Mana Fukushima

High Serum IgG4 Concentrations in Patients with Sclerosing Pancreatitis

BACKGROUND Sclerosing pancreatitis is a unique form of pancreatitis that is characterized by irregular narrowing of the main pancreatic duct, lymphoplasmacytic inflammation of the pancreas, and hypergammaglobulinemia and that responds to glucocorticoid treatment. Preliminary studies suggested that serum IgG4 concentrations are elevated in this disease but not in other diseases of the pancreas or biliary tract. METHODS We measured serum IgG4 concentrations using single radial immunodiffusion and an enzyme-linked immunosorbent assay in 20 patients with sclerosing pancreatitis, 20 age- and sex-matched normal subjects, and 154 patients with pancreatic cancer, ordinary chronic pancreatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or Sjögrens syndrome. Serum concentrations of immune complexes and the IgG4 subclass of immune complexes were determined by means of an enzyme-linked immunosorbent assay with monoclonal rheumatoid factor. RESULTS The median serum IgG4 concentration in the patients with sclerosing pancreatitis was 663 mg per deciliter (5th and 95th percentiles, 136 and 1150), as compared with 51 mg per deciliter (5th and 95th percentiles, 15 and 128) in normal subjects (P<0.001). The serum IgG4 concentrations in the other groups of patients were similar to those in the normal subjects. In patients with sclerosing pancreatitis, serum concentrations of immune complexes and the IgG4 subclass of immune complexes were significantly higher before glucocorticoid therapy than after four weeks of such therapy. Glucocorticoid therapy induced clinical remissions and significantly decreased serum concentrations of IgG4, immune complexes, and the IgG4 subclass of immune complexes. CONCLUSIONS Patients with sclerosing pancreatitis have high serum IgG4 concentrations, providing a useful means of distinguishing this disorder from other diseases of the pancreas or biliary tract.

Autoimmune pancreatitis is closely associated with gastric ulcer presenting with abundant IgG4-bearing plasma cell infiltration ☆

BACKGROUND Autoimmune pancreatitis is characterized by high serum IgG4 concentrations and lymphoplasmacytic infiltration. Because of the diversity of extrapancreatic involvement in this disease, the present study sought to identify other associated GI-tract lesions. METHODS EGD findings were compared between a group of 23 patients with autoimmune pancreatitis undergoing ERCP for obstructive jaundice and 230 age- and gender-matched control patients. To clarify the histopathologic differences found between these two groups, the histopathologic findings (Updated Sydney System) and the immunohistochemistry of each IgG subclass were compared between 8 patients with autoimmune pancreatitis and gastric ulcer, and 23 control patients with gastric ulcer from which biopsy specimens had been obtained. RESULTS Gastric ulcer was found significantly more frequently in patients with autoimmune pancreatitis compared with control patients (34.8% vs. 13.5%; p=0.007). There was no significant difference between the groups with respect to the frequency of other GI lesions. Four of 8 gastric ulcers in patients with autoimmune pancreatitis were linear, with the long axis perpendicular to the incisura on the lesser curvature of the stomach. The activity score for the gastric lesions was significantly lower in patients with autoimmune pancreatitis compared with control patients (mean score 0.38 vs. 1.08; p=0.012). There were no significant differences in histopathologic findings with respect to inflammation, atrophy, metaplasia, or Helicobacter pylori scores between the two groups. IgG4-bearing plasma cells were significantly more abundant in gastric lesions in patients with autoimmune pancreatitis compared with those in control patients (mean score 1.75 vs. 0.39; p=0.0008). CONCLUSIONS Autoimmune pancreatitis is closely associated with gastric ulcer with abundant IgG4-bearing plasma cell infiltration.

Intraoperative ultrasonographic localization of pulmonary ground-glass opacities

OBJECTIVES Ground-glass opacities are typically difficult to inspect and to palpate during video-assisted thoracic surgery. We therefore examined whether ultrasonographic assessments could localize ground-glass opacities and help to achieve adequate resection margins. METHODS An intraoperative ultrasonographic procedure was prospectively performed on 44 patients harboring ground-glass opacities of less than 20 mm in diameter to localize these lesions and to achieve adequate margins. We also examined whether there were any complications resulting from the intraoperative ultrasonogram, such as lung injury, heart injury, or arrhythmia. We excluded patients with both asthma and chronic obstructive pulmonary disease from this study inasmuch as the intraoperative ultrasonographic procedure is more difficult to interpret when residual air is present in the lung. RESULTS A total of 53 ground-glass opacities were successfully identified by intraoperative ultrasonography without any complications. Of the 20 mixed ground-glass opacities that we examined, 15 were found on palpation. However, only 4 (12.1%) of the 33 pure ground-glass opacities could be palpated. In all instances in which complete collapse of the lung was achieved (30/53 of these cases), high-quality echo images were obtained. Additionally, a strong correlation was found between the resection margins measured by ultrasonogram and the margins determined by histologic examination in the resected lung specimens (r(2) = 0.954, P < .001). CONCLUSIONS Intraoperative ultrasonography can both safely and effectively localize pulmonary ground-glass opacities in a completely deflated lung. This procedure is also useful for the evaluation of surgical margins in a resected lung. Hence, ultrasonography may assist surgeons to perform minimally invasive lung resections with clear surgical margins during the treatment of solitary lung ground-glass opacity.

GlcNAc6ST-1-mediated decoration of MAdCAM-1 protein with L-selectin ligand carbohydrates directs disease activity of ulcerative colitis.

Background: A diffuse lymphocyte infiltrate is 1 of the characteristic features of ulcerative colitis (UC). Such lymphocyte recruitment requires lymphocyte rolling mediated by L‐selectin ligand carbohydrates (6‐sulfo sialyl Lewis X‐capped O‐glycans) and/or mucosal addressin cell adhesion molecule 1 (MAdCAM‐1) expressed on high endothelial venule (HEV)‐like vessels. The present study was undertaken to elucidate the role of MAdCAM‐1 posttranslationally modified (“decorated”) with L‐selectin ligand carbohydrates in UC pathogenesis and consequent clinical outcomes. Methods: Biopsy specimens composed of active and remission phases of UC as well as normal colonic mucosa were immunostained for CD34, MAdCAM‐1, and MECA‐79, and the immunostained sections were quantitatively analyzed. Reverse‐transcriptase polymerase chain reaction (RT‐PCR) was carried out to evaluate transcripts of MAdCAM‐1 and N‐acetylglucosamine‐6‐O‐sulfotransferases (GlcNAc6STs). CHO and Lec2 cells transfected with CD34 and MAdCAM‐1 together with enzymes involved in L‐selectin ligand carbohydrate biosynthesis were analyzed by immunofluorescence, FACS, and Western blotting to characterize the biochemical properties of GlcNAc6STs. Results: The number of MAdCAM‐1+ vessels was increased in UC, with no significant difference between active and remission phases. An increased ratio of MECA‐79+ to MAdCAM‐1+ vessels with preferential GlcNAc6ST‐1 transcripts was observed in the active phase of UC compared to the remission phase. MAdCAM‐1 protein was colocalized with L‐selectin ligand carbohydrates at the luminal surface of HEV‐like vessels in situ. GlcNAc6ST‐1 preferentially utilizes MAdCAM‐1 as a scaffold protein for GlcNAc‐6‐O‐sulfation in L‐selectin ligand carbohydrate biosynthesis. Conclusions: UC disease activity is not regulated by expression of MAdCAM‐1 protein itself, but rather by GlcNAc6ST‐1‐mediated decoration of MAdCAM‐1 protein with L‐selectin ligand carbohydrates.

Comparative Immunohistochemical Analysis of IMP3, GLUT1, EMA, CD146, and Desmin for Distinguishing Malignant Mesothelioma From Reactive Mesothelial Cells

OBJECTIVES To identify useful biomarkers for differentiating between malignant mesothelioma (MM) and reactive mesothelial cells (RMCs). METHODS Formalin-fixed, paraffin-embedded (FFPE) tissues from 34 MM and 40 RMC samples were analyzed using immunohistochemistry, and the findings were compared. RESULTS Positive markers for MM included insulin-like growth factor 2 messenger RNA binding protein 3 (IMP3), glucose transporter 1 (GLUT1), epithelial membrane antigen (EMA), and CD146, which showed sensitivities of 94%, 85%, 79%, and 71% and specificities of 78%, 100%, 88%, and 98%, respectively. In sarcomatoid MM, EMA had significantly lower expression than did IMP3, GLUT1, and CD146 (P < .001). The areas under receiver operating characteristic curves were the highest for IMP3 (0.95), followed by GLUT1 (0.93). When the optimal cutoff points for IMP3 (30%) and GLUT1 (10%) were used, the sensitivity of IMP3 and GLUT1 for MM was 100%, and the specificity of both for MM was 95%. CONCLUSIONS The combination of IMP3 and GLUT1 is most appropriate for distinguishing MM from RMC using FFPE sections.

Cell Lineage Specificity of Newly Raised Monoclonal Antibodies Against Gastric Mucins in Normal, Metaplastic, and Neoplastic Human Tissues and Their Application to Pathology Diagnosis

The specificity of monoclonal antibodies against gastric mucins (designated as HIK1083, PGM 36, and PGM 37) was studied immunohistochemically in normal, metaplastic, and neoplastic human tissues. These antibodies labeled class III mucin-producing cells identified by paradoxical concanavalin A staining in normal stomach, duodenum (Brunner gland), biliary tract, and main pancreatic duct; in mucinous metaplasia of pancreas and gallbladder; and in adenocarcinomas of stomach (90%), bile duct (80%), gallbladder (100%), pancreas (80%), lung (100% of goblet cell type adenocarcinomas), ovary (67% of mucinous carcinomas), and uterine cervix (100% of adenoma malignum tumors). Normal and neoplastic cells of esophagus, colon, salivary gland, kidney, endometrium, breast, prostate, and liver, as well as normal small intestine, lung, and uterine cervix, were all negative. The antibodies used should be valuable for the detection of class III mucin and class III mucin-producing cells in normal, metaplastic, and neoplastic tissues.

Large cell carcinoma of the lung with a rhabdoid phenotype.

A variant of large cell carcinoma showing a rhabdoid phenotype, which is rare among primary lung cancers, is presented. A 59‐year‐old man was admitted to hospital for an operation. Computed tomography scans showed a mass with a smooth border, invading the thoracic wall. A right upper lobe lobectomy was carried out with resection of a part of the thoracic wall. Pathological examination showed that the tumor was mostly composed of cells with prominent eosinophilic cytoplasmic globules and giant cells, which did not adhere to each other. Cytologically, the tumor cells contained nuclei with a reticular chromatin pattern and one to two prominent nucleoli, and hyaline‐like and reticular inclusion bodies, which were immunohistochemically positive for vimentin, but not for α‐smooth muscle actin, myoglobin or pan‐actin. Radiological and laboratory examinations did not detect the presence of the tumor in other organs, indicating that the primary lesion was not situated elsewhere. Metastasis to the right adrenal gland was observed 1 year and 4 months after the operation; however, the patient has been free of the disease 3 years and 11 months after the second operation of an adrenalectomy. This case showed a relatively good prognosis, which is rare among rhabdoid tumors of various organs that generally have poor prognoses with rapid, fatal progression.

A case of well-differentiated cholangiolocellular carcinoma visualized with contrast-enhanced ultrasonography using Sonazoid

We here report the first case of cholangiolocellular carcinoma (CoCC) visualized with contrast‐enhanced ultrasonography (CEUS) using a second‐generation contrast agent, Sonazoid. A 76‐year‐old man was admitted to our hospital for evaluation of a hepatic tumor. The tumor was described as having hyper‐enhancement in the early phase and persistent enhancement in the late phase by contrast‐enhanced computed tomography (CT) and magnetic resonance imaging (MRI), as well as hypervascularity by angiography. CEUS assessment of the nodule showed diffuse and homogeneous enhancement in the pure arterial phase, which became progressively hypoechoic relative to the adjacent liver parenchyma during the portal vein and late phases (mixed vascular phase), and showed a contrast defect with an unclear border in the Kupffer phase. Histologically we diagnosed this hepatic tumor as CoCC. In light of the above findings and the rarity of CoCC, it is helpful to incorporate the results of several imagings, such as CT, MRI, angiography and CEUS with a second‐generation contrast agent when clinically diagnosing CoCC.

A case of primary Epstein-Barr virus-associated cutaneous diffuse large B-cell lymphoma unassociated with iatrogenic or endogenous immune dysregulation.

Cutaneous Epstein‐Barr virus (EBV)‐associated B‐cell lymphoma (EBVBL) in non‐immunocompromised patients is very rare. Here, we report a case of cutaneous EBVBL in a 72‐year‐old Japanese woman without any signs of immunosuppression. She showed repeated high fever and skin eruptions on the face, limbs and palms. Histological diagnosis was diffuse large B‐cell lymphoma. EBV infection was detected by in situ hybridization and Southern blotting. Immunostaining for viral proteins showed the patient to be positive for latent membrane protein 1 (LMP‐1) and negative for Epstein‐Barr virus nuclear antigen‐1 (EBNA‐2), indicating that a type II latency EBV infection pattern.

Spontaneous regression of multicentric pilocytic astrocytoma with CSF dissemination in an adult

We present a case of spontaneous regression of multicentric pilocytic astrocytoma with cerebrospinal fluid (CSF) dissemination without neurofibromatosis type 1 (NF1) in an adult, the first such case reported. Magnetic resonance imaging (MRI) showed multiple low signal intensity lesions on T1-weighted images and high signal intensity areas on T2-weighted images in the bilateral thalamus, basal ganglia and midbrain. Contrast-enhanced MRI revealed that small, enhanced lesions were seen in the basal ganglia and the pineal region. Neuroendoscopic biopsy and third ventriculostomy were performed. Intraoperative findings demonstrated CSF dissemination. Histologically, the specimens showed pilocytic astrocytoma. Serial MRIs showed regression of the tumor without any additional treatment. The clinical features of spontaneous regression of pilocytic astrocytoma are discussed.