Prostate-Specific Membrane Antigen (PSMA) Expression in The Neovasculature of High Grade Gliomas (Histopathological and Immunohistochemical Study).

BACKGROUND: Prostate-specific membrane antigen (PSMA) was first noticed in prostate cancer cells, thereafter, It has been found in the endothelial cells of neovasculature in a variety of tumors, but not in normal vascular endothelium, This specificity makes PSMA an ideal molecule for vascular targeting in Cancer theranostics (i.e., combined diagnostic and therapeutic). OBJECTIVES: The objective of this study was to evaluate the immunohistochemical (IHC) expression of PSMA in the neovasculature (identified by CD 31) of high-grade gliomas (HGGs) and to Correlate PSMA IHC expression in HGGs with clinicopathological features, to detect its possible role in tumor angiogenesis, where PSMA can be used as a future diagnostic and therapeutic target. MATERIALS AND METHODS: This retrospective study included a total of 69 archived, formalin-fixed, paraffin-embedded tissue blocks of HGGs, including 52 cases classified as WHO grade IV (75.4%) and 17 cases as WHO grade III (24.6%). The samples were immunohistochemically analyzed for PSMA expression (in both TMV and parenchymal tumor cells) which was assessed using the composite PSMA immunostaining score. A score (0) was considered negative while scores 1-7 were considered positive (1-4, 5-6, or 7; weak, moderate, or strong respectively). RESULTS: PSMA is expressed specifically and significantly in endothelial cells of tumor microvessels (TMV) of HGGs, A statistically significant relationship was detected between PSMA IHC expression in both TMV and in parenchymal tumor cells (TC) and various glioma subtypes (P-value < 0.05 and <0.001 respectively).  Positive PSMA immunostaining in TMV was detected in all anaplastic ependymoma cases and in near all cases of classic GB and GB with oligodendroglial features more than other subtypes, with P-value specifically for PSMA positivity/negativity in TMV statistically significant (0.022). While for Tumor cells, Positive PSMA immunostaining was detected in all anaplastic ependymoma, most anaplastic astrocytoma and classic GB cases in contrary to other variants, with P-value statistically extremely significant (< 0.001). Comparing PSMA IHC expression in TMV and its expression in TC, it was significantly expressed in TMV of 82.7% versus TC of 51.9% of grade IV cases. Likewise, in GB with oligodendroglial features and gliosarcoma, the majority of cases showed positive staining in their TMV [8/8 (100%), 9/13 (69.2%) respectively], and, the reverse occurs in tumor cells where the majority of cases did NOT show staining in the tumor cells for PSMA (5/8 (62.5%), 11/13 (84.6%) of cases respectively), which was statistically significant (P-value ≤ 0.05) besides the significant difference in the pattern of staining according to composite PSMA scoring (P-value ≤ 0.05). CONCLUSION: PSMA has a possible role in tumor angiogenesis, therefore it might be considered a potential promising endothelial target for Cancer theranostics with PSMA-based agents, in addition, PSMA was expressed significantly in TC of HGGs, thus, it appears to be involved in biologic behavior, carcinogenesis and tumor progression.

Role of CD10 Marker in Differentiating Malignant Thyroid Neoplasms from Benign Thyroid Lesions (Immunohistochemical & Histopathological Study).

BACKGROUND: CD10 was initially recognised as a cell-surface antigen expressed by acute lymphoblastic leukaemias, and hence it's early designation as Common Acute Lymphoblastic Leukemia Antigen (CALLA). Also, it has been proven to be reactive in various non-lymphoid cells and tissue and different types of neoplasms. AIM: To evaluate the immunohistochemical expression of CD10 in malignant thyroid neoplasms and different benign lesions and to assess whether CD10 can be used as a malignancy marker in thyroid pathology or not. MATERIAL AND METHODS: A total of 83 archived, formalin fixed, paraffin embedded tissue blocks of 83 cases of malignant thyroid neoplasms and different benign lesions. The samples were immunohistochemically analysed for CD10 expression. A p-value of less than 0.05 was considered statistically significant. RESULTS: CD10 was expressed in 91% of the studied malignant thyroid neoplasms and 58% of benign thyroid lesions. It was expressed in 26 of 28 (92.9%) conventional papillary carcinomas, ten of 10 (100%) follicular variants of papillary carcinoma, seven of nine (77.8%) minimally invasive follicular carcinomas, two of three (66.7%) widely invasive follicular carcinomas, and seven of 7 (100%) undifferentiated carcinomas, seven of 11 (66.7%) adenomatous nodules and eight of 15 (53.3%) follicular adenomas. No statistically significant correlations were detected between CD10 expression and patients' age, sex, lymph node metastasis, tumour stage and capsular invasion. CONCLUSION: CD10 shows strong sensitivity (91.2%) and moderate specificity (42.3%) in the diagnosis of malignancy overall and shows strong sensitivity (86.4%) and moderate specificity (42.3%) in the diagnosis of malignancy in the follicular-patterned lesions. So, CD10 might be useful in differentiating malignant from benign thyroid lesions (good positive test) and in the diagnosis of follicular variant of papillary carcinoma.

Chronic renal allograft dysfunction in Egyptian population: Histopathological and immunohistochemical study.

The chronic dysfunction stands as the most common cause of renal allograft loss. During the nineties of the past century, this condition was referred to as chronic allograft nephropathy (CAN). Since 2005, CAN has been assigned by the eighth Banff schema to four main categories via histopathological and immunohistochemical findings including chronic antibodymediated rejection (CAMR), chronic T-cell-mediated rejection (CTMR), chronic cyclosporine toxicity (CNITOX), and "interstitial fibrosis (IF)/tubular atrophy; not otherwise specified (NOS)" to eliminate the term CAN. We conducted a retrospective study of renal allograft cases with biopsy-proven chronic damage diagnosed at our nephropathology units, between January 2007 and September 2013, to assign them to the defined categories. Differences between groups were tested using one-way analysis of variance. The frequencies of the diagnostic categories were as follow: CNITOX (43.1%), CAMR (27.5%), CTMR (17.6%), and NOS (11.8%). The serum creatinine level, time posttransplant, and global sclerosis frequency were insignificant among the categories. Nine categorized cases showed transplant glomerulopathy; five of them were seen in association with CAMR. There was a positive relationship between the number of interstitial CD8 + T cells and the degree of IF in CTMR cases. Two cases showed combined features of CAMR and CTMR. Protocol renal allograft biopsy starting 3 months after transplantation with proper monitoring and adjustment of the calcineurin inhibitors level may reduce the potential risk of chronic damage in renal allograft.

MDM2 Expression in Serous and Mucinous Epithelial Tumours of the Ovary.

BACKGROUND: Different types of cancer exhibit abnormalities in cell cycle regulators. The murine double minute2(MDM2) cell cycle regulator is a protooncogene that negatively regulates the P53 tumour suppressor gene. Surface epithelial tumours constitute approximately two thirds of ovarian neoplasms. Each histologic type can be classified as benign, borderline and malignant. This study aimed to examine immunohistochemical expression of the MDM2 protein in ovarian serous and mucinous epithelial tumours (benign, borderline and malignant). MATERIALS AND METHODS: This study included forty five ovarian tumours, subdivided into fifteen cystadenomas (5 serous and 10 mucinous), fifteen borderline tumours (11 serous and 4 mucinous) and fifteen cystadenocarcinomas (9 serous and 6 mucinous). Paraffin sections were stained with haematoxylin and eosin for histopathologic study, and with mouse monoclonal antiMDM2 antibody for immunohistochemistry. RESULTS: MDM2 positivity was detected in 28.9% of the studied ovarian tumours. All benign tumours were negative and positivity was significantly higher in malignant than borderline tumours (P value of chisquare test =0.000). Significantly, all MDM2 positive mucinous tumours were malignant with no positive mucinous borderline tumours. Malignant tumours showed positive MDM2 expression in 83.3% of mucinous type and in 55.6% of serous type. Borderline serous tumours showed negative MDM2 in 72.7% of cases (P value of Z test =0.04). CONCLUSIONS: Alterations in the expression of the cell cycle regulator (MDM2) occur early in the process of tumourigenesis in serous and mucinous ovarian tumours. We suggest that MDM2 may be used in those tumours as a marker for risk stratification and identification of cases with cancer development and progression. We recommend further studies on MDM2 immunohistochemistry, in conjunction with adjuvant methods as DNA ploidy and FISH gene amplification, focusing on the mucinous tumours and differentiating between the three tumour categories, benign, borderline and malignant.

Low-density lipoprotein receptor genetic polymorphism in chronic hepatitis C virus Egyptian patients affects treatment response.

AIM: To correlate a genetic polymorphism of the low-density lipoprotein (LDL) receptor with antiviral responses in Egyptian chronic hepatitis C virus (HCV) patients. METHODS: Our study included 657 HCV-infected patients with genotype 4 who received interferon-based combination therapy. Patients were divided into two groups based on their response to therapy: 356 were responders, and 301 were non-responders. Patients were compared to 160 healthy controls. All patients and controls underwent a thorough physical examination, measurement of body mass index (BMI) and the following laboratory tests: serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, total bilirubin, direct bilirubin, prothrombin time, prothrombin concentration, INR, complete blood count, serum creatinine, fasting blood sugar, HCV antibody, and hepatitis B surface antigen. All HCV patients were further subjected to the following laboratory tests: HCV-RNA using quantitative polymerase chain reaction (PCR), antinuclear antibodies, thyroid-stimulating hormone, an LDL receptor (LDLR) genotype study of LDLR exon8c.1171G>A and exon10c.1413G>A using real-time PCR-based assays, abdominal ultrasonography, ultrasonographic-guided liver biopsy, and histopathological examination of liver biopsies. Correlations of LDL receptor polymorphisms with HAI, METAVIR score, presence of steatosis, and BMI were performed in all cases. RESULTS: There were no statistically significant differences in response rates between the different types of interferon used or LDLR exon10c.1413G>A. However, there was a significant difference in the frequency of the LDL receptor exon8c.1171G>A genotype between cases (AA: 25.9%, GA: 22.2%, GG: 51.9%) and controls (AA: 3.8%, GA: 53.1% and GG: 43.1%) (P < 0.001). There was a statistically significant difference in the frequency of the LDLR exon 8C:1171 G>A polymorphism between responders (AA: 3.6%, GA: 15.2%, GG: 81.2%) and non-responders (AA: 52.2%, GA: 30.6%, GG: 17.2%) (P < 0.001). The G allele of LDL receptor exon8c.1171G>A predominated in cases and controls over the A allele, and a statistically significant association with response to interferon was observed. The frequency of the LDLR exon8c.1171G>A allele in non-responders was: A: 67.4% and G: 32.6 vs A: 11.2% and G: 88.8% in responders (P < 0.001). Therefore, carriers of the A allele exhibited a 16.4 times greater risk for non-response. There was a significant association between LDL receptors exon8 c.1171G>A and HAI (P < 0.011). There was a significant association between LDL receptors exon8c.1171G>A and BMI. The mean BMI level was highest in patients carrying the AA genotype (28.7 ± 4.7 kg/m(2)) followed by the GA genotype (28.1 ± 4.8 kg/m(2)). The lowest BMI was the GG genotype (26.6 ± 4.3 kg/m(2)) (P < 0.001). The only significant associations were found between LDL receptors exon8 c.1171G>A and METAVIR score or steatosis (P < 0.001). CONCLUSION: LDL receptor gene polymorphisms play a role in the treatment response of HCV and the modulation of disease progression in Egyptians infected with chronic HCV.

Impact of epidermal growth factor receptor and transforming growth factor-α on hepatitis C virus-induced hepatocarcinogenesis.

Epidermal growth factor receptor system plays a central hepato-protective and pro-regenerative role in liver. Transforming growth factor-α (TGF-α) is an important autocrine growth regulator of hepatocytes that plays a role in development of hepatocellular carcinoma (HCC) among patients with chronic hepatitis C (CHC). This study was done on 40 core liver biopsies from patients with CHC, 20 liver specimens from HCC cases on top of CHC as well as five normal controls. All were immunohistochemically stained with epidermal growth factor receptor (EGFR) and TGF-α antibodies. Some selected HCC cases were submitted for FISH technique to detect EGFR gene alteration. By immunohistochemistry EGFR and TGF-α were overexpressed in HCC and cirrhotic cases compared to CHC cases without cirrhosis. Also, their expression was stronger in CHC cases with higher grades of activity and stages of fibrosis compared to lower ones. FISH positive results for EGFR were detected in 33.3% of the examined HCC cases. EGFR and TGF-α can be used as predictive markers for activity, fibrosis, and carcinogenesis in CHC patients. Overexpression of EGFR in HCC patients can be promising in selecting those who can get benefit from anti-EGFR target therapy.

Low-grade endometrial stromal sarcoma with intravenous extension to the heart.

Endometrial stromal sarcoma (ESS) is a rare neoplasm of uterine origin. Intracardiac metastasis from this tumor is extremely infrequent. This report describes a 24-year-old woman from Yemen who had irregular vaginal bleeding shortly after spontaneous abortion. She developed left-lower-limb swelling, diagnosed by duplex scanning and magnetic resonance imaging as deep venous thrombosis in the inferior vena cava (IVC) that extended into the iliac veins on both sides, as well as the left femoral vein and right atrium. She developed acute respiratory distress, from which she recovered after transfer to the intensive care unit. Transesophageal echocardiography showed a large mass occupying the right atrium and ventricle and another mass in the right ventricular outflow tract with areas of cavitations. The tumor appeared to come from the IVC and extended through the right atrium and right ventricle into the pulmonary artery, ending in several digit-like projections. After surgical resection of the intracardiac mass, pathologic examination revealed a low-grade ESS that was confirmed by immunohistochemistry. The patient underwent panhysterectomy and IVC debridement. Pathologic examination revealed infiltrating low-grade endometrial sarcoma invading the myometrium and left adnexa, with intravenous extension into the pelvic veins and the IVC to the right side of the heart. This case shows that despite its well-known good prognostic nature, low-grade ESS may behave as an aggressive malignancy.

Immunohistochemical study of CD99 and EMA expression in ependymomas.

Tumors of the central nervous system (CNS) represent a unique, heterogeneous population of neoplasms and include both benign and malignant tumors. The present study was carried out on a total of 79 archival cases of ependymal tumors in addition to a variety of other primary CNS tumors. The study entailed the use of CD99 monoclonal antibody and epithelial membrane antigen (EMA). It was found that all 38 ependymoma cases (classic and nonclassic) showed positive membranous and intracytoplasmic CD99 immunoreactivity. Upon comparing with other CNS tumors (41 cases), it was found that CD99 could differentiate between ependymomas and nonependymal tumors, but intensity and pattern of staining were of no consequence in determining variant type or degree of histologic aggressiveness. In regard to EMA immunoreactivity, which was restricted to the ependymoma group, 2 patterns of staining could be detected--the intracytoplasmic dotlike pattern and the ringlike pattern--but some cases were completely negative. Thus, EMA was found to be of little value in the diagnosis of ependymoma and in the differentiation between different types and grades. CD99 can hence be recommended for use as a good marker for differentiation between ependymal and other CNS tumors. EMA expression and pattern of distribution, on the other hand, cannot be employed to determine the type of variant or the degree of tumor aggressiveness, and hence cannot predict the behavior of ependymal neoplasms.

Expression of estrogen receptor-B ( ER-B ) in bengin and malignant prostatic epithelial cells and its correlation with the clinico-pathological features.

The role of estrogen and its receptors in the etiology and progression of prostate cancer ( PC ) is poorly understood. In normal and malignant human prostate, estrogen receptor-a is expressed only in the stroma, whereas estrogen receptor-Beta ( ER-Beta ) is present in both normal stroma and epithelium. Because loss of ER-Beta expression is associated with prostate hyperplasia in ER-Beta null mice, this study determined patterns of ERBeta expression in hyperplastic, PIN ( prostatic intraepithelial neoplasia ) and malignant human prostate and associations with tumor progression. Formalin-fixed, paraffin-embedded blocks were obtained from thirty-five patients who underwent radical prostatectomy and pelvic lymphadenectomy for prostate cancer, 15 core biopsies diagnosed as PIN and 10 TURP ( transurethral prostatic resection ) diagnosed as BPH ( benign prostatic hyperplasia ) were assessed for ER-Beta expression using immunohistochemistry. ER-Beta positivity was defined as 5% of cells demonstrating nuclear immunoreactivity. Nine ( 90% ) of the studied BPH cases showed ER-Beta positive expression where they showed 5% ER-Beta positive cells, while eight ( 53% ) of the studied 15 PIN cases were negative for ER-Beta expression. Twenty-nine ( 82.8% ) of the studied adenocarcinoma cases were negative for ERBeta expression, p<0 .0001. The loss of ER-Beta expression is associated with progression from hyperplastic prostate epithelium to PC. The ER-Beta expression is inversely proportional to PCs stage and grade. From these data we can conclude that estrogen can affect prostatic cancerogenesis and neoplastic progression through an ER-Beta mediated process in human prostate tissue. Our data also identify the need for additional studies to address the potential role of ERBeta in the regulation of prostate epithelial cell proliferation at different stages in the development of PC. Key Words:ER Beta - Prostatic hyperplasia - PIN - Prostatic carcinoma.