Tomoko Inagaki

Podocyte Injury Promotes Progressive Nephropathy in Zucker Diabetic Fatty Rats

The zucker diabetic fatty (ZDF-fa/fa) rat is one of the attractive models for type II diabetes based on impaired glucose tolerance caused by the inherited insulin-resistance gene fa. Characterization of nephropathy in this model may provide useful insights into the mechanism of the progression of diabetic nephropathy. The present study analyzed the pathophysiology of diabetes and nephropathy, including the process of glomerulosclerosis in this model by biochemical and morphometric analyses. In addition, we conducted studies in podocytes in culture to examine the direct effects of high glucose on podocytes. ZDF-fa/fa rats showed overt diabetes despite hyperinsulinemia as early as 3 months of age. Blood glucose levels increased further with a considerable decrease of insulin levels at 5 months. Glomerular filtration rate (GFR) was significantly elevated until 3 months, but fell to the level seen in lean rats by 7 months. Proteinuria started to rise during the period of increased GFR, and increased further after GFR had fallen to within the normal range. Renal fibronectin, collagen iv, and vascular endothelial growth factor mRNA levels were increased at 7 months. Glomerulosclerosis commenced as early as 5 months of age, and was associated with glomerular hypertrophy and mild mesangial expansion with evidence of accentuated podocyte injury, as revealed by increased expression of desmin. Electron microscopy suggested that degeneration of podocytes and the development of tuft adhesions were responsible for the glomerular sclerosis in this model. In addition, glomeruli from the diabetic rats showed up-regulation of the cyclin kinase inhibitors, p21 and p27. Further studies suggested that the increase in p27 expression was predominantly caused by podocytes, because predominant immunolocalization of p27 in podocytes in diabetic rats and high glucose medium induced cell hypertrophy accompanied by p27 up-regulation in differentiated podocyte cell lines. In conclusion, progressive diabetic nephropathy in ZDF-fa/fa rats is associated with evidence of podocyte injury. High concentrations of ambient glucose induced podocyte hypertrophy and stress in vitro, suggesting that the podocyte is a likely target of the diabetic milieu.

Intraductal Tubular Neoplasms of the Pancreas : Histogenesis and Differentiation

Objectives: Intraductal neoplasms of the pancreas are generally referred to as intraductal papillary mucin-producing neoplasms (IPMNs), according to the WHO classification system. Herein, we report that morphologic and immunohistochemical features of intraductal tubular carcinoma (ITC) are quite different from those of intraductal papillary mucinous carcinoma (IPMC). Methods: We analyzed histogenesis and differentiation of ITC by light microscopy and immunohistochemistry. Results: Histologically, ITC was characterized as an intraductal nodular appearances with a monotonous tubular growth pattern without papillary projection. ITC showed de novo-like appearance without sequential progression usually observed in IPMC, suggesting that ITC is a homogeneous neoplasm. Cuboidal tumor cells in ITC resembled normal pancreatic duct epithelia, and the characteristic growth pattern of ITC replaced that of normal pancreatic duct epithelium. Immunohistochemically, ITC cells were positive for MUC-1 on the apical side of the cell membrane. In contrast to ITC cells, IPMC cells were negative for MUC-1, and ductal adenocarcinoma cells were strongly positive for MUC-1, as was the stroma around the cancer. The immunohistochemical staining pattern of DUPAN-2 resembled that of MUC-1. Interestingly, localization of MUC-1 and DUPAN-2 staining in ITC cells was similar to that in normal pancreatic ductules. ITC cells were negative for MUC-2 and MUC-5AC. In contrast, most IPMC cells were positive for MUC-2 and MUC-5AC. Conclusion: Based on our histologic and immunohistochemical findings, the intraductal pancreatic neoplasm (IPN) can be classified into 2 groups: IPN with gastrointestinal differentiation and IPN with pancreatic duct differentiation. Our present data indicated that ITC cells may arise directly from duct epithelia without progression and possessed pancreatic duct differentiation. On the basis of our data, we suggest that classification of pancreatic neoplasms in the WHO and The Armed Forces Institute of Pathology (AFIP) systems should be reconsidered.

Carcinosarcoma with rhabdoid features of the urinary bladder in a 2-year-old girl: possible histogenesis of stem cell origin.

A case of carcinosarcoma of the urinary bladder in a 2‐year‐old girl is reported. The tumor, measuring 34 × 20 × 18 mm, was located in the peri‐trigone area of the urinary bladder with polypoid features. Histologic examination revealed transitional cell carcinoma at the tumor surface with downward invasion. Concurrently, a sarcomatous area was found beneath the carcinoma, with these two different malignant components sharing on apparent transition without dis‐tinct boundaries. Sarcomatous components included immature round cells focally showing rhabdoid features. No rhabdomyomatous component was observed. Immunohistochemistry disclosed vimentin and cytokeratin‐double positive cells at the transposition between carcinoma and sarcomatous components. In addition, ultrastructural analysis revealed that the epithelial cells had a distinct junctional complex, and the sarcomatous cells occasionally had a meshwork of cytoplasmic intermediate filaments, indicat‐ing bidirectional cytodifferentiation to epithelial and mesenchymal elements. The extremely young age at which this case of carcinosarcoma occurred suggests that the tumor may be of mesodermal stem cell origin.

Cytopathologic and Histologic Features of Biphasic Pulmonary Blastoma

Background Biphasic pulmonary blastoma is a rare malignant neoplasm of debatable histogenesis. Although well described histologically, it is scarcely mentioned in the cytologic literature. Case A 78-year-old man reporting intermittent hemoptysis was admitted to the hospital. Chest radiography revealed a right-sided pulmonary mass. Cytologic examination of tumor specimens revealed 2 types of malignant cells. The smears were highly cellular, with a necrotic background. The stromal cells had predominantly round to ovoid or spindle-shaped nuclei and scant cytoplasm, and the nucleoli had slightly irregular borders with coarsely aggregated chromatin. The epithelial cells were arranged in sheets and glandular configurations. The cytoplasm of these cells was finely vacuolated or foamy, with indistinct cellular boundaries; eccentrically located nuclei were hyperchromatic and had irregularly shaped nucleoli. The cell block preparation showed a distinctly biphasic malignant tumor with the classic morphologic features of pulmonary blastoma. Conclusion A preoperative diagnosis of pulmonary blastoma is difficult to obtain by cytopathologic methods. A diagnosis of biphasic pulmonary blastoma should be considered whenever epithelial cells and a separate population of stromal cells are seen in a pulmonary exfoliative cytology specimen.

A fibrolamellar carcinoma of the liver with a marked solid component

in advanced gastrointestinal stromal tumors. New Engl J Med 2002;347: 472–80. 2. Miettinen A, Sarlomo-Rikala M, Lasota J. Gastrointestinal stromal tumors: recent advances in understanding of their biology. Hum Pathol 1999;30:1213–30. 3. Heinrich MC, Corless CL, Blanke C, Demetri GD, Joensuu H, von Mehren M, et al. KIT mutational status predicts clinical response to STI571 in patients with metastatic gastrointestinal stromal tumors (GISTs) (abstract). Proc Am Soc Clin Oncol 2002;21:2a. 4. Verweij J, Judson I, van Oosterom A. STI571: a magic bullet? Eur J Cancer 2001;37:1816–9.

Mucinous cystadenoma of the pancreas 17 years after excision of gallbladder because of a choledochal cyst.

A 56-year-old woman who had undergone excision of the gallbladder because of a choledochal cyst had a tumorous lesion of the pancreas identified by upper abdominal ultrasonography, but an operation was not carried out, because there was no apparent increase in the cystic mass and no elevation of serum tumor markers. In October 2001, she was admitted to our hospital to check for malignancy because of elevated levels of the tumor marker Dupan-2. Abdominal enhanced computed tomography and upper abdominal ultrasonography revealed a large multilocular cystic mass in the body to tail of the pancreas. Endoscopic retrograde cholangiopancreatography showed elongation of the common duct that communicates with the common bile duct and the main pancreatic duct, indicating an anomalous arrangement of the biliary and pancreatic duct system. No apparent communications between the cystic mass and the main pancreatic duct were observed. In January 2002, the patient underwent a spleen-preserving distal pancreatectomy, and histopathological and immunohistochemical examinations led to the diagnosis of pancreatic mucinous cystadenoma with ovarian-like stroma. The mucinous cystadenoma was detected 17 years after the operation for the choledochal cyst. To the best of our knowledge, no documented case reports of mucinous cystadenoma of the pancreas associated with a choledocal cyst have been reported to date. We present here the first case report of pancreatic mucinous cystadenoma occurring in the body to tail of the pancreas, associated with a choledocal cyst.

Intraductal oncocytic papillary carcinoma of the pancreas showing numerous hyaline globules in the lumen

Two cases of intraductal oncocytic papillary carcinoma (IOPC) treated surgically were analyzed on light microscopy and immunohistochemistry: that of a 61‐year‐old man and that of a 55‐year‐old man. There were no clinical symptoms in either case. Pancreatic abnormalities were discovered incidentally on CT. Various clinical examinations were carried out, and the preoperative diagnosis was intraductal papillary mucinous carcinoma (IPMC) in both cases. Surgery was performed. Macroscopic observation of tissue cross‐sections indicated multilocular cystic mass containing polypoid lesions encapsulated by the dilated pancreatic duct. Histologically, the cyst walls were lined by columnar epithelial cells with complex papillary projections associated with oxyphilic cytoplasm, and they were strongly immunoreactive with anti‐mitochondrial antibody in the cytoplasm. Electron microscopy showed numerous mitochondria in the cytoplasm. IOPC was diagnosed. Interestingly, amorphous hyaline globules were produced from the oxyphilic cells, which exhibited a bud‐like appearance. The hyaline globules were not positive for mucin staining. No case of IPMC with hyaline globules has been reported to date. The production of hyaline globules may be related to oncocytic differentiation. It is suggested that hyaline globules should be regarded as a characteristic of IOPC.

A case of multiple colonic lymphangiomas causing intussusception

occur. Therefore, there is an extraordinary need for preventing them. A new device was developed that was successful and safe for the procedure of gastrostomy tube replacement (Fig. 1). The device was made of a stainless plate and consisted of two parts, a handle part, measuring 2.5cm 2cm, and an inserted part with concave curvature, like a spatula (0.7cm width and 5cm length). This device was put through the gastrostomy tract along the tube before drawing out the tube. This made it easy to keep the tract straight and guide the tube bumper into the gastric lumen (Fig. 2). In 59 patients who underwent replacement using this device, the procedure was completely successful, and they had no negative effects. We hope to have a chance of marketing this instrument.

Immunohistochemical evaluation of tissue-specific proteolytic enzymes in adenomas containing foci of early carcinoma: correlations with cathepsin D expression and other malignant features.

Background: Cathepsin D (CD) is an aspartyl lysosomal protease, and the prognostic value of CD expression has been studied in a variety of tumors, however, its role in early adenocarcinomas remains unclear.Aim of the Study: We evaluated the expression of CD in a series of colorectal adenomas with severe dysplasia containing foci of early carcinoma and compared the results to several histopathological and immunohistochemical features.Methods: Adenomas were obtained by endoscopic polypectomy from 33 patients. Twenty-four of the 33 adenomas contained well-differentiated adenocarcinomas and nine adenomas contained moderately differentiated adenocarcinomas.Results: Positive CD expressions were observed in 25% of well-differentiated adenocarcinomas and in 66.7% of moderately differentiated adenocarcinomas (p<0.05). Of the 12 adenocarcinomas with positive CD expression, four had positive CD expression in their adenomas (p<0.01), 6 showed positive Ki-67 expression in their adenomas (NS), and 10 had positive p53 expression in their adenomas (p<0.05). No significant association was seen between the level of CD expression and adenoma size.Conclusions: The expression of CD in adenocarcinoma correlated significantly with differentiation, and with the levels of CD and p53 expression in the adenomas of the polyp.

A resected case of adenoneurofibroma of the colon: is it a new entity of the colonic tumor?

to achieve an activated PTT ratio of 2–3. A repeat sigmoidoscopy showed lack of endoscopic response after 3 days of heparin therapy. However, hematoxylin-eosin staining of the rectal and sigmoid biopsies revealed striking cytopathic changes of cytomegalovirus infection further confirmed on specific immunohistochemistry for cytomegalovirus antigen. Serum cytomegalovirus DNA also tested positive. Intravenous gancyclovir (5 mg/kg b.i.d.) was commenced. He failed to improve after 5 days of anticytomegalovirus therapy and underwent a subtotal colectomy with ileostomy on day 15 of his admission. The resection specimen confirmed active cytomegalovirus pancolitis on a background of chronic UC. Postoperative recovery was unremarkable, and the patient was offered the option of a pouch-anal anastomosis at a later date. Cytomegalovirus colitis is an opportunistic infection in the context of immunosuppression often seen in posttransplant and HIV-infected individuals. It is extremely rare in immunocompetent patients with IBD. Papadakis et al. (1) reported the largest cohort, 12 patients with IBD who developed cytomegalovirus colitis. Ten of these (83%) were receiving immunosuppressive agents including thiopurines and cyclosporin. However, i.v. steroid therapy alone may predispose to cytomegalovirus complicating a refractory acute colitis (5). In the current case report, the previous use of a specific cyclo-oxygenase-2 inhibitor may have triggered the relapse and altered the gut permeability to allow cytomegalovirus colonization and infection. Whether this association is causal or coincidental, the temporal relationship between a specific cyclo-oxygenase-2 inhibitor and cytomegalovirus infection in UC has not been described previously. A putative mechanism for an adverse effect of conventional nonsteroidal anti-inflammatory drugs and specific cyclo-oxygenase-2 inhibitors on IBD may be the inhibition of the prostaglandins (PGE2 and PGI2) that may have a major protective role in IBD mucosa (6). Unless future data indicate otherwise, it is probably wise to avoid the use of cyclo-oxygenase-2 inhibitors, specific or otherwise, in patients with IBD.