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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.

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.

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.

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 β‐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.

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.

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.

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 relevance This retrospective multicenter study analyzed adventitial matrix metalloproteinases (MMPs) production in 19 patients with IgG4-related abdominal aortic aneurysms (AAAs) and 40 control cases. Adventitial MMP-9 production by various kinds of immune cells was increased in patients with IgG4-related AAAs and concerned with IgG4-AAA activity to cause aneurysmal progression and adventitial fibrosis, compared with aAAA. Serum MMP-9 levels reflected histologic MMP-9. Adventitial MMP-2 and MMP-14 were less concerned with IgG4-AAA activity. Thus, for IgG4-AAA patients, monitoring serum MMP-9 level might be the exacerbating factors related to adverse events during the treatment course.

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.

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.

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 Sjogren 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.

A 65-year-old man was admitted for productive cough and dyspnea. Bilateral pleural effusions were observed on chest X-ray. Although the bilateral pleural effusions were exudative with an increased number of lymphocytes, bacterial culture and polymerase chain reaction analysis for Mycobacterium tuberculosis were negative. Immunological examinations showed high levels of immunoglobulin G4 (IgG4) in both serum and pleural effusion fluid. Pathologic evaluation of a left pleural biopsy specimen using hematoxylin and eosin staining and immunohistochemical staining showed fibrosis-associated lymphoplasmacytic infiltration, 50 IgG4-positive plasma cells per high-power field, and an IgG4/IgG ratio of 40%. Thus, a diagnosis of IgG4-related pleuritis without other systemic manifestations was established. The bilateral pleural effusion improved following corticosteroid therapy. This is a rare case of IgG4-related pleuritis with no other organ involvement.

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.

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.).

Immunoglobulin (IgG) 4-related diseases (IgG4-RDs) are fibro-inflammatory conditions characterized by tumorous swelling and serum IgG4 levels. Intrapelvic IgG4-RD has been subclassified according to the localization site and aortic shape as IgG4-related aortic aneurysms (IgG4-AAs), periaortitis (IgG4-PA), and retroperitoneal fibrosis (IgG4-RF). The IgG4-AA pathogenesis would involve interleukin (IL)-6 upregulation, and Th2-predominant and Treg-activated immune conditions. We characterized the features of intrapelvic IgG4-RD lesions, including presence of vascular lesions. The clinical, serological, and pathological features, including cytokines concerning Th1/2 and Treg (IL-4, IL-6, IL-10, IL-13, and interferon-gamma) of patients with IgG4-AAs (n = 24), IgG4-PA (n = 8), and IgG4-RF (n = 10) were retrospectively compared. Clinical symptoms, such as low-grade fever, abdominal/lumber pain, and anemia, were frequently detected in IgG4-AAs but rarely in IgG4-RF. Serum IL-6 and C-reactive protein (CRP) were significantly higher in IgG4-AAs and IgG4-PA than in IgG4-RF. Pathologically, IL-6+ cells were more frequently detected in IgG4-PA and IgG4-AAs than in IgG4-RF. There were no noteworthy differences in the clinical complications, white blood cell counts, serum IgE, and serum and immunopositive cells of other cytokines between the subgroups. Among IgG4-AAs and IgG4-PA, serum IL-6 and IL-6+ cells correlated with CRP, aortic diameter, and periaortic fibrosis. IgG4-AA and IgG4-PA, but not IgG4-RF, were characterized by "inflammatory" features, such as increased CRP and serum/pathological IL-6, and clinical inflammatory symptoms; thus, IgG4-AA and IgG4-PA belong to the same group as IgG4-related vascular disease. High levels of CRP and IL-6 would be hallmarks of IgG4-related vascular disease.

Objective Immunoglobulin (Ig) G4-related aortic aneurysms (IgG4-AAs) are a special aortic aneurysm among IgG4-related diseases (IgG4-RDs), which are inflammatory and fibrous conditions characterized by tumorous swelling of affected organs and high serum IgG4 concentrations. Recently, IgG4-RD pathogenesis was shown to be associated with T-helper-2 (Th2) and regulatory T (Treg) dominant cytokine production, such as interleukin (IL)-4, IL-10, and IL-13. IL-6 is a key proinflammatory cytokine contributing to lymphocyte and plasmacyte maturation and to atherosclerosis and aneurysm development. We serologically and histopathologically evaluated the cytokine profile in IgG4-AA patients. Methods Patients with IgG4-AAs (n = 10), non-IgG4-related inflammatory abdominal aortic aneurysms (non-IgG4-AAAs; n = 5), atherosclerotic AAAs (aAAAs; n = 10), and normal aortas without dilatation (n = 10) were examined for serum IL-10, IL-13, and IL-6 levels. Resected aortic tissues were evaluated for cluster of differentiation (CD) 34 (in the endothelial cells and mesenchymal cells) and CD163 (by macrophages) expression using immunohistochemistry and in situ hybridization. Results Serum IL-10 levels were rather higher in IgG4-AA patients (median, 1.3 pg/mL) than in non-IgG4-AAA and aAAA patients and in patients with normal aortas. Elevated serum IL-13 levels relative to standard values were detected in two IgG4-AA patients but not in the other groups. Cells immunopositive for IL-10 and IL-13 were more frequent in IgG4-AAs and significantly correlated with serum IgG4 levels. Serum IL-6 levels (median, 78.5 pg/mL) were also significantly higher in IgG4-AA patients than in non-IgG4-AAA and aAAA patients and control patients with normal aortas ( P = .01, P = .001, and P = .004, respectively). They positively correlated with serum IgG4 levels and adventitial thickness, but other cytokines did not. The number of IL-6-immunopositive cells in the adventitia was significantly higher in IgG4-AA patients (median, 17.8/high-power field) than in aAAA patients or patients with normal aortas ( P =.001 and P = .002, respectively). In situ hybridization confirmed frequent IL-6 messenger (m)RNA expression in the endothelium, mesenchymal cells, and histiocytes in IgG4-AA adventitia. In the same cells of IgG4-AAs, coexpression of IL-6 and CD34 mRNA or CD163 mRNA was detected. Conclusions The cytokine profiles of IgG4-AA patients had two characteristics: local IL-10 and IL-13 upregulation in IgG4-AAs was related to Th2 and Treg-predominant cytokine balance, similar to other IgG4-RDs, and IL-6 upregulation in the adventitia was characterized by activated immune reactions in IgG4-AA patients. IL-6 synthesis, through contributions of mesenchymal cells and macrophages in the adventitia, is strongly involved in IgG4-AA pathogenesis or progression, or both.

Immunoglobulin G4-related diseases (IgG4-RD) are systemic inflammatory conditions, characterized by high serum IgG4 concentrations, and pathologically IgG4-positive plasmacytes infiltrations and storiform fibrosis. We described IgG4-related inflammatory abdominal aortic aneurysm in 2008, and revealed the existence of vascular lesions. IgG4-related vascular lesions frequently occur in the aorta and branching medium-sized arteries with or without aneurysmal change. The inflammatory lesion mainly involves in the adventitia, indicating remarkable adventitial fibrous thickening with infiltration of inflammatory cells. Clinical symptoms associated with IgG4-related vascular lesions might be fever, abdominal pain, hydronephrosis, or few subjective symptoms. Comprehensive diagnostic criteria is applied according to image findings of thickening lesions, high serum IgG4 levels, and histopathological findings. As a treatment, open surgical repair or endovascular aneurysm repair is performed for the aneurysmal cases, and steroid administration is used for the cases with strong inflammation. This disease can lead to a lethal situation due to the rupture following aneurysmal formation, thus special attention is needed unlike IgG4-RD occupying in the other organs. (This is a translation of Jpn J Vasc Surg 2017; 26: 129-134.).

Several reports on immunoglobulin (Ig)G4-related disease (IgG4-RD) with gastrointestinal involvement (IgG4-related gastrointestinal disease; IgG4-GID) have been published, although this entity has not been fully established clinicopathologically. Thus, we carried out a multicenter survey. Patients with possible IgG4-GID who underwent resection were collected. Histologic slides were reevaluated, and eight cases with diffuse lymphoplasmacytic infiltration but without numerous neutrophils, granulations or epithelioid granulomas were further analyzed. Overall, the IgG4 counts (87–345/high-power field) and IgG4/IgG-positive ratio were high (44–115%). The demographic findings included advanced age among the patients (55–80 years) and male preponderance (six cases). Six lesions (five gastric, one esophageal), consisting of lymphoplasmacytic infiltration with neural involvement in the muscularis propria and/or bottom-heavy plasmacytosis in the gastric mucosa, were histologically regarded as highly suggestive of IgG4-RD. Storiform fibrosis and obliterative phlebitis were found in two cases, and the former gave rise to a 7-cm-sized inflammatory pseudotumor (IPT) in one case. Ulceration and carcinoma co-existed in three and two lesions, respectively. All the patients had other organ involvement (OOI), and serum IgG4 levels were markedly elevated (four of five patients). The remaining two cases with gastric IPTs featuring reactive nodular fibrous pseudotumor or nodular lymphoid hyperplasia were regarded as possible cases of IgG4-RD because of the histologic findings and lack of OOI. IgG4-GID is found in the setting of IgG4-RD, often with ulceration or cancer. Characteristic histologic findings are observed in the muscularis propria and gastric mucosa. Cases with IPT may be heterogeneous, and there may be mimickers of IgG4-GID.

Purpose: To compare the follow-up results of endovascular aneurysm repair (EVAR) vs open surgery (OS) for inflammatory abdominal aortic aneurysms (IAAAs) with regard to immunoglobulin G4–related di...

Myxoinflammatory fibroblastic sarcoma (MIFS) is rare low-grade soft-tissue tumor that occurs in extremities. Clinically it is difficult to differentiate from benign lesions, such as nodular fasciitis, and malignant tumors, such as liposarcoma. We report a case of MIFS in the forearm of a 34-year-old man. The resected tumor measured 5.3 × 2.7 × 2.5 cm3, had a lobular structure with indistinct boundary, and consisted of a large amount of translucent and yellow mucous-like substrate. Cytological examination of a preoperative puncture aspiration specimen showed histiocyte- and fibroblast-like tumor cells in a mucous-like matrix together with scattered lipoblast- and ganglion-like cells. Nuclear chromatin of the tumor cells showed a fine granular appearance but no notable hyperchromasia. There were no clear malignant findings. On Giemsa staining of the tumor cells, there were fine granular and hyaline intracytoplasmic substances that showed purple to reddish-purple metachromaticity. Prominent inflammatory cells were not observed in the specimens. MIFS should be considered in the differential diagnosis for a myxoid tumor in the extremities.

Diagnosing sepsis can be very difficult and without prompt treatment, sepsis frequently results in death. No definitive biomarker for diagnosing sepsis currently exists, although the use of various biomarkers, includ- ing procalcitonin (PCT), as diagnostic indicators has been considered valuable. The biomarker presepsin (P- SEP) has gained attention as a diagnostic tool for sepsis since health insurance coverage approval in Japan in 2014. In this study, we categorized 156 children into five groups based on the presence or absence of sys- temic inflammatory response syndrome and infection, and compared the levels of P-SEP and PCT among these groups. Furthermore, they were categorized into five groups based on the diagnosed disease, and the P-SEP and PCT levels were compared among these groups. The P-SEP levels exceeded the cut-off value in all patients with sepsis, and patients of other groups hardly exceeded the cut-off value. In contrast, the PCT levels increased in patients with sepsis, but those in other groups, particularly in local infection, also exceed- ed the cut-off value. Similarly, during the diagnosed disease classification, PCT levels also increased in Ka- wasaki disease. In conclusion, P-SEP could be a useful biomarker for the diagnosis of sepsis in children and should be studied further. [Short Communication].

Introduction Sevelamer is an anion exchange resin used to treat hyperphosphatemia. A common adverse effect of sevelamer is constipation. According to a review of the available literature, colon perforation associated with this resin agent was less common. Presentation of case A 66-year-old man complaining of lower abdominal pain was transferred to our hospital. The patient had been undergoing hemodialysis for chronic renal failure due to rapidly progressive glomerulonephritis, and had been receiving sevelamer hydrochloride 4.5 g/day for 8years as treatment for hyperphosphatemia. Abdominal computed tomography revealed ascites, free air in the abdominal cavity, multiple diverticula of the sigmoid colon, as well as increased fat tissue surrounding the sigmoid colon. We diagnosed colonic perforation and performed emergency surgery, which revealed a 5 × 5 mm perforation in the sigmoid colon surrounded with soft stool. Histopathologically, sevelamer crystals were detected at the perforation site. Discussion We theorize that physical stimulation by sevelamer crystals contributed to colon perforation at the already vulnerable diverticulum site. Conclusion When sevelamer is administered to patients with hemodialysis, the risk of intestinal perforation should be considered., Highlights • Sevelamer may contribute to colonic perforation in hemodialysis patients. • Our patient underwent resection of a perforated portion of sigmoid colon. • Histopathologically, sevelamer crystals were detected at the site of perforation.

Syringocystadenoma papilliferum (SP) is a rare and benign cutaneous adnexal tumor, particularly infrequent in the breast, with only one previous case affecting a female nipple. The present tumor was located at the nipple of a 23-year-old man. This tumor consisted of several cysts and satisfied the characteristic microscopic features of SP: numerous papillary projections of double-layered glandular epithelium and a fibrovascular core with lymphoplasmacytic infiltration. Interestingly, many cysts were lined by stratified squamous epithelium with transition to glandular epithelium. Immunohistochemically, almost all structures were negative for gross cystic disease fluid protein-15, androgen receptor, estrogen receptor and progesterone receptor. The immunoprofiles of glandular epithelium were inadequate for the mature two-cell pattern of skin adnexal glands and mammary glands; most basal cuboidal cells lacked α-smooth muscle actin, and some of the luminal columnar cells were negative for cytokeratin 7 and cytokeratin 19. The clinical and pathological features of this uncommon tumor are presented, along with a review of the literature of SP of the breast.

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.

Recently, morbidities due to primary cytomegalovirus (CMV) infection have increased in young Japanese adults because of decreased anti-CMV antibodies in them. CMV infections are typically resolved naturally in immunocompetent individuals, and complications rarely occur. Here we present the case of an immunocompetent adult with CMV infection complicated by splenic infarctions and an esophageal ulcer.A 37-year-old male complaining of a prolonged fever and liver injury was admitted to hospital for a closed examination. The patient had general malaise and mild appetite loss but no abdominal pain. Symptoms of infectious mononucleosis, including liver injury, appearance of atypical lymphocytes in the blood, and hepatosplenomegaly, were observed. A primary CMV infection was confirmed by CMV-IgM positive and CMV-IgG negative serological tests. Enhanced abdominal computed tomography confirmed hepatitis and splenic infarction, and an upper gastrointestinal endoscopy revealed an esophageal ulcer. The patient exhibited no predisposing risk factors for thrombosis, and he was diagnosed with splenic infarctions associated with CMV infection. Because the patient was immunocompetent, he underwent symptomatic therapy without antiviral or anticoagulant therapies. The treatment improved his overall condition. Including the present case, only 11 cases of CMV infections with splenic infarction in immunocompetent individuals have been reported. Contrary to what is observed in immunocompromised hosts, upper gastrointestinal lesions with CMV infection are rare in immunocompetent individuals. The esophageal lesion observed in our patient was a typical punched-out ulcer. The immunohistochemical staining of the tissue biopsies revealed that the ulcer was associated with CMV.Although splenic infarctions and esophageal ulcers are rare, they should be considered as potential complications accompanying CMV infection in immunocompetent individuals. The administration of symptomatic therapy should be considered even when the patient is immunocompetent.

Myxoinflammatory fibroblastic sarcoma (MIFS) is rare low-grade soft-tissue tumor that occurs in extremities. Clinically it is difficult to differentiate from benign lesions, such as nodular fasciitis, and malignant tumors, such as liposarcoma. We report a case of MIFS in the forearm of a 34-year-old man. The resected tumor measured 5.3 × 2.7 × 2.5 cm

Purpose To report a rare and complicated case of immunoglobulin (Ig) G4-related periaortitis involving both the aortic wall and the retroperitoneum without aneurysmal formation. Case report A 79-year-old man with IgG4-related periaortitis suffered aortic rupture despite a normal caliber aorta after 6 months of steroid therapy (20 mg/d). Endovascular repair with an aortic cuff sealed the rupture. Steroid therapy was halted 2 weeks later due to infection. Four months later, a biopsy during esophagogastroduodenoscopy to investigate gastrointestinal bleeding suggested a relapse of IgG4-RD in the duodenum. Subsequent aortoduodenal fistula formation proved fatal. Generally, IgG4-related periaortitis does not result in such complications due to the absence of aneurysm formation and a thick aortic wall. Conclusions Our report highlights a rare case of IgG4-related periaortitis where complications resulted following steroid therapy and surgical intervention, emphasizing the difficulties in dealing with IgG4-related cardiovascular lesions.

Aim Primary biliary cirrhosis (PBC) is characterised by antimitochondrial antibody against the pyruvate dehydrogenase complex (PDC) and chronic non-suppurative destructive cholangitis (CNSDC). Pyruvate oxidation to acetyl-CoA by PDC is a key step in the glycolytic system. Oestrogen-related receptor-α (ERRα) is functionally activated by inducible coactivators such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and Bcl-3. Moreover, the PGC-1α–ERRα axis interrupts glycolytic metabolism through the upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4), which functionally inhibits PDC-E1α and stimulates fatty acid oxidation. In this study, we investigated the PGC-1α–ERRα axis to clarify PDC dysfunction in CNSDC of PBC. Methods The expression of PGC-1α, Bcl-3, ERRα, PDK4 and PDC-E1α was examined by immunohistochemistry in liver sections from patients with PBC and controls. The expression of these molecules, the activity of mitochondrial dehydrogenase and PDC, and their alterations by starvation, a treatment used to induce PGC-1α expression, were examined in cultured human biliary epithelial cells (BECs). Results The nuclear expression of PGC-1α, Bcl-3 and ERRα was exclusively observed in CNSDC of PBC. Moreover, the expression of PDK4 and PDC-E1α was enhanced in CNSDC of PBC. In cultured BECs, the amplification of Bcl-3 and PDK4 mRNAs by reverse-transcription-PCR and mitochondrial dehydrogenase activity were markedly increased but PDC activity was decreased according to the upregulation of PGC-1α. Conclusions In CNSDC of PBC, the activation of the ERRα–PGC-1α axis was exclusively observed, suggesting the interference of PDC-related glycolytic function and the induction of the fatty acid degradation system. The switching of the cellular energy system is possibly associated with the pathogenesis of CNSDC in PBC.

Recently, our research team proposed a new histologic staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histologic heterogeneity. The present study aimed to confirm the usefulness of the new evaluation system. A total of 152 liver biopsy specimens and clinical data (including outcomes in patients with PBC before treatment with ursodeoxycholic acid) were analyzed with respect to the new system. Staging was evaluated on the basis of 3 histologic components (fibrosis, bile duct loss, and deposition of orcein-positive granules), and grading was assessed on the basis of chronic cholangitis activity and hepatitis activity. Concurrently, the classical systems, that is, the Scheuer and Ludwig staging systems, were also assessed and compared with our new system. PBC cases showed different distributions in each stage of the 3 systems. The new staging and grading system reflected liver dysfunctions before specific treatment. This was on a par with the results obtained using the classical systems. Development of cirrhosis-related conditions correlated well with the new staging system compared with the 2 classical staging systems, and in particular, the amount of deposition of orcein-positive granules could reflect development of cirrhosis-related conditions (scores 0-1 versus scores 2-3 groups, P < .0001). In conclusion, the new PBC staging system was demonstrated to reflect clinicolaboratory features, and its progression was associated with the development of cirrhosis-related conditions. © 2013 Elsevier Inc. All rights reserved.

Background The diagnosis of Immunoglobulin G4 (IgG4)-related disease (IgG4-RD), in general, depends on serum IgG4 concentrations and histopathological findings; therefore, diagnosis of IgG4-RD in cardiovascular organs/tissues is often difficult owing to the risk of tissue sampling. Methods Prevalence of IgG4-positive lymphoplasmacytic infiltration in 103 consecutive cardiovascular surgical samples from 98 patients with various cardiovascular diseases was analyzed immunohistochemically. Results The diagnoses of the enrolled patients included aortic aneurysm (abdominal, n = 8; thoracic, n = 9); aortic dissection (n = 20); aortic stenosis (n = 24), aortic regurgitation (n = 10), and mitral stenosis/regurgitation (n = 17). In total, 10 (9.7%) of the 103 specimens showed IgG4-positive cell infiltration with various intensities; five of these were aortic valve specimens from aortic stenosis, and IgG4-positive cell infiltration was present at >10 /HPF in three of them. In one aortic wall sample from an abdominal aortic aneurysm, various histopathological features of IgG4-RD, such as IgG4-positive cell infiltration, obliterating phlebitis, and storiform fibrosis, were observed. Conclusions IgG4-positive cell infiltration was observed in 9.7% of the surgical cardiovascular specimens, mainly in the aortic valve from aortic stenosis and in the aortic wall from aortic aneurysm. Whether IgG4-positive cell infiltration has pathophysiological importance in the development or progression of cardiovascular diseases should be investigated in future studies.

A 5-year-old Japanese girl presented with a 4-month history of a solid dermal tumor on the left side of her forehead. She had neither diathesis for autoimmune disorders nor family history of alopecia areata. Her left eyebrow and vellus hairs around the tumor had been lost as the tumor grew. Examination revealed a 1 cm, bluish, solid, dermal tumor surrounded by a 5-cm diameter alopecia, where the left eyebrow and the vellus hairs on the forehead were missing (figure 1A). A presumptive clinical diagnosis [...]

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.

Kasashima S, Kawashima A, Ozaki S & Nakanuma Y (2012) Histopathology 60, E51–E57 Expression of 5α-reductase in apocrine carcinoma of the breast and its correlation with clinicopathological aggressiveness Aims: Apocrine carcinomas of the breast frequently lack oestrogen and progesterone receptors and often express androgen receptor. However, little is known about the role of androgen in apocrine carcinoma. Androgen-producing enzymes, such as 5α-reductase (5αR), which converts testosterone locally to the potent androgen dihydrotestosterone, have recently gained attention in studies of the intratumoural actions of androgens. The goal of this study was to examine 5αR expression and its relationship to other clinicopathological factors in apocrine carcinoma. Methods and results: Of 48 cases of infiltrating apocrine carcinoma, 30 cases (62.5%) were immunopositive for 5αR. Twenty-seven of the 5αR-positive cases were also positive for androgen receptor. In comparison to 5αR-negative cases, 5αR-positive cases showed clinicopathological aggressiveness characterized by significantly larger infiltrating tumour size (P = 0.001), higher frequency of lymphatic (P = 0.029) and vascular invasion (P = 0.009), higher histological grade (P = 0.048) and shorter recurrence-free survival time (P = 0.047). No significant differences in nuclear grade, hormonal receptors, human epidermal growth factor receptor 2 (HER2) or p53 protein were detected between two groups. All five cases of intraductal apocrine carcinoma lacked 5αR. Conclusion: Approximately 60% of infiltrating apocrine carcinomas were immunopositive for 5αR. The 5αR-positive apocrine carcinomas were clinicopathologically more aggressive than 5αR-negative cases. Our findings suggest that autocrine androgen synthesis accelerates tumour aggressiveness in apocrine carcinoma.

Ehlers-Danlos syndrome Type IV, the vascular type, is a rare hereditary condition. Major arteries are often affected in this type. In this paper, we present the first case report in the world in which forearm compartment syndrome caused by the bilateral ulnar artery rupture in this type. Successful treatment such as incision of the forearm fascia and ligation of the ulnar artery was performed.

金沢大学医薬保健研究域医学系, Aims: Monocyte chemoattractant protein-1 (MCP-1) is a major chemotactic factor for hepatic stellate cells (HSCs) associated with hepatic fibrosis. In this study, among several fibrogenetic factors derived from biliary epithelial cells (BECs), MCP-1 produced by the biliary innate immune system was found to be most critical in the histogenesis of hepatic fibrogenesis. Methods: Using cultured human BECs, the expression of five fibrogenetic factors including MCP-1 on stimulation with Toll-like receptor ligands, inflammatory cytokines or bile acids was examined. Moreover, in situ detection of MCP-1 and α-smooth muscle actin proteins was performed using sections from normal and diseased livers by immunohistochemistry. Results: All fibrogenetic factors were detected in BECs, but only MCP-1 expression was upregulated, by all the Toll-like receptor ligands, IL-1β, and tumour necrosis factor-alpha. Proliferating bile ductules in interface areas expressed MCP-1 in diseased livers accompanying α-smooth muscle actin-positive activated HSCs. Conclusions: Bile ductules proliferate in various hepatobiliary diseases, and its significance is still unknown. This study demonstrated that BECs in bile ductules could produce MCP-1, particularly, via biliary innate immunity, suggesting that MCP-1 derived from BECs plays an important role in the recruitment of HSCs to interface areas and the activation of HSCs resulting in the progression of periportal fibrosis. Copyright Article author (or their employer) 2011.

IgG4-related systemic disease is a recently proposed entity characterized by high serum IgG4 concentrations, sclerosing inflammation containing numerous IgG4-positive plasmacytes, dramatic responsiveness to steroid therapy, and occurrence of multiple organs. This review described that some cases of inflammatory abdominal aortic aneurysm (IAAA) have similar clinicopathological features that are now considered to represent aortic lesions of IgG4-related systemic disease under the concept of IgG4-related IAAA.IgG4-related IAAA is characterized by high serum IgG4 and immunoglobulin E levels, high titers of antinuclear antibodies, and high prevalence of allergic disorders such as bronchial asthma. The patients show a risk of developing IgG4-related systemic diseases in other organs during their life. Histologically, sclerosing inflammation containing numerous IgG4-positive plasmacytes is observed predominantly in the adventitia. Similar lesions have also been reported in the thoracic aorta and large arteries.Recognition of the fact that IgG4-related systemic disease could involve the vascular lesions offers potential new management of those. However, only 3 years have passed since the first report of IgG4-related IAAA. Further studies are necessary to elucidate other vascular lesions associated with IgG4-related systemic disease, the usefulness of steroid therapy for the management of IgG4-IAAA, and underlying pathological and immunological characteristics.

Background/aims: To clarify the primary biliary cirrhosis (PBC)-specific antigen-presenting mechanism, we examined the distribution and phenotypic characteristics of infiltrating dendritic cells (DCs) with respect to bile ducts and the mechanism of migration in terms of the periductal cytokine milieu and biliary innate immunity. Methods and results: Immunohistochemistry using liver sections from patients with PBC and controls revealed that blood dendritic cell antigen (BDCA)-2 1 plasmacytoid DCs were found mainly in the portal tracts in PBC and the controls, but their distribution was not related to bile ducts. BDCA-1 1 and CD19 � myeloid DCs were also found in portal tracts in PBC and the controls and, in particular, Langerin1Langerhans cells (LCs) were dominantly scattered around or within biliary epithelial layers of the damaged bile ducts in PBC. Moreover, experiments with cultured human biliary epithelial cells (BECs) showed that an LC-attracting chemokine, macrophage inflammatory protein-3a, was produced by BECs in the response to cytokines [interleukin (IL)-1b, tumour necrosis factor-a and IL-17] and pathogen-associated molecular patterns. Conclusions: LCs existing around or within biliary epithelial layers are important as periductal antigen-presenting cells in PBC and the migration of LCs into bile ducts is closely associated with the periductal cytokine milieu and biliary innate immunity in PBC.

Inflammatory abdominal aortic aneurysm (IAAA) is a subtype of abdominal aortic aneurysm (AAA) showing aortic wall thickening and inflammatory cell infiltration.1–5) Idiopathic retroperitoneal fibrosis (IRF) is characterized by fibrous tissue proliferation with an unclear boundary surrounding the aorta and ureter,6–9) and its association with systemic sclerosing disease has been reported.6–8) Because of similar histological features, IAAA is considered to be closely IRF. In the inclusion of these diseases, the spectrum of chronic periaortitis (CP) has been suggested since the initial reports of IAAA.1,7–9) Immunoglobulin G4-related sclerosing disease (IgG4-SD) is a disease group characterized by high serum IgG4 levels, and histological infiltration by many IgG4-positive plasma cells with dense fibrous proliferation.10–12) In 2001, Hamano et al. described that patients with autoimmune pancreatitis have a high serum concentration of IgG4.10) Since then, IgG4-SD has been attracting a lot of attention and has been expanded to general organs.13–17) Now, IgG4-SD is recognized as a systemic sclerosing disease.12) Recently, several cases of IRF have been reported to belong to IgG4-SD,11, 14) thus, we focused on the relationship between IRF and IAAA, and elucidated that IAAA is also partially an IgG4-SD.18, 19) Here, we firstly review the clinicopathological features of IAAA, compare it with atherosclerotic AAA (aAAA), and explain the general concept of IgG4-SD. Next, we describe the differences in subgroups of IgG4-related and non-related cases of IAAA. Next, we mention that IgG4-SD can occur with other vascular lesions. Finally, we discuss that etiopathogenisis of IgG4-related vascular lesions with regard to CP. 1. Disease concept of IAAA There is no doubt that atherosclerotic features are involved in the pathogenesis of AAA, but atherosclerotic features alone are insufficient to induce aneurysm formation, and hemodynamics and factors destroying the wall structures have been investigated. In this report, in order to compare with IAAA, AAA other than IAAA is simply designated as aAAA. Clinically, IAAA accounts for 3–10% of all cases of AAA.3, 5) IAAA often occurs in the 50–60s, and this is 5–10 years younger than that of aAAA. The incidence is higher in men, with a male: female ratio of 7–9:1.1, 3, 5) Many aAAA cases are asymptomatic, whereas IAAA cases often manifest subjective symptoms, such as fever, dull pain and weight loss.2, 3) When pain is acute and severe, differentiation from an impending rupture is necessary.2) IAAA is frequently located in the abdominal aorta lower than the renal artery and may extend to the thoracic aorta and iliac arteries.2) The ureter is frequently involved, and the complication rates with hydronephrosis and urethral disorders are high. Serologically, inflammatory features are observed, such as a high erythrocyte sedimentation rate (ESR) value, and elevation of C-reactive protein (CRP) and white blood cell count (WBC).1, 3) In terms of fever and serological inflammatory findings, it is sometimes difficult to distinguish IAAA from infectious aneurysms (bacterial, fungus, syphilitic and tuberculosis). IAAA and infectious AAA should be very carefully differentiated referring to blood culture examination and the serum procalcitonin level.20) Many IAAA cases are followed for a prolonged period because the tumor size slowly increases, but infectious AAA progresses rapidly and tends to develop multiple aneurysms. Radiologically, IAAA is detected as a dilated aorta with a periaortic mantle and adhesions to adjacent organs. Enhanced computed tomography (CT) revealed a ‘mantle sign’, which is composed of an enhanced inner lumen, a non-enhanced thrombus layer, and an enhanced thickening of the tunica adventitia and surrounding fibrous tissue. Positron emission tomography and computed tomography (PET/CT) are useful to identify inflammatory changes in the aneurismal wall. Imaging has a major role in the diagnosis of IAAA and FDG-PET/CT is regarded as a promising technique to detect the degree of inflammation of the aneurismal wall. As for treatment, strong fibrous adherence with the periaortic organs in IAAA frequently causes surgical difficulties with a high fatality rate.1, 2) Steroid treatment may be recommended when the tumor is small and symptoms are severe. The macroscopic appearance of white glistening perianeurysmal fibrosis with tumorous lesions is characteristic.1–3) Histologically, IAAA is defined by severe thickening of the aortic wall, particularly fibrous proliferation of the tunica adventitia, and lymphocyte and plasma cell infiltration.1) The tunica adventitia thicknesses of the normal aorta and aAAA are thinner than 0.1 mm,18) but this increases to about 5 mm or thicker in IAAA, and the overall aortic wall thickness exceeds 10 mm in many cases.18) The pathogenesis of IAAA remains to be clarified. It was previously considered to be a simple terminal phase of aAAA, that is, some researchers thought that IAAA could not be designated as a subtype because of the absence of significant clinicopathological differences from aAAA.4) However, since IAAA cases complicated by autoimmune diseases and a high antinuclear antibody-positive rate were reported, an association with systemic autoimmune abnormalities has been considered most likely. Familial incidence also occurred at a rate of 6–15%, and an association with human leukocyte antigen-DRB1*15 (HLA-DRB1*15 ) and HLA-DRB1*0404 has been reported.7) Further, an association with local chronic infection has been attracting attention.

Summary Background Extramammary Paget disease is an uncommon skin tumour occurring mostly in the genitoperineal region. Previous reports have shown frequent expression of androgen receptor, suggesting a tumour-proliferative effect of androgens on Paget cells. Androgen-converting enzymes such as 5α-reductase, which locally produces a bioactive androgen, have recently gained attention in studies of the intratumoral actions of androgens. Objectives We investigated correlations between the androgenic microenvironment and invasiveness in extramammary Paget disease, particularly in terms of sex differences. Methods We examined 58 cases of extramammary Paget disease (32 men, 26 women; 42 noninvasive, 16 invasive) using immunohistochemistry for androgen receptor and 5α-reductase. Results In all 58 cases, expression rates were 57% for androgen receptor and 55% for 5α-reductase, with 38% double-positivity for androgen receptor and 5α-reductase. Only 5α-reductase expression rate was significantly higher in invasive cases (81%) than in noninvasive cases (45%; P = 0·042). For invasive cases, numbers of double-positive results for androgen receptor and 5α-reductase were significantly higher in men (70%) than in women (17%; P = 0·039). Conclusions Double positivity for androgen receptor and 5α-reductase in Paget cells suggests autocrine synthesis of androgens in extramammary Paget disease. The different hormonal microenvironments in male and female cases and intratumoral androgen levels affect the invasiveness of extramammary Paget disease.

Immunoglobulin G4 (IgG4)-related disease can occur in various organs, most of which are glandular or ductal tissues. Here, we report a case of multiple IgG4-related vascular lesions. A 63-year-old patient was found to have an abdominal aortic aneurysm and a tumorous lesion around the right coronary artery. The surgically resected aneurysmal wall and a tumorous lesion of the right coronary artery showed similar histologic features including diffuse lymphoplasmacytic infiltration, occasional eosinophils, and obliterative phlebitis. Immunohistochemically, numerous IgG4-positive plasma cells were evident within the lesions. The serum concentrations of IgG4 in the preoperative period was 456 mg/dL (reference range

Alveolar soft part sarcoma (ASPS) is a rare tumor of uncertain histogenesis, mainly localized in the extremities. ASPS originating in the uterine corpus is quite rare; only eight such cases have been reported in the literature. We here present another case of ASPS found in the endometrium in a 50-year-old woman. Metastatic malignant tumor, including ASPS from other organs, was excluded by physical examination and imaging modalities. Thallium 201 was only localized in the uterus. The tumor showed characteristic histological features of ASPS: alveolar architecture with fibrovascular septa and abundant eosinophilic granular cytoplasm with periodic acid-Schiff-positive crystalline material. Diffuse nuclear immunoreactivity for TFE3, a marker recently reported to be specific for ASPS, further supported the diagnosis of ASPS. Interestingly, this tumor was negative for myogenic markers, but positive for CD10, progesterone receptor, and estrogen receptor. These immunohistochemical results and the tumor location suggest a possible link between endometrial stromal cells and the development of this tumor.

A man in his 60s visited our hospital because of a pancreatic head tumor. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) revealed that the tumor consisted of a neuroendocrine carcinoma (NEC) and adenocarcinoma, including signet-ring cell carcinoma, and that the ratio of these components was approximately 50:50. Therefore, he was diagnosed with mixed adenoneuroendocrine carcinoma (MANEC). Because of liver and lymph node metastases, systemic chemotherapy was initiated using a regimen for the NEC component based on an increase in neuron-specific enolase (NSE). Although the patient achieved stable disease after two chemotherapy cycles, the tumor increased in size after three cycles, which was associated with a gradual increase in carcinoembryonic antigen and a decrease in NSE level. An EUS-FNA reexamination revealed that the adenocarcinoma component accounted for 90 % of the tumor. Thus, an adenocarcinoma chemotherapy regimen was started, and a slight reduction in tumor size was observed. Here, we report an extremely rare and remarkable case of MANEC of the pancreas that demonstrates the effectiveness of EUS-FNA for helping to decide the chemotherapy regimen.

In the immunological fecal occult blood test, an antibody to hemoglobin (Hb) is primarily used. For such a test, the usefulness of an antibody to transferrin (Tf) has not been well examined. To compare Tf and Hb as markers of gastrointestinal hemorrhage, we conducted a quantitative enzyme-linked immunosorbent assay (ELISA) for both proteins in 53 cases, with subsequent analysis based on lesion groups (malignant tumor, benign tumor, or inflammation). Hb testing showed no differences among the lesion groups, whereas the positive rate of Tf was significantly higher in the malignant group than in the inflammatory group. Moreover, the case positive for only Tf corresponded to one malignant case among the 53 cases. On the basis of this result, using a qualitative test, we further tested 878 cases that were positive for only Tf. We found that 81 cases positive for only Tf corresponded to various lesions, particularly 4 cases that corresponded to a malignant tumor. In conclusion, our results suggest that concurrent measurement of Hb and Tf should be a more effective test for gastrointestinal hemorrhage.

Recently, attention has been drawn to papillary neoplasm of the pancreatobiliary systems. In the pancreas, the disease entity of intraductal papillary mucinous neoplasm (IPMN-P) is widely recognized. In contrast, the pathological characteristics of biliary papillary tumors, such as biliary papilloma(tosis) and papillary cholangiocarcinoma, have not yet been well documented. In this study, we compared the pathological features and post-operative prognosis among biliary papillary tumors (10 cases of biliary papilloma(tosis) and 22 cases of papillary cholangiocarcinoma), conventional non-papillary cholangiocarcinoma (15 cases), and IPMN-P (31 cases). Macroscopically, all biliary papillary tumors were characterized by the prominent intraductal papillary proliferation, and macroscopic mucin-hypersecretion was seen in 9 of 32 cases (28%). Histologically, biliary papillary tumors consisted of three types of tumor cells (pancreaticobiliary, intestinal and gastric types), whereas only the pancreaticobiliary type was observed in non-papillary cholangiocarcinoma. Immunohistochemically, biliary papillary tumors were characterized by the common expression of MUC2, CDX2 and cytokeratin 20. In addition, biliary papillary tumors could be associated with two types of invasive lesions: tubular adenocarcinoma (9 cases) and mucinous carcinoma (5 cases). Patients with tubular adenocarcinoma had a poor prognosis compared to non-invasive papillary tumor or papillary tumor with mucinous carcinoma. These pathological characteristics and the survival status of biliary papillary tumors were different from those of non-papillary cholangiocarcinoma, and rather closely resembled those of IPMN-P. In conclusion, biliary papillary tumors may be the biliary counterpart (intraductal papillary neoplasm of the bile duct) of IPMN-P.