Ola A. Harb

Primary diffuse large B-cell non-Hodgkin's lymphoma of the breast—A case report and review of the literature

Primary breast lymphoma (PBL) is considered a rare clinical entity forming about 0.4%-0.5% of all breast tumors. In this report we have presented a case of PBL in a 56-year-old female complaining of a mass in the upper medial quadrant of the breast. PBL suspicion of our case was made by breast radiology and the sure diagnosis was reached by the immunohistochemistry results; CD (cluster of differentiation) 20: was diffusely positive; Pan-CK (pan-cytokeratin): was diffusely negative in tumor cells. Hence, the case was finally diagnosed as a primary breast a primary breast diffuse large B-cell non-Hodgkins lymphoma of lymphoma. The management and outcome of PBL and carcinoma are totally different. Accurate diagnosis of PBL by true cut needle biopsy and immunocytochemistry is important to avoid unnecessary mastectomies.

The role of neural precursor cell-expressed developmentally down-regulated protein 9 in predicting bacillus Calmette-Guerin response in nonmuscle invasive bladder cancer

OBJECTIVE To report the sensitivity and specificity of neural precursor cell-expressed developmentally down-regulated protein 9 (NEDD9) protein high expression in predicting BCG response and its effect on recurrence or progression free survivals. PATIENTS AND METHODS Between May 2014 and April 2017, a prospective cohort study was conducted on 105 patients with intermediate or high-risk nonmuscle invasive bladder cancer. Immunohistochemical staining with mouse monoclonal anti-NEDD9 antibody was done. Examination of the slides was done to detect NEDD9 cytoplasmic expression. Intravesical induction bacillus Calmette-Guerin (BCG) instillation therapy was started for all patients 2 to 4 weeks after endoscopy with once weekly instillation for 6 weeks. Intravesical maintenance BCG instillation was then continued every 3 months for at least 1 year. Follow up with cystoscopy every 3 months for 2 years and every 6 months after that. RESULTS The mean age ± SD of the patients was 57 ± 4.5 years. The median follow-up period was 25 (12-36) months. NEDD9 protein was highly expressed in 61 (58.1%) patients, whereas low expression was in 44 (41.9%) patients. Sensitivity and specificity of NEDD9 high expression in predicting recurrence were 83.6% and 64.2%, respectively. Its sensitivity and specificity in predicting progression to muscle invasion or distant metastases were 91.3% and 51.2%, respectively. Its sensitivity and specificity in predicting complete response to BCG therapy were 84.1% and 80.9%. Kaplan-Meier test showed highly significant difference (P<0.0001) in survival without recurrence or progression between patients showing high expression and those showing low expression. CONCLUSION NEDD9 protein tissue marker could be used as a predictive marker for BCG response in nonmuscle invasive bladder cancer with reasonable sensitivity and specificity.

SPOP, ZEB-1 and E-cadherin expression in clear cell renal cell carcinoma (cc-RCC): Clinicopathological and prognostic significance

BACKGROUND Clear cell renal cell carcinoma (cc-RCC), is a serious cancer regarding; its fatality, liability for metastases and chemoresistance, so identification of recent therapeutic targets to improve the patients prognosis is needed. SPOP is a BTB/POZ domain containing speckle-type POZ protein, has been identified as an E3 ubiquitin ligase component. ZEB1 is an essential epithelial mesenchymal transition (EMT) activator; E-cadherin is a cell adhesion protein that had been detected in normal epithelial cells membrane. AIM Was to assess the tissue protein markers SPOP, ZEB1 & E-cadherin expressions in benign areas of neoplastic kidney specimens and in cc-RCC patients, then correlating their expression levels with patients clinicopathological and prognostic data. METHODS We evaluated SPOP, ZEB-1 & E-cadherin expression using immunohistochemistry in samples from 50 cc-RCC and 20 benign areas of neoplastic kidney specimens, then we followed our patients for 5 years and finally we have analyzed correlations between the levels of markers expressions with patients clinicopathological and prognostic criteria in cc-RCC. RESULTS Positive expression of SPOP & ZEB1 in addition to negative E- cadherin expression was detected in cc-RCC more than benign areas of neoplastic kidney specimens (p = 0.004 and p < 0.001 respectively). In cc-RCC Positive expression of SPOP, ZEB1 and negative E- cadherin expression was associated with higher grade (p = 0.006, 0.007 & <0.001 respectively), advanced AJCC stage (p = 0.013, 0.023 & <0.001 respectively), presence of L.N metastases (p = 0.002 = 0.010 and <0.001 respectively), distant metastases (p = 0.001, 0.003 & 0.035 respectively), poor PFS and OS rates (p < 0.001 and p = 0.013 respectively). CONCLUSION Positive expression of SPOP& ZEB1 in addition to negative E- cadherin are associated with poor prognosis in cc-RCC patients.

The Value of FAK and SLUG Expression in Patients with Breast Carcinoma and Relation of Their Expression to Clinicopathological and Prognostic Parameters

Background: Although there is marked improvement in breast carcinoma (BC) management, it is still the leading cause of cancer death in middle-aged and old females, which leads to emergence of many studies about recent prognostic biomarkers that aimed to discover new therapeutic targets for BC. Focal adhesion kinase (FAK) is a member of protein tyrosine kinase (PTK) family. Slug is a member of the Snail family that is a C2H2-type zinc-finger transcription factor and plays an essential role in Epithelialmesenchymal transition [EMT] process activation in cancer. Our study aimed: To evaluate FAK and SLUG expressions in BC, to correlate their expressions with differentiation, invasiveness, metastatic potential of such type of cancer in addition to correlation with recurrence free and overall survival rates of female patients with breast cancer. Methods: We have assessed FAK and SLUG expressions in sections from 50 paraffin blocks of breast carcinoma using immunohistochemistry. We analysed correlations between their levels of expressions, clinic-pathological and prognostic criteria of our BC patients. Results: FAK and SLUG positive expression in breast carcinoma was related to positive expression in breast carcinoma was significantly correlated with aggressive molecular subtypes as HER2 amplified and triple negative subtypes, presence of lymph node metastases, high KI67 index, presence of distant metastasis (p<0.001 for all of them), negative ER & PR (p= 0.08), The expression of both markers was significantly positively correlated with each other (p<0.001). FAK and SLUG positive expression in breast carcinoma was associated with shortened recurrence free and overall survival rates (p<0.00). Conclusion: FAK and SLUG are markers of poor prognosis of breast carcinoma patients.

Panel of villin, pro-ex-c, estrogen receptor and progesterone receptor expressions could help in differentiation between endocervical and endometrioid adenocarcinoma

OBJECTIVE Endocervical and endometrioid adenocarcinoma have marked overlapping features and the differentiation between them is important for their accurate management. Villin is an actin-binding protein which has an important role in the maintenance of microvilli in epithelial cells and epithelial cell-specific anti-apoptotic protein processes. Pro-Ex-C is a marker for higher-risk human papilloma virus (HPV) which targets the cell cycle proteins causing their overexpression. The aim of the study was to clarify the diagnostic and predictive role of villin, Pro-Ex-C, estrogen receptor (ER) and progesterone receptor (PR) expression in endocervical and endometrioid adenocarcinoma. MATERIAL AND METHOD We evaluated villin, Pro-Ex-C, ER and PR expressions in 15 cases of endocervical adenocarcinoma and 30 cases of endometrioid adenocarcinoma. We analyzed the diagnostic and predictive role of that panel in both carcinoma subtypes. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated. RESULTS Positive villin and Pro-Ex-C expressions were positively correlated with the presence and pattern of cervical stromal invasion (p < 0.05). ER was positive in all cases of endometrioid adenocarcinoma. PR was detected in most cases of endometrioid adenocarcinoma. The differences of villin, Pro-Ex-C, ER and PR expression in endocervical and endometrioid adenocarcinoma was statistically significant (p < 0.05). This methodology for distinguishing endocervical and endometrioid adenocarcinoma had a sensitivity of 100%, a specificity of 100% and a significant prognostic and predictive role. CONCLUSION In conclusion, villin, Pro-Ex-C, ER and PR expressions have diagnostic and predictive roles in endocervical and endometrioid adenocarcinoma.

The Value of HER2 neu and EphA2 expressions in Gastric Adenocarcinoma Prognosis

Background: Gastric adenocarcinoma (GAC) is a serious disease with poor outcome. Discovering novel molecular targeted therapies is a recent point of research to improve prognosis. One of the newly discovered targets is the receptor tyrosine kinases (RTKs); it is a member of trans-membrane receptors which had important roles in proliferation and apoptosis. RTKs were found to have different expression patterns in several malignancies. HER2 neu which is a member of HER family is a proto-oncogene that is formed of four receptor tyrosine kinases. Erythropoietinproducing hepatocellular (Eph) molecules are major RTKs members and one of those molecules is EphA2 which has many different functions in cancer as tumor initiation, progression, angiogenesis and spread. We aimed to explore the expression patterns of both HER2 neu and EphA2 in GAC patients using immunohistochemistry, and to correlate their expressions with clinico-pathological factors and prognosis of our patients Methods: HER2 neu and EphA2 expressions were assessed in sections from forty blocks of paraffin which were diagnosed as GAC. Then we analyzed the correlations between their expressions and disease outcome of GAC patients. Results: HER2 neu and EphA2 positive expressions in GAC were positively correlated with tumor grade and stage (p<0.001 and p=0.002 respectively), inadequate response to therapy (p<0.001 and p=0.002 respectively), increase recurrence rate of GAC (p=0.002), and with poor survival (p<0.001). Conclusion: GAC patients with high expressions of both HER2 neu and EphA2 had unfavorable prognosis.

Prognostic Implications of Hyaluronic Acid Binding Protein 1 (HABP1) Expression, Estrogen Receptor (ER) and Progesterone Receptor (PR) Loss in Endometrial Carcinoma

Background: Endometrial carcinoma (EC) is the 4th commonest female cancer and the commonest gynecological tract malignancy. The prevalence rate is increasing; mainly in developing countries and the prognosis for recurrent or advanced EC are poor. The 5-year survival rates of EC patients are poor especially in women with metastatic EC. These bad outcomes need novel prognostic and predictive markers for EC for better managements of patients. Hyaluronic acid binding protein 1 (HABP1), which has a specific affinity toward hyaluronan (HA), was primarily discovered in cervical carcinoma (HeLa) cells. It is a eukaryotic protein conserved and ubiquitously found in multiple organisms; yeasts and humans. HABP1 expression, clinicopathological and prognostic importance in endometrial carcinoma is still not sufficiently clarified. Estrogen Receptor (ER) and Progesterone Receptor (PR) are biological molecules that have been studied as prognostic markers because of their essential physiological rules. Molecular biology advancements allow introduction of these hormone receptors to expect outcome of many cancers, e.g. ovarian, breast and EC. Aim: The aim of that study was to explore the expressions of HABP1, ER and PR in endometrial carcinoma patients, correlating their expressions with clinic-pathological factors and prognosis of patients. Methods: HABP1, ER and PR expressions were evaluated in sections from 60 paraffin blocks of EC. We analyzed correlations between the levels of markers expressions and prognosis of our patients. Results: HABP1 was expressed in 61% of EC. ER and PR were high in 56% and 63% of the patients, respectively. HABP1 expression, ER and PR loss were significantly associated with disease progression, disease free survival and poor overall survival (p=0.001, p=0.001and p=0.001, respectively). Conclusion: HABP1 high expression with ER and PR loss are markers of poor pognosis of EC patients.

Prognostic Impact of 25-Hydroxyvitamin D Levels in Egyptian Patientswith Breast Cancer

Background: According to the literature, vitamin D (Vit D) deficiency is a risk factor for breast cancer developing with lack of information on its direct prognostic effects in breast cancer. Patients and methods: A total of 168 women with proven breast cancer diagnosed in Zagazig university hospitals- Egypt were enrolled in this study. Serum level of 25 (OH) Vit D was measured in stored blood just after diagnosis. Vit D levels were classified into three groups: deficient: 30 ng/ml. Clinical-pathological data and disease outcome were accessed to examine prognostic effect of vitamin D in breast cancer. Results: Median age was 51.5 (26-77) years, Metastasis was present in 13.1% of the cases. The median serum level of 25(OH) Vit D was 20 (5-98) ng/ml; it was deficient in 36.9% of patients, insufficient in 32.1% of patients, and sufficient in 31% of patients. Serum level of 25 (OH) VitD levels decreased significantly with increasing body mass index (BMI) (P=0.00), also the relations of 25 (OH) Vit D level with the number of positive lymph nodes, tumor size, tumor stage and KI 67 level were statistically significant (p= 0.01, p=0.011, p=0.002, p= 0.001 respectively). The level of 25 (OH) vitamin D was significantly low in metastatic patients (p=0.01). For those non -metastatic BC patients; there was no statistically significant difference in mean Disease-Free Survival (DFS) times across the 3 categories of serum Vitamin D (p=0.13), also for metastatic patients, serum vit D level didn’t affect the median PFS (p=0.98). The mean OS of the 3 different categories of serum vit D (sufficient, insufficient and deficient) were 45.8 months, 39.7 months and 39 months respectively (p=0.047). Univariate analysis, showed that OS was significantly affected by age, BMI, grade, stage, molecular type and vit D levels (p=0.014, p=0.002, p=0.002, p<0.0001, and p=0.047 respectively), but in Multivariate analysis: age, BMI, stage, and vit D levels were the only independent factors significantly affect the OS (p=0.01, 0.001, p<0.0001 and p=0.022, respectively). Conclusion: There may be an association between serum 25 (OH) Vit D level and breast cancer prognosis.

The diagnostic utility of carbonic anhydrase IX, α-methylacyl-coenzyme A racemase, and BSND in classifying renal cell carcinoma: an immunohistochemical study

Background Renal cell carcinoma (RCC), the most common malignant renal epithelial tumor, has three main subtypes – clear cell renal cell carcinoma (cc-RCC), papillary renal cell carcinoma (pp-RCC), and chromophobe renal cell carcinoma (cp-RCC). These subtypes have overlapping cytoarchitectural features, especially in inadequate tissue samples. As each subtype has a different course and prognosis, it is important to classify them accurately using novel biomarkers. Objective The objective of this study was to evaluate the diagnostic ability of carbonic anhydrase IX (CA IX), &agr;-methylacyl-coenzyme A racemase (AMACR), and Bartter-syndrome, type-4a Sensorineural-deafness & renal dysfunction (BSND) expression in differentiating the three main types of RCC – cc-RCC, pp-RCC, and cp-RCC. Patients and methods Immunohistochemical expressions of CA IX, AMACR, and BSND were assessed in 50 paraffin blocks from patients with RCC. Results CA IX was significantly positive in cases of cc-RCC (P<0.001); AMACR was significantly positive in pp-RCC (P<0.001); and BSND expression was significantly positive (P<0.001) in cp-RCC. Conclusion An immunohistochemical panel of the three markers AMACR, CA IX, and BSND could differentiate between the three main subtypes of RCC with high sensitivity and specificity.

Co-expression of epithelial mesenchymal transition markers NEDD9 and Twist-1 in carcinoma of the uterine cervix and their clinical significances

Aims: Aims of our study were to detect NEDD9 and Twist1 co-expressions in carcinoma of the uterine cervix, to correlate such expressions with clinicopathological criteria of the patients and to explore their significances in response to cancer therapy, progression, recurrence and patients’ survival. Methods: This is a prospective cohort study where we assessed NEDD9 and Twist1 co-expressions by immunohistochemicaltechnique in fifty paraffin blocks of carcinoma of the uterine cervix, we have followed our patients for three years then we detect relations between markers expressions, pathological criteria, and cancer response to therapy, progression, recurrence and patients’ survival rates. Results: We detected high expression of NEDD9 in 29 out of 50 (58%) cases and high expression of Twist1 in 23 out of 50 (46%) cases of carcinoma of the uterine cervix. High-expression of both NEDD9 and Twist1 was positively correlated with carcinoma higher grade, advanced FIGO Ola A. Megahed1, Ola A. Harb1, Rham Z. Ahmed2, Safa A. Balata3, Amr AbdAlmohsen Alnemr4 Affiliations: 1Department of Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt; 2Department of medical oncology, Faculty of Medicine, Zagazig University, Zagazig, Egypt; 3Department of clinical oncology and nuclear medicine, Faculty of Medicine, Zagazig University, Zagazig, Egypt; 4Department of Gynecology and obstetrics, Faculty of Medicine, Zagazig University, Zagazig, Egypt. Corresponding Author: Ola A. Harb MD, PhD, Department of Pathology, Faculty of, 44519 Zagazig University, Zagazig, Egypt; Email: olaharb2015@gmail.com Received: 24 March 2017 Accepted: 12 May 2017 Published: 06 July 2017 stage, presence of lupus nephritis & distant metastases, higher incidence of carcinoma progression, poor response to therapy, higher rate of recurrence, poor progression free and three year overall survival rates (p < 0.001). Conclusion: NEDD9 and Twist1 are markers of poor prognosis and can be used as therapeutic targets in carcinoma of the uterine cervix patients.