The controversial ovary

Routine removal of ovaries at hysterectomy has been urged as a means of preventing ovarian carcinoma. Proponents of this policy, however, have not submitted the crucial datum: What proportion of women undergoing hysterectomy for benign conditions will later have ovarian carcinoma if the ovaries are not removed. Granting that oophorectomy will effectively prevent ovarian carcinoma, it creates an endocrine imbalance that cannot be corrected artificially, and the lack of ovarian hormones may precipitate osteoporosis or cardiovascular disease. If the ovaries appear normal, if there is no history of carcinoma, and if the patient understands and accepts the risk, the ovaries usually can be conserved at hysterectomy for benign conditions.     

Primary papillary serous carcinoma of the peritoneum: report of a case with diagnosis by fine needle aspiration and immunocytochemistry

BACKGROUND: Primary papillary serous carcinoma (PPSC) of the peritoneum is a rare neoplasm, histologically indistinguishable from papillary serous carcinoma of the ovary, which diffusely involves the peritoneum but spares or minimally invades the ovaries. To the best of our knowledge, the preoperative and the fine needle aspiration diagnosis of this disorder have not been reported before. CASE: A woman developed an extensive peritoneal neoplasm 4 years after hysterectomy and bilateral salpingo-oophorectomy for benign disease. Fine needle aspiration of the tumor was performed, and the cytologic and immunocytochemical findings were consistent with papillary serous carcinoma. A diagnosis of PPSC of the peritoneum was rendered because review of all slides from previous surgical specimens showed no evidence of carcinoma and no other primary tumors were found elsewhere. CONCLUSION: Fine needle aspiration cytology coupled with immunocytochemical and clinical data allows an unequivocal preoperative diagnosis of papillary serous carcinoma (primary peritoneal or with an ovarian origin). The sole limitation to establish a primary peritoneal origin before surgery is the requirement to histologically study the ovaries. Based on this fact, the preoperative fine needle aspiration cytology diagnosis of PSCP should be restricted to oophorectomized patients.     

Metastatic Breast Cancer Presenting As an Ovarian Cyst: Diagnosis By Fine Needle Aspiration Cytology

A fifty-year-old woman with a history of breast cancer presented with a clinically benign ovarian cyst. Laparoscopic aspiration of cyst fluid was performed and the cytology was suspicious of epithelial neoplasia. At subsequent hysterectomy and bilateral salpingo-oophorectomy, the specimen showed extensive metastatic breast carcinoma. Although the cytological examination of fluid from ovarian cysts is often unrewarding, this case shows that metastatic carcinoma may occasionally be diagnosed in this fashion.     

Ovarian carcinoma of low malignant potential treated at the 1(st) Department of Obstetrics and Gynecology Semmelweis University Faculty of Medicine,between 1990 and 2000

The authors analyzed the epidemiologic and histological characteristics and the management of ovarian carcinoma of low malignant potential (LMP) at a university hospital between 1990 and 2000. The authors carried out a retrospective study reviewing hospital charts. Based on the records experience with 29 such tumors is peresented. Of these 20 (74%) were of the serous variety, 7 (26%) were mucinous. LMP tumors accounted for 16% of proliferating epithelial ovarian tumors. They occured at a mean age of 45 years. The LMP tumors were bilateral in 12% of the cases. The majority of patients (87%) with LMP tumors presented with early stage disease. Tumor markers such as CA-125 were not always elevated as in invasive ovarian carcinoma. Laboratory investigations have not demonstrated that these tumors represent an intermediate step between benign ovarian tumors and carcinoma. The recommended therapy is surgical, consisting of total abdominal hysterectomy, bilateral salpingo-oophorectomy, peritoneal washings, and tumor debulking. Conservative surgery consisting of unilateral salpingo-oophorectomy is considered to be an appropriate treatment for young women with early stage LMP ovarian tumors who wish to retain their fertility potential. 50 percent of women who underwent conservative surgery subsequently conceived in this study. There were no recurrences in the study group, so the authors conclude that the long term outcome of LMP tumors is extremely favorable.     

Toll-like receptor expression in normal ovary and ovarian tumors

Recent studies have implicated inflammation in the initiation and progression of ovarian cancer, though the mechanisms underlying this effect are still not clear. Toll-like receptors (TLRs) allow immune cells to recognize pathogens and to trigger inflammatory responses. Tumor cell expression of TLRs can promote inflammation and cell survival in the tumor microenvironment. Here we sought to characterize the expression of TLRs in normal human ovaries, benign and malignant ovarian tumors from patients, and in established ovarian tumor cell lines. We report that TLR2, TLR3, TLR4, and TLR5 are strongly expressed on the surface epithelium of normal ovaries. In contrast to previous studies of uterus and endocervix, we found no cyclic variation in TLR expression occurred in murine ovaries. TLR2, TLR3, TLR4, and TLR5 are expressed in benign conditions, epithelial tumors, and in ovarian cancer cell lines. Variable expression of TLR6 and TLR8 was seen in benign and malignant epithelium of some patients, while expression of TLR1, TLR7, and TLR9 was weak. Normal and malignant ovarian stroma were negative for TLR expression. Vascular endothelial cells, macrophages, and occasional fibroblasts in tumors were positive. Functional activity for TLRs was demonstrated by stimulation of cell lines with specific ligands and subsequent activation and translocation of NFκB and release of the proinflammatory cytokines interleukin-6 and CCL-2. These studies demonstrate expression of multiple TLRs in the epithelium of normal ovaries and in ovarian tumor cells, and may indicate a mechanism by which epithelial tumors manipulate inflammatory pathways to facilitate tumor progression.     

卵巢上皮性癌中干扰素介导的跨膜蛋白1的表达意义

目的:探讨干扰素介导的跨膜蛋白1(Interferon-induced transmembrane protein 1,IFITM1)基因在卵巢上皮性癌中表达的相关性及其意义。方法:应用Western blotting检测正常卵巢、卵巢良性肿瘤、卵巢交界性肿瘤和卵巢上皮性癌组织中IFITM1蛋白表达。免疫组织化学检测12例正常卵巢、21例卵巢良性肿瘤、18例卵巢交界性肿瘤和85例卵巢上皮性癌组织中IFITM1的蛋白表达,同时分析IFITM1表达状况与临床病理因素之间的相关性。结果:Western blotting显示卵巢上皮性癌和卵巢交界性肿瘤中IFITM1表达水平明显高于正常卵巢组织和卵巢良性肿瘤。免疫组化显示在正常卵巢组织中IFITM1阳性表达率为41.7%(5/12),在卵巢良性肿瘤组织中71.4%(15/21),在卵巢交界性肿瘤组织中为72.2%(13/18),在卵巢上皮性癌中为77.6%(66/85),IFITM1蛋白表达强度在正常卵巢、良性卵巢肿瘤、交界性卵巢肿瘤、上皮性卵巢癌间的比较有统计学意义(P0.05)。IFITM1蛋白表达与病理类型、肿瘤分化程度、肿瘤FIGO分期有关(P0.05),与淋巴结转移、腹水无明显相关性。化疗敏感组和耐药组的IFITM1表达强度间差异有统计学意义(P0.05)。结论:IFITM1在正常卵巢、卵巢良性肿瘤、卵巢交界性肿瘤和卵巢上皮性癌组织中的表达依次升高,并与卵巢癌以铂类为基础的化疗耐药性产生有相关性,为进一步研究IFITM1在卵巢癌诊治及化疗中的应用前景提供依据。     

Runx3蛋白在卵巢上皮性癌中的表达及临床意义

目的:探讨Runx3蛋白在卵巢癌的发生发展、浸润转移和化疗耐药中的作用,为以Runx3作为分子治疗靶点的抗肿瘤基因治疗提供理论依据。方法:运用组织芯片技术联合免疫组化法检测27例卵巢癌、20例正常卵巢组织、30例卵巢良性肿瘤中抑癌基因Runx3的表达情况,分析其与卵巢癌临床病理特征的关系,并进行临床随访分析Runx3基因与卵巢癌化疗耐药的关系。结果:1.Runx3蛋白在卵巢癌组织中的表达明显低于正常卵巢组织及卵巢良性肿瘤中的表达,两两比较,差异有统计学意义(P0.05);Runx3蛋白表达与肿瘤的临床分期和病理学分级有关,差异有显著性(P0.05);与肿瘤的组织学类型、患者年龄、是否绝经、及有无腹水形成无关(P0.05)。2.Runx3蛋白在化疗敏感组中高表达。结论:Runx3蛋白低表达对卵巢癌的发生发展及化疗耐药中起重要作用。     

Selective gene expression profiling of mTOR-associated tumor suppressor and oncogenes in ovarian cancer

The aim of this study was to selectively profile the activation status of mammalian target of rapamycin (mTOR)-associated oncogenes and tumor suppressor genes (TSGs) in ovarian cancer specimens, healthy ovaries and benign ovarian tumors, including endometrial cysts. We used a novel type of microfluidic gene array to examine the expression of 15 human tumor suppressors and oncogenes in ovarian cancer specimens of 53 patients, benign ovarian cysts of 29 women (endometrial and simple) and 11 healthy ovaries of individuals in whom the material was obtained during total hysterectomies performed because of fibroid changes. The array was custom-designed to include the following genes: NF1, RHEB, mTOR1, AKT-1, PTEN, TSC1, TSC2, KRAS, RPS6KB1, 4EBP1, TP53, EIF4E, STK11, PIK3CA and BECN1. Confirmatory immunohistochemical detection was performed for a group of selected proteins. Particularly significant differences were observed as to the expression of PTEN (p < 0.0001), TP53 (p = 0.0003), PIK3CA (p = 0.0003) and BECN1 (p = 0.0014) which were shown to be downregulated in cancer patients when compared to healthy ovaries and benign ovarian cysts (endometrial and simple). These markers did not show association with grade or stage of the tumor. Immunohistochemistry showed that PTEN, TP53, PIK3CA and BECN1 proteins are expressed in ovarian cancer. Our results indicate that there are significant differences in the expression of some of the mTOR-related tumor suppressors and oncogenes which could be associated with the pathogenesis of ovarian cancer.     

Immunohistochemical profile of ovarian inclusion cysts in patients with and without ovarian carcinoma

Summary The expression of cytokeratin, epithelial membrane antigen, Leu-M1, B72.3, carcinoembryonic antigen, human placental lactogen, proliferating cell nuclear antigen, p53, and ovarian carcinoma-associated antigen OC-125 was evaluated in inclusion cysts in contralateral ovaries of patients with unilateral ovarian carcinoma. The findings were compared with the findings in inclusion cysts in ovaries of patients without ovarian carcinoma. Although there was more frequent expression of tumour markers B72.3 and CEA in patients with ovarian carcinoma, these differences did not reach statistical significance.     

Orthotopic transplantation of LH receptor knockout and wild-type ovaries

Luteinizing hormone (LH) receptor knockout animals have an ovarian failure due to an arrest in folliculogenesis at the antral stage. As a result, the animals have an infertility phenotype. The present study was undertaken to determine whether this phenotype could be reversed by orthotopic transplantation of wild-type ovaries. The results revealed that transplanting wild-type ovaries into null animals did not result in resumption of estrus cycles. Although the number of different types of follicles increased, none progressed to ovulation. The serum hormone profiles improved, reflecting the ovarian changes. The wild-type animals with null ovaries also failed to cycle and their ovaries and serum hormone levels were more like null animals with their own ovaries. Although the lack of rescue of null ovaries placed into wild-type animals was predicted, the failure of wild-type ovaries placed in null animals was not, which could be due to chronic exposure of transplanted tissue to high circulating LH levels and also possibly due to altered internal milieu in null animals. These findings may have implications for potential future considerations of grafting normal donor ovaries into women who have an ovarian failure resulting from inactivating LH receptor mutations.     

HMGB1在卵巢癌中的表达及临床意义

目的：探讨高迁移率组蛋白B1（HMGB1）在卵巢癌患者血清及组织中的表达及临床意义。方法：采用ELISA技术检测96例女性血清中HMGB1水平,其中盆腔肿物住院患者66例按照术后病理结果分为卵巢良性肿瘤组40例和卵巢癌组26例,健康女性30例作为正常对照组,并通过免疫组织化学技术进一步检测卵巢癌、卵巢良性肿瘤组织中的表达情况。结果：卵巢癌组HMGB1水平明显高于其他两组,差异有统计学意义（P〈0.05）,正常对照组和卵巢良性肿瘤组比较差异无统计学意义（P〉0.05）。结论：HMGB1测定有助于鉴别卵巢良恶性肿瘤。     

Transabdominal ultrasound screening for early ovarian cancer.

OBJECTIVE--To assess the value of ultrasonography in a screening procedure for early ovarian cancer. DESIGN--Prospective study of at least 5000 self referred women without symptoms of ovarian cancer. Each woman was scheduled to undergo three annual screenings (consisting of one or more scans) to detect grossly abnormal ovaries or non-regressing masses. SETTING--The ovarian screening clinic at King''s College Hospital, London. SUBJECTS--5479 Self referred women without symptoms (aged 18-78, mean age 52). INTERVENTIONS--Women with a positive result on screening were referred for laparoscopy or laparotomy, or both. MAIN OUTCOME MEASURES--Findings at surgery and from histology of abnormal ovaries. RESULTS--A total of 14,594 screenings (15,977 scans) were performed. A positive result was obtained at 338 screens (2.3%) comprising 326 subjects (5.9%). Five patients with primary ovarian cancer (four stage Ia, one stage Ib; two at first screening three at second) were identified (prevalence 0.09%). An additional four patients had metastatic ovarian cancer (three at first screening, one at second). The apparent detection rate was 100%. It was not possible to differentiate between the ultrasonic appearance of early malignant and benign tumours. The rate of false positive results for primary ovarian cancer was 3.5% at the first screening, 1.8% at the second, and 1.2% at the third. Overall the rate of false positive results was 2.3%; the specificity was 97.7% and the predictive value of a positive result on screening was 1.5%. The odds that a positive result on screening indicated the presence of an ovarian tumour, any ovarian cancer, or primary ovarian cancer were about one to two, one to 37, and one to 67 respectively. CONCLUSION--Ultrasonography can be used to screen women without symptoms for persistent ovarian masses that will include early ovarian cancer.     

Towards whole sheep ovary cryopreservation

Cryopreservation of ovarian tissue aims to assist young women who require treatments that may lead to sterility or infertility. Cryopreservation procedures should therefore be as simple and efficient as possible. This study investigates rapid cooling outcomes for whole sheep ovaries. Ovaries were perfused with VS4 via the ovarian artery, and cooled by quenching in liquid nitrogen in less than a minute (estimated cooling rate above 300 °C/min till the vitreous transition temperature). The ovaries were rewarmed in two stages: slow warming (12–16 °C/min from −196 to −133 °C) in liquid nitrogen vapour, followed by rapid thawing in a 45 °C water bath at about 200 °C/min. DSC measurements showed that under these cryopreservation conditions VS4 would vitrify, but that VS4 perfused ovarian cortex fragments did not vitrify, but formed ice (around 18.4%). Immediately following rewarming, a dye exclusion test indicated that 61.4 ± 2.2% of small follicles were viable while histological analysis showed that 48 ± 3.8% of the primordial follicles were normal. It remains to be clarified whether follicle survival rates will increase if conditions allowing complete tissue vitrification were used.     

The role of chemotherapy and prophylactic bilateral oophorectomy in a case of colorectal adenocarcinoma with ovarian metastases

A 66-year-old female presented with a large abdominal mass and accompanying systemic complaints of abdominal pain, constipation. and fever. On exploratory laparotomy, the mass was found to be a moderately differentiated adenocarcinoma of the sigmoid colon with metastasis to the left ovary. A primary colorectal carcinoma that has metastasized to the ovaries can be difficult to distinguish clinically from an advanced primary ovarian tumor. Histology and tumor markers are currently the most useful tools available in making an accurate diagnosis. If the nature of the primary tumor is uncertain and the initial response to chemotherapy is poor, the patient's prognosis will also he poor. Though controversy exists regarding the role of prophylactic bilateral oophorectomy during resection for primary colorectal cancer, later confusion can be avoided by performing this procedure when the colorectal carcinoma is first diagnosed. However the possibility of a concurrent primary ovarian tumor must not be overlooked.     

Hysterectomy and risk of epithelial ovarian cancer by histologic type,endometriosis, and menopausal hormone therapy

BackgroundThis nationwide, register-based case-control study investigated the association between hysterectomy and risk of epithelial ovarian cancer according to histology and by history of endometriosis and menopausal hormone therapy (MHT) use.MethodsFrom the Danish Cancer Registry, all women registered with epithelial ovarian cancer at age 40–79 years during 1998–2016 were identified (n = 6738). Each case was sex- and age-matched to 15 population controls using risk-set sampling. Information on previous hysterectomy on benign indication and potential confounders was retrieved from nationwide registers. Conditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for the association between hysterectomy and ovarian cancer according to histology, endometriosis, and use of MHT.ResultsHysterectomy was not associated with risk of epithelial ovarian cancer overall (OR=0.99; 95% CI 0.91 –1.09) but was associated with reduced risk of clear cell ovarian cancer (OR=0.46; 95% CI 0.28–0.78). In stratified analyses, decreased ORs associated with hysterectomy were seen in women with endometriosis (OR=0.74; 95% CI 0.50–1.10) and in non-users of MHT (OR=0.87; 95% CI 0.76–1.01). In contrast, among long-term MHT users, hysterectomy was associated with increased odds for ovarian cancer (OR=1.20; 95% CI 1.03–1.39).ConclusionHysterectomy was not associated with epithelial ovarian cancer overall but with reduced risk of clear cell ovarian cancer. Our findings may suggest a reduced risk of ovarian cancer after hysterectomy in women with endometriosis and in MHT non-users. Interestingly our data pointed to an increased ovarian cancer risk associated with hysterectomy among long-term users of MHT.     

High-affinity folate receptor in human ovary, serous ovarian adenocarcinoma, and ascites: radioligand binding mechanism, molecular size, ionic properties, hydrophobic domain, and immunoreactivity.

High-affinity folate receptors are expressed in normal ovaries and ovarian carcinomas. Binding of [3H]folate in human ovary, serous ovarian carcinoma tissue, and ascites is a complex process that has not been well characterized. This study shows changes in binding affinity and mechanism of binding with decreasing receptor concentration, inhibition by folate derivatives, and a slow radioligand dissociation at pH 7.4 becoming rapid and complete at pH 3.5. The receptor seems to be positively charged since it elutes in the front effluent of a DEAE-Sepharose CL-6B ion-exchange column at pH 6.3. The gel filtration profile of Triton X-100-solubilized tissue and ascites contained two peaks of radioligand-bound receptor (25 and 100 kDa). Exposure of ascites to cleavage by phosphatidylinositol-specific phospholipase C resulted in a partial conversion of the 100-kDa peak to a 25-kDa peak. This suggests that the receptor may be anchored to the membrane by a glycosylphosphatidyl residue that inserts into Triton X-100 micelles, resulting in a large molecular size on gel filtration. The receptor in ovarian carcinoma tissue immunoreacts with antibodies against purified human milk folate receptor protein as shown by enzyme-linked immunosorbent assay, immunoprecipitation, sodium dodecyl sulfate-polyacrylamide gel electrophoresis immunoblotting (a single band of 45 kDa), and immunohistochemistry. In only three of seven ovarian carcinomas did expression of radioligand-bound receptors exceed levels found in five normal ovaries. However, only receptors in ovarian carcinoma specimens showed a high degree of immunoreactivity. Hence, even without elevations of the total receptor level, a folate receptor isoform homologous to human milk folate receptor protein seemed to prevail in serous ovarian carcinomas.     

Hormone concentrations in the homogenates of ovarian tissue and blood serum in postmenopausal women not using hormone therapy

Ovaries in postmenopausal women synthesize steroids, mostly androgens. Removal of the ovaries after menopause may be reflected by menopausal symptoms and arterial hypertension observed during postoperative period, along with a significantly increased risk of death due to cardiovascular complications. It is not understood if the clinical consequences of gonad removal at different time points after menopause are similar. The aim of this study was to evaluate ovarian steroidogenesis and consequently to define the role of the ovaries in postmenopausal women depending on the time after menopause. Concentrations of hormones were determined in ovarian homogenates and serum of postmenopausal women. This study included 207 postmenopausal women. They were divided into groups depending on the time after menopause. All participants had laparotomic removal of the ovaries. Concentrations of estradiol, testosterone and androstenedione were measured in ovarian homogenate and serum. The study revealed that ovarian homogenate and serum concentrations of estradiol, testosterone and androstenedione were the highest in women up to 5 years after menopause and since then significantly decreased. This study showed that testosterone, androstenedione and estradiol are synthesized in the postmenopausal ovaries. The peak synthesis of these hormones occurs up to 5 years after menopause and significantly decreases thereafter.     

Towards whole sheep ovary cryopreservation

Cryopreservation of ovarian tissue aims to assist young women who require treatments that may lead to sterility or infertility. Cryopreservation procedures should therefore be as simple and efficient as possible. This study investigates rapid cooling outcomes for whole sheep ovaries. Ovaries were perfused with VS4 via the ovarian artery, and cooled by quenching in liquid nitrogen in less than a minute (estimated cooling rate above 300 °C/min till the vitreous transition temperature). The ovaries were rewarmed in two stages: slow warming (12–16 °C/min from −196 to −133 °C) in liquid nitrogen vapour, followed by rapid thawing in a 45 °C water bath at about 200 °C/min. DSC measurements showed that under these cryopreservation conditions VS4 would vitrify, but that VS4 perfused ovarian cortex fragments did not vitrify, but formed ice (around 18.4%). Immediately following rewarming, a dye exclusion test indicated that 61.4 ± 2.2% of small follicles were viable while histological analysis showed that 48 ± 3.8% of the primordial follicles were normal. It remains to be clarified whether follicle survival rates will increase if conditions allowing complete tissue vitrification were used.     

Genetic Analysis of the Early Natural History of Epithelial Ovarian Carcinoma

Background

The high mortality rate associated with epithelial ovarian carcinoma (EOC) reflects diagnosis commonly at an advanced stage, but improved early detection is hindered by uncertainty as to the histologic origin and early natural history of this malignancy.

Methodology/Principal Findings

Here we report combined molecular genetic and morphologic analyses of normal human ovarian tissues and early stage cancers, from both BRCA mutation carriers and the general population, indicating that EOCs frequently arise from dysplastic precursor lesions within epithelial inclusion cysts. In pathologically normal ovaries, molecular evidence of oncogenic stress was observed specifically within epithelial inclusion cysts. To further explore potential very early events in ovarian tumorigenesis, ovarian tissues from women not known to be at high risk for ovarian cancer were subjected to laser catapult microdissection and gene expression profiling. These studies revealed a quasi-neoplastic expression signature in benign ovarian cystic inclusion epithelium compared to surface epithelium, specifically with respect to genes affecting signal transduction, cell cycle control, and mitotic spindle formation. Consistent with this gene expression profile, a significantly higher cell proliferation index (increased cell proliferation and decreased apoptosis) was observed in histopathologically normal ovarian cystic compared to surface epithelium. Furthermore, aneuploidy was frequently identified in normal ovarian cystic epithelium but not in surface epithelium.

Conclusions/Significance

Together, these data indicate that EOC frequently arises in ovarian cystic inclusions, is preceded by an identifiable dysplastic precursor lesion, and that increased cell proliferation, decreased apoptosis, and aneuploidy are likely to represent very early aberrations in ovarian tumorigenesis.