Combined morphologic and cytochemical grading of serous ovarian tumors

The potentiality of DNA analysis to complement morphologic evaluation in classifying serous ovarian tumors as adenoma, borderline malignancy, or invasive adenocarcinoma was investigated in a series of 54 tumors. The DNA analyses were performed on histologic tumor sections. The primary diagnoses were borderline tumor in 24 cases and invasive adenocarcinoma in 30 (World Health Organization classification). When the specimens were reviewed, 17 of the 54 tumors were reclassified, after which the series consisted of 9 adenomas, 24 borderline tumors, and 21 invasive adenocarcinomas. Rising histologic malignancy grade was associated with increasing numbers of cells showing high DNA content. The DNA levels in the adenomas thus were within the diploid range of a normal cell population. They were somewhat higher in the borderline tumors and were highest in the invasive adenocarcinomas. Though no clear-cut intergroup demarcation was discernible, there was a subgroup of adenocarcinomas with greatly elevated DNA levels, indicating high biologic malignancy. The observations suggested that DNA analyses can complement histologic malignancy grading and can be useful for the recognition or highly malignant tumors among invasive adenocarcinomas.     

Comparison of the usefulness between a new universal grading system for epithelial ovarian cancer and the FIGO grading system

OBJECTIVE: The aim of this study was to compare the usefulness of a new universal grading system for ovarian cancer proposed by Shimizu et al. (Cancer 82 (1998), 893; Gynecol. Oncol. 70 (1998), 2) with that of the FIGO grading system as a prognostic factor of ovarian cancer. METHODS: We reviewed all paraffin-embedded tissues of epithelial ovarian cancer obtained from 130 women who underwent initial treatment including primary surgery in our hospital between January 1990 and December 2000. The scores of the specimens were obtained according to both the universal grading system and the FIGO grading system. RESULTS: Both the FIGO grading system and the universal grading system worked as significant prognostic indicators. Patients with Grades 1 and 3 of the universal grading system had high and low 5-year survival rates, respectively, compared to those of the FIGO grading system. Inconsistencies in histologic grade between the FIGO and universal grading systems were observed in 22 patients. The positive rate of lymph node metastasis in patients with Grade 3 of the universal grading system was significantly high compared to those of the FIGO grading system (P = 0.03). Patients with Grade 3 of the universal grading system with residual tumor of not less than 2 cm in diameter were observed more frequently than those of the FIGO grading system. C4ONCLUSION: The universal grading system was superior to the FIGO grading system in terms of the prediction of malignancies such as the potential of lymph node metastasis and invasion and the adaptability to clear cell cancer.     

Letrozole may be a valuable maintenance treatment in high-grade serous ovarian cancer patients

Objectives

Endocrine therapy is used as maintenance in estrogen receptor (ER) positive breast cancers and has been proposed in low-grade serous ovarian cancers (LGSOC). Here we examine a rationale for its use as maintenance in high-grade serous ovarian cancers (HGSOC).

Prognostic role of E-cadherin in patients with advanced serous ovarian cancer

Purpose

To analyse correlation between expression of E-cadherin and clinical and pathological features and overall survival in advanced-stage serous ovarian carcinoma.

Methods

The expression of E-cadherin was analysed immunohistochemically in formalin-fixed, paraffin-embedded samples from 54 patients with advanced-stage serous ovarian cancer and related to clinicopathological characteristics and patients survival. The clinicopathological characteristics included the stage according to the International Federation of Gynecology and Obstetrics (FIGO), tumour differentiation, number of mitoses per 10 high-power fields (HPF), residual tumour size, and vascular invasion. Only patients with serous ovarian cancer FIGO stages III–IV were included. Overall survival (OS) was defined as time from surgery to the last follow-up date on 01.10.2010. OS was evaluated using Kaplan–Meier method, and log-rank test was used to asses the differences between the positive and E-cadherin negative group. Multivariate analysis was completed using the Cox proportional hazard regression model.

Results

E-cadherin immunoreactivity was not associated with FIGO stage, tumour grade, number of mitotic figures per 10 HPF, residual tumour volume or vascular invasion. Negative E-cadherin expression significantly predicted shorter OS (p < 0.001). The multivariate analyses showed that negative E-cadherin (p < 0.001), FIGO stage (p = 0.012) and residual tumour size >1 cm after the initial cytoreductive surgery (p < 0.001) were predictors of shorter OS.

Conclusion

Negative E-cadherin expression like presence of residual tumour after primary cytoreductive surgery and higher FIGO stage seem to predict unfavourable clinical outcome in patients with advanced-stage serous ovarian cancer. Negative expression of E-cadherin was shown to be a significant independent predictor of poorer OS. E-cadherin as marker has prognostic value.     

Histochemical distribution of CA-125 as a prognostic indicator in patients with serous ovarian cancer

Abstract. The study comprises 66 patients with stage III and IV serous ovarian carcinomas of whom 64 had CA-125 positive tumors.
While the percentage of CA-125 positive cells and the staining intensity showed no correlation to patient survival, the pattern of CA-125 distribution, membranous versus cytoplasmic, was significantly correlated to survival. In accordance with other observations on switching of the antigen reaction from membrane to cytoplasm with increasing grade of atypia or malignancy, patients with membrane positive CA-125 tumors had a significantly better prognosis than did patients with CA-125 in the cytoplasm.
Furthermore, there was excellent agreement between, on the one hand, the binding pattern of CA-125 and, on the other, the ploidy of the tumor cells and the HGI histopathologic grading index, both previously shown to be of prognostic significance.     

Peritoneal serous papillary carcinoma, a phenotypic variant of familial ovarian cancer: implications for ovarian cancer screening

OBJECTIVE: Our purpose was to report the cancers arising during a familial ovarian cancer screening program and investigate the tumor's clonality and association with BRCA1 and BRCA2 mutations. STUDY DESIGN: Program participants with a diagnosis of ovarian cancer or peritoneal serous papillary carcinoma were identified and their demographic characteristics, ultrasonographic findings, CA 125 results, operative reports, and pathology slides reviewed. Immunohistochemical analysis of p53, bcl-2, HER-2/neu, and nm23 H1 expression was performed on tumor tissues from multiple metastatic sites, and germline BRCA1 and BRCA2 mutations were identified. RESULTS: Three stage I ovarian cancers and 7 cases of peritoneal serous papillary carcinoma were diagnosed from among 1261 program participants. Ultrasonographic abnormalities triggered surgical exploration in all 3 cases of stage I disease. Elevated levels of CA 125 were the harbinger in 2 of 7 cases of peritoneal serous papillary carcinoma, abnormal ultrasonographic findings prompted diagnosis in 2 of 7 cases, and 3 of 7 women had abdominal symptoms 5, 6, and 16 months after screening. Results of immunohistochemical studies suggested multifocal disease in 5 of 7 patients with peritoneal serous papillary carcinoma. At least 3 of the patients with peritoneal serous papillary carcinoma carry BRCA1 185delAG mutations. CONCLUSION: Multifocal peritoneal serous papillary carcinoma may be a phenotypic variant of familial ovarian cancer, and screening strategies for these women cannot rely on ultrasonography and CA 125 testing to detect early disease.     

Frequency of serous tubal intraepithelial carcinoma (STIC) in patients with high grade serous ovarian cancer

ObjectiveSerous tubal intraepithelial carcinoma (STIC) is a known precursor of high-grade serous ovarian cancer (HGSOC). This study aimed to evaluate the proportion of STIC in patients with HGSOC and analyze the STIC-related prognosis in patients with HGSOC.Materials and methodsAll pathology reports at our institution that included bilateral salpingectomies of patients with HGSOC from January 2013 to December 2018 were reviewed by two experienced pathologists. The specimens from the ovaries and the salpinx including fimbria were examined. We analyzed the correlation between STIC and HGSOC and compared the clinical characteristics and STIC-related prognostic outcomes in patients with HGSOC.ResultsEleven of the 76 cases were STIC. BRCA mutations were found in 16.9% of patients with HGSOC. STIC was observed in 30.0% of patients with BRCA mutations and in 14.3% of patients without BRCA mutations. The incidence of STIC in patients with BRCA mutations was approximately twice that in patients without BRCA mutations; however, the difference was not statistically significant (P = 0.231). Further, the 5-year survival rate of patients without STIC appeared to be high; nevertheless, the difference was not statistically significant (59.7% vs. 47.4%, P = 0.633). Moreover, there was no significant difference in disease-free survival rate according to STIC (36.4% vs. 33.1%, P = 0.956).ConclusionSTIC was identified in patients with HGSOC, and STIC incidence was prominent in HGSOC related to BRCA mutation. Although low frequency, STIC was detected in patients without BRCA mutation. Therefore, prophylactic salpingectomy may be useful for prevention of HGSOC.     

Oncogene expression in ovarian cancer: a pilot study of c-myc oncoprotein in serous papillary ovarian cancer

The nuclear-associated protein product of the c-myc gene, p62c-myc, was assayed simultaneously with total DNA using flow cytometry in nuclei extracted from archival biopsies of serous papillary carcinoma of the ovary. The oncoprotein was probed with a synthetic peptide-induced mouse monoclonal antibody which was subsequently labeled with a fluorescent rabbit anti-mouse immunoglobulin and DNA was assayed using the nucleic acid fluorochrome propidium iodide. Serous papillary ovarian carcinoma expressed significantly higher p62c-myc levels compared with normal ovary (P less than 0.00003 Mann-Whitney U test). Biopsies classified as "borderline" low-potential malignancy exhibited levels between normal ovary and carcinoma. The difference between normal and "borderline" was significant at P less than 0.003, but no difference between "borderline" and frankly invasive biopsies was observed, P = 0.149. There was no difference among the histological grades of carcinomas. All normal ovaries had diploid DNA content as did 5/6 cases of "borderline" malignancy. The majority of cases of carcinoma, 28/36, were aneuploid. There was a statistically significant difference in the distribution of aneuploidy, P less than 0.005, between invasive carcinomas and those classified as "borderline" low-potential malignancy.     

Propensity score matching confirms that primary surgery or neoadjuvant chemotherapy result in equivalent survival within a comprehensive cohort of patients with high-grade serous ovarian cancer

ObjectiveOur objective was to investigate whether trial evidence showing that neoadjuvant chemotherapy is non inferior to primary surgery for the primary treatment of advanced ovarian cancer could be extrapolated to groups of patients that were not included in the trials.MethodsUsing a detailed retrospective cohort of all patients managed through a single tertiary hospital we carried out a propensity score analysis, principal component analysis, and cox proportional hazard analysis to compare survival in matched cohorts.ResultsA propensity score analysis showed that for at least 41% of all patients with advanced high-grade serous cancer neoadjuvant chemotherapy is non inferior to primary surgery (median survival primary surgery: 38 months, neoadjuvant chemotherapy: 35 months. P = 0.39). However, principal component analysis, supported by cox modelling, suggests that for some subgroups, including patients with subdiaphragmatic nodal disease, primary surgery may be associated with improved survival (HR 0.11, CI 0.026–0.48).ConclusionsWe have shown that the findings of previous trials can be extrapolated to a wider population and that statistical modelling can be used to identify groups or patients who benefit from specific modalities of treatment.     

A binary histologic grading system for ovarian serous carcinoma is an independent prognostic factor: a population-based study of 4317 women diagnosed in Denmark 1978-2006

Objective

To evaluate the prognostic significance of histologic grade on survival of ovarian serous cancer in Denmark during nearly 30 years.

Methods

Using the nationwide Danish Pathology Data Bank, we evaluated 4317 women with ovarian serous carcinoma in 1978-2006. All pathology reports were scrutinized and tumors classified as either low-grade serous carcinomas (LGSC) or high-grade serous carcinomas (HGSC). Tumors in which the original pathology reports were described as well-differentiated were classified as LGSC, and those that were described as moderately or poorly differentiated were classified as HGSC. We obtained histologic slides from the pathology departments for women with a diagnosis of well-differentiated serous carcinoma during 1997-2006, which were then reviewed by expert gynecologic pathologists. Data were analyzed using Kaplan-Meier methods and Cox proportional hazards regression analysis with follow-up through June 2009.

Results

Women with HGSC had a significantly increased risk of dying (HR = 1.9; 95% CI: 1.6-2.3) compared with women with LGSC while adjusting for age and stage. Expert review of 171 women originally classified as well-differentiated in 1997-2006 were interpreted as LGSC in 30% of cases, whereas 12% were interpreted as HGSC and 50% as serous borderline ovarian tumors (SBT). Compared with women with confirmed LGSC, women with SBT at review had a significantly lower risk of dying (HR = 0.5; 95% CI: 0.22-0.99), and women with HGSC at review had a non-significantly increased risk of dying (HR = 1.6; 95% CI: 0.7-3.4).

Conclusions

A binary grading system is a significant predictor of survival for ovarian serous carcinoma.     

Assessment of the AgNORs count in serous ovarian cancer

OBJECTIVE: The survival rate of patients with ovarian cancer strongly depends on staging and grading. The next potential, independent prognostic factor might be the amount of nucleolar organizer regions (AgNORs) in cancer cells. DESIGN: To assess the relationship between AgNORs count in serous ovarian cancer and grading, the size of primary tumor, the evaluation of peritoneal fluid and clinical staging. MATERIAL AND METHODS: 69 women who underwent surgical procedure due to serous ovarian cancer between 1998-2002 were included into the study. In each case the clinical and histopathological assessment of neoplastic disease was made. In all cases the specimens were prepared according to the method described by Howell and Ploton. In cancer cells the mean number of AgNORs per nucleus (mAgNOR) and the mean percentage of nuclei with five or more AgNORs per nucleus (pAgNOR) were counted. RESULTS: The mAgNOR in cancer cells varied from 3.22 to 7.19 (mean 4.31+/-0.81), and the pAgNOR varied from 5% to 84% (mean 39.74+/-20.58%). According to the grading of cancers it was as follows: 3.74+/-0.25 and 22.12+/-10.03 in G1 tumors, 4.13+/-0.56 and 35.52+/-13.94 in G2 tumors, and 4.75+/-0.92 and 52.26+/-20.65 in G3 tumors. All the differences were statistically significant. We did not find any correlation between the size of primary tumor and mAgNOR as well as pAgNOR. There were no correlations between the presence as well as the amount of ascitic fluid, and mAgNOR as well as pAgNOR. The positive correlation between the presence of cancer cells in peritoneal fluid and pAgNOR, but not mAgNOR was found. The values of mAgNOR and pAgNOR in clinical stages were respectively: 3.94+/-0.44 and 27.11+/-15.71 for stage I, 4.14+/-0.62 and 39.25+/-22.53 for stage II, 4.27+/-0.79 and 38.76+/-19.79 for stage III, 4.55+/-0.92 and 46.42+/-20.71 for FIGO stage IV. The positive correlations between staging and mAgNOR as well as pAgNOR were found. CONCLUSIONS: The number of AgNORs per cell is one of the sensitive methods in the assessment of ovarian cancer agressiveness and positively correlates with grading and staging of the disease.     

Cost-effectiveness of maintenance hormonal therapy in patients with advanced low grade serous ovarian cancer

ObjectivesTo assess the cost-effectiveness of using maintenance hormonal therapy in patients with low grade serous ovarian cancer (LGSC).MethodsA simulated decision analysis with a Markov decision model over a lifetime horizon was performed using the base case of a 47-year old patient with stage IIIC, LGSC following first-line treatment with primary cytoreductive surgery and adjuvant chemotherapy. Two treatment strategies were analyzed - maintenance daily letrozole until disease progression and routine observation. The analysis was from the perspective of the healthcare payer. Direct medical costs were estimated using public data sources and previous literature and were reported in adjusted 2018 Canadian dollars. The model estimated lifetime cost, quality-adjusted life years (QALY), life years (LY), median overall survival (OS), and number of recurrences with each strategy. Cost-effectiveness was compared using an incremental cost-effectiveness ratio (ICER). A strategy was considered cost-effective when the ICER was less than the willingness to pay (WTP) threshold of $50,000 CAD per QALY. Deterministic sensitivity analysis was performed to assess the impact of changing key clinical and cost variables.ResultsMaintenance letrozole was the preferred strategy with an associated lifetime cost of $69,985 CAD ($52,620 USD) and an observed improvement of 0.91 QALYs and 1.55 LYs. The ICER for letrozole maintenance therapy was an additional $11,037 CAD ($8298 USD) per QALY. The modeled median OS was 150 months with maintenance letrozole and 126 months in the observation strategy. The maintenance letrozole strategy resulted in 34% and 17% fewer first recurrences at 5-year and 10-year follow-up, respectively.ConclusionMaintenance letrozole is a cost-effective treatment strategy in patients with advanced LGSC resulting in clinically-relevant improvement in QALYs, LYs, and fewer disease recurrences.