Haitham Arabi

Molecular Typing of Epithelial Ovarian Carcinomas Using Inflammatory Markers

Ovarian epithelial carcinomas have recently been classified as slow growing type I tumors and rapidly growing highly aggressive type II tumors. The present study sought to molecularly characterize type I and II tumors using known molecular markers.

Expression of GLUT-1 in epithelial ovarian carcinoma: Correlation with tumor cell proliferation, angiogenesis, survival and ability to predict optimal cytoreduction

OBJECTIVE GLUT-1 is involved at various steps in the processes of tumor progression. The objective of this study was to examine the relationship between GLUT-1 expression and tumor proliferation and angiogenesis in epithelial ovarian carcinoma. MATERIALS AND METHODS Specimens from 213 patients with epithelial ovarian carcinoma were evaluated by immunohistochemistry for GLUT-1, Ki-67, and vascular endothelial growth factor. Tumor microvessel density was assessed with CD34 immunostaining. We investigated the relationships between GLUT-1 expression and clinicopathologic characteristics, tumor angiogenesis (tumor MVD and vascular endothelial growth factor expression), and tumor proliferation (Ki-67). The effect of GLUT-1 expression on patient survival and on the volume of residual disease after cytoreduction was determined. RESULTS There was a significant positive correlation between expression of GLUT-1, Ki-67, and microvessel density. In univariate survival analysis, high GLUT-1 expression, high Ki-67 expression and high tumor microvessel density showed a significant impact on patient survival (p=0.0001). In multivariate analysis including patients with all tumor stages, after controlling for age, race, stage, grade, MVD, and the 3 markers (GLUT-1, Ki-67 and VEGF), only age (HR 1.5; 95% CI 1-2.3), stage (HR 3.6; 95% CI 1.8-7.5) and grade (HR 2.3; 95% CI 1.2-4.5) retained their significance as independent poor prognostic factors. Tumors simultaneously overexpressing GLUT-1 and Ki-67 were less likely to be optimally cytoreduced as compared to tumors overexpressing only one or neither of those two markers (OR: 3.8, p=0.01). CONCLUSION Expression of GLUT-1 correlates with tumor proliferation and microvessel density in epithelial ovarian carcinoma. In addition, patients with rapidly proliferating advanced stage tumors overexpressing GLUT-1 have a lesser chance for optimal cytoreduction.

Impact of microsatellite instability (MSI) on survival in high grade endometrial carcinoma

OBJECTIVE Although microstellite instability (MSI) is a prognostic marker in colorectal cancer, its relation with prognosis in the endometrial cancer is controversial. The goal of this study is to identify the correlation between MSI and clinicopathologic markers along with survival in high grade endometrial carcinoma EC. METHODS Between 1995 and 2004, we identified 119 patients (57 type-I, and 62 type-II) diagnosed with high grade EC and underwent hysterectomy. Sections were immunostained using antibodies against MLH1, MSH2, and MSH6. Semi-quantitative scoring of immunoreactivity was based on percentage of tumor staining and staining intensity. Statistical analysis and survival were assessed using the Kaplan-Meier method and Cox regression. RESULT Tumors were considered microsatellite unstable (MSI) when at least 2/3 markers tested negative on IHC. Overall, there was no statistically significant difference in survival between patients with MSI tumors and those with microsatellite stable tumors (MSS) (p value=0.70). However, MSI tumors which tested negative for all three markers had markedly poor survival (median survival 3 months vs 71 months, p=0.04) when compared to MSS tumors. The risk of death was 13.2 times greater among women with MSI tumors (with 3 negative markers) compared to women with MSS tumors (OR=13.20 95% CI 3.50-49.76). CONCLUSION Although this study has its limitation due to the small sample size, it raises the question of the prognostic significance of MSI in high grade endometrial carcinoma. It also points to the importance of evaluating three mismatch repair genes (MLH1, MSH2, and MSH6) as a prognostic indicator.

Hyperammonemic Encephalopathy: A Rare Presentation of Fibrolamellar Hepatocellular Carcinoma

Fibrolamellar carcinoma (FLC) is a rare malignant hepatocellular tumor of unknown etiology, arising almost exclusively from noninfected, noncirrhotic liver of young adults. FLC has traditionally been considered to have better survival than hepatocellular carcinoma; however, this notion might be highly erroneous. Patients with metastatic disease at presentation have a dismal prognosis with 5-year survival of only 15%. We describe a case of highly aggressive metastatic FLC that presented as hyperammonemic encephalopathy, which has never been previously reported in the literature.

Prognosis and reproducibility of new and existing binary grading systems for endometrial carcinoma compared to FIGO grading in hysterectomy specimens.

Background: The current International Federation of Gynecology and Obstetrics (FIGO) grade in endometrial carcinomas requires the evaluation of histologic features with proven prognostic value but with questionable reproducibility. This study tests the prognostic power and reproducibility of a new binary grading system. Study Design: Specimens from 254 hysterectomies were graded according to the new 3- and 2-tiered FIGO grading systems described by Alkushi et al. The selected morphologic parameters for the new grading system included the presence of predominant solid or papillary architecture pattern, severe nuclear atypia, tumor necrosis, and vascular invasion. The Cox proportional hazards and κ statistics were used for comparisons. Results: On multivariate analysis, and looking at all tumor cell types, the 4 tested grading systems were independent predictors of survival, with the 3-tiered FIGO grading system being the most predictive (P = 0.005). In the subset of endometrioid tumors, the 3- and 2-tiered FIGO grading systems and the new grading system retained their statistical significance as predictors of survival (P = 0.004, P = 0.03, and P = 0.007, respectively), whereas the grading system of Alkushi et al did not (P = 0.1). In nonendometrioid tumors, the new grading system proved to be the best predictor of survival, reaching near statistical significance (P = 0.06). The new grading system had acceptable intraobserver and interobserver reproducibility assessment (κ = 0.87 and κ = 0.45, respectively). Conclusion: The 3-tiered FIGO grading system retained its superior prognostic power. However, available binary grading systems remain an attractive option by being highly reproducible and by eliminating the clinical ambiguity of intermediate grades of disease.

Can problematic fibroepithelial lesions be accurately classified on core needle biopsies

Fibroepithelial lesions (FEL) of the breast are notoriously difficult to classify on core needle biopsies. The goal of this study was to evaluate interobserver variability and accuracy of subclassifying difficult FELs into fibroadenoma (FA) and phyllodes tumors (PTs). We identified 50 breast core needle biopsies, initially diagnosed generically as FEL, with subsequent excision and final diagnosis of either FA or benign PT. Five surgical pathologists from one institution independently reviewed these in 3 rounds. The pathologists were blinded to the final excisional diagnosis. Two diagnostic categories were allowed: FA and PT. A set of histologic criteria was provided including the presence of subepithelial condensation, stromal heterogeneity, overgrowth, pleomorphism, fragmentation, cellularity, adipose tissue entrapment, and mitotic count and asked to review the slides for the second round. A third round of interpretations was conducted after each criterion was defined. Interobserver agreement for the diagnosis and each criterion was evaluated using the κ level of agreement. Accuracy of ratings to final diagnosis was calculated using Wilcoxon signed-rank test. κ Values for interobserver agreement were fair for the first and second rounds varying from 0.20 to 0.22, respectively. This increased to 0.27 in round 3. When considering each category, the κ value varied from 0.26 to 0.29 for FA and 0.28 to 0.14 for PT. Overall, there was fair agreement between the pathologists in all categories. The rate of correctly diagnosed cases ranged from 40% in the first round, to 48% in the second round, to 67% in round 3. Overall the pathologists performed better in identifying FA than PT. The accuracy of interpretations was significantly different between the first (40%), second (48%), and third rounds (67%).

Accuracy and added value of triage beyond segregating potentially neoplastic effusions in immediate wet preparation.

OBJECTIVE To sudy the accuracy and value of immediate wet preparation (WP) procedure on effusion and washing cytologic specimens. STUDY DESIGN Two hundred specimens were identified over 3 months in our cytology laboratory, including 102 pleural effusion, 59 peritoneal effusion, 28 pelvic washing and 11 pericardial fluid specimens. WP slides were prepared, stained with toluidine blue (TB) and .. evaluated. Findings were reported as negative, suspicious or positive for malignant cells. For negative specimens, the remaining prepared slides were stained together. For suspicious or positive interpretation, slides were stained separately. Accuracy and additional benefits from this immediate triage step were studied. RESULTS Interpretation ofslides resulted in 152 negative, 34 positive and 14 suspicious for malignancy. Analysis for additional values resulted in immediate interpretation relayed to clinicians, additional fluid centrifuged for adequate sediment in samples with scant cellularity, selection of bloody specimens for acid washing procedures, selection of cases to optimize cell block preparation when pivotal histologic evaluation or immunohistochemistry was anticipated and selection of cases for potentially needed ancillary studies. Accuracy, sensitivity, specificity and positive and negative predictive values were high. CONCLUSION WP using the TB is accurate, sensitive and highly specific and has considerable value beyond segregating potential neoplastic cases.

Abstract P4-14-06: Characteristics of benign breast disease and subsequent risk of breast cancer differ by age among African Americans

Introduction: A history of benign breast disease (BBD) is common and certain established pathologic features are associated with increased breast cancer risk. These associations have been reported primarily from studies of white women, where incidence of BBD peaks in the 4th or 5th decade of life. Previous work in an African American (AA) cohort of women with BBD showed AA women were younger at their first BBD diagnosis. Thus investigating whether different features of benign lesions may be associated with age and/or subsequent breast cancer risk in this population is warranted. Methods: Benign breast biopsies from 1,867 AA women with BBD diagnosed from 1997-2003 were microscopically reviewed for 15 benign features (apocrine metaplasia (AM), ductal hyperplasia (DH), atypical ductal hyperplasia (ADH), lobular hyperplasia (LH), calcifications (Calc), cysts, duct ectasisa (DE), fibroadenoma (FA), fibrosis, intraductal papilloma (IDP), radial scar (RS), sclerosing adenosis (SA), columnar cell alterations (CC), mucocele-like tumors (MLT), and atropy), and followed for subsequent breast cancer in metropolitan Detroit, Michigan. Data from 439 women under 40 and 1,428 women 40 and older at BBD diagnosis were available for analysis, with a mean follow-up time of 14 years. Differences between age categories for BBD features were compared using chi-square tests, and risk of breast cancer was estimated with odds ratios (OR) and 95% confidence intervals (95% CI) calculated from logistic regression analysis. Results: Women 40 and over were more likely to be diagnosed with nearly all of the benign characteristics compared to younger women, including: AM, DH, Calc, cysts, CC, and ADH (all p-values Conclusions: Characteristics of BBD differ by age, with more women over the age of 40 being diagnosed with various conditions. Risk of subsequent cancer also varies, although RS, CC and ADH appear to increase risk in both age groups. Citation Format: Michele L Cote, Julie J Ruterbusch, Sudeshna Bandyopadhyay, Quratulain Ahmed, Barra Alosh, Eman Abdulfatah, Haitham Arabi, Rouba Lynn Ali-Fehmi. Characteristics of benign breast disease and subsequent risk of breast cancer differ by age among African Americans [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-14-06.