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Supplementary Figures S1-S3.

Purpose: Peritoneal carcinomatosis, often associated with malignant ascites, is the most frequent cause of death in patients with advanced gastric cancer. We previously showed that the CXCR4/CXCL12 axis is involved in the development of peritoneal carcinomatosis from gastric cancer. Here, we investigated whether epidermal growth factor receptor (EGFR) ligands are also involved in the development of peritoneal carcinomatosis from gastric cancer.Experimental Design: The functional involvement of expression of the ErbB family of receptors and/or EGFR ligands was examined in CXCR4-expressing human gastric cancer cells and fibroblasts, clinical samples (primary tumors and ascites), and an animal model.Results: High concentration of the EGFR ligands amphiregulin and heparin-binding EGF-like growth factor (HB-EGF), as well as of CXCL12, were present in malignant ascites. Human gastric cancer cell lines and primary gastric tumors, with high potential to generate peritoneal carcinomatosis, expressed high levels of EGFR and CXCR4 mRNA and protein. Both amphiregulin and HB-EGF enhanced the proliferation, migration, and functional CXCR4 expression in highly CXCR4-expressing gastric cancer NUGC4 cells. Amphiregulin strongly enhanced the proliferation of NUGC4 cells, whereas HB-EGF markedly induced the migration of fibroblasts. Moreover, HB-EGF and CXCL12 together enhanced TNFα-converting enzyme (TACE)-dependent amphiregulin shedding from NUGC4 cells. In an experimental peritoneal carcinomatosis model in mice, cetuximab effectively reduced tumor growth and ascites formation.Conclusions: Our results strongly suggest that the EGFR ligands amphiregulin and HB-EGF play an important role, interacting with the CXCL12/CXCR4 axis, in the development of peritoneal carcinomatosis from gastric cancer, indicating that these two axes may be potential therapeutic targets for peritoneal carcinomatosis of gastric carcinoma. Clin Cancer Res; 17(11); 3619–30. ©2011 AACR.

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.

Pancreatic lymphoepithelial cysts (LECs) are rare cystic lesions filled with a keratinous substance and lined by squamous epithelium with underlying lymphoid tissue. Because pancreatic LECs are entirely benign, correct preoperative diagnosis is important to avoid unnecessary surgery. However, the imaging features of pancreatic LECs are not specific and preoperative diagnosis has proven difficult. A pancreatic mass was incidentally detected through abdominal ultrasonography in a 63-year-old male presenting without any symptoms. Computed tomography showed an exophytic cystic lesion in the pancreatic head. The lesion had heterogeneous high signal intensity with partial low intensity on T2-weighted magnetic resonance imaging (MRI) and high signal intensity on diffusion MRI. Endoscopic ultrasound (EUS) examination showed an encapsulated cystic lesion with relatively homogenous and highly echoic contents. EUS-guided fine-needle aspiration (EUS-FNA) revealed caseous appearance and rare fragments of apparently benign squamous epithelium on a background of keratinous debris, cyst contents, and scattered lymphocytes. We diagnosed a pancreatic LEC and opted for conservative management without surgery. Pathological evaluation based on images obtained through EUS-FNA showed macro- and microscopic features that were critical to determining the management strategy. In conclusion, the imaging and pathological features of pancreatic LECs can inform preoperative diagnosis, which may enable conservative management.

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 We aimed to examine the dynamics of serum Wisteria floribunda agglutinin-positive human Mac-2-binding protein glycosylation isomer (M2BPGi) in patients with acute liver injury. Methods Serum M2BPGi levels at the time of the diagnosis (n=77) and normalization of the serum alanine aminotransferase (ALT) level (n=26) were examined retrospectively. The difference in the serum M2BPGi level according to the etiology, and the correlations with other laboratory parameters were evaluated. Results The serum M2BPGi level at the time of the diagnosis was increased in 59 of 77 patients [2.3 cutoff index (COI); range, 0.31-11.1 COI] and was significantly decreased at the time of serum ALT normalization (0.68 COI; range, 0.15-1.87 COI; p

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.

Scirrhous gastric cancer frequently develops into peritoneal carcinomatosis with malignant ascites, leading to an extremely poor prognosis. We had demonstrated that paracrine hepatocyte growth factor (HGF)-induced MET activation promotes peritoneal carcinomatosis with ascites formation. The vascular endothelial growth factor (VEGF) receptor (VEGFR)/VEGF axis facilitates tumor progression and formation of malignant ascites. This study investigated the role of MET and VEGFR2 in the development of peritoneal carcinomatosis with malignant ascites. Cabozantinib is a dual inhibitor of MET and VEGFR2. We examined the effects of cabozantinib on MET- and VEGFR2-mediated progression of peritoneal carcinomatosis in human scirrhous gastric cancer in vitro and in vivo. Cabozantinib inhibited HGF-stimulated proliferation of scirrhous cancer cell lines NUGC4 and GCIY, with a high potential to generate peritoneal carcinomatosis with ascites fluid, as well as the constitutive proliferation of MKN45 cells with MET amplification. Cabozantinib also inhibited the phosphorylation of both MET and VEGFR2 in scirrhous cancer cells and HGF- or VEGF-stimulated HUVECs. It effectively reduced ascitic fluid and prolonged the survival of NUGC4-inoculated nude mice. In clinical specimens, malignant ascites fluid from patients with peritoneal carcinomatosis contained high levels of HGF and VEGF. Our results strongly suggest that MET- and VEGFR2-mediated signaling pathways play pivotal roles in the pathogenesis of peritoneal carcinomatosis in scirrhous gastric cancer. Thus, the dual blockade of MET and VEGFR2 signaling may be a potential therapeutic maneuver for peritoneal carcinomatosis in scirrhous gastric cancer.

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.

An 84-year-old man was referred to our out-patient clinic with an elongated mass localized to the retrosternal area that was incidentally identified by computed tomography. On 18F-fluorodeoxyglucose-positron emission tomography, this lesion showed intense tracer uptake. Thus, a surgical biopsy under thoracoscopy was performed. Histological examination revealed dense fibrous tissue associated with inflammatory cell infiltration. The immunoglobulin (Ig) G4/IgG plasma cell ratio was over 90%. Serum IgG4 levels were normal. According to the Umehara criteria for IgG4-related disease, a final diagnosis of a "possible" IgG4-related fibrosing mediastinitis was made. Oral glucocorticoid treatment with 30 mg/day prednisolone reduced the mass.

The patient was an 81-year-old man who presented with a complaint of hoarseness. When he was 80 years old, he had developed superficial esophageal cancer and had undergone endoscopic submucosal dissection (ESD) at our hospital. Two months after the ESD, he developed hoarseness. Computed tomography (CT) scan showed no abnormal findings at that time;therefore, he was diagnosed with idiopathic vocal cord paralysis, and followed up with symptom treatment in the Gastroenterology and Otolaryngology Departments. Ten months after the ESD, a CT scan revealed mediastinal lymph node swelling. He was admitted to our hospital for histopathological examination of the lymph node using endoscopic ultrasound-fine needle aspiration (EUS-FNA). The histopathological examination revealed squamous cell carcinoma of the lymph node, similar to the primary esophageal tumor. This result suggests that laryngeal nerve paralysis involving hoarseness is caused by lymph node metastasis of superficial esophageal cancer. We report that histopathological examination with EUS-FNA helps in determining the cause of hoarseness that develops after ESD.

Patient: Female, 45-year-old Final Diagnosis: Neuroendocrine tumor Symptoms: Bleeding Medication:— Clinical Procedure: Pancreaticoduodenectomy Specialty: General and Internal Medicine Objective: Rare disease Background: Type 1 neurofibromatosis (NF1) is known to be associated with not only neurogenic tumors but also gastrointestinal (GI) neoplasms. However, there are few reports on vascular lesions and the incidence is unknown. Case Report: We report here the case of a 45-year-old woman with a history of NF1 referred to our hospital for the purpose of detailed examination for positive fecal occult blood test. On the basis of the investigation reports, she was diagnosed with a neuroendocrine tumor (NET)-G1. We planned a subtotal stomach-preserving pancreaticoduodenectomy. The abdominal structures, including the vascular system, were abnormally fragile, and it was very difficult to achieve satisfactory hemostasis. The total amount of intraoperative blood loss was 7580 mL. Fulminant intra-abdominal bleeding occurred on postoperative day (POD) 3. Urgent angiography showed a rupture of the gastroduodenal artery. Transarterial embolization was performed, but the patient died of multiorgan failure on POD5. On histological examination, neurofibroma cells proliferating into the surrounding blood vessels were seen; moreover, immunohistochemistry staining with S-100 antibody showed positive neurofibroma cells surrounding the vascular wall. The pathological diagnosis was duodenal NET-G1 with multinodal involvement. Conclusions: This case is a rare presentation of a NET with multiple gastrointestinal stromal tumors associated with NF1, which led to a fatal outcome due to the extreme fragility of the vessel walls. Since patients with NF1 might have vulnerable vessel walls, adequate surgical preparation for major surgical treatment is necessary.

A 65-year-old woman presented with mycosis fungoides and an anterior mediastinal tumor. Stage Ⅱa mycosis fungoides was treated with bath psoralen plus ultraviolet A, topical corticosteroids, and oral bexarotene. One month later, a surgical resection was performed for the anterior mediastinal tumor, which was a stage Ⅱ thymoma with membrane invasion. Furthermore, adjuvant radiotherapy was performed for anterior mediastinum. The mycosis fungoides lesion exacerbated after 3 months;thus, chemotherapies were performed. The patient died of respiratory insufficiency due to multiple pulmonary metastases of mycosis fungoides 1 year after the operation.

Pouchitis is a frequent complication of surgical treatment of ulcerative colitis (UC), and is typically treated using antimicrobials. If pouchitis is refractory to antimicrobials, screening for complications, such as cytomegalovirus (CMV) infection, is necessary. However, the optimal approach to management of pouchitis complicated by CMV infection is unclear. We report the case of a 41-year-old female patient with UC presenting with pouchitis associated with CMV infection; she had received subtotal colectomy/ileal pouch anal anastomosis (IPAA). She was admitted to hospital with persistent fever, epigastric discomfort, and watery diarrhea despite receiving antibiotics. Laboratory findings showed inflammation and reactivation of CMV infection accompanied by liver injury. The endoscopic findings showed inflammation of the pouch and ileal mucosa on the oral side with extensive and deep punched-out ulcers. Immunohistological staining of biopsy specimens from an ulcerated lesion demonstrated CMV infection. Therefore, we diagnosed the patient with pouchitis complicated by CMV infection. The patient was treated with ganciclovir and infliximab, which resolved her symptoms and led to the disappearance of CMV-positive cells. There has been no recurrence of pouchitis. CMV infection should be considered in patients with UC who develop refractory pouchitis.

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 37-year-old obese man who was a social drinker was admitted to our hospital to undergo a detailed examination for liver injury with anti-mitochondrial antibody positivity. Abdominal ultrasonography revealed moderate fatty liver. A histological analysis showed steatosis of approximately 30% of the hepatocytes, focal necrosis, a few ballooning hepatocytes and lobular inflammation suggestive of steatohepatitis, epithelioid granuloma and irregularity of the sequence of the bile duct epithelium accompanied by lymphocyte infiltration suggestive of chronic cholangitis. He was diagnosed with non-alcoholic steatohepatitis complicated with primary biliary cholangitis. His liver injury was improved by weight loss and high-dose ursodeoxycholic acid treatment.

A 60-year-old man with an unruptured cerebral aneurysm and family history of moyamoya disease was admitted to our hospital with epigastric pain since the previous day. Serum levels of pancreatic enzyme were elevated and abdominal contrast-enhanced computed tomography showed localized enlargement of the pancreatic tail in the arterial phase and revealed numerous areas of fine mesh-like vascular hyperplasia consistent with an enlarged pancreatic tail. We diagnosed pancreatic arteriovenous malformation (P-AVM) with acute pancreatitis. Furthermore, in the pancreatic body, endoscopic ultrasonography showed lobularity (honeycombing type) and hyperechoic foci (non-shadowing), which suggests chronic pancreatitis. Acute management was performed with conservative treatment including administration of replacement fluids and proteolytic enzyme inhibitor. Distal pancreatectomy for P-AVM was performed because P-AVM is associated with acute pancreatitis recurrence, development of portal hypertension, progression of chronic pancreatitis, and refractory duodenal bleeding. Histological findings on the resected specimens revealed the anastomosis of abnormal arteries and veins, which suggested P-AVM. In addition, inflammation accompanied by fat necrosis due to ischemic infarction in the pancreatic tail, which suggested acute pancreatitis, and mild fibrosis in the pancreatic body, which suggested chronic pancreatitis, were shown. Although P-AVM is associated with various complications, symptomatic P-AVM should be considered a chronic and progressive disease.

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.

Since diffuse hepatic hemangiomatosis (DHH) is an extremely rare disease especially in adults, the etiology and natural course of adult-onset DHH has not been well understood. We report a case of DHH complicated with multiple organic dysfunction and Kasabach-Merritt syndrome (KMS) in an 83-year-old female. She presented with mild abdominal distension and laboratory findings revealed thrombocytopenia and abnormal coagulation, indicating disseminated intravascular coagulation (DIC). Enhanced computed tomography revealed diffuse, hypodense hepatic nodules with delayed enhancement involving the whole liver, and multiple hypodense splenic legions. To obtain a definitive diagnosis, laparoscopic-guided biopsy was performed. Histological findings revealed irregularly dilated non-anastomotic vascular spaces, which were lined with flat endothelial cells without cellular atypia. We diagnosed this as DHH complicated with splenic lesions and KMS. Although the patient was treated with symptomatic treatment, such as anti-coagulation therapy, hemangiomatous lesions, especially in the spleen, progressed rapidly, leading to worsening of DIC. Finally, the patient died of multiple organ failure at 12 months after diagnosis. A postmortem examination demonstrated diffuse hemangiomatosis of not only the liver and spleen, but also the adrenal glands and bone marrow. Despite no malignant histologically, DHH can be fatal if it progresses rapidly within a short period of time.

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.).

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.

Tocilizumab, an anti-human interleukin 6 receptor (IL-6R) monoclonal antibody, is widely used to treat rheumatoid arthritis (RA) and is expected to exhibit clinical efficacy when used to treat other autoimmune diseases. However, a risk of opportunistic infection is occasionally recognized. A 54-year-old woman had received an oral corticosteroid and methotrexate to treat RA. Despite receiving these treatments, she received additional treatment with tocilizumab due to poor control of the disease activity. She presented at our hospital with a high fever and epigastralgia 19 days after receiving this treatment. A laboratory evaluation revealed liver injury and cytomegalovirus (CMV) viremia. Abdominal ultrasonography and computed tomography (CT) revealed hepatosplenomegaly, but no ascites. Upper gastrointestinal endoscopy revealed gastric erosions induced by CMV, which were confirmed immunohistochemically. Hence, we diagnosed the patient with CMV reactivation-induced acute hepatitis and gastric erosions under tocilizumab treatment. She received an anti-cytomegalovirus drug, ganciclovir, for 14 days due to her viremia and impaired general condition, which was suggestive of a severe infection. Her general condition subsequently improved, the liver function test results normalized, and the gastric erosions disappeared. In conclusion, although tocilizumab is very useful for treating certain autoimmune and inflammatory diseases, and will be prescribed more widely in the future, associated CMV infections must be closely monitored, as these can be lethal.

Background Most colorectal cancer liver metastases form nodules within the hepatic parenchyma, and hepatectomy is the only radical treatment for synchronous metastases. There is concern about intrabiliary tumor growth which may affect the surgical margin, resulting in local recurrence after hepatectomy for colorectal cancer liver metastasis; however, there has been no report of the dissemination in the bile duct after hepatectomy. Here, we report an unusual case of biliary dissemination of colorectal cancer that caused recurrent intrabiliary growth after hepatectomy, and discuss the management of intrabiliary metastasis of colorectal cancer. Case presentation A 69-year-old Japanese man underwent treatment for liver dysfunctions 3 years after aortic valve replacement. Computed tomography revealed an enhanced tumor within the hilar bile duct and dilatation of the left hepatic duct, typical of hilar cholangiocarcinoma. Endoscopic retrograde cholangiopancreatography revealed tumor shadow in his bile duct, and the cytology confirmed malignant cells in the bile. We performed extended left hepatectomy with bile duct resection; his postoperative course remained good without acute complications. After 3 months postoperatively, he was readmitted for subacute cholangitis and obstructive jaundice. Immediately, percutaneous transhepatic cholangiography drainage was performed, followed by cholangiography that exhibited intrabiliary tumor growth in the remnant liver. On immunohistochemical examination, tumor cells were positive for cytokeratin 20 and CDX2 but negative for cytokeratin 7. Then, computed tomography revealed an enhanced tumor-like lesion at the descending colon. After 3 months, left hemicolectomy was performed. Meanwhile, the percutaneous transhepatic cholangiography drainage fluid turned bloody, which was considered to be bleeding from a residual bile duct tumor. Accordingly, radiotherapy was initiated to prevent tumor bleeding around the hilar bile duct, but, unfortunately, the effects were short-lived, and cholangitis rebooted after 1 month leading to our patient’s death due to septic liver failure. Autopsy revealed a remnant tumor in the bile duct, but no noticeable nodular metastasis was observed, except for a single small metastasis in the lower lobe of the left lung. Conclusions The intrabiliary growth of metastatic colorectal cancer mimics cholangiocarcinoma occasionally. To date, as the effect of chemotherapy or radiotherapy remains uncertain, the complete resection of a bile duct tumor is the only method which could result in a better prognosis.

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.

Mucosa-associated lymphoid tissue (MALT) lymphomas arise from various anatomic sites, mostly observed in the gastrointestinal tract; however, involvement of the kidney is extremely rare. We report a case of MALT lymphoma involving the kidney in a 70-year-old man. Radical nephrectomy was performed under the diagnosis of renal cell carcinoma preoperatively. However, the renal specimen showed that the diffuse small- to medium-sized lymphocytes were scattered and formed colonies, and the neoplastic lymphoid cells were positive for CD20, CD79α, and Bcl-2, but negative for CD10 and Cyclin D1; therefore, the final histological diagnosis was MALT lymphoma involving the renal pelvis. Although he was referred to the department of hematology, no additional treatment was given postoperatively, and he has survived for 4 months without evidence of a recurrence of lymphoma at the last follow-up. To the best of our knowledge, to date 37 reports of MALT lymphoma involving the kidney have been published in the literature. We report a case of MALT lymphoma involving the kidney, and review the existing literature.

A 66-year-old man was admitted to our hospital with acute paraplegia. He has suffered from hypertension with renal dysfunction for 7 years. Five months before admission, hemodialysis was introduced to him because of chronic renal failure due to renal sclerosis. One week before hospitalization, he noticed dizziness, sensory disturbance below the chest, and a urinary difficulty. Two days prior to admission, he could not walk independently. Spinal MRI revealed a mass at the 7th level of the cervical spine, showing low intensity on T(1)-weighted image and surrounding hypointensity with inner mixed intensity on T(2)-weighted image. An urgent surgery removed the cervical epidural mass and the following pathological evaluation established the diagnosis of β2-microglobulin amyloidoma. Hemodialysis-related amyloidoma generally emerges after a long duration of hemodialysis, demonstrates an insidious onset of symptoms, and is very rare. The current case indicates that we need to be aware of the possibility of β2-microglobulin amyloidoma even in patients with a short history of hemodialysis with a rapid presentation.

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.

A 40-year-old man complaining of abdominal distention was referred to our hospital. Computed tomography of the abdomen demonstrated a very large abdominal mass with fat and calcification. The size of the mass rapidly increased from 30cm to 40cm over two weeks. The tumor was removed and diagnosed by pathological examination to be a retroperitoneal mature cystic teratoma that contained a 40-cm long, mature intestinal tract-like cyst, together with bone marrow and fat. The rapid growth of the tumor may have been caused by an increased secretion in the cyst.

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