Benign Serous Tumors Research Articles

Morphological Types of Epithelial Origin Ovarian Tumours

Aim: To assess the various morphological types of epithelial origin ovarian tumors. Methods: The study involved cases that were presented to the Pathology department between January 2015 to December 2020. Epithelial ovarian tumors that were diagnosed as either benign, borderline, or malignant were analyzed. The inclusion criteria involved pathological specimens of ovarian tumors consisting of cells that are epithelial in origin. Clinical records, ultrasounds, and histopathological investigations of the patients were accessed from the hospital database for analysis. Results: A total of 309 cases were reviewed. Out of these, ovarian epithelial tumors made up at least four-fifths of the total tumors i.e. 258(83.5%). Non-epithelial origin of ovarian tumors only consisted of 51(16.5%) cases. Out of these 153(49.84%) cases were diagnosed as serous, 88(28.48%) as mucinous. A total of 175(61.4%) tumors were benign, 15(5.81%) were borderline, and 68 (26.3%) were malignant. The patients with malignant serous tumors (43.24±13.99 years) were considerably older than individuals with benign (34.54 ± 13.16 years) and borderline (32.71±13.79 years) serous tumors. Conclusion: The present study concludes that epithelial ovarian cancer is the most commonly encountered lesion in our population. Benign and borderline tumors involve slightly younger age groups, mostly below forty years of age. Keywords: Carcinoma, Epithelial-origin tumors, malignancy, ovarian tumors

A cross-sectional study of immunohistochemical evaluation of surface epithelial ovarian tumors

Background: Ovarian cancer is one of the most common malignancies in female patients. In recent years, immunohistochemistry (IHC) has emerged as an important tool in the diagnosis of ovarian tumors. The study aimed to assess estrogen receptors (ERs), progesterone receptors (PRs), Her-2-neu, and Ki-67 by IHC in surface epithelial ovarian tumors and to correlate the findings with different variables. Materials and Methods: It was a cross-sectional study. Oophorectomy/salpingo-oophorectomy/cystectomy specimens were included in this study. IHC was done on 10% neutral buffer formalin-fixed paraffin-embedded tissue sections by using Dako FLEX Ready to use mouse monoclonal antibodies and DakoEnvisionTM FLEX/HRP detection reagent. Results: The study includes 81 cases of surface epithelial ovarian tumors (a benign serous tumor [20], a benign mucinous tumor [18], a borderline mucinous tumor [5], low-grade serous carcinoma [8], high-grade serous carcinoma [19], mucinous carcinoma [7], endometrioid carcinoma [2], borderline Brenner tumor [1], and malignant Brenner tumor [1]. ER had higher expression in malignant cases (51.33%) than in benign cases (15.8%). PR had higher expression in malignant tumors (54.05%) incomparable to benign (18.42%) and borderline tumors (16.66%). PR had higher expression in high grade. Expression of Her-2-neu positivity was found to be 29.7% out of the total 81 cases. Her-2-neu was found in 11 high-grade tumors among 31 malignant cases. CA-125 levels were significantly higher in malignant ovarian tumors (P = 0.0143). Proliferation activity was considered low if proliferation index (PI) <10% and high if PI >10%. The study showed high PI in malignant tumors. Conclusion: Expression of these marks in adjunct to H&E diagnosis may prove beneficial in differentiating benign, borderline, and malignant cases, in which a diagnosis of borderline cases based on sole H & E is doubtful.

Application of Deep Convolutional Neural Networks for Discriminating Benign, Borderline, and Malignant Serous Ovarian Tumors From Ultrasound Images.

ObjectiveThis study aimed to evaluate the performance of the deep convolutional neural network (DCNN) to discriminate between benign, borderline, and malignant serous ovarian tumors (SOTs) on ultrasound(US) images.Material and MethodsThis retrospective study included 279 pathology-confirmed SOTs US images from 265 patients from March 2013 to December 2016. Two- and three-class classification task based on US images were proposed to classify benign, borderline, and malignant SOTs using a DCNN. The 2-class classification task was divided into two subtasks: benign vs. borderline & malignant (task A), borderline vs. malignant (task B). Five DCNN architectures, namely VGG16, GoogLeNet, ResNet34, MobileNet, and DenseNet, were trained and model performance before and after transfer learning was tested. Model performance was analyzed using accuracy, sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC).ResultsThe best overall performance was for the ResNet34 model, which also achieved the better performance after transfer learning. When classifying benign and non-benign tumors, the AUC was 0.96, the sensitivity was 0.91, and the specificity was 0.91. When predicting malignancy and borderline tumors, the AUC was 0.91, the sensitivity was 0.98, and the specificity was 0.74. The model had an overall accuracy of 0.75 for in directly classifying the three categories of benign, malignant and borderline SOTs, and a sensitivity of 0.89 for malignant, which was better than the overall diagnostic accuracy of 0.67 and sensitivity of 0.75 for malignant of the senior ultrasonographer.ConclusionDCNN model analysis of US images can provide complementary clinical diagnostic information and is thus a promising technique for effective differentiation of benign, borderline, and malignant SOTs.

Immunohistochemical Expression of SOX2 in Benign and Malignant Ovarian Serous Tumors at the Anatomic Pathology Unit H. Adam Malik Hospital Medan

Background: Ovarian neoplasms are most often found in women with an incidence of 80% of benign tumors and the rest are malignant tumors of the ovary. Ovarian cancer in Indonesia ranks third most cases that occur in women after breast cancer and liver cancer. Serous epithelial ovarian tumors are the most common subtype of ovarian cancer. SOX2 (SRY/sex determining region Y-box2) is a transcription factor that plays a role in cell proliferation and is also a marker of cancer stem cells. The presence of these cancer stem cells will affect the success of therapy because they are resistant to chemotherapy and radiotherapy. Aim: Knowing how to assess the expression and how the immunohistochemical expression of SOX2 in benign and malignant ovarian serous tumors. Method: This study is a descriptive analytic study using surgical tissue paraffin block preparations from patients with a diagnosis of benign and malignant ovarian serous tumors in the Anatomical Pathology Unit of HAM Hospital Medan with 39 cases. This research has been approved by the Health Research Ethics Commission, Faculty of Medicine, University of North Sumatra. Results: Based on the immunohistochemical staining of SOX2, the benign subtype was found to be low in expression (71.4%), the low-grade subtype to have high expression (18.2%) and the high-grade subtype to have more high expression (81.8%). Conclusion: In this research it was found that the highest expression of SOX2 was found in the benign subtype with low expression, but in the high-grade serous subtype high expression was found.

Diagnosis of Ovarian Neoplasms Using Nomogram in Combination With Ultrasound Image-Based Radiomics Signature and Clinical Factors.

Objectives: To establish and validate a nomogram integrating radiomics signatures from ultrasound and clinical factors to discriminate between benign, borderline, and malignant serous ovarian tumors. Materials and methods: In this study, a total of 279 pathology-confirmed serous ovarian tumors collected from 265 patients between March 2013 and December 2016 were used. The training cohort was generated by randomly selecting 70% of each of the three types (benign, borderline, and malignant) of tumors, while the remaining 30% was included in the validation cohort. From the transabdominal ultrasound scanning of ovarian tumors, the radiomics features were extracted, and a score was calculated. The ability of radiomics to differentiate between the grades of ovarian tumors was tested by comparing benign vs borderline and malignant (task 1) and borderline vs malignant (task 2). These results were compared with the diagnostic performance and subjective assessment by junior and senior sonographers. Finally, a clinical-feature alone model and a combined clinical-radiomics (CCR) model were built using predictive nomograms for the two tasks. Receiver operating characteristic (ROC) analysis, calibration curve, and decision curve analysis (DCA) were performed to evaluate the model performance. Results: The US-based radiomics models performed satisfactorily in both the tasks, showing especially higher accuracy in the second task by successfully discriminating borderline and malignant ovarian serous tumors compared to the evaluations by senior sonographers (AUC = 0.789 for seniors and 0.877 for radiomics models in task one; AUC = 0.612 for senior and 0.839 for radiomics model in task 2). We showed that the CCR model, comprising CA125 level, lesion location, ascites, and radiomics signatures, performed the best (AUC = 0.937, 95%CI 0.905–0.969 in task 1, AUC = 0.924, 95%CI 0.876–0.971 in task 2) in the training as well as in the validation cohorts (AUC = 0.914, 95%CI 0.851–0.976 in task 1, AUC = 0.890, 95%CI 0.794–0.987 in task 2). The calibration curve and DCA analysis of the CCR model more accurately predicted the classification of the tumors than the clinical features alone. Conclusion: This study integrates novel radiomics signatures from ultrasound and clinical factors to create a nomogram to provide preoperative diagnostic information for differentiating between benign, borderline, and malignant ovarian serous tumors, thereby reducing unnecessary and risky biopsies and surgeries.

English

The differential diagnosis of an abdominal mass in young teenage girls include pelvic inflammatory disease, pelvic abdominal Koch’s, endometriosis, pedunculated uterine leiomyomata, colonic mass, and germ cell tumour. There is a strong possibility of benign, borderline, or malignant ovarian carcinoma to be diagnosed in young girls with abdominal mass. Preoperative diagnosis depends on age, menopausal status, serum cancer antigen (CA) level of 125, ultrasound and radiological imaging of the mass. For better diagnosis of benign borderline serous tumours, borderline ovarian tumours (BOTs) and invasive cancers, magnetic resonance imaging (MRI) and positron emission tomography has to be done. However, among patients with benign cysts, BOTs and invasive cancers, CA-125 levels can be same. Likewise, the imaging results are not unique to BOTs. The diagnosis of BOTs can therefore be not established before surgery and intraoperative decisions regarding the extent of surgical management are based on the results of frozen section examination. In BOTs, an effective frozen section diagnosis is of considerable significance. Women of reproductive age always want traditional fertility-sparing surgery. Benign cysts should be distinguished from BOTs. Inadequate surgical staging of BOT may result in misdiagnosis of BOT as a benign tumour, leading to more vigorous treatment and possible tumour spread.1

A mini-review regarding the carcinogenesis and morphology of serous tumors of the ovary, fallopian tube and peritoneum

Similar to the already well-recognized adenoma-carcinoma sequence in colorectal cancer pathogenesis, it has been believed for many decades that the progression of ovarian epithelial tumors occurs from benign serous cystadenomas to borderline tumors, to well-differentiated carcinomas, and ultimately, to poorly differentiated carcinomas. However, it is currently accepted that low-grade serous carcinoma (LGSC) and high-grade serous carcinoma (HGSC) are fundamentally different tumor types and, consequently, different diseases. In fact, whereas the benign-borderline-malignant sequence seems to apply quite well to low-grade serous carcinoma, the sequence of genetic alterations in high-grade serous carcinoma is substantially different. In this mini-review, we included the current consensus regarding the morphological and etiopathogenic results regarding serous tumors of the ovary, fallopian tube and peritoneum. It also briefly describes the history of benign, borderline and malignant serous tumors, discussing multiple types of dichotomies in serous carcinomas of the female genital tract and summarizing the current molecular classification.

The Epithelial-Mesenchymal Transition, E-cadherin and Tumor Progression in Ovarian Serous Tumors.

The epithelial-mesenchymal transition (EMT), which is a change in the cell phenotype from epithelial to mesenchymal morphology, is an important step in the invasion process and metastasis of ovarian carcinomas. It is known that the suppression of cell adhesion molecules such as E-cadherin and the expression of mesenchymal markers such as Vimentin are key processes in EMT. There is controversy in the literature about the EMT status of ovarian carcinomas. To investigate EMT status using immunohistochemical expression of E-cadherin in benign, primary malignant serous ovarian tumors and metastases from them in order to assess their significance in tumor progression. The study included a retrospective investigation of 217 ovarian epithelial tumors. Ninety-two cases of serous ovarian tumors and metastases were examined for expression of E-cadherin. In our study, the predominant histological subtype in benign ovarian tumors and carcinomas was serous (73% and 61%, respectively). 65% of benign tumors demonstrated EMT negative status. The majority of carcinomas demonstrated EMT positive status (82%), whereas negative EMT status was only observed in 18% of cases. 89% of the metastases showed EMT positive status, whereas only 11% of them showed negative EMT status. In 6 selected cases with positive EMT status we found Vimentin expression in tumor cells. Positive EMT status (reduced E-cadherin expression) is a characteristic of ovarian carcinomas and metastases, but not of benign serous ovarian tumors.

A rat model of serous borderline ovarian tumors induced by 7,12-dimethylbenz[a]anthracene.

Serous borderline ovarian tumors (SBOTs) behave between benign cystadenomas and carcinomas, and the effective detection and clinical management of SBOTs remain clinical challenges. Because it is difficult to isolate and enrich borderline tumor cells, a borderline animal model is in need. 7,12-dimethylbenz[a]anthracene (DMBA) is capable of inducing the initiation, promotion, and progression of serous ovarian tumors. This study aims to investigate the proper dosage and induction time of DMBA for rat models of SBOTs, and explore their morphological features demonstrated by magnetic resonance (MR) imaging and molecular genetic characteristics. Rats were randomly divided into six groups (1 mg/70 D, 2 mg/70 D, 3 mg/70 D, 2 mg/50 D, 2 mg/90 D, and 2 mg/110 D). The 3 mg/70 D group induced the most SBOTs (50.0%, 12/24). The micropapillary projections were shown on MR imaging, which was the characteristic of SBOTs. The Cyclin D1 characterizing an early pathogenetic event strongly expressed in induced serous benign tumors (SBTs). The immunoreactivity staining scores of P53 expression significantly increased from SBTs, SBOTs to serous ovarian carcinomas (SCAs), which elucidate that P53 might be a promising biomarker to grade serous ovarian tumors. Based on morphological and molecular genetic similarities, this rodent SBOT model was suitable for investigating the pathogenesis of serous ovarian tumors and developing an early detection strategy.

Significance of E-cadherin and KI67 expression in ovarian serous tumors

Background Ovarian serous carcinoma (OSC) is the most common subtype of epithelial ovarian cancer, accounting for ∼50–60% of all cases. The prognosis for OSC patients depends largely on tumor grade, stage, and prognostic markers such as E-cadherin and KI67. Aim To study the diagnostic and prognostic values of E-cadherin and KI67 expression in ovarian serous tumors. Materials and methods E-cadherin and KI67 immunostaining was performed on paraffin-embedded tissue sections of 50 ovarian serous tumors (12 cases benign, eight cases borderline, and 30 cases of OSC). Results E-cadherin was expressed in all benign ovarian serous tumors, whereas it was expressed in only six (75%) cases of borderline tumors and in eight (26.7%) cases of OSC. The proliferation rate evaluated by KI67 expression in the serous cells was found to be high in 21 (70%) cases of OSC compared with two (25%) cases of borderline tumors, whereas none of the benign tumors showed KI67 expression. When taken together, E-cadherin and KI67, statistically significant differences were documented between benign and malignant serous tumors, but this was not evident between borderline and the other two groups. For OSCs, a statistically significant decrease in E-cadherin expression was observed with an increase in tumor grade and advanced stage. Conversely, a statistically significant increase in KI67 expression was observed only with an increase of tumor grade. Conclusion Study of E-cadherin and KI67 expression can be of value in differentiating between benign and malignant ovarian serous tumors. The expression of both markers taken together may be of value in predicting the biologic behavior of the tumor.

Fallopian Tube Epithelial Changes in Ovarian Serous Tumors Compared with Control Group: A Single-Center Study.

Background:Recent studies have hypothesized that distal end of fallopian tube is a possible origin of ovarian serous carcinoma. This study investigated histopathological changes in fallopian tube epithelium (FTE) of the patients with ovarian serous tumors compared with control group.Materials and Methods:In a prospective cross-sectional study, fallopian tubes (right and left) of 34 cases with ovarian serous tumors were collected from patients who underwent surgery in two major gynecological centers affiliated to Shiraz University of Medical Sciences, Shiraz, Iran (2012–2015). They are composed of 21 (61.8%) high-grade serous carcinomas (HGSCs), 5 (14.7%) borderline ones, and 8 (23.5%) benign serous tumors. As control group, fallopian tubes of 72 hystrectomy cases without ovarian tumor were added to the study. Both tubes of all of the cases were submitted entirely, according to the protocol of sectioning and extensively examining the fimbriated end. The results were statistically analyzed using SPSS-PC windows and Chi-square tests.Results:Significant differences were found between the cases and control group in tubal epithelial cell stratification (especially >3 cell layers thickness), atypia, mitosis, glandular complexity, tufting, and detached epithelial cells (P < 0.05). These findings particularly atypia and mitosis were more frequently seen in the ampulla and fimbriated end of high-grade ovarian serous carcinomas.Conclusion:Our results showed that premalignant epithelial changes of the ampulla and the distal end of FTE were seen in some of the patients with ovarian HGSCs. Therefore, FTE could be one of the sources of ovarian serous carcinoma.

Assessment of the clinicopathological relevance of mesothelin level in plasma, peritoneal fluid, and tumor tissue of epithelial ovarian cancer patients.

Ovarian cancer remains the most lethal gynecologic malignancy. This is due to lack of effective screening, diagnosis predominance in late stage of disease, a high recurrence rate after primary therapy, and poor treatment response in platinum-resistant tumor. Thus, unique biomarkers, predictive of individual disease course, and prognosis are urgently needed. The aim of our study was to assess the clinicopathological significance of plasma, peritoneal fluid, and tumor tissue levels of mesothelin in epithelial ovarian cancer patients. Plasma and peritoneal fluid levels of mesothelin were measured by enzyme-linked immunosorbent assay. Tissue expression of MSLN was evaluated using quantitative real-time polymerase chain reaction. Preoperative plasma mesothelin levels were significantly higher in epithelial ovarian cancer patients in comparison to the patients with benign tumor and controls. There have been noticed significant differences in the plasma mesothelin levels based on International Federation of Gynecology and Obstetrics stage, grade, and histology type. No significant changes were observed between Kurman and Shih type I versus type II epithelial ovarian cancer. Interestingly, peritoneal fluid mesothelin levels revealed significant differences based on both grade and Kurman and Shih-type epithelial ovarian cancer. There were no relevant changes in the mesothelin level in peritoneal fluid between different stages and histology types compared to benign tumor. MSLN expression level in tumor tissue was significantly higher based on stage, grade, and Kurman and Shih-type epithelial ovarian cancer than in the benign masses. In addition, data showed significant higher MSLN expression in endometrioid tumors compared to benign masses and serous tumors. Plasma, peritoneal fluid, and tumor tissue levels of mesothelin positively correlated with level of CA125. Low mesothelin concentrations in plasma were also associated with prolonged patient survival. More importantly, we revealed that plasma mesothelin level was correlated with both peritoneal fluid mesothelin level and tumor MSLN expression. This study highlights that plasma mesothelin level may be a useful noninvasive biomarker surrogate for local tumor mesothelin status in monitoring of epithelial ovarian cancer patients.

Serous ovarian tumors: Immunohistochemical profiling as an aid to grading and understanding tumorigenesis

BackgroundThe aim of this study was to evaluate the expression of p53, p16, Wilms tumor gene (WT1), and Mindbomb E3 Ubiquitin Protein Ligase 1 (MIB-1) index by immunohistochemical (IHC) staining in benign, low-grade, and high-grade serous ovarian tumors. MethodsForty-one cases of ovarian serous tumors were included in the study (benign serous tumor [n = 10], low-grade ovarian serous carcinoma [n = 8], and high-grade ovarian serous carcinoma [n = 23]). Expression of p53, p16, WT1, and MIB-1 by IHC was evaluated statistically with the grade of tumor. Semiquantitative scoring system for percentage (0–5) and intensity (1–3) of staining pattern was used to bring about objectivity. Resultsp53, p16, and WT1 showed significantly higher staining scores in ovarian serous carcinoma group than in the benign group (p < 0.05). However, p16 score was not significant in benign versus low-grade tumors. In the carcinoma group, the high-grade serous tumors showed significantly higher staining scores of p53, p16, and WT1 than the low-grade serous tumors (p < 0.05). Papillary serous tumors had comparatively lower p53 and WT1 scores for the same grade of tumor. MIB-1 scores were not significant. Conclusionp53, p16, and WT1 are helpful for the subtyping of serous ovarian tumors as low grade and high grade. WT1 is helpful in establishing primary ovarian serous tumors. The combination of moderate-to-high p53 and WT1 scores provides a robust way of confirming high-grade tumors.

Malignant peritoneal mesothelioma: clinical aspects, and therapeutic perspectives.

Malignant peritoneal mesothelioma (MPM) is a rare disease with a wide clinical spectrum. It arises from the peritoneal lining and commonly presents with diffuse, extensive spread throughout the abdomen and, more rarely, metastatic spread beyond the abdominal cavity. Computed tomography, magnetic resonance imaging and positron-emission tomography are important diagnostic tools used for the preoperative staging of MPM. The definitive diagnosis is based on histopathological analysis, mainly via immunohistochemistry. In this regard, paired-box gene 8 negativity represents a useful diagnostic biomarker for differentiating MPM from ovarian carcinoma. In addition, BRCA1-associated protein-1 (BAP1) loss is specific to MPM and allows it to be distinguished from both benign mesothelial lesions and ovarian serous tumors. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has become an increasingly important therapeutic approach, while systemic therapies are still being developed. Histology, Ki-67, completeness of cytoreduction, age, sex, and baseline thrombocytosis are commonly used to optimize patient selection for CRS with HIPEC. Additionally, it is well recognized that, compared to other subtypes, an epithelial morphology is associated with a favorable prognosis, whereas baseline thrombocytosis predicts an aggressive biologicalbehavior. Platelets and other immunologic cytokines have been evaluated as potential novel therapeutic targets. Epigenetic modifiers, including BAP1, SETD2 and DDX3X, are crucial in mesothelial tumorigenesis and provide opportunities for targeted treatment. Overexpression of the closely interacting phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways appears crucial in regulation of the malignant phenotype. The use of targeted therapies with PI3K-mTOR-based inhibitors requires further clinical assessment as a novel approach.

Cancer Stem Cell-Related Marker NANOG Expression in Ovarian Serous Tumors: A Clinicopathological Study of 159 Cases.

The objectives of this study were to assess cancer stem cell-related marker NANOG expression in ovarian serous tumors and to evaluate its prognostic significance in relation to ovarian serous carcinoma. NANOG protein expression was immunohistochemically evaluated in the ovarian tissue microarrays of 20 patients with benign ovarian serous tumors, 30 patients with borderline ovarian serous tumors, and 109 patients with ovarian serous carcinomas, from which 106 were of high-grade and 3 of low-grade morphology Immunohistochemical reaction was scored according to signal intensity and the percentage of positive cells in tumor samples. Pursuant to our summation of signal intensity and positive cell occurrence, we divided our samples into 4 groups: NANOG-negative, NANOG-slightly positive, NANOG-moderately positive, and NANOG-strongly positive group. Complete clinical data were obtained for the ovarian serous carcinoma group, and correlation between clinical data and NANOG expression was analyzed. A specific brown nuclear, or cytoplasmic reaction, was considered a positive NANOG staining. In terms of the ovarian serous carcinoma group, 69.7% were NANOG positive, 22.9% slightly positive, 22.9% moderately positive, and 23.9% strongly positive. All NANOG-positive cases were of high-grade morphology. Benign and borderline tumors and low-grade serous carcinomas were NANOG negative. There was no significant correlation between NANOG expression and clinical parameters in terms of the ovarian serous carcinoma group. Positive NANOG expression is significantly associated with high-grade ovarian serous carcinoma and is absent in benign, borderline, and low-grade serous lesions. In our study, there was no correlation between NANOG expression and clinical parameters, including its use in the prognosis of ovarian serous carcinoma.

Serum and peritoneal fluid concentrations of soluble human leukocyte antigen, tumor necrosis factor alpha and interleukin 10 in patients with selected ovarian pathologies

BackgroundAlthough immune system plays a key role in the pathogenesis of both endometriosis and ovarian cancer, its function is different. Therefore, we hypothesized, that selected immune parameters can serve as diagnostic markers of these two conditions. The aim of this study was to compare serum and peritoneal fluid concentrations of sHLA-G, IL-10 and TNF-alpha in women with selected ovarian pathologies: benign serous cysts, endometrioma and malignant tumors. Clinical significance of using them for diagnostic purposes in women with serous ovarian cysts, endometriosis, and ovarian cancer, which in the future may improve the early diagnosis of ovarian diseases.Case PresentationThe study included women treated surgically for benign serous ovarian cysts, ovarian endometrioma and serous ovarian adenocarcinomas. Peripheral blood and peritoneal fluid samples were obtained intraoperatively. Patients with benign serous cysts, endometrioma and ovarian malignancies did not differ significantly in terms of their serum and peritoneal fluid concentrations of sHLA-G. Ovarian cancer patients presented with significantly higher median serum concentrations of IL-10 and TNF-alpha than other study subjects. Median concentrations of IL-10 and TNF-alpha in peritoneal fluid turned out to be the highest in ovarian cancer patients, followed by women with endometrioma and subjects with benign serous cysts. All these intergroup differences were statistically significant. Irrespective of the group, median concentrations of sHLA-G, IL-10 and TNF-alpha in peritoneal fluid were higher than serum levels of these markers.ConclusionsElevated serum and peritoneal fluid concentrations of IL-10 and TNF-alpha distinguish ovarian malignancies and endometriomas from benign serous ovarian cysts. In contrast to endometriosis, ovarian malignancies are characterized by elevated peritoneal fluid concentrations of IL-10 and TNF-alpha, elevated serum concentrations of IL-10 and low serum levels of TNF-alpha. Serum and peritoneal fluid concentrations of sHLA-G have no diagnostic value in differentiating between ovarian malignancies and endometriomas.

EphA5 protein, a potential marker for distinguishing histological grade and prognosis in ovarian serous carcinoma.

BackgroundOvarian serous carcinoma (OSC) is the most common ovarian epithelial malignancy. Disregulation of Eph/ephrin signaling has been implicated in oncogenesis and tumor progression. EphA5 receptor is one of large families of Eph tyrosine kinase receptor and is documented in the development of nervous system. Till now, there is no published data about the role of EphA5 in ovarian epithelial neoplasmas.MethodsThis study aims to investigate the expression of EphA5 protein in ovarian serous carcinoma, and its relationship to clinical pathological characteristics. Sixty-one cases of ovarian serous carcinoma, 24 cases of benign ovarian serous tumors, 42 cases of serous borderline tumors and 20 cases of normal fallopian tubes were examined using immunohistochemical staining. The relationship between EphA5 expression and pathological parameters was analyzed. Kaplan-Meier survival function was used to analyze prognosis of patients.ResultsImmunostaining analysis demonstrated that the EphA5 protein was highly expressed in 100% (20/20) of normal fallopian tube samples, 100% (24/24) of benign epithelial ovarian tumors, 76% (32/42) of ovarian serous borderline tumors, and 31% (19/61) of ovarian serous carcinomas. Loss of EphA5expression was associated with tumor grade (P < 0.001) and FIGO stage (P = 0.005). The survival analysis showed that patients with negative or weak expression of EphA5 protein had a poor outcome than those with positive expression (P = 0.004).ConclusionsOur results show that EphA5 may be a potential biomarker for distinguishing high-and low-grade ovarian serous carcinoma and a potential prognostic marker.

Clinical implication of Tiam1 overexpression in the prognosis of patients with serous ovarian carcinoma.

T lymphoma invasion and metastasis 1 (Tiam1), a guanine nucleotide exchange factor, was originally identified as an invasion- and metastasis-inducing gene in T lymphoma cells. High expression levels of the human Tiam1 gene have been found in numerous human malignancies, suggesting a potential role as a modifier of tumor initiation and progression. However, little is known about the status of Tiam1 in ovarian carcinoma. The present study aimed to investigate the clinicopathological significance of high Tiam1 expression in serous ovarian carcinoma. Immunohistochemical staining for Tiam1 was performed in 182 patients with serous ovarian carcinoma, in 76 patients with ovarian borderline tumors and in 72 patients with benign ovarian tumors. Immunofluorescence staining was also performed to detect the subcellular localization of Tiam1 protein in SK-OV-3 ovarian carcinoma cells. The correlations between high Tiam1 expression and the clinicopathological features of the ovarian carcinomas were evaluated by the χ2 test and Fisher's exact test. The overall survival (OS) rates were calculated by the Kaplan-Meier method, and the association between prognostic factors and patient survival was analyzed by the Cox proportional hazard model. Tiam1 protein showed a cytoplasmic and nuclear staining pattern in ovarian carcinoma. Strongly-positive Tiam1 protein expression was observed in 59.3% (108/182) of ovarian carcinomas, which was significantly higher than in benign serous tumors (12.5%; 9/72). Moreover, the rate of strongly-positive Tiam1 expression in borderline serous tumors (31.6%; 24/76) was also significantly higher than that in benign serous tumors. High Tiam1 protein expression was closely associated with a high histological grade, metastasis, advanced clinical stage and lower OS rates in ovarian carcinoma. Multivariate analysis indicated that Tiam1 was an independent prognostic factor, along with metastasis and clinical stage, in patients with ovarian carcinoma. In conclusion, Tiam1 expression is strongly associated with grade and outcome in ovarian carcinoma, and may serve as a useful molecular marker for clinical management.

A proteomic signature of ovarian cancer tumor fluid identified by highthroughput and verified by targeted proteomics

Tumor fluid samples have emerged as a rich source for the identification of ovarian cancer in the context of proteomics studies. To uncover differences among benign and malignant ovarian samples, we performed a quantitative proteomic study consisting of albumin immunodepletion, isotope labeling with acrylamide and in-depth proteomic profiling by LC-MS/MS in a pool of 10 samples of each histological type. 1135 proteins were identified, corresponding to 505 gene products. 223 proteins presented associated quantification and the comparative analysis of histological types revealed 75 differentially abundant proteins. Based on this, we developed a panel for targeted proteomic analysis using the multiple reaction monitoring (MRM) method for validation of 51 proteins in individual samples of high-grade serous ovarian tumor fluids (malignant) and benign serous cystadenoma tumor fluids. This analysis showed concordant results in terms of average amounts of proteins, and APOE, SERPINF2, SERPING1, ADAM17, CD44 and OVGP1 were statistically significant between benign and malignant group. The results observed in the MRM for APOE were confirmed by western blotting, where APOE was more abundant in malignant samples. This molecular signature can contribute to improve tumor stratification and shall be investigated in combination with current biomarkers in larger cohorts to improve ovarian cancer diagnosis. Biological significanceDespite advances in cancer research, ovarian cancer has a high mortality and remains a major challenge due to a number of particularities of the disease, especially late diagnosis caused by vague clinical symptoms, the cellular and molecular heterogeneity of tumors, and the lack of effective treatment. Thus, efforts are directed to better understand this neoplasia, its origin, development and, particularly the identification and validation of biomarkers for early detection of the disease in asymptomatic stage. In the present work, we confirmed by MRM method in individual ovarian tumor fluid samples the regulation of 27 proteins out of 33 identified in a highthroughput study. We speculate that the presence and/or differential abundance observed in tumor fluid is a cooperation primarily of high rates of secretion of such tumor proteins to extra tumor environment that will at the end accumulate in plasma, and also the accumulation of acute-phase proteins throughout the entire body. On top of that, consideration of physiological influences in the interpretation of expression observed, including age, menopause status, route-of-elimination kinetics and metabolism of the tumor marker, coexisting disease, hormonal imbalances, life-style influences (smoking, alcoholism, obesity), among others, are mandatory to enable the selection of good protein tumor marker candidates for extensive validation.

Epithelial membrane protein 1 expression in ovarian serous tumors.

The present study aimed to analyze the clinical significance of epithelial membrane protein 1 (EMP1) expression in ovarian serous tumors. A total of 84 cases of ovarian serous tumor (50 patients with malignant ovarian serous tumors and 34 patients with borderline and benign serous tumors) were retrospectively analyzed. Differences in the expression levels of EMP1 between the malignant and non-malignant tumor groups were evaluated by immunohistochemical staining. In addition, the association between EMP1 expression and prognostic factors in malignant ovarian serous tumors was investigated. The expression levels of EMP1 were significantly reduced in all the 50 malignant ovarian serous tumors, compared with the 34 non-malignant ovarian serous tumors (P<0.000). Reduced expression of EMP1 was correlated with high grade (P=0.009) and stage (P<0.000) of malignant tumors. EMP1 expression was not observed to be correlated with any other investigated parameters, including surgery, type of operation and chemotherapy response (P>0.005). These results indicated that EMP1 may have a significant role as a negative regulator in ovarian serous tumors, and reduced EMP1 expression in serous tumors may be associated with increased disease severity.