Ovarian Surface Epithelial Tumors Research Articles

The Comparative Study of the Frequency of P53 and Ki67 Markers in Ovarian Epithelial Tumors and Their Relationship with Survival in Patients Presenting to Shahid Sadoughi Hospital of Yazd in 2013–2017

Ovarian cancer is the fifth cause of cancer death among women. P53 gene and Ki67 can play a significant role in the progression of tumors. This study was conducted to review the frequency of P53 and Ki67 markers in different types of ovarian epithelial tumors and their relationship with the prognosis of the disease. This descriptive analytical study was done on all paraffin-embedded blocks of patients with ovarian surface epithelial tumors (malignant, benign, and borderline) referred to pathology ward of Shahid Sadoughi educational General Hospital from 2013 to 2017 by using the census method. Ki67 and P53 immunohistochemical tests were then performed on all the samples. Data such as (age, pathology report, survival status, affected side, size of tumor) were extracted from the hospital folders. Data were analyzed in SPSS version 22. P < 0.05 was set as the level of statistical significance. A total of 86 cases, including 40 serous and mucinous carcinomas, 36 serous and mucinous cystadenomas, and ten serous and mucinous borderline tumors, were examined. The mean age of the patients was 44.29 ± 16.91 years, and their age range was 15–79. A significant relationship was found between the type of tumor and the frequency of P53 and Ki67 (P < 0.05). Nonetheless, no significant relationships were observed between tumor grade and these two markers. Ki67 staining susceptibility was significantly higher in the undifferentiated tumors than in the others (P < 0001). The mean survival was 40.67 months, and a significant relationship was observed between age and survival (P < 0.002) and age and the frequency of P53 and Ki67 and tumor type (P < 0.05). The results of this study showed that both P53 and Ki67 are predictors of overall survival, tumor type, disease grade, and disease prognosis in patients with different ovarian epithelial tumors and can be used in them alongside biopsy.

The Association Between Endometriosis and Surface Epithelial Ovarian Tumors: A Review of Pathological Data

Background: Endometriosis is a prevalent benign condition arising from female reproductive system and affects about 7% to 10% of females. The association of this disorder with epithelial ovarian tumors has been a matter of interest in gynecology. Objectives: The present study was conducted to assess the association between endometriosis and different types of surface epithelial ovarian tumor. Methods: Microscopic slides of 182 cases with the diagnosis of surface epithelial ovarian carcinoma and borderline tumor from 2007 to 2014 were reviewed for the presence of endometriosis in a tertiary gynecological center. Additional data included age, tumor size and laterality, site of endometriosis, presence of atypical endometriosis, and concomitant uterine endometrial carcinoma. Results: Endometriosis was found in 32 out of the 182 (17.58%) of reviewed ovarian epithelial tumor cases. They included endometrioid carcinoma (46.87%), clear cell carcinoma (18.75%), borderline epithelial tumor (31.25%), and low-grade serous papillary carcinoma (3.12%). Conclusions: Endometrioid and clear cell types of ovarian tumors were most frequently associated with endometriosis.

Expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2/neu in surface epithelial ovarian tumors and its clinicohistopathological correlation

BACKGROUND: Ovarian cancers represent the 4th most frequent type of cancers among females and are the most common cause of death from gynecological cancers in the world. AIMS AND OBJECTIVES: The aim is to evaluate the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2/neu) immunohistochemical markers in surface epithelial ovarian tumors and its clinicopathological correlation with CA-125 level, histological type, grading of tumors, and prognosis of ovarian tumors. MATERIALS AND METHODS: This study included 48 cases of surface epithelial ovarian tumors including serous, mucinous, and adenocarcinoma Not Otherwise Specified (NOS). After grossing and processing, H and E sections were examined and representative 3–4 μm sections taken from blocks for immunohistochemistry which was performed with specific antibodies against ER, PR, and HER2/neu as per standard protocol. Statistical analysis was performed using Chi-square test. DISCUSSION AND RESULTS: ER expression was higher in malignant, borderline, serous tumors as compared to benign and mucinous tumors. PR expression was higher in borderline, serous tumors as compared to malignant and mucinous tumors. HER2/neu positive cases were higher in malignant, serous as compared to borderline and mucinous tumors. CONCLUSIONS: ER expression was found to be positive in most of serous tumors, have variable role in prognosis. PR expression showed protective role in survival of patients. Her2/neu was found to be expressed in higher grade and associated with poor prognosis. Together expression of ER and Her2/neu associated with decreased survival rates.

VEGF Expression to Support Targeted Therapy in Ovarian Surface Epithelial Neoplasms.

Vascular Endothelial Growth Factor (VEGF), a promoter of angiogenesis, is a promising target for anti-angiogenic therapy in ovarian cancer. In our study, we examined the expression of VEGF in the spectrum of epithelial ovarian neoplasms (benign, borderline and malignant) by Immunohistochemistry (IHC). Diagnosing ovarian epithelial neoplasms, examining the expression of VEGF in benign, borderline and malignant neoplasms and correlating it with histological grade and stage of malignant cases. This is a cross-sectional, observational study where, total of 50 cases of surface epithelial ovarian neoplasms were examined for expression of VEGF by IHC. Scoring for VEGF expression was done for each case. A total of 42 of the 50 cases (84%) showed VEGF expression. Out of the 42 positive cases, 19 were high VEGF expressors and 23 were low VEGF expressors. VEGF expression was significantly higher in carcinomas as compared to benign and borderline neoplasms (p=<0.001). All neoplasms of serous morphology were positive for VEGF. High VEGF expression was significantly associated with high grade (p=0.003) and stage (p=0.001) of disease. Ovarian surface epithelial neoplasms significantly express VEGF. Though, some VEGF expression was noted in benign and some borderline neoplasms, high VEGF expression was noted only in carcinomas and one case of borderline serous papillary tumour. Thus, these results suggest that epithelial ovarian tumours are candidates for VEGF targeting therapy as most of them are dependent on VEGF for progression.

Ovarian Yolk Sac Tumor With High-Grade Serous Carcinoma in a 62-Year-Old Woman

Ovarian yolk sac tumors are germ cell tumors that usually present in children and young women. Rarely, these tumors can arise in older women, usually in conjunction with surface epithelial tumors, suggesting divergent differentiation from the latter. The combination of mixed ovarian yolk sac tumor and high-grade serous carcinoma is rare, with only one case documented in the literature. We present a case of mixed ovarian yolk sac tumor and high-grade serous carcinoma in a postmenopausal woman, including a brief discussion of the immunohistochemical findings and differential diagnosis. Despite the rarity of mixed ovarian yolk sac tumor and surface epithelial tumors, it is important to recognize the biphasic nature of the tumor, which should prompt a thorough immunohistochemical evaluation. The therapeutic and prognostic implications of proper diagnosis cannot be overemphasized.

Abstract 260: In vivo efficacy of intraperitoneal anti-PD-L1 therapy in ovarian cancer

Abstract Objectives: Programmed cell death ligand 1 (PD-L1) is an immune checkpoint cell surface molecule expressed on many types of cancers including ovarian cancer. Its interaction with the programmed death (PD-1) receptor on T cells essentially halts the immune response and allows tumor escape. Monoclonal antibodies to either PD-L1 or PD-1 block this interaction and show efficacy in a variety of cancers, though to a lesser degree in ovarian cancer. We have evaluated the efficacy of intraperitoneal anti-PD-L1 therapy in two ovarian cancer mouse models. Methods: Murine 2F8 tumor cells derived from an orthotopic tumor isolated from a triple transgenic MUC1+/−KrasG12D/+PtenloxP/loxP (MKP) mouse as we recently described. MUC1 transgenic (MUC1.Tg) mice received an intraperitoneal inoculation of 8×105 syngeneic 2F8 cells. Untreated mice develop extensive tumor burden and expire around 29 days. Mice were treated with 200 μg anti-PD-L1 antibody (or rat IgG as control) every two weeks for three doses starting at 21 days post-inoculation, thus corresponding with late tumor stage. C57BL/6 mice were inoculated via intraperitoneal (IP) injection with 1×106 IG10 (spontaneously transformed mouse ovarian surface epithelial) tumor cells. Treatment with anti-PD-L1 (or rat IgG as control) started 22 days following inoculation when the mice began showing ascites. Immunohistochemistry for perforin was performed on tumor tissue sections. Immune gene profiling of spleen cells collected at necropsy was performed via Nanostring, using 561 mouse immunology-related genes. Results: The 2F8 tumors are aggressive with little T cell infiltration. The anti-PD-L1 treated MUC1.Tg mice showed substantial infiltration of perforin positive cells within the tumor and significantly increased survival (p = 0.001) compared to isotype control- treated mice. Splenocyte profiling of 561 immune genes via Nanostring revealed a treatment-induced immune gene signature that points to T cell functions and cytotoxic anti-tumor immune responses. A similar gene signature favoring cytotoxic anti-tumor activity was also revealed in IG10 tumor bearing C57Bl/6 mice treated with anti-PD-L1. Conclusion: These preclinical results from two different ovarian cancer tumor models demonstrate that targeting PD-L1 is a viable therapeutic strategy in ovarian cancer and increases survival despite (1) non-immunogenic tumors, (2) late treatment initiation, (3) low dose and administration frequency. The tumors respond well to anti-PD-L1 blockade, due to increased systemic T cell responses and intratumoral T cell accumulation, without changing tumor-specific antibody levels. Our studies have high translational potential and support IP administration of PD-L1 blockers in ovarian cancer patients. Citation Format: Shannon Grabosch, Jyothi T. Mony, Lixin Zhang, Tianzhou Ma, Tejas Tirodkar, Joan Brozick, George Tseng, Esther Elishaev, Robert P. Edwards, Xin Huang, Anda M. Vlad. In vivo efficacy of intraperitoneal anti-PD-L1 therapy in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 260. doi:10.1158/1538-7445.AM2015-260

The role of Wilm’s Tumor1 immunohistochemical marker in surface epithelial ovarian tumors

Background: Wilms’ tumor 1 is a tumor suppressor gene. The gene is located in chromosome 11p13. And its expression was found in many solid tumors (including ovarian tumor) and also expressed in hematologic malignancies, Recent studies found that WT1 to be involved in angiogenesis.Objectives: To evaluate the expression of WT1 in surface epithelial ovarian tumorand study the possibility of using WT1 as replacement of both;ovarian tumor marker CA125 and a endothelial cell phenotypic marker CD34.Patients and methods: This is a study of a retrospective ( cross sectional ) of sixty cases with total abdominal hysterectomy and bilateral salpingo - oopherectomy collected from department of Histopathology – Teaching Laboratories / Medical City Teaching Hospital , as well as Al alwya hospital and Al Habibia hospital in Baghdad during the period of study from December 2007 to December 2012. Thirty cases diagnosed as surface epithelial ovarian tumors and thirty cases of histologically normal ovarian tissue which were included as a control group. Formalin - fixed, paraffin - embedded ovarian tissue blocks from 60 cases were used . Three section of 4 micron for each taken and stained with WT1, CD34, and CA125 immunohistochemical marker on positively charged slides.Results: there were a significant correlation between expression of WT1 and histological types of surface epithelial ovarian tumor with a higher expression in serous tumors among other cancer types (P-value &lt; 0.001).There was a significant positive correlation between the expression of WT1 and CA125 scores ( p-value &lt; 0.001).There was a significant correlation between WT1microvessel density (MVD) expression and CD34- microvessel density (MVD) expression in ovarian tumors (P-value = 0.05).On the other hand, there were no significant correlation of WT1 with the age of cases (P-value = 0.9) and with the grade of ovarian tumors ( P-value = 0.23) .Conclusions: The present study demonstrates high expression of WT1 in both tumor and endothelial cells in surface epithelial ovarian tumors, and it had dual usages in evaluation of both ovarian tumor cells and the vascular density. That was proved by demonstrating a significant correlation between WT1 and CA125 expression, and between WT1-MVD and CD34- MVD . There was no statistically significant association between WT1 expression and different tumor grades. There was significance differences in WT1expression among different histological subtypes of primary ovarian carcinomas, with serous carcinoma as the most frequent type.

دور المناعي النسيجي للمعلم WT1 في أورام المبيض الطلائية السرطانية

دور المناعي النسيجي للمعلم WT1 في أورام المبيض الطلائية السرطانية

Napsin A is a specific marker for ovarian clear cell adenocarcinoma

Ovarian clear cell adenocarcinoma has a relatively poor prognosis among the ovarian cancer subtypes because of its high chemoresistance. Differential diagnosis of clear cell adenocarcinoma from other ovarian surface epithelial tumors is important for its treatment. Napsin A is a known diagnostic marker for lung adenocarcinoma, and expression of napsin A is reported in a certain portion of thyroid and renal carcinomas. However, napsin A expression in ovarian surface epithelial tumors has not previously been examined. In this study, immunohistochemical analysis revealed that in 71 of 86 ovarian clear cell adenocarcinoma patients (83%) and all of the 13 patients with ovarian clear cell adenofibroma, positive napsin A staining was evident. No expression was observed in 30 serous adenocarcinomas, 11 serous adenomas or borderline tumors, 19 endometrioid adenocarcinomas, 22 mucinous adenomas or borderline tumors, 10 mucinous adenocarcinomas, or 3 yolk sac tumors of the ovary. Furthermore, expression of napsin A was not observed in the normal surface epithelium of the ovary, epithelia of the fallopian tubes, squamous epithelium, endocervical epithelium, or the endometrium of the uterus. Therefore, we propose that napsin A is another sensitive and specific marker for distinguishing ovarian clear cell tumors (especially adenocarcinomas) from other ovarian tumors.

Epithelial ovarian tumors: Clinicopathological correlation and immunohistochemical study.

Background:Ovarian cancer is the third leading site of cancer among women, trailing behind cervix and breast cancer.Aim:This study was undertaken to analyze the immunohistochemical (IHC) profile of estrogen receptors (ER), progesterone receptors (PR), Ki-67, and p53 in various ovarian epithelial tumors and attempt correlation with clinical and histopathological findings.Materials and Methods:The present study was conducted over a period of 4 years. A technique of manual tissue array was employed for cases subjected for IHC. The primary antibodies used were ER, PR, p53, and Ki-67. A correlation was attempted between histopathological and IHC findings. Results were subjected to statistical analysis. Software program “the primer of biostatistics 5.0” was used for calculation of interrelationships between the analyzed ER, PR, p53, and Ki-67 expression and histological factors by Pearson's Chi-square test. The results were considered to be significant when the P < 0.05.Results:There were 110 cases of surface epithelial ovarian tumors (SEOT) encountered over the period of 4 years. The expression of ER was more in malignant tumors (13/16, 81.25%) than borderline (9/12, 75%) and benign (20/82, 24.39%). As compared to ER, the expression of PR was more in benign (51/82, 62.19%) than borderline (8/12, 66.67%) and malignant tumors (9/16, 56.25%). The expression of PR was more in benign tumors than borderline and malignant tumors. However, this was not statistically significant (Chi-square = 0.335 with 2 degrees of freedom; P = 0.846). The expression of p53 was less in benign (5/82, 6.1%) than borderline (9/12, 75%) and malignant tumors (13/16, 81.25%). The expression of Ki-67 was more in malignant (4/82, 4.88%) than borderline (10/12, 83.33%) and benign tumors (15/16, 93.75%). In all the above cases, the difference was statistically significant (P < 0.05). There was statistically significant difference in the expression of ER, PR, p53, and Ki-67 in the patients with age <40 years and above 40 years (P = 0.912). A positive correlation was observed in p53 expression and tumor grade. Similar correlation was seen in Ki-67 and tumor grade. It was also noted that mean Ki-67 labeling index (Li) had also increased with tumor grade. In the case of serous tumors, ER was expressed in all high- and low-grade tumors. The expression of PR was more in low-grade tumors than high-grade ones. P53 expression was seen in all high-grade tumors and 33.34% of low-grade tumor. The Ki-67 Li was more in high-grade tumors than low-grade tumors. Expression of ER, p53, and Ki-67 was higher in tumor showing metastasis. The mean Ki-67 Li was also higher in metastasizing tumors. However, PR expression was less in metastasizing tumors than nonmetastasizing tumors.Conclusion:IHC marker report of ER, PR status, and Ki-67 if included in each pathology report will pave the way for better understanding of biological behavior and modify treatment strategies.

Diagnosis, surgical treatment, and management of borderline ovarian surface epithelial neoplasms: Report of 2 cases and review of literature

Abstract Ovarian borderline surface epithelial neoplasms occur infrequently in the pediatric population. Preoperative diagnostic criteria include ultrasound and serum tumor markers with definitive diagnosis made on pathologic examinations intraoperatively. Treatment typically involves resection of the tumor with an emphasis on preserving fertility. Patients diagnosed with borderline tumors generally have a good prognosis; however the possibility of recurrence remains. Two cases of 15 year-old females with borderline ovarian tumors are presented that add to the current literature by highlighting the diagnosis, clinical management, and follow-up postoperatively.

Cystatin B is a progression marker of human epithelial ovarian tumors mediated by the TGF-β signaling pathway

Advanced ovarian cancer is a devastating disease. Gaining biomarkers of early detection during ovarian tumorigenesis may lead to earlier diagnosis and better therapeutic strategies. Cystatin B (CSTB) functions as an inhibitor to suppress intracellular cysteine proteases and has been implicated in several types of cancers. The present study explored the expression of CSTB in human ovarian tumors, to investigate CSTB expression associated with clinicopathological features, and to examine the effect of transforming growth factor-β (TGF-β), which plays a key role in ovarian tumorigenesis, on CSTB expression in ovarian cancer cells. The ovarian tissue samples from 33 patients were retrieved. The expression of CSTB in ovarian tissue was examined by immunohistochemistry. We found that CSTB was over-expressed in human ovarian surface epithelial tumors, including serous, mucinous and clear cell tumors. The immunoreactive staining of CSTB was strong in borderline and malignant tumors, weak in benign tumors, and negative in normal tissue counterparts, but was not correlated with the clinicopathological features of patients with ovarian tumors, such as age, histological types, tumor size, lymph node metastasis and clinical stages. The CSTB at mRNA and protein levels in two types of epithelial ovarian cancer cells, OVCAR-3 and SK-OV-3, was decreased after TGF-β1 treatment detected by quantitative PCR and western blot analysis, respectively. The inhibitory effect of TGF-β1 on CSTB expression was abolished in the presence of SB-431542, a TGF-β type I receptor kinase inhibitor. Our data suggest that CSTB is tumor tissue-specific and overexpressed in ovarian borderline and malignant tumors. The increased CSTB expression in ovarian tissue represents tumor progression and is dysregulated by the TGF-β signaling pathway. CSTB may become a novel diagnostic intracellular biomarker for the early detection of ovarian cancer.

Proliferative Brenner Tumor with Borderline Mucinous Cystadenocarcinoma of the Ovary in a 75-Year-Old Woman

We report here an extremely rare case of proliferative Brenner tumor with borderline mucinous cystadenocarcinoma of the ovary, metastasizing to the pleura in a 75-year-old woman. Massive pleural effusion were present due to metastasis and pseudo-Meigs’ syndrome. The cytological findings from pleural effusion, ascites and tumor imprint were similar, suggesting mucus-producing malignant tumors. After receiving a thoracic drainage for pleural effusion, the patient underwent an exploratory laparotomy to remove the left-ovarian tumor. Histopathological examination revealed proliferative Brenner ovarian tumor with borderline mucinous cystadenocarcinoma, and immunohistochemical examinations for the tumors, even mucus-rich tumor cells were positive for CK 7 and negative for CK 20, suggesting the tumor arising from transitional cells, not from mucus-producing ovarian surface epithelial tumor cells. She underwent four courses of chemotherapy with paclitaxel and carboplatin. The patient showed no signs of recurrence 16 months after the surgery.

Death Domain-associated Protein DAXX Promotes Ovarian Cancer Development and Chemoresistance

The role of DAXX in ovarian cancer development and metastasis has not been investigated before now. Overexpression of DAXX enhanced ovarian cancer cell proliferation, colony formation, and migration, whereas Daxx depletion had the opposite effects. DAXX promotes ovarian cancer cell proliferation and chemoresistance. ModulatingDAXXmay be an effective strategy for preventing the recurrence and chemoresistance of ovarian cancers. Understanding the genes involved in apoptosis and DNA damage responses may improve therapeutic strategies for ovarian cancer. The death domain-associated protein DAXX can be either a pro-apoptotic or an anti-apoptotic factor, depending on the cell type and context. In this study, we found that DAXX was highly expressed in human ovarian surface epithelial tumors but not in granulosa cell tumors. In cultured ovarian cancer cells, DAXX interacted with promyelocytic leukemia protein (PML) and localized to subnuclear domains (so-called PML nuclear bodies). A role for DAXX in ovarian cancer cell proliferation, metastasis, and radio/chemoresistance was examined. Overexpression of DAXX enhanced multiple ovarian cancer cell lines' proliferation, colony formation, and migration, whereas Daxx depletion by RNA interference had the opposite effects. When transplanted into nude mice, ovarian cancer cells that overexpressed DAXX displayed enhanced tumorigenesis capability in vivo, whereas Daxx depletion inhibited tumor development. Importantly, Daxx induced tumorigenic transformation of normal ovarian surface epithelial cells. Daxx also protected ovarian cancer cells against x-irradiation- and chemotherapy-induced DNA damage by interacting with PML. Taken together, our results suggest that DAXX is a novel ovarian cancer oncogene that promotes ovarian cancer cell proliferation and chemoresistance in ovarian cancer cells. Thus, modulating DAXX-PML nuclear body activity may be an effective strategy for preventing the recurrence and chemoresistance of ovarian cancers.

Ovarian Surface Epithelial Neoplasms in the Pediatric Population

Surface epithelial neoplasms account for a small but significant proportion of pediatric ovarian tumors. The overall incidence, prevalence of histologic subtypes, and natural history of these neoplasms has not been thoroughly evaluated. A retrospective review of the pathology archives of Stanford University School of Medicine yielded 69 surface epithelial ovarian tumors in 64 pediatric patients 18 years of age or younger from 1974 to 2010. Tumors comprised benign (57.8%), borderline/low malignant potential (LMP) (37.5%), and malignant (4.7%) subgroups and exhibited serous, mucinous, and mixed histology; there were no clear cell, pure endometrioid, or transitional (Brenner) tumors. In addition, no high-grade carcinomas were identified. Clinical follow-up data were available in a subset of patients (maximum follow-up, 22 y). Similar numbers of recurrences were found in each of the 3 subgroups. However, overall survival was 100% for benign and borderline/LMP tumors and 50% for carcinomas. The type of surgical management and the use of chemotherapy varied; 2 patients with borderline/LMP tumors were treated by sterilizing procedures and/or chemotherapy. These data suggest that surface epithelial neoplasms comprise a small but significant proportion of ovarian tumors in the pediatric population, and they exhibit a marked preponderance for benign, borderline, and low-grade malignant subgroups. In contrast to their adult counterpart, high-grade serous carcinoma in children is extraordinarily rare and not seen in this series. Given this difference, uniform treatment modalities with consideration for ovarian conservation and fertility preservation should be rigorously adopted in any pediatric patient with a suspected ovarian surface epithelial neoplasm.

Clinicopathologic Analysis of Low-stage Sporadic Ovarian Carcinomas

Current histologic criteria endorsed by World Health Organization for surface epithelial ovarian tumors suffer from less than optimal reproducibility and correlation with clinical outcomes. A modified approach for histologic subclassification of ovarian carcinomas (OCs), proposed by the group of Gilks and colleagues, has been shown to be reproducible and clinically meaningful. We hypothesized that this approach could be validated using a well-annotated, external cohort of OCs with detailed immunophenotypic, genotypic, and clinical data. The cohort comprised 91 patients with low-stage (FIGO stage I/II) OC who underwent primary surgical management at our institution from 1980 to 2000. The clinical and histologic features of this cohort were reported in 2004. In this study we rereviewed the hematoxylin and eosin slides and reassigned histologic type using the criteria proposed by Gilks and colleagues. p53 and Wilms tumor 1 (WT1) expressions were evaluated using standard immunohistochemical techniques on a tissue microarray. Absence of (null) or strong and diffuse p53 staining in >75% of tumor cells (overexpression) was interpreted as aberrant p53 expression, in contrast to the 2004 study in which the "null" result had been interpreted as negative. Direct TP53 gene sequencing of the entire coding region had been performed on all cases with available tissue. Relationships between survival and the following parameters were studied: tumor cell type, histologic grade, stage, p53 and WT1 expression, TP53 mutation, and presence of associated endometriosis. Results were compared with those of the 2004 study, at which time only TP53 mutation was shown to correlate with adverse survival; notably, TP53 mutation did not correlate with p53 expression by immunohistochemical analysis. After review, presence of TP53 mutations, WT1 positivity, and aberrant p53 expression were strongly associated with high-grade serous histology (P=0.0001). Modification of p53 staining assessment revealed strong correlations with TP53 mutation status, which was superior to the positive versus negative approach used previously (P=0.0005). Redefined histologic criteria revealed a stronger association between the high-grade serous type and WT1 positivity (P=0.02). Prolonged 10-year disease-specific and progression-free survival were associated with endometrioid histology (P<0.02; 94%±4% vs. 53%±7% and 96%±4% vs. 50%±7%, respectively). Inferior 10-year disease-specific survival and progression-free survival were associated with high histologic grade (vs. low and intermediate; P<0.01; 54%±7% vs. 89%±6% and 56%±7% vs. 89%±6%, respectively), presence of TP53 mutation (P<0.04; 54%±12% vs. 64%±10% and 34%±12% vs. 70%±6%, respectively), aberrant p53 expression (P<0.02; 35%±12% vs. 75%±7% and 36%±12% vs. 73%±7%, respectively), and absence of associated endometriosis (P=0.01; 48%±9% vs. 80%±6% and 51%±9% vs. 80%±6%, respectively). In addition, inferior 10-year PFS was associated with WT1 positivity (P=0.01; 42%±7% vs. 72%±7%) and high substage (IA-IB vs. IC-IIC; P=0.04; 53%±7% vs. 81%±8%). These results validate updated approaches to scoring p53 expression as well as the revised criteria proposed by the group of Gilks and colleagues.

Differences in the Angiogenesis of Benign and Malignant Surface Epithelial Ovarian Tumors Demonstrated by Microvessel Density and Immunohistochemistry

OBJECTIVES: Angiogenesis plays a key role in tumor growth and metastasis. The analysis of tumor vascularization by microvessel density (MVD) and its prognostic significance has been evaluated in many tumors including ovary. However, very few studies have tried to evaluate the characteristics of these vessels. This study aims to quantitatively assess the characteristics of tumor vessels with the aid of immunohistochemistry and thus, establish its role in difference in biological behavior of benign and malignant surface epithelial ovarian tumors. METHODS: We examined 42 cases of surface epithelial ovarian tumors and divided them in two groups (14 malignant and 28 benign tumors). Both study groups were compared for smooth muscle and endothelial cells in tumor vessels using monoclonal antibodies against smooth muscle actin (SMA) and CD34 (endothelial cell marker) respectively. MVD, SMA expression index and CD34 intensity index was calculated in both groups. RESULTS: The malignant surface epithelial ovarian tumors showed higher MVD (34.48±12.87) as compared to benign ovarian tumors (16.49±6.17) (p

Detection of cancer stem cells in ovarian malignant surface epithelial tumors by immunohistochemical expression of CD133

BackgroundCancer stem cells (CSCs) are believed to comprise a limited percentage of the malignant tumor cells; yet, they are considered the driving force behind cancer. The presence of such cells could explain why cancer often relapses despite a complete clinical remission with initial therapy; with

Differential expression of Fas family members and Bcl-2 family members in benign versus malignant epithelial ovarian cancer (EOC) in North Indian population

Epithelial ovarian cancer (EOC) represents the most challenging of gynecological malignancies. Defective apoptosis is a major causative factor in the development and progression of cancer. The two important pathways of apoptosis are extrinsic death receptor pathway (Fas family) and intrinsic mitochondrial pathway (Bcl-2 family). In this study, differential protein expression of the major Fas family members (Fas, FasL, and FAP-1) and Bcl-2 family members (Bax, Bcl-2, and Bcl-X(L)) in benign versus malignant surface epithelial ovarian tumors was evaluated at the protein level by immunohistochemistry. The expression of these molecules was compared in 30 benign versus 35 malignant surface epithelial ovarian tumors. The findings of the present study showed that there was no significant difference in the expression of the Fas family members in benign and malignant ovarian tumors. However, benign tumors showed higher levels of anti-apoptotic Bcl-2 protein levels (p < 0.009), whereas malignant tumors showed higher levels of pro-apoptotic Bax (p < 0.001). In general, there was no significant difference in Bcl-X(L) protein levels. The observations made in the present study suggest that alterations in expression of the Fas family and the Bcl-2 family members occur and play a key role in the deregulated growth of epithelial ovarian cancer.

Abstract 1271: Aberrant activation of Spleen Tyrosine Kinase in ovarian cancer identified through a global phosphorylation profiling of protein tyrosine kinases

Abstract Aberrations in protein kinase activity and the consequent deregulation of downstream signaling pathways are considered a hallmark of oncogenesis. The purpose of this study was to investigate the phosphorylation state, the ultimate readout of dysregulated activity, of protein tyrosine kinases in ovarian tumors. An innovative Luminex multiplex platform was employed to systematically determine phosphorylation status of protein tyrosine kinases in a total of 69 protein lysates derived from normal human ovarian surface epithelial (HOSE) cells, ovarian tumors, and cancer cell lines. Significance Analysis of Microarrays (SAM) was performed to identify the signature of phosphorylated kinases with statistical significance. Profiling results were confirmed by using phosphor-specific kinase antibodies in immunoblot analysis of the profiled lysates and immunohistochemistry on formalin-fixed paraffin-embedded archived ovarian and fallopian tissues, as well as immunofluorescence of ovarian cancer cells growing as monolayer or 3D Matrigel cell cultures. A signature of twenty-two phosphorylated protein tyrosine kinases was identified by SAM analysis of the profiling data. Spleen Tyrosine Kinase (SYK), a novel tyrosine kinase included in the signature, was found significantly phosphorylated in lysates from ovarian cancer tissues compared to normal tissues by both Western blot analysis and immunohistochemistry on 94 clinical ovarian tissues (P=0.024). SYK phosphorylation was also identified in tubal intraepithelial carcinomas, the hypothesized precursors of high-grade serous ovarian carcinomas. However, SYK activation was not observed in ovarian cancer cell lines growing as attached monolayer cells, but was present when they grew as mouse xenografts or in 3D Matrigel in vitro cultures. We are the first to report that SYK, an extensively investigated tyrosine kinase in hematopoietic cells, is aberrantly phosphorylated and activated in ovarian cancer. SYK phosphorylation in ovarian cancer might be induced by extracellular stimuli that are exclusively present in the tumor microenvironment. These findings provide additional options in targeted therapy for ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1271. doi:1538-7445.AM2012-1271