF) 2018, and Proposal of a Revised 2023 Version for IgG4-Related Cardiovascular/Retroperitoneal Disease.

BACKGROUND: In 2018, diagnostic criteria were introduced for IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis (PA/RPF). This study assessed the existing criteria and formulated an improved version.Methods and Results: Between August 2022 and January 2023, we retrospectively analyzed 110 Japanese patients diagnosed with IgG4-related disease (IgG4-RD) involving cardiovascular and/or retroperitoneal manifestations, along with 73 non-IgG4-RD patients ("mimickers") identified by experts. Patients were stratified into derivation (n=88) and validation (n=95) groups. Classification as IgG4-RD or non-IgG4-RD was based on the 2018 diagnostic criteria and various revised versions. Sensitivity and specificity were calculated using experts' diagnosis as the gold standard for the diagnosis of true IgG4-RD and mimickers. In the derivation group, the 2018 criteria showed 58.5% sensitivity and 100% specificity. The revised version, incorporating "radiologic findings of pericarditis", "eosinophilic infiltration or lymphoid follicles", and "probable diagnosis of extra-PA/-RPF lesions", improved sensitivity to 69.8% while maintaining 100% specificity. In the validation group, the original and revised criteria had sensitivities of 68.4% and 77.2%, respectively, and specificities of 97.4% and 94.7%, respectively. CONCLUSIONS: Proposed 2023 revised IgG4-related cardiovascular/retroperitoneal disease criteria show significantly enhanced sensitivity while preserving high specificity, achieved through the inclusion of new items in radiologic, pathological, and extra-cardiovascular/retroperitoneal organ categories.

A case of hepatitis-associated aplastic anaemia following living-donor liver transplantation for fulminant hepatitis showing loss of heterozygosity in the 6p chromosome in the affected liver.

The mechanisms underlying hepatitis-associated aplastic anaemia (HAAA) that occurs several weeks after the development of acute hepatitis are unknown. A 20-year-old male developed HAAA following living-donor liver transplantation for fulminant hepatitis. The patient's leucocytes lacked HLA-class I due to loss of heterozygosity in the short arm of chromosome 6p (6pLOH). Interestingly, the patient's liver cells resected during the transplantation also exhibited 6pLOH that affected the same HLA haplotype as the leucocytes, suggesting that CD8+ T cells recognizing antigens presented by specific HLA molecules on liver cells may have attacked the haematopoietic stem cells of the patient, leading to the HAAA development.

Disordered Balance of T-Cell Subsets in Arterial Tertiary Lymphoid Organs in Immunoglobulin G4-Related Vascular Disease.

BACKGROUND: Arterial/aortic tertiary lymphoid organs (ATLOs), characterized by germinal centers, control local arterial immune responses. T follicular helper cells (Tfh), resident in germinal centers, regulate immunoglobulin production and germinal center development. They consist of Tfh1, Tfh2, and Tfh17 subsets. T follicular regulatory (Tfr) cells possess suppressive functions as regulatory T cells and migrate into germinal centers. Immunoglobulin G4 (IgG4)-related diseases manifest in vascular lesions as frequently formed inflammatory aneurysms (IgG4-related abdominal aortic aneurysm [IgG4-AAAs]). IgG4-AAAs contain several ATLOs. METHODS AND RESULTS: We performed whole-slide immunohistochemical image analysis in surgical specimens of IgG4-AAAs (n=21), non-IgG4-related inflammatory AAAs (n=17), atherosclerotic AAAs (n=10), and Takayasu arteritis (n=5). IgG4-AAA was characterized by numerous, large, irregular-shaped ATLOs, and higher numbers of Tfr and Tfh2 cells than Tfh1 cells were present compared with others. The morphologic abnormalities (in number, area, and form) of ATLOs in IgG4-AAAs and the increased number of Tfr cells are closely related to the activity of IgG4-related diseases. All T-cell subsets were more enriched within ATLOs than outside ATLOs. In particular, an increase in Tfr cells in IgG4-AAAs was associated with ATLO formation. Increased Tfh17 cells were found in Takayasu arteritis, and atherosclerotic AAA and non-IgG4-related inflammatory AAAs were characterized by increased Tfh1 cells. CONCLUSIONS: In the classification of vascular lesions, considering the imbalance in T-cell subsets, IgG4-AAA should be positioned as adventitial vasculitis with predominant Tfr and Tfh2 cells, accompanied by the abnormal appearance of ATLOs.

Solitary recurrence of IgG4-related giant coronary aneurysm: Case report and review of the literature focusing on treatment strategies and complications.

Coronary periarteritis is a dangerous manifestation of IgG4-related disease, because it forms coronary artery aneurysms, which may cause sudden cardiac death. We report the case of a 78-year-old woman with IgG4-related coronary periarteritis and a coronary aneurysm, which showed progressive enlargement despite maintenance therapy for Type 1 autoimmune pancreatitis. This case was unique, in that coronary periarteritis was the only active lesion that recurred. Low-dose glucocorticoids suppressed the progression of periarterial lesions but led to rapid thinning of the aneurysmal wall and an increase in the size of mural thrombi, which pose a risk of myocardial infarction. Our systematic literature review including 98 cases of 86 articles was performed to examine its treatment strategies and complications. Among the cases in which the effect of immunosuppressive therapy could be followed radiologically, 33 of 37 (89.1%) cases showed improvement in wall thickening/periarterial soft tissue, while 6 of 13 (46.2%) showed worsening increase in the outer diameter of the coronary aneurysms. We propose a draft treatment algorithm and suggest that immunosuppressive therapy for IgG4-related coronary periarteritis with coronary aneurysms should be conducted only after the therapeutic benefit has been determined to outweigh the risks. Because coronary periarteritis can occur without other organ involvement, as in our case, all cases of IgG4-related disease require careful monitoring of coronary artery lesions.

Immunoglobulin G4-related solitary aneurysm of the deep femoral artery.

We have reported the case of an 83-year-old man with a rare immunoglobulin G4 (IgG4)-related solitary deep femoral artery aneurysm. The patient successfully underwent aneurysmectomy and vascular reconstruction with an expanded polytetrafluoroethylene graft. A definitive diagnosis was determined from the comprehensive diagnostic criteria, including histopathologic features of chronic inflammation indicated by massive infiltration of IgG4-positive plasma cells. IgG4-related aneurysmal diseases should be included in the differential diagnosis of deep femoral artery aneurysms, which have traditionally been considered to develop owing to previous trauma or surgery, intervention, infection, and autoimmune or collagen disease.

The disturbance of the distribution of T helper cell subsets in the mantle area surrounding germinal centers in immunoglobulin G4-related sclerosing sialadenitis.

The function of germinal centers (GCs) is an important factor in the pathogenesis of immunoglobulin G4 (IgG4)-related disease, in which inflammatory and fibrotic processes are controlled by type 2 helper T (Th) cells and regulatory T cells. T follicular helper cells (Tfh), which are present in GCs, regulate GC development, and they consist of Tfh1, Tfh2, and Tfh17 subsets. This study examined the association of Th cell subsets in IgG4-RD and pathogenesis of the disease using whole-slide image analysis for immunohistochemistry. IgG4-related sclerosing sialadenitis (IgG4-SS, n = 19) was characterized by higher numbers of Tfh2 and Tfh17 cells than Tfh1 cells compared to the findings in patients with chronic sialadenitis (n = 18) or Sjögren syndrome (n = 17). The number of Tfh2 cells was significantly associated with all parameters of GC structures and the number of IgG4 + plasmacytes, whereas the number of Tfh1 cells was inversely associated with the aforementioned parameters. Concerning extrafollicular helper T (Teh) cells, among three groups, the Tfh2/Teh2 ratio was highest and the Tfh1/Teh1 ratio was lowest in the IgG4-SS group, which exhibited a characteristically regional distribution of Tfh and Teh subsets, especially higher numbers of Teh2 cells and lower numbers of Teh1 cells in the mantle areas surrounding GCs. Mantle Teh2 cells and central Tfh17 cells were significantly correlated with morphological abnormalities of GCs. Our results indicated that the peculiar regional distribution and altered balance of Tfh and Teh subsets are novel hallmarks of IgG4-SS that are associated with GC formation in IgG4-SS.

Ultrasonic Wave Pericardiectomy for IgG4-Related Constrictive Pericarditis.

An 80-year-old woman presented with rare immunoglobulin G4 (IgG4)-related constrictive pericarditis. She underwent pericardiectomy, pericardiotomy, and crosshatching incision of the epicardium using an ultrasonic wave scalpel suitable for the feature of IgG4-related disease. Thereafter, her cardiac function improved remarkably. Additional corticosteroid therapy contributed to maintaining her healthy condition. Definitive diagnosis was based on novel organ-specific criteria. Herein, we highlight that the most important point in the pathological diagnosis of IgG4-related constrictive pericarditis is to determine the presence of IgG4-positive plasma cell infiltration and storiform fibrosis or obstructive phlebitis specific to chronic inflammation.

Concordance of the histological diagnosis of type 1 autoimmune pancreatitis and its distinction from pancreatic ductal adenocarcinoma with endoscopic ultrasound-guided fine needle biopsy specimens: an interobserver agreement study.

The histological diagnosis of type 1 autoimmune pancreatitis (AIP) based on the findings obtained by an endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) is feasible, but the diagnostic consistency of this method has not been confirmed. We determined the interobserver agreement among 20 pathologists regarding the diagnosis of type 1 AIP, including the distinction from pancreatic ductal adenocarcinoma (PDAC) using large tissue samples obtained by EUS-FNB. After guidance for diagnosing AIP with biopsy tissues was provided, a round 2 was performed. The median sensitivity and specificity for diagnosing PDAC vs. non-neoplastic diseases were 95.2% and 100%, respectively. In groups of specialists (n = 7) and the generalists (n = 13), Fleiss' к-values increased from 0.886 to 0.958 and from 0.750 to 0.816 in round 2. The concordance was fair or moderate for obliterative phlebitis and storiform fibrosis but slight for ductal lesion of type 1 AIP. Discordant results were due to ambiguous findings and biopsy tissue limitations. Among the specialists, the ratio of cases with perfect agreement regarding the presence of storiform fibrosis increased in round 2, but agreement regarding obliterative phlebitis or ductal lesions was not improved. Although the histological definite diagnosis of type 1 AIP was achieved by most observers in > 60% of the cases, the confidence levels varied. Because some ambiguities exist, the histological diagnostic levels based on the diagnostic criteria of type 1 AIP should not be taken for granted. Guidance is effective for improving accurate PDAC diagnoses (notably by recognizing acinar-ductal metaplasia) and for evaluating storiform fibrosis.

Regional disturbance of the distribution of T regulatory cells and T helper cells associated with irregular-shaped germinal centers in immunoglobulin G4-related sialadenitis.

Although many germinal centers (GCs) have been reported in immunoglobulin (Ig) G4-related disease, the significance of GCs in IgG4-related disease has not received attention. Both T follicular regulatory cells (Tfr), which are regulatory T cells (Treg) in GCs, and T follicular helper cells (Tfh) produce the cytokine interleukin (IL)-10 and regulate GC development. In whole-slide image analysis in surgical specimens using immunohistochemistry, IgG4-related sclerosing sialadenitis (IgG4-SS, n = 17) was characterized by markedly numerous, large, and irregular-shaped GCs with increased IL-10 + cells and Tfr and Tfh in the total area of the salivary gland compared with controls, including patients with chronic sialadenitis (n = 17) and Sjögren syndrome (n = 15). In particular, the central area of GC in IgG4-SS showed a higher Tfr number and Tfr/Tfh ratio than controls. The number of Tfr in the central area was significantly correlated with the number of IgG4 + plasmacytes and the number, size, and irregularity of GCs. In the mantle area, which surrounds GCs, IgG4-SS showed a higher Treg number and Treg/T helper cells (Th) ratio than controls. In IgG4-SS, the Treg/Th ratio was highest in the mantle area outside GCs and the Tfr/Tfh ratio was highest in the central area inside GCs. However, in controls, the Treg/Th ratio gradually decreased from outside to inside GCs. Our findings reveal that the morphological abnormality of GCs and the characteristic localization and altered balance of Treg and Th in the different compartments of inside and outside GCs would be the novel hallmarks of IgG4-SS.

Suitability of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration versus Paired Transbronchial Biopsy Specimens for Evaluating Programmed Death Ligand-1 Expression in Stage III and IV Lung Cancer: A Comparative Retrospective Study.

Objectives: Cancer cells usually escape tumor-reactive T-cell responses using immune checkpoint proteins, such as programmed death protein-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1). These proteins can be blocked by immune checkpoint inhibitors (ICIs); the decision on ICI-based first-line treatment for advanced lung cancers depends on the PD-L1 levels in tumor specimens. Determining the PD-L1 expression conventionally requires histological specimens from resected tumors and core biopsy specimens. Non-small cell lung cancer (NSCLC) is usually diagnosed at stage III or IV; therefore, only small biopsy specimens, such as those obtained via endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are available. However, the suitability of EBUS-TBNA specimens determining the PD-L1 expression levels in advanced lung cancers remains unclear. Materials and Methods: Here, we investigated the concordance rate of PD-L1 expression between EBUS-TBNA and matched transbronchial biopsy (TBB) specimens. Using the 22C3 anti-PD-L1 antibody (immunohistochemistry), we determined the PD-L1 expression levels in paired specimens obtained from 69 patients (50 with advanced NSCLC and 19 with small cell lung cancer [SCLC]), as well as the efficacy of ICIs in these patients. Results: The concordance rate of PD-L1 expression between the EBUS-TBNA and TBB specimens was 78.3%. The κ values referent to the PD-L1-positive expression rate between EBUS-TBNA and TBB specimens were 0.707 and 0.676 at cutoff limits of ≥1% and ≥50%, respectively. Among the 19 SCLC patients, 16 (84.2%) exhibited no PD-L1 expression in both EBUS-TBNA and TBB specimens. Notably, the progression-free survival of patients with ≥50% PD-L1 expression in the paired specimens who received ICI treatment was 8.3 months. Conclusion: Collectively, our results validate the use of EBUS-TBNA specimens for the determination of the PD-L1 expression levels in the context of NSCLC and SCLC.

Guidance for diagnosing autoimmune pancreatitis with biopsy tissues.

The biopsy-based diagnosis of autoimmune pancreatitis (AIP) is difficult but is becoming imperative for pathologists due to the increased amount of endoscopic ultrasound-guided biopsy tissue. To cope with this challenge, we propose guidance for the biopsy diagnosis of type 1 AIP. This guidance is for pathologists and comprises three main parts. The first part includes basic issues on tissue acquisition, staining, and final diagnosis, and is intended for gastroenterologists as well. The second part is a practical guide for diagnosing type 1 AIP based on the AIP clinical diagnostic criteria 2018. Inconsistent histological findings, tips for evaluating IgG4 immunostaining and key histological features including the ductal lesion and others are explained. Storiform fibrosis and obliterative phlebitis are diagnostic hallmarks but are sometimes equivocal. Storiform fibrosis is defined as spindle-shaped cells, inflammatory cells and fine collagen fibers forming a flowing arrangement. Obliterative phlebitis is defined as fibrous venous obliteration with inflammatory cells. Examples of each are provided. The third part describes the differentiation of AIP from pancreatic ductal adenocarcinoma (PDAC), focusing on histological features of acinar-ductal metaplasia in AIP, which is an important mimicker of PDAC. This guidance will help standardize pathology reports of pancreatic biopsies for diagnosing type 1 AIP.

Exacerbation of immunoglobulin G4-related inflammatory abdominal aortic aneurysm after endovascular repair.

A 78-year-old male was admitted to our hospital with lumbar pain and was found to have an abdominal aortic aneurysm (AAA) and femoral artery aneurysm (FAA). Initially, the patient underwent endovascular aneurysm repair (EVAR) for the AAA and aneurysmectomy for the FAA. The FAA was diagnosed by histology as immunoglobulin G4-related disease (IgG4-RD). The preoperative serum IgG4 level was within the normal range, although a slight serum interleukin-6 (IL-6) elevation was observed. Four years later, the AAA-sac diameter had expanded and the serum levels of both IgG4 and IL-6 levels had increased. Six years after the initial EVAR, aneurysmorrhaphy of AAA-sac was performed. The resected specimen revealed adventitial fibrosis and prominent lymphoplasmacytic infiltrate with regulatory T cells, satisfying histological diagnostic criteria for IgG4-RD. Immunoreactive matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, and IL-6 were detected within numerous spindle cells in the adventitia of both the FAA and the AAA-sac. Five months after the aneurysmorrhaphy, the residual AAA-sac was again enlarged with a thickened wall that accumulated [18 F] fluoro-2-deoxy-D-glucose (FDG-PET) on positron emission tomography; these findings were paralleled by increased levels of serum IgG4 and IL-6. Therefore, persistent inflammation after EVAR may be attributed to the inflammatory sequelae of IgG4-RD.

Integrated genetic and epigenetic analysis of cancer-related genes in non-ampullary duodenal adenomas and intramucosal adenocarcinomas.

The molecular and clinical characteristics of non-ampullary duodenal adenomas and intramucosal adenocarcinomas are not fully understood because they are rare. To clarify these characteristics, we performed genetic and epigenetic analysis of cancer-related genes in these lesions. One hundred and seven non-ampullary duodenal adenomas and intramucosal adenocarcinomas, including 100 small intestinal-type tumors (90 adenomas and 10 intramucosal adenocarcinomas) and 7 gastric-type tumors (2 pyloric gland adenomas and 5 intramucosal adenocarcinomas), were investigated. Using bisulfite pyrosequencing, we assessed the methylation status of CpG island methylator phenotype (CIMP) markers and MLH1. Then using next-generation sequencing, we performed targeted exome sequence analysis within 75 cancer-related genes in 102 lesions. There were significant differences in the clinicopathological and molecular variables between small intestinal- and gastric-type tumors, which suggests the presence of at least two separate carcinogenic pathways in non-ampullary duodenal adenocarcinomas. The prevalence of CIMP-positive lesions was higher in intramucosal adenocarcinomas than in adenomas. Thus, concurrent hypermethylation of multiple CpG islands is likely associated with development of non-ampullary duodenal intramucosal adenocarcinomas. Mutation analysis showed that APC was the most frequently mutated gene in these lesions (56/102; 55%), followed by KRAS (13/102; 13%), LRP1B (10/102; 10%), GNAS (8/102; 8%), ERBB3 (7/102; 7%), and RNF43 (6/102; 6%). Additionally, the high prevalence of diffuse or focal nuclear ß-catenin accumulation (87/102; 85%) as well as mutations of WNT pathway components (60/102; 59%) indicates the importance of WNT signaling to the initiation of duodenal adenomas. The higher than previously reported frequency of APC gene mutations in small bowel adenocarcinomas as well as the difference in the APC mutation distributions between small intestinal-type adenomas and intramucosal adenocarcinomas may indicate that the adenoma-carcinoma sequence has only limited involvement in duodenal carcinogenesis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Efficacy and limitations of the histological diagnosis of type 1 autoimmune pancreatitis with endoscopic ultrasound-guided fine needle biopsy with large tissue amounts.

OBJECTIVES: We examined the efficacy and limitations of acquiring large specimens by endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) for diagnosing type 1 autoimmune pancreatitis (AIP). METHODS: Patients from 12 institutions with non-neoplastic diseases or pancreatic ductal adenocarcinoma (PDAC) with large EUS-FNB specimens were investigated. Slides stained with hematoxylin-eosin, elastic, IgG4, and IgG stains were evaluated. The IgG4- and IgG-positive cell numbers were counted in three foci. The diagnoses were based on the Japan Pancreas Society 2011 (JPS 2011) criteria and the International Consensus Diagnostic Criteria (ICDC). RESULTS: We analyzed 85 non-neoplastic (definite type 1 AIP in 73/85 based on the ICDC) cases and 64 PDAC cases. IgG4-positive cells were numerous (>10 in 85.9%), and the IgG4/IgG ratios were high (>40% in 81.2%). Plasma cell crushing by an artifact caused unsuccessful immunostaining, notably in smaller samples. Tissue lengths were an important factor for the presence of storiform fibrosis and obliterative phlebitis, but storiform fibrosis was equivocal even in large tissues. A definite or possible histological diagnosis was achieved in 45.9% (39/85) and 41.2% (35/85), respectively, and contributed to the definite final diagnosis of type 1 AIP in 33.3% (ICDC) and 55.6% (JPS 2011) in cases with segmental/focal lesions. In the PDAC group, >10 IgG4-positive cells was rare (2/58), but elastic stains revealed fibrous venous occlusions in 10.3% (6/58). CONCLUSIONS: EUS-FNB with large tissue amounts was useful for diagnosing type 1 AIP, notably by facilitating successful IgG4 immunostaining, but definite diagnosis may not be achieved even in cases with large specimens.

Adventitial matrix metalloproteinase production and distribution of immunoglobulin G4-related abdominal aortic aneurysms.

OBJECTIVE: IgG4-related diseases are systemic inflammatory fibrous lesions characterized by elevated serum IgG4 and infiltration of IgG4-positive plasmacytes. They can manifest in vascular lesions as frequently formed aneurysms with prominent thickening of the adventitia (IgG4-related abdominal aortic aneurysm; IgG4-AAA). Matrix metalloproteinases (MMPs) degrade the extracellular matrix, mainly in the tunica media, resulting in destruction of aortic structures to cause enlargement of the aneurysm. However, the expression of adventitial MMPs in IgG4-AAAs is poorly understood. METHODS: MMPs and MMPs-presenting cells in the adventitia of IgG4-AAAs (n = 19) of human surgical specimens were evaluated by immunohistochemistry and dual messenger RNA in situ hybridization. The results were compared with those from control groups of non-IgG4-related inflammatory AAA (n = 18), atherosclerotic AAA (aAAA; n = 11), and autopsy cases (n = 11). Preoperative serum MMPs levels of these groups were compared with the histologic data. RESULTS: Expression of MMP-9, MMP-2, and MMP-14 at the protein and messenger RNA levels in the adventitia was significantly higher in IgG4-AAAs than in controls. Other MMPs were scarce. The total number of MMP-9-positive cells was positively correlated with the diameter of the aneurysm (R = 0.461; P = .031), the adventitial thickness (R = 0.688; P < .001), and the number of IgG4-positive cells (R = 0.764; P < .001). Within lymphoid follicles, MMP-9-presenting cells were predominantly detected in large follicular dendritic cells, followed by histiocytes, fibroblasts, and plasmacytic dendritic cells. Outside lymphoid follicles, fibroblasts, and histiocytes mainly expressed MMP-9, and tissue dendritic cells also produced MMP-9. The levels of MMP-9 derived from follicular dendritic cells and histiocytes and plasmacytic dendritic cells outside lymphoid follicles were significantly higher in IgG4-AAA group than in other groups. Expression of adventitial MMP-2 and MMP-14 by histiocytes and fibroblasts was predominantly detected outside lymphoid follicles. Serum MMP-9 levels were significantly higher in IgG4-AAAs (835 ng/mL) than in controls, and correlated with serum IgG4 levels and the total numbers of adventitial MMP-9-positive cells, whereas serum MMP-2 levels did not differ among the three aneurysmal groups. CONCLUSIONS: MMP-9 production in adventitial immune cells concerning lymphoid follicles was characteristic of IgG4-AAAs and might work in its activity with aneurysmal dilatation and adventitial thickening. Expressions of adventitial MMP-2 and MMP-14 were detected in histiocytes and fibroblasts outside lymphoid follicles, and were less concerned with the activity of IgG4-AAAs.

Clinical and Pathological Characteristics of IgG4-Related Periaortitis/Periarteritis and Retroperitoneal Fibrosis Diagnosed Based on Experts' Diagnosis.

IgG4-related disease is a systemic disease, characterized by elevation of serum IgG4 and, histopathologically, massive infiltration of IgG4+ lymphocyte and plasma cell infiltration, storiform fibrosis, causing enlargement, nodules or thickening. It may affect various organs simultaneously or metachronously. Here we analyzed the clinical and pathological characteristics of 99 patients diagnosed with IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis. Of 99 patients (women/men, 15/84; mean age 67.3±9.5 years), 33 were diagnosed based on the histopathological findings of perivascular/retroperitoneal lesions, 50 were diagnosed based on the characteristic imaging findings of perivascular/retroperitoneal lesions and the presence of definitive IgG4-related disease in other organ(s), and the remaining 16 patients were diagnosed by experts based on the characteristic imaging findings of perivascular/retroperitoneal legions, serological findings, response to glucocorticoid treatment, and/or the presence of suspected IgG4-related disease in other organ(s). According to the new organ-specific criteria proposed by experts, 73 (73.7%) diagnoses were categorized to be definitive, and 6 (6.1%) and 17 (17.2%) diagnoses were categorized to be probable and possible, respectively. Further analyses are needed to clarify the optimal diagnostic and therapeutic strategy of IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis. (This is a translation of J Jpn Coll Angiol 2018; 58: 117-129.).

Clinicopathological features of immunoglobulin G4-related pleural lesions and diagnostic utility of pleural effusion cytology.

OBJECTIVE: Immunoglobulin (Ig)G4-related disease is a recently described systemic immune-mediated fibro-inflammatory disease that frequently occurs in tumorous form. Herein, we elucidated the clinicopathological and cytological characteristics of IgG4-related pleural lesions (PLs). PATIENTS AND METHODS: Among 22 patients with fibro-inflammatory PLs of idiopathic aetiology, eight cases were diagnosed as IgG4-PL and the remaining 14 as non-IgG4-PL according to comprehensive diagnostic criteria for IgG4-related disease. Cell block examination of pleural effusion (CBPE) was performed in five patients with IgG4-PL and in six with non-IgG4-PL. Both groups were compared in terms of clinical presentation, laboratory data, histopathological features of resected pleura, and cytological features of pleural effusion (PE). RESULTS: PE was the most common (six patients, 75%) clinical presentation of IgG4-PL. IgG4-PL comparatively showed significantly more frequent concomitant allergic disease (P = .021), higher serum IgE levels (P = .012), higher adenosine deaminase levels in pleural fluid (P = .005), and rare spontaneous recovery without treatment (P = .046). The IgG4-PL group was histologically characterised by thicker fibrous pleura, storiform fibrosis, and infiltration of regulatory T cells, eosinophils and basophils. Using CBPE, IgG4-PL was cytologically distinct with numerous IgG4+ cells and eosinophils. The cytology of CBPE positively correlated with the histology of pleural tissue in the number of IgG4+ cells and eosinophils (R = .769 and .803, respectively). CONCLUSION: IgG4-PL frequently presents with PE and is histologically and cytologically characterised by abundant infiltration of IgG4+ cells and eosinophils. We believe that CBPE with immunohistochemistry/special staining could assist in the auxiliary diagnosis of IgG4-PL.

IgG4-related periaortitis/periarteritis: An under-recognized condition that is potentially life-threatening.

Periaortitis and periarteritis are one of the clinical features of IgG4-related disease. Such vascular manifestations are reported to be present in 10-30% of overall IgG4-related disease, and they may also appear as an isolated lesion of IgG4-related disease. As other types of large vessel vasculitis, IgG4-related vasculitis may cause significant clinical consequences. On the other hand, the diagnosis of IgG4-related periaortitis/periarteritis seems to have been made on the basis of different diagnostic criteria in reported studies; thus far, difficulty seems to be present in assessing the true frequency of the disease as well as determining the optimal therapeutic strategy. In this review, in addition presenting the clinical and pathological features of IgG4-related periaortitis/periarteirtis, we would like to discuss on what kind of points should be resolved for the better understanding of vascular involvement of IgG4-related disease in terms of diagnosis and treatment.

A Case of Aortic Stenosis with Serum IgG4 Elevation, and IgG4-Positive Plasmacytic Infiltration in the Aortic Valve, Epicardium, and Aortic Adventitia.

A 74-year-old man was admitted for preoperative screening of aortic stenosis. Five months before this admission, he was found to have elevated serum immunoglobulin G4 (IgG4; 2,010 mg/dL). Computed tomography (CT) showed a soft tissue mass surrounding the abdominal aorta, suggestive of IgG4-related periaortitis. CT coronary angiography showed perivascular thickening of the right coronary artery, and subsequent coronary angiography showed a multi-vessel disease. The patient underwent aortic valve replacement and coronary bypass surgery. Immunohistochemical analysis showed IgG4-positive plasmacytic infiltration in specimens from the aortic valve, epicardium, and aortic adventitia, suggestive of the possible role of IgG4-related immune inflammation for the pathogenesis.