Is the two-tier ovarian serous carcinoma grading system potentially useful in stratifying uterine serous carcinoma? A large multi-institutional analysis.

OBJECTIVE: A subset of uterine serous carcinoma (USC) may have better clinical behavior bringing up the possibility that there may be morphologic features, which would help in their categorization. The aim of this study is to evaluate the potential use of the MD Anderson Cancer Center 2-tier grading system for ovarian carcinoma in USC. METHODS: Tumors assigned a combined score included in this analysis were 1) low-grade: tumors without marked atypia and 12 mitoses/10 high power field (HPF) and 2) high grade: tumors with severe nuclear atypia and >12 mitoses/10 HPF. Clinicopathologic parameters evaluated included patients' age, tumor size, myometrial invasion (MI), lymphovascular invasion (LVI), lymph node (LN), FIGO stage, and patient outcome. RESULTS: 140 patients with USC were included, 30 low grade uterine serous carcinoma (LGUSC) and 110 high grade uterine serous carcinoma (HGUSC). Of all parameters only 2 (MI and stage IA) reached statistical significance. 67% of LGUSC cases showed myometrial invasion versus 93.6% HGUSC cases (p = 0.003). A higher percentage of LGUSC (63.3%) versus HGUSC (32.7%) were in stage IA (p = 0.01). However, by multivariate analysis including age, LVI, stage and tumor grade only stage was an independent prognostic factor. CONCLUSION: The presence of atypia and mitosis across a uterine serous carcinoma is notoriously variable in magnitude and extent, potentially making evaluation of these features difficult and subsequent grading subjective. Our findings thus show that actual prognostic utility of application of MDACC two-tier grading system to uterine serous carcinoma may not be applicable.

Overexpression of enhancer of zeste homolog 2 (EZH2) and focal adhesion kinase (FAK) in high grade endometrial carcinoma.

OBJECTIVE: The deregulation of E-cadherin is associated with Src/FAK signaling axis and histone deacetylase (HDAC)/EZH2 activity. However, the association between EZH2 and FAK and its clinical significance in endometrial carcinoma has not been reported. METHODS: 202 archived cases of endometrial carcinoma (1996-2000) were reviewed and divided into two subtypes. TMAs were developed as per established procedures. EZH2, FAK, and pFAK immunohistochemical stains were performed and the expression was scored as negative (0), low (1) and high (2). Proper statistical analysis was used to assess the correlation between the expression profiles and the clinicopathological parameters and clinical outcome. RESULTS: A total of 141 (69.8%) type-1 tumors and 61 (30.2%) type-2 tumors were identified. EZH2 overexpression was identified in 7.6% of type-1 tumors vs. 63% of type-2 tumors (p<0.001). FAK and pFAK overexpression was only seen in 24.8% and 1.7% of Type-1 tumors as compared to 72% and 58.8% of type-2 tumors, respectively (p<0.001). A positive correlation between the expression of EZH2, FAK, pFAK and PTEN (p<0.0001) was found. The overexpression of EZH2, FAK, and pFAK were significantly associated with high histologic grade, angiolymphatic invasion, lymph node metastasis, myometrial invasion and cervical involvement (p<0.01). Kaplan-Meier analysis demonstrates that the overexpression of EZH2 (p=0.0024), FAK and pFAK (p=0.0001) was significantly associated with decreased overall survival. CONCLUSION: The overexpression of EZH2, FAK and pFAK correlates with well established pathologic risk factors and may predict a more aggressive biologic behavior in endometrial carcinoma, transforming these proteins into potential therapeutic targets for treatment of endometrial cancer.

Clinical and pathologic characteristics of serous carcinoma confined to the endometrium: a multi-institutional study.

The objective of this study was to analyze the clinical and pathologic factors in patients with uterine serous carcinoma confined to the endometrium. A total of 236 uterine serous carcinoma patients from the pathology databases of 4 large academic institutions were included in the study. Clinical and pathologic variables were analyzed, including patient demographics, tumor size (≤2 vs. >2 cm), myometrial invasion, lymphovascular invasion, lymph node status, tumor location (endometrium vs. polyp), cervical involvement, lower uterine segment involvement, FIGO stage, pelvic washings, recurrence, overall survival, and progression-free survival. Of 236 patients, 55 (23%) had tumors limited to the endometrium. Forty-four patients (80%) had Stage IA tumors. The tumor was confined to a polyp in 17 (30.9%) patients. Twenty patients (36.4%) had tumor sizes >2 cm and 12 (21.8%) exhibited lymphovascular invasion. Only 3 patients (5.4 %) had cervical stromal involvement. Thirty-three (66%) patients underwent pelvic and para-aortic lymphadenectomy with 2 positive para-aortic lymph nodes identified. Seven (12.7%) patients had positive washings, whereas 8 patients (14.5 %) had disease recurrence. At a median follow-up of 46 months, there was no difference in overall survival (P = 0.216) or progression-free survival (P=0.063) between patients with tumors confined to a polyp, patients with tumors confined to the endometrium, and patients with tumors present in both polyp and the endometrium. Uterine serous carcinoma with only endometrial involvement, even when confined to a polyp, can be associated with poor prognosis, further stressing the importance of complete surgical staging and adjuvant treatment in this setting.

Prognostic analysis of ovarian cancer associated with endometriosis.

OBJECTIVE: The objective of the study was to evaluate the prognosis of ovarian cancer arising in endometriosis. STUDY DESIGN: We retrospectively compared 42 cases of endometriosis-associated ovarian cancer (EAOC) with 184 cases of ovarian carcinoma without endometriosis (OC). RESULTS: The median age in the EAOC group was 52 vs 59 years in OC (P < .05). In comparison with OC, the EAOC patients were more likely to have low-grade (21% vs 8%; P = .04) and early-stage tumors (International Federation of Gynecology and Obstetrics I and II combined) (49% vs 24%; P = .002). Clear cell (21% vs 2%) and endometrioid (14% vs 3%) tumors were more frequent in EAOC, whereas mucinous tumors were more prevalent in OC (P = .001). The median survival (199 vs 62 months) and the 5 year survival (62% vs 51%) were better for EAOC when compared with OC (P = .038). After controlling for age, stage, grade, and treatment, association with endometriosis was not an independent predictor of better survival in ovarian cancer. CONCLUSION: As such, EAOC has a much better survival rate than OC. This could be explained by the higher prevalence of early-stage and low-grade tumors in EAOC when compared with OC.

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%).

Comparative Analysis of Differentially Expressed miRNAs and their Downstream mRNAs in Ovarian Cancer and its Associated Endometriosis.

OBJECTIVE: There is an increased risk of developing ovarian cancer (OC) in patients with endometriosis. Hence, development of new biomarkers may provide a positive clinical outcome for early detection. MicroRNAs (miRNAs) are small non-coding RNAs that play an important role in biological and pathological process and are currently used as diagnostic and prognostic markers in various cancers. In the current study, we assessed the differential expression of miRNAs from 19 paired ovarian cancer and its associated endometriosis tissue samples. In addition we also analyzed the downstream targets of those miRNAs. METHODS: Nineteen paired cases of ovarian cancer and endometriosis foci were identified by a gynecologic pathologist and macro-dissected. The total RNAs were extracted and subjected to comprehensive miRNA profiling from the pooled samples of these two different entities using microarray analysis. Later, the abnormal expressions of few selected miRNAs were validated in individual cases by quantitative real-time PCR (qRT-PCR). Ingenuity pathway analysis revealed target mRNAs which were validated by qRT-PCR. RESULTS: The miRNA profiling identified deregulation of greater than 1156 miRNAs in OC, of which the top seven were further validated by qRT-PCR. The expression of miR-1, miR-133a, and miR-451 were reduced significantly (p<0.0001) in the OC patients compared to its associated endometriosis. In contrast, the expression of miR-141, miR-200a, miR-200c, and miR-3613 were elevated significantly (p<0.05) in most of the OC patients. Furthermore, among the downstream mRNAs of these miRNAs, the level of PTEN expression was significantly (p<0.05) reduced in OC compared to endometriosis while no significant difference was observed in NF-κB expression. CONCLUSION: The expression of miRNAs and mRNAs in OC were significantly different compared to its concurrent endometriosis. These differential expressed miRNAs may serve as potential diagnostic and prognostic biomarkers for OC associated with endometriosis.