Expression of Syndecan-1 in Chronic Liver Diseases: Correlation With Hepatic Fibrosis.

BACKGROUND/AIM: The mechanisms underlying the contribution of the heparan sulfate proteoglycan syndecan-1 to liver tissue injury and to crucial biological processes, such as fibrogenesis, remain to be elucidated. Therefore, we investigated the immunohistochemical expression of syndecan-1 in chronic liver diseases (CLDs) and its probable role in hepatic fibrosis. MATERIALS AND METHODS: Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue sections of biopsy material obtained from 128 patients diagnosed with CLDs. The correlation between syndecan-1 expression and the stage of fibrosis was investigated. RESULTS: According to the severity of fibrosis, cases were categorized into three groups: early fibrosis; intermediate fibrosis; advanced fibrosis. Syndecan-1 expression was significantly enhanced in advanced fibrosis compared to early (p<0.012) and intermediate (p<0.003) fibrosis. CONCLUSION: In CLDs, syndecan-1 immunohisto-chemical overexpression was found to be positively correlated with the severity of fibrosis, suggesting its probable role in hepatic fibrogenesis.

Alterations of p53 and Rb Pathways Are Associated with High Proliferation in Bladder Urothelial Carcinomas.

BACKGROUND/AIM: Since most cancers are associated with alterations of the p53 and Rb pathways, the expression of p53, p21, Rb, p16, p27, cyclin D1, cyclin A, cyclin B1 and Ki67 proteins were analyzed in bladder urothelial carcinomas (BUC). MATERIALS AND METHODS: One hundred twenty-two cases of BUC were studied by immunohistochemistry. RESULTS: The pathways p53/p21 and Rb/p16/cyclin D1 exhibited alterations in 81/115 and 63/84 cases, respectively. Alterations of the p53/p21 and Rb/p16/cyclin D1 pathways were positively correlated with high cyclin A expression. High expression of p53, Ki67, cyclin A and cyclin B1 was inversely correlated with the papillary morphology of the tumor and positively with tumor grade and T-stage. CONCLUSION: The results showed that a) alterations of the p53 and Rb pathways are associated with high proliferation of tumor cells in BUC and b) high expression of cell-cycle proteins is associated with adverse histopathological parameters of these tumors.

Altered expression of cell cycle and apoptotic proteins in human liver pathologies.

Τhe expression of cell cycle (P53, Ki-67, P21, and P27) and apoptotic proteins (BCL-2 and BAX) was investigated by immunohistochemistry in paraffin-embedded formalin-fixed tissues of normal and pathologic liver. An increased frequency of expression of P21 in cirrhosis and hepatocellular carcinoma (HCC) (p=0.003 and p=0.001 respectively) was found; P27 protein expression was more frequent in hepatitis (p=0.001) and HCC (p=0.003) when compared with normal tissue. BCL-2 protein was markedly more frequent in steatohepatitis (p<0.05) as compared to normal liver, in hepatitis cases (p=0.002) and in metastases (p<0.033). The expression of BAX was more frequent in hepatitis (p=0.001) and cirrhosis (p<0.001). We demonstrated in our study the expression of these proteins at different levels in liver pathologies. These findings have implications for understanding the evolution from liver inflammation to cirrhosis and associated carcinogenesis.

Differential expression of dysadherin in papillary thyroid carcinoma and microcarcinoma: correlation with E-cadherin.

Dysadherin is a novel glycoprotein, with an anti-cell-cell adhesion function. The aim of the present study was to examine the expression of dysadherin in thyroid papillary microcarcinoma (PMC), to associate it with the expression of E-cadherin and to investigate whether there are differences with papillary carcinoma (PC). A statistically significant difference in dysadherin and E-cadherin expression between PC and PMC and a negative correlation between E-cadherin and dysadherin expression regardless of tumor size were noted. Based on these findings it is hypothesized that retained cell-cell adhesion, through maintenance of the E-cadherin adhesion system, in PMC prevents neoplastic cells from dissociating easily from each other and metastasizing. Increased dysadherin expression is possibly one of the post-transcriptional mechanisms responsible for E-cadherin downregulation in thyroid papillary neoplasia.

Prognostic impact of lymphangiogenesis and lymphatic invasion (CD105 expression) in small cell lung carcinoma.

BACKGROUND: Lymphangiogenesis, an essential process in the metastasis of malignant tumors, has not been thoroughly studied. The possibility of using it to define subsets of patients with different prognosis in cancer could be of vital clinical importance. MATERIALS AND METHODS: Fifty patients (5 women, 45 men; mean age, 64.47 years) with SCLC were retrospectively studied. Tumor specimens were stained for CD105, and intratumoral lymphatic microvessel density (ILMVD) and lymphatic invasion were determined. RESULTS: Twenty-five patients were diagnosed with limited and 25 with extensive SCLC. All patients received chemotherapy and 32.7% radiation therapy. A direct association between ILMVD (CD105 expression) and lymphatic invasion was observed (p<0.046). CD105 expression was significantly associated with the stage of the disease (p=0.004) and the presence of metastasis (p=0.05). CONCLUSION: CD105 expression and lymphatic invasion correlated significantly with the clinical parameters and patient outcome, therefore, constituting an important prognostic role in SCLC.

Immunohistochemical expression of cell-cycle proteins in gastric precancerous lesions.

BACKGROUND: The early indicator for the subject predisposed to gastric cancer is abnormal proliferation of gastric epithelial cells, such as atrophic gastritis (AG), intestinal metaplasia (IM), and dysplasia, which have been considered as precancerous lesions of gastric cancer. To determine whether p53 protein, cyclins D1, and D3, and p27(kip1) play a role in the carcinogenesis pathway of gastric cancer, we performed an immunohistochemical study of their expression in gastric precancerous lesions. METHODS: A total of 1 45 endoscopic gastric biopsy specimens of AG, IM, and gastric dysplasia were studied. These molecular markers were localized by immunohistochemistry. RESULTS: P53 was expressed in 15% of cases with gastric dysplasia and not in the pre-dysplastic stages of the gastric mucosa. All cases were concerning high-grade dysplasia. Cyclin D1 protein was almost undetectable in the precancerous lesions of gastric cancer. Cyclin D3 protein overexpression was seen in 10% of biopsies with IM, and 50% of biopsies with gastric dysplasia. High expression of p27(kip1) protein was demonstrated in all cases of chronic gastritis. As atrophy, IM, and dysplasia develop, expression of p27(kip1) protein is suppressed. In total, 15% of dysplastic cases showed no expression of p27(kip1) protein. CONCLUSIONS: (i) P53 mutation must be a late event during the development of gastric cancer. (ii) Cyclin D1 protein overexpression may not play a role in the progression from normal to neoplastic gastric mucosa, while overexpression of cyclin D3 is an earlier event during gastric carcinogenesis, and its role must be further evaluated. (iii) Reduced expression of p27(kip1) is a rather early event in gastric tumorigenesis, before dysplastic changes occur.

Orbital metastasis from verrucous carcinoma of the oral cavity: case report and review of the literature.

A rare case of metastatic verrucous carcinoma (VC) of the oral cavity is presented. The patient was referred to the Ophthalmology Department due to diplopia. The patient reported history of diagnosis of verrucous squamous carcinoma in the oral cavity occuring 6 years earlier that although excised presented several recurrences. The lesion metastasized to local lymph nodes and after being characterized as inoperable the patient underwent thirty-seven sessions of radiation therapy. Two months after completion of radiation therapy, the patient underwent an orbital CT scan that revealed a mass with morphological features consistent with secondary involvement of the orbit from the known VC. Although treated with chemotherapy, the patient died 5 months later. No other case of this entity, which usually presents as a slow-growing lesion enlarging with direct extension rather than frank invasion, metastasizing to the orbit has been reported in relevant literature.

Apoptosis bcl-2 and nitrotyrosine expression in an angioplasty-restenosis rabbit: an experimental model.

Apoptosis has been suggested to have an important role in the pathogenesis of restenosis in addition to cell migration and proliferation. The aim of the present study was to investigate in an experimental in vivo model the occurrence of apoptosis postangioplasty and its relation to bcl-2 and peroxynitrite detection. Eighteen hypercholesterolemic rabbits underwent transluminal angioplasty of the right iliac artery. The rabbits were sacrificed on the 1st, 2nd, 3rd, 7th, 15th, and 28th day postangioplasty (3 animals per time point) and both the angioplasted and non-injured arteries were studied. Apoptosis was assessed by the terminal uridine nick-end labeling method (TUNEL). Bcl-2 and peroxynitrite were detected by immunochemistry using anti-bcl-2 and anti-nitrotyrosine antibodies. In the angioplasted arteries the number of apoptotic cells was

Early gastric carcinoma with oncocytic features and extensive metastases.

We present the case of a 63-year-old Caucasian woman with early gastric adenocarcinoma, suffering from extensive metastases at the time of initial presentation. Microscopic examination of the gastrectomy specimen revealed an invasive adenocarcinoma with oncocytic features. Interestingly, despite the fact that the carcinoma was pT1, it also was found to be N2, stage IV. The biologic behavior of oncocytic adenocarcinoma of the stomach is still unclear. We would like to present this case, so that its clinicopathological characteristics can be added to the few cases already published.

A new concept of melanocytic neoplasia pathogenesis based on the phenotype of common acquired nevi.

Common melanocytic nevi are ubiquitous lesions which in some cases constitute a risk factor for the development of melanoma. To date, despite long term research there are no known molecular hallmarks for nevus development. We have observed that common acquired nevi excised from the same individual share remarkable similarity in their microscopic appearance and in the immunohistochemical expression of E-cadherin. Based on these observations, we hypothesize that all melanocytes are genetically similar in the same individual and changes predisposing to neoplasia are a global melanocytic event characteristic for each person and propose a microgenomics/proteomics approach to test this hypothesis.

Primary mantle cell lymphoma of the conjunctiva: a case report.

Primary non-Hodgkin's lymphomas of the conjunctiva are uncommon. They are almost exclusively extranodal marginal zone B-cell lymphomas/mucosa-associated lymphoid tissue lymphomas. In this study, we report an extremely rare case of conjunctival mantle cell lymphoma in a 78-year-old man, presenting as a unilateral epibulbar mass.

Sudden death due to primary intracranial neoplasms. A forensic autopsy study.

Although most fatal tumors are diagnosed well before a patient's death, occasionally forensic pathologists encounter cases in which the presence of a primary tumor of the central nervous system had not been suspected prior to death. A search for cases of sudden death due to intracranial tumors from a total of 1985 autopsies from the archives of the Department of Forensic Pathology, University of Ioannina, Greece, in the period 1998-2005, was undertaken. Two such cases in which a medico-legal autopsy had disclosed brain tumors were found. The first case was a 34-year-old man who had been found unconscious in bed, and died a few hours after hospitalization. His autopsy had revealed a 7-cm glioblastoma at the level of the third ventricle. The second case involved a 67-year-old man presenting with brain tumor, diagnosed 1.5 months previously. The patient had died after 16 hours of hospitalization. A 4-cm astrocytoma of the left temporal lobe had been found at autopsy. In both cases, the tumors may, directly or indirectly, have been the underlying cause of death. The importance of a thorough neuropathological examination in all cases of sudden death, in which no extracerebral cause had been found, is emphasized.

Endoglin (CD105) as a prognostic factor in head and neck squamous cell carcinoma.

Endoglin (CD105) is a proliferation-associated protein abundantly expressed in angiogenic endothelial cells. Recent studies revealed that CD105 is intensively expressed in tumor vasculature, whereas intratumoral microvessel density (MVD) determined with the use of antibodies to CD105 has been found to be an important prognostic indicator for the outcome in a number of malignancies. In the current study, we investigated endoglin expression and evaluated MVD in 108 patients with head and neck squamous cell carcinoma. Endoglin was intensively expressed in intratumoral blood vessels, whilst lymphatics were rarely positive for CD105. High microvessel density was associated with a more aggressive tumor phenotype, including advanced clinical stage (p = 0.008) and the presence of lymph node metastasis at the time of diagnosis (p = 0.02). When microvessel counts were assessed for their prognostic values (high vs low MVD), there was a statistically significant difference in the overall survival among patients with tumors of the oral cavity and larynx (p < 0.001) and in the disease-free survival among patients with tumors of the lower lip (p = 0.01). The prognostic impact of microvessel density was not dependent on clinical stage or lymph node status. The results of the current study suggest that CD105 is a promising target for tumor imaging and prognosis.

Expression patterns of dysadherin and E-cadherin in lymph node metastases of colorectal carcinoma.

Reduction/loss of E-cadherin is associated with the development and progression of many epithelial tumors, while in a limited number of neoplasms, E-cadherin is re-expressed in metastases. Dysadherin, recently characterized by members of our research team, has an anti-cell-cell adhesion function and downregulates E-cadherin in a posttranscriptional manner. Colorectal cancer (CRC) is one of the most common tumors in the developed world, and lymph node metastases are harbingers of aggressive behavior. The aim of the present study was to examine the dysadherin and E-cadherin expression patterns in lymph node metastases vs primary CRC. Dysadherin and E-cadherin expression was examined immunohistochemically in 78 patients with CRC, Dukes' stage C in the primary tumor and in one lymph node metastasis. Dysadherin was expressed in 42% while E-cadherin immunoreactivity was reduced in 45% of primary tumors. In lymph nodes, 33 and 81% of metastatic tumors were positive for dysadherin and E-cadherin, respectively. Dysadherin expression was not correlated with E-cadherin expression in the primary tumor with a reverse correlation evident in the lymph node metastases. Our results suggest that different mechanisms govern E-cadherin expression in the primary tumor and the corresponding lymph node metastases.

Dysadherin expression in head and neck squamous cell carcinoma: association with lymphangiogenesis and prognostic significance.

Dysadherin is a recently characterized cancer-associated cell membrane glycoprotein that has a crucial role to cell-cell adhesiveness. The aim of this study was to examine dysadherin expression in head and neck squamous cell carcinoma (HNSCC). A total of 108 tissue specimens of patients with HNSCC were examined using immunostaining for dysadherin, E-cadherin, and the specific lymphatic endothelium marker D2-40. We quantified dysadherin and E-cadherin expression, assessed intratumoral (ILD) and peritumoral lymphatic density (PLD), and examined the possible associations of all the above parameters with clinicopathologic features and outcome. Finally, we used double staining with dysadherin and D2-40 to examine the expression pattern of dysadherin simultaneously with the lymphovasculature environment of HNSCC. High dysadherin expression was correlated with higher clinical stage (chi2, P = 0.01), with the presence of lymph node metastasis at the time of diagnosis (chi2, P = 0.02), and with increased ILD (chi2, P = 0.001). We observed an impressive reverse association between increased dysadherin expression and decreased E-cadherin expression (chi2, P < 0.001). Surprisingly, dysadherin-positive cancer cells usually gathered around areas of high intratumoral lymphatic vessel concentration, surrounding and invading small intratumoral lymphatics. Higher clinical stage and increased dysadherin expression were found to be the only significant independent prognostic factors for overall survival (hazard ratio, 3.94; 95% confidence interval, 1.09-14.27 for clinical stage; hazard ratio, 3.92; 95% confidence interval, 1.46-10.51 for dysadherin). The loss of intercellular adhesiveness and increased dysadherin expression seems to be related to lymphangiogenesis in HNSCC, but this should be confirmed by additional studies. Dysadherin expression might be a promising prognostic marker for separation of patients at higher risk.

Estrogen receptor beta (ERbeta) protein expression correlates with BAG-1 and prognosis in brain glial tumours.

Estrogen receptor beta (ERbeta) is an important mediator of estrogen function in a variety of tissues. Its expression declines in breast, ovarian, prostatic and colon carcinomas as well as in astrocytic tumours. BAG-1 is a multifunctional protein with an important role in neoplasia and is possibly regulated by estrogen receptors. One of the direct targets of BAG-1 is HSP70. The purpose of this study was to analyse the expression pattern of these proteins in two distinct types of glial neoplasms, to investigate their possible correlation and probe their impact on prognosis. ERbeta, BAG-1 and HSP70 protein expression was monitored immunohistochemically in 66 cases of astrocytomas and 20 oligodendrogliomas. In astrocytic tumours low ERbeta expression correlated significantly with high grade (P < 0.001), higher expression of cytoplasmic BAG-1 (P < 0.001) and worse survival (log rank P = 0.02). Multivariate analysis revealed that ERbeta expression had a prognostic value for overall survival in these patients (Cox P = 0.03), which was not dependent on grade. There was also statistically significant association of BAG-1 nuclear expression with HSP70 cytoplasmic expression. Our results strengthen the hypothesis that ERbeta, BAG-1 and HSP70 play an important role in the pathogenesis and progression of glial neoplasms. Moreover, ERbeta expression in astrocytic tumors might be an important prognostic factor for survival.

Giant lipoma: an unusual cause of intrathoracic mass.

Postmortem examination performed in a 39-year-old woman revealed a well-circumscribed, round, large mass in the right hemithorax. The tumor was attached with its pedicle to the ventral pericardium and adjoined the diaphragm with compression of the right lower lobe of the lung. Histologic examination confirmed the diagnosis of giant lipoma.

The lipophilic extract of Hypericum perforatum exerts significant cytotoxic activity against T24 and NBT-II urinary bladder tumor cells.

Hypericum perforatum L. (St. John's wort) is a medicinal plant used for many pathologies, especially for the treatment of mild to moderate depression. In the present study we have investigated the cytotoxic activity of the locally collected (Epirus region) Hypericum perforatum L. against cultured T24 and NBT-II bladder cancer cell lines. The lipophilic extract of the herb, prepared using petroleum ether, induced apoptosis displaying LC(50) values at concentrations as low as 4 and 5 microg/mL. A fraction of this extract displayed 60 % cell growth inhibition at a concentration of 0.95 microg/mL. Evaluating the importance of various biologically active components of the extract, it was found that hypericins (hypericin, pseudohypericin, etc.) were identified only in the methanolic (lipophobic) extract of the herb, and not in the active lipophilic extract. In addition, hyperforin concentrations in the lipophilic extract and its most active fraction, were 0.94 microg/mL, and 0.17 microg/mL, respectively, while the active cytotoxic concentration of pure hyperforin appeared in the range of 1.8 microg/mL - 5.0 microg/mL. Therefore, pure hyperforin does not seem to contribute significantly to the cytotoxicity activity. Chlorophylls were identified in low, not significantly different, concentrations in all extracts and fractions and were not correlated to the biological activity. Owing to the combination of significant cytotoxic activity, natural abundance and low toxicity, the lipophilic extract of Hypericum perforatum holds the promise of being an interesting, new, antiproliferative agent against bladder cancer that deserves further investigation.

Mucosa-associated lymphoid tissue lymphoma of the lacrimal gland--a case report.

MALT lymphoma of the ocular adnexa, an indolent B-cell lymphoma, rarely affects the lacrimal gland. The case of a 73-year-old man with ptosis and edema of the left upper eyelid, due to lacrimal gland swelling, is presented. Clinical evaluation and imaging examination led to excision biopsy. The mass histopathology, presenting organized lymphoid tissue, composed mainly of small B-cells, accompanied by immunophenotypic characteristics, was compatible with MALT lymphoma. Treatment with monoclonal antibody against CD-20 achieved a successful long-term disease control (4 years). The diagnostic approach is described and the pathological features and clinical signs of this rare entity are discussed, based on recent literature. The indolent clinical course of this lymphoma, either remaining localized or disseminating to other mucosal sites, is a distinct characteristic affecting prognosis.

Bax and Bcl-2 protein expression in gastric precancerous lesions: immunohistochemical study.

BACKGROUND AND AIMS: Bcl-2 protein prolongs cell survival in the face of classical apoptotic stimuli, and is considered to be a suppressor of apoptosis. Bax plays a key role in apoptosis by accelerating cell death after an apoptotic stimulus. The aim of our study was to determine the roles of the Bax proapoptotic gene and the Bcl-2 antiapoptotic gene in the carcinogenesis of gastric cancer. METHODS: One hundred and forty-five gastric biopsy specimens of chronic gastritis, atrophic gastritis, intestinal metaplasia and gastric dysplasia were studied. Using immunohistochemical methods, Bax and Bcl-2 protein expression was observed. RESULTS: Bax was expressed in epithelial cells in all cases of chronic gastritis. Bax was not detected in 26% of specimens of atrophic gastritis. As intestinal metaplasia develops, Bax is further suppressed. In biopsy samples with dysplasia, Bax expression was demonstrated only in 12% of biopsy samples. Although Bcl-2 protein was not detected in chronic gastritis, aberrant expression was found in gastric epithelial intestinal metaplasia and dysplasia. CONCLUSIONS: The suppression of Bax and overexpression of Bcl-2 protein is an early event in gastric tumorigenesis, before gastric dysplastic changes occur.