Association of p62/SQSTM1 excess and oral carcinogenesis.

p62/SQSTM1 (sequestosome1) has never been evaluated in oral epithelium. In order to clarify the role of p62/SQSTM1 in carcinogenesis in oral epithelium, both p62/SQSTM1 and Nrf2 were immunohistochemically evaluated in 54 carcinomas and 14 low grade dysplasias. p62/SQSTM1 knockdowns were also designed in oral cancer cells, and we analyzed the Nrf2 pathway, GSH contents and ROS accumulation. The association between p62/SQSTM1 excess and prognosis was addressed in a clinical cohort of oral carcinoma cases. p62/SQSTM1 excess was more obvious in carcinomas, but Nrf2 was abundant in almost all samples of the oral epithelium. In oral carcinoma cells, p62/SQSTM1 knockdown did not affect the Nrf2-Keap1 pathway but did significantly reduce GSH content with subsequent ROS accumulation, and caused cell growth inhibition in the irradiated condition. Finally, p62/SQSTM1 excess was associated with poor prognosis in a clinical cohort. In oral epithelial carcinogenesis, p62/SQSTM1 excess played a role in GSH induction rather than Nrf2 accumulation, and may cause resistance to cytotoxic stresses such as radiation or chemotherapy. Immunohistochemical evaluation of p62/SQSTM1 may be a potential significant marker to identify early carcinogenesis, chemo-radiotherapeutic resistance or poor prognosis of oral squamous cell carcinomas.

Hepatocellular carcinoma occurring in a Crohn's disease patient.

We report a case of hepatocellular carcinoma (HCC) occurring in a patient with Crohn's disease (CD) without chronic hepatitis or liver cirrhosis, and review the clinicopathological features of HCC in CD patients. A 37-year-old Japanese man with an 8-year history of CD and a medication history of azathioprine underwent resection of a liver tumor. The histopathology of the liver tumor was pseudoglandular type HCC. In the non-neoplastic liver, focal hepatocyte glycogenosis (FHG) was observed, however, there was no evidence of liver cirrhosis or primary sclerosing cholangitis. Only nine cases of HCC in CD patients have been reported previously in the English-language literature. Eight of 10 cases (including the present case) had received azathioprine treatment, and four of these cases also showed FHG, which is considered a preneoplastic liver lesion, within the non-neoplastic liver. Although the precise mechanism of the development of HCC in CD patients is controversial, these results suggest that azathioprine therapy and FHG in the non-neoplastic liver contribute to the development of HCC. These findings also indicate that it is important to survey CD patients treated with prolonged azathioprine therapy for potential liver tumors.

CD8-positive granulomatous mycosis fungoides: a case report with review of the literature.

Granulomatous mycosis fungoides (GMF) represents an uncommon variant of mycosis fungoides (MF) characterized by the presence of an associated granulomatous reaction. Most cases of GMF are CD4 positive, and CD8 positive cases are extremely rare. Herein, we report a case of CD8-positive GMF. A 75-year-old Japanese woman presented with brownish maculae on the trunk and upper and lower extremities. She had been diagnosed with MF, and most of the eruption improved by psoralen ultraviolet A therapy. However, the eruption relapsed and gradually expanded 5 months prior to her visit to our hospital. Histopathology showed an atypical lymphocytic infiltrate in the dermis accompanied by granulomatous reaction with multinucleated giant cells. Epidermotropism was evident and elastophagocytosis was also found. Immunohistochemically, the atypical lymphocytes expressed betaF1, CD3 and CD8, and some of the atypical lymphocytes were also T cell intracellular antigen-1 positive. These findings were consistent with CD8-positive GMF. The dermatopathological diagnosis of GMF is challenging in some cases because of the prominent secondary granulomatous reaction. Therefore, when dermatopathologists diagnose granulomatous skin lesions, GMF should also be considered. In addition, the prognosis of GMF, especially CD8-positive GMF, is still controversial. Additional studies are required to clarify the clinicopathological features of CD8-positive GMF.

Claudin expression profiles in Epstein-Barr virus-associated nasopharyngeal carcinoma.

Claudins are a family of proteins that are structural and functional components of tight junctions and have crucial roles in the maintenance of cellular arrangement, adhesion and paracellular transport. Recent studies have shown that changes and/or loss of claudin expression plays an important role in tumorigenesis and tumor progression, and altered expression of claudins has been reported in various human carcinomas. Non-keratinizing nasopharyngeal carcinoma (NPC) is a common Epstein-Barr virus (EBV)-associated carcinoma with characteristic clinicopathological features. The aim of this study was to investigate claudin expression profiles in EBV-associated non-keratinizing NPC. We analyzed expressions of claudin-1, -2, -3, and -4 in 18 cases of EBV-associated non-keratinizing NPC by immunohistochemical methods. Claudin-1 was expressed in all 18 cases, but claudin-2 was not expressed in any of the 18 cases. Claudin-3 expression was variable, with 8 of the 18 cases (45%) showing no immunoreactivity for claudin-3. Claudin-4 displayed positive immunoreactivity in all cases, even in claudin-3-negative cases. Claudin-3 and -4 are receptors for cytotoxic Clostridium perfringens enterotoxin (CPE) and CPE has emerged as a potential therapeutic target for malignant tumors expressing claudin-3 and/or -4, because CPE specifically and rapidly lyses cells expressing these proteins. Clinically, treatment of distant metastases is a serious problem in EBV-associated non-keratinizing NPC, because frequently there is lymph node involvement and distant metastasis before detection of the primary tumor. Therefore, CPE therapy may be a potential therapeutic target for EBV-associated non-keratinizing NPC, since our results clearly showed claudin-3 and/or -4 expression in all cases studied.

A case of multifocal fibrosclerosis with intracardiac solid masses.

We report an extremely rare case of multifocal fibrosclerosis (MFS) with intracardiac solid masses. A 70-year-old woman with Hashimoto's disease had pericardial thickening and intracardiac masses. Histology of pericardiectomy showed only fibrosis. The clinical diagnosis was constrictive pericarditis. She died of postoperative infectious mediastinitis and cerebral infarction. Postmortem examination revealed intracardiac solid masses contiguous to thickened pericardium. Multifocal areas of fibrosis were also seen in the pericardium, mediastinum, abdominal cavity, and the retroperitoneum. The intracardiac masses and the areas of fibrosis were composed of collagenous fibers with various intensities of inflammatory infiltrates and sclerotic changes. Neoplastic changes were not observed. These histological features were similar to that of MFS. The intracardiac masses are interpreted as one of the manifestations of MFS. This is the first case of MFS accompanied with intracardiac solid masses.

Activation of Src kinase in platelet-derived growth factor-B-dependent tubular regeneration after acute ischemic renal injury.

We previously reported that the platelet-derived growth factor B-chain (PDGF-B)/PDGF receptor (PDGFR) axis is involved in tubular regeneration after ischemia/reperfusion injury of the kidney. In the present study, we examined the activation of Src tyrosine kinase, a crucially important signaling molecule for PDGFR, and assessed the role of Src in PDGF-B-dependent renal tubular regeneration afterischemia/reperfusion injury. Immunoblot using clone 28, a monoclonal antibody specific for the active form of Src kinases, demonstrated increased active Src expression in the injured rat kidney 6 hours after reperfusion with peak activation at 12 hours. In vitro kinase assay confirmed increased Src activity that concurred with PDGFR-beta activation as detected by the increment of receptor-phosphorylated tyrosine. Immunohistochemistry using clone 28 demonstrated that active Src was preferentially expressed in the S3 segment of the proximal tubule in reperfused kidney, where it is not normally expressed. This enhanced expression of active Src was co-localized with the increased PDGFR expression in the tubular cells that were undergoing cell proliferation cycle. Trapidil administration suppressed Src and PDGFR-beta activation in the reperfused kidney and resulted in deteriorated renal function. These findings suggest that active Src participates in PDGF-B-dependent regeneration of tubular cells from acute ischemic injury.