Intraductal papillary neoplasm of the bile duct with metachronous development in the downstream bile duct after radical resection.

We report a case of intraductal papillary neoplasms of the bile duct (IPNB) that metachronously developed twice in the downstream bile duct after radical resection. The first lesion was located in the left intrahepatic bile duct, the second lesion in the perihilar bile duct, and the third lesion in the distal bile duct. All lesions were IPNBs with associated invasive carcinoma (pancreatobiliary type). The depth of invasion was to the Glisson's capsule in the first lesion, to the subserosa in the second lesion, and to the fibromuscular layer in the third lesion, without lympho-vascular/perineural invasion and lymph-node metastasis. These were resected radically and had no biliary intraepithelial neoplasia and hyperplasia in the surrounding mucosa. In immunohistochemical examination, each lesion showed a different pattern. Although the downstream occurrence suggests intrabiliary dissemination, the mechanism of these metachronous developments may be multicentric. A literature review revealed that most metachronous cholangiocarcinomas have a grossly papillary appearance and tend to arise downstream. Our findings suggest that IPNB may develop metachronously in the residual bile duct after radical surgery, which may assist in early detection.

A case of large cell neuroendocrine carcinoma exhibiting rhabdoid features in the esophagogastric junction.

We report a case of large cell neuroendocrine carcinoma with rhabdoid features in the esophagogastric junction. An 81-year-old man presented to Saku Central Hospital Advanced Care Center with a tumor in the esophagogastric junction. During upper gastrointestinal endoscopy, an ulcerative tumor, measuring 4 × 3 cm in diameter, was observed. Computed tomography revealed lymph node metastasis, but no metastasis to other organs was observed. A thoracoscopic subtotal esophagectomy was performed. Histopathologically, anaplastic large cells exhibited a solid growth pattern with focal and geographic necrosis. Approximately half of the tumor cells exhibited large nuclei with conspicuous nucleoli; an eosinophilic "rhabdoid" cytoplasmic inclusion; and a nucleus displaced eccentrically by the cytoplasmic inclusion body. Immunohistochemically, tumor cells, including rhabdoid cells, were focally positive for pan-cytokeratin and diffusely positive for vimentin and synaptophysin. Additionally, electron microscopy identified dense-core granules in the tumor cells. Therefore, a diagnosis of large cell neuroendocrine carcinoma with rhabdoid features was made. A few cases of esophageal neuroendocrine tumors with rhabdoid features have been reported in the lung and pancreas; however, this is the first report of large cell neuroendocrine carcinoma with rhabdoid features in the esophagogastric junction.

A case of spheroid-type localized lactoferrin amyloidosis in the bronchus.

We report a case of localized bronchial lactoferrin amyloidosis. A 47-year-old man presented with a complaint of persistent dry cough for two months. Chest computed-tomography revealed a calcification shadow of the right main bronchus; hence, a biopsy was performed, showing layered spheroid-type eosinophilic deposits in the bronchial wall. These deposits were positive for Congo red staining, exhibiting apple-green birefringence under polarized light. In addition, an electron microscopic examination demonstrated that this layered structure was formed by very thin cord-like amyloid deposits. By proteomics analysis using liquid chromatography-tandem mass spectrometry and immunohistochemistry, we confirmed that the deposited amyloid was composed of lactoferrin. While lactoferrin is known to be a precursor protein of localized corneal and seminal vesicle amyloidosis, localized lactoferrin amyloidosis of the bronchus has not been reported in the English literature. Our pathological findings suggested that localized lactoferrin amyloidosis may be caused by long-term tissue damage, and the characteristic spheroid-type appearance is thought to be associated with unique, thin cord-like amyloid deposits.

Tranilast modulates fibrosis, epithelial-mesenchymal transition and peritubular capillary injury in unilateral ureteral obstruction rats.

AIM: Tranilast is an anti-allergic compound suppressing transforming growth factor-beta 1 (TGF-ß1) induced fibrosis. This study evaluated the efficacy of tranilast to attenuate renal fibrosis induced by unilateral ureteral obstruction (UUO) in rats in relation to epithelial-mesenchymal transition (EMT) and peritubular capillary injury. METHODS: Rats were divided into four groups: UUO with vehicle or tranilast and sham operation with vehicle or tranilast. Tranilast (400 mg/kg/day) was administrated to rats for 7 and 14 days after UUO. RESULTS: Fibrosis and tubular injuries were attenuated in UUO kidneys with tranilast (Tr-UUO kidneys) compared with UUO kidneys with vehicle (V-UUO kidneys). Decreased E-cadherin and increased vimentin expression in the tubular epithelium and Snail expression in V-UUO kidneys were also attenuated in Tr-UUO kidneys in which heparan sulfate proteoglycan in the tubular basement membrane was preserved and matrix metalloproteinase-2 expression was attenuated. Increased TGF-ß1 and phospho-Smad2 expression and increased numbers of myofibroblasts and macrophages in V-UUO kidneys were attenuated by tranilast. Decreased VE-cadherin expression and cytoplasmic swelling of the endothelium of peritubular capillaries that occurred in V-UUO kidneys was prevented by tranilast. CONCLUSIONS: Tranilast modulates fibrogenesis by reducing EMT, preventing disintegration of the tubular basement membrane, and reducing peritubular capillary injury in UUO kidneys.

Granulomatous transformation of capillary lesions in pulmonary-renal syndrome autologously induced anti-glomerular basement membrane disease in Wistar-Kyoto rats.

BACKGROUND: Pulmonary-renal syndrome is characterized by pulmonary hemorrhage and rapidly progressive glomerulonephritis in various immunological states. Histopathological analysis of pulmonary-renal syndrome is not yet complete. METHODS: Wistar-Kyoto (WKY) rats were sensitized using the noncollagenous (NC1) domain of type IV collagen from bovine kidney as an antigen. Histopathology of the kidneys and lungs was investigated with light microscopy, immunohistochemistry and electromicroscopy. Expression levels of cytokine mRNA were determined by real-time RT-PCR using renal tissue of rats. RESULTS: Macrophage-rich granulomatous glomerulonephritis and alveolar capillaritis accompanied with pulmonary hemorrhage were induced by the sensitization. The humoral antibody against NC1 was detected on the glomerular and alveolar capillary walls. Th2 cytokine IL-10 was dominant over Th1 cytokine IFN-gamma in renal tissues of WKY rats. CONCLUSION: The granulomatous transformation seemed to be induced by macrophage conspicuous capillaritis under dominant cellular immune reactions in WKY rats. In addition to Th1 cytokines, Th2 cytokines may also participate in the formation of granulomatous lesions.

Genetic heterogeneity of EGFR mutation in pleomorphic carcinoma of the lung: response to gefitinib and clinical outcome.

Somatic epidermal growth factor receptor (EGFR) mutations in exons 19 and 21 have been found in non-small cell lung cancer (NSCLC) and are associated with the therapeutic response to gefitinib in patients with advanced NSCLC. We report a case of pleomorphic carcinoma of the lung with different EGFR mutations. Prior to gefitinib treatment, an exon 19 deletion of EGFR mutation was positive in the specimens obtained from pleural effusion and left cervical lymph node, histologically proven to be adenocarcinoma. However, the response to gefitinib was poor and the patient died of progressive disease 4 months after the initiation of gefitinib therapy. Postmortem examination revealed the major histological component to be of the sarcomatoid or pleomorphic type with scant mixed adenocarcinoma, resulting in a histological diagnosis of pleomorphic carcinoma of the lung. Although the adenocarcinomatous tissue was still positive for exon 19 deletion of EGFR mutation alone, sarcomatous components had both the exons 19 deletion and 20 T790M mutation concomitantly, thought to be a gefitinib resistance mutation. Pulmonary pleomorphic carcinoma is a rare NSCLC composed of biphasic and heterogeneous malignant cell populations. The present case suggested that expression of different EGFR mutations is related to the biphasic histological appearance in pulmonary pleomorphic carcinoma.

Postinflammatory glomerular recanalization is established under the accommodation of transformed mesangial cells.

BACKGROUND: The relationship between mesangial cell proliferation and sclerosis has been studied using rat Thy-1.1 nephritis. The reconstruction of capillary lumina is essential for the repair of postinflammatory tissue damage in this type of glomerulonephritis. METHODS: We administered thalidomide or STI571 to Thy-1.1 nephritic rats. Thalidomide was intended to be a sup-pressor of capillary proliferation, and STI571, which is known to be a tyrosine kinase receptor inhibitor, was used for preventing mesangial proliferation. RESULTS: The thalidomide-treated group showed a significant increase of urinary protein on day 3. ED-1-positive cells stagnated longer and the matrix increase was delayed. STI571 caused suppression of mesangial proliferation, and microaneurysm remained longer than in the other 2 groups, which resulted in delay of glomerular capillary reconstruction. The number of alfa-SMA-positive cells appeared to be smaller in both the thalidomide- and the STI571-treated groups. CONCLUSIONS: Thalidomide had an effect in the early period of the experiment; however, there was no influence on the repair of glomerular capillary at the end. STI571 treatment, which inhibited proliferation of alfa-SMA-positive cells, seems to show that some degree of mesangial cell proliferation is necessary to reconstruct capillary structures and to regain glomerular function.

Post-inflammatory glomerular remodeling is influenced by transformed mesangial cells.

To identify the role of transformed mesangial cells (MC) during glomerular remodeling, anti-thymocyte-1 (Thy1) nephritis; modified Thy1 nephritis (injections of anti-Thy1 antibody four times, weekly); and Thy1 nephritis treated with signal transduction inhibitor 571 (Thy1 + STI); were analyzed. At week 1 the index of MC proliferation in modified Thy1 nephritis and in mesangiolysis in Thy1 + STI nephritis was highest among the three models. From week 4, the index of alpha-smooth muscle actin (alpha-SMA) was significantly higher in modified Thy1 nephritis than the other two models. Production of the mesangial matrix including type IV collagen was increased in modified Thy1 but inhibited in Thy1 + STI nephritis. In contrast to modified Thy1 nephritis, the capillary numbers in glomeruli recovered to normal at week 4 in Thy1, and at week 8 in Thy1 + STI nephritis. At week 12, both the adhesive and sclerotic index was significantly higher in modified Thy1 than in the other two models. Data suggest that a moderate amount of mesangial matrix results in a complete repair of capillary loops. Overproduction of the mesangial matrix retards capillary remodeling and finally induces glomerulosclerosis. Insufficient mesangial matrix delays the repair of capillary loops. In conclusion, transformed MC may influence glomerular remodeling by changing the amount of mesangial matrix.