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Background: In the last decade, technical innovations have resulted in the development of several minimally invasive diagnostic cancer tools. Within women at high risk of developing ovarian or endometrial cancer (EC) due to hereditary cancer syndrome, there is an urgent need for minimally invasive and patient‐friendly methods to detect ovarian cancer and EC at an early stage. Materials and Methods: We performed a systematic search of studies using DNA methylation or mutation analysis, microbiome, or proteomics performed on cervicovaginal specimens (smear, swab, or tampon) intended to detect ovarian and EC published until January 2024. Results: Included studies (n = 36) showed high heterogeneity in terms of biomarkers used and outcomes, and only a few studies reported on the detection of biomarkers in high‐risk subgroups. Conclusion: Based on the findings in this review, DNA methylation techniques seem to be the most promising for detecting ovarian and EC at early stages in the general population. Future validation of cervicovaginal DNA methylation techniques is needed to determine whether this technique might be beneficial in hereditary high‐risk subgroups. [ABSTRACT FROM AUTHOR]

Objective: To assess the association between pretreatment thrombocytosis, anemia, and leukocytosis and overall survival (OS) of advanced-stage EOC. Furthermore, to develop nomograms using established prognostic factors and pretreatment hematologic parameters to predict the OS of advanced EOC patients. Methods: Advanced-stage EOC patients treated between January 1996 and January 2010 in eastern Netherlands were included. Survival outcomes were compared between patients with and without pretreatment thrombocytosis (≥450,000 platelets/µL), anemia (hemoglobin level of <7.5 mmol/L), or leukocytosis (≥11.0 × 109 leukocytes/L). Three nomograms (for ≤3-, ≥5-, and ≥10-year OS) were developed. Candidate predictors were fitted into multivariable logistic regression models. Multiple imputation was conducted. Model performance was assessed on calibration, discrimination, and Brier scores. Bootstrap validation was used to correct for model optimism. Results: A total of 773 advanced-stage (i.e., FIGO stages IIB–IV) EOC patients were included. The median [interquartile range, IQR] OS was 2.3 [1.3–4.2] and 3.0 [1.4–7.0] years for patients with and without pretreatment thrombocytosis (p < 0.01). The median OS was not notably different for patients with and without pretreatment leukocytosis (p = 0.58) or patients with and without pretreatment anemia (p = 0.07). The final nomograms comprised established predictors with either pretreatment leukocyte or platelet count. The ≥5- and ≥10-year OS models demonstrated good calibration and adequate discrimination with optimism-corrected c-indices [95%-CI] of 0.76 [0.72–0.80] and 0.78 [0.73–0.83], respectively. The ≤3-year OS model demonstrated suboptimal performance with an optimism-corrected c-index of 0.71 [0.66–0.75]. Conclusions: Pretreatment thrombocytosis is associated with poorer EOC survival. Two well-performing models predictive of ≥5-year and ≥10-year OS in advanced-stage EOC were developed and internally validated. [ABSTRACT FROM AUTHOR]

Women at high inherited risk of ovarian cancer are offered risk‐reducing salpingo‐oophorectomy (RRSO) from age 35 to 45 years. Although potentially life‐saving, RRSO may induce symptoms that negatively affect quality of life and impair long‐term health. Clinical care following RRSO is often suboptimal. This scoping review describes how RRSO affects short‐ and long‐term health and provides evidence‐based international consensus recommendations for care from preoperative counselling to long‐term disease prevention. This includes the efficacy and safety of hormonal and non‐hormonal treatments for vasomotor symptoms, sleep disturbance and sexual dysfunction and effective approaches to prevent bone and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Up to 40% of vulvar cancer patients present with local recurrence within 10 years of follow-up. An inguinofemoral lymphadenectomy (IFL) is indicated if not performed at primary treatment. The incidence and risk factors for lymph node metastases (LNM) at first local recurrence, however, are unclear. Our aim was to determine the incidence of LNM at first local recurrence, in relation to previous groin treatment and clinicopathological factors. Methods: A multicenter cohort study including vulvar cancer patients with a first macroinvasive local recurrence after primary surgical treatment between 2000 and 2015 was conducted in the Netherlands. Groin status at local recurrence was defined as positive (N+), negative (N−) or unknown (N?) and based on histology, imaging and follow-up. Patient-, tumour- and treatment characteristics of primary and recurrent disease were analysed. Results: Overall, 16.3% (66/404) had a N+groin status at first local recurrence, 66.4% (268/404) N− and 17.3% (70/404) N?groin status. The incidence of a N+groin status was comparable after previous SLN and IFL, 11.5% and 13.8%, respectively. A N+ groin status was related to tumour size (25 vs.12 mm; P < 0.001), depth of invasion (5 vs. 3 mm; P < 0.001) and poorly differentiated tumours (22.9 vs. 11.9%; P = 0.050) at local recurrence. Conclusions: The incidence of LNM at first local recurrence in vulvar cancer patients was 16.3%, and independent of previous type of groin surgery. In accordance with primary diagnosis, tumour size, depth of invasion, and tumour grade were significantly associated with a positive groin status. [ABSTRACT FROM AUTHOR]

Simple Summary: There has been a growing interest in the interplay between the immune system and the prognosis of epithelial ovarian cancer (EOC). It has become clear that EOC has the ability to escape destruction by the immune system by creating a highly immunosuppressive microenvironment in the abdominal cavity. The first case of an advanced-stage EOC patient who experienced the complete disappearance of her cancer following sepsis without undergoing cancer treatment was reported in 2018. Sepsis has the ability to both activate and suppress the immune system, presenting potential beneficial as well as detrimental effects. It is still unclear what impact sepsis has on the prognosis of advanced-stage EOC. This study's aim was to assess the impact of sepsis on the oncologic outcomes of advanced-stage EOC patients. Of 215 OC patients, a total of 18 advanced-stage EOC patients experienced sepsis. Their survival outcomes were compared with 3988 unmatched and 54 matched patients from the Netherlands Cancer Registry (NCR). The overall and progression-free survival was similar between the sepsis and (un)matched patients from the NCR. Our study suggests that sepsis and its subsequent immune response, overall, does not substantially influence the prognosis of EOC patients. Objective: The sepsis-induced inflammatory response may potentially affect malignant cells. Recently, a case of spontaneous regression of a histologically confirmed International Federation of Gynecology and Obstetrics (FIGO) stage IIIC epithelial ovarian cancer (EOC) following sepsis was reported. The aim of our study was to assess the impact of sepsis on the oncologic outcomes of advanced-stage EOC patients. Methods: Gynecologic oncologic patients admitted to the Intensive Care Unit of three oncologic centers between 2006 and 2019 were identified and patients who experienced sepsis following advanced-stage EOC diagnosis were selected. Survival outcomes were compared with advanced-stage EOC patients from the Netherlands Cancer Registry (NCR). To correct for case-mix differences, propensity score matching using 1:3 nearest neighbor matching was conducted after which survival analyses were repeated. Results: A total of 18 of 215 patients with advanced-stage EOC experienced sepsis. Sepsis patients had similar distributions of patient, tumor, and treatment characteristics to 3988 patients from the NCR cohort. A total of 3 of 18 patients died from the complications of sepsis. While the remaining patients initially responded to treatment, 14/15 patients relapsed. The median (IQR) overall survival was 31 (24–44) and 35 (20–60) months for the sepsis and unmatched NCR cohort (p = 0.56), respectively. The median (IQR) progression-free survival was 16 (11–21) and 16 (11–27) months (p = 0.90), respectively. Survival outcomes did not differ following propensity matching (overall survival of 31 (24–44) vs. 36 (20–56) months, p = 0.40; progression-free survival of 16 (11–21) and 16 (12–21) months, p = 0.72). Conclusion: In this observational study, the occurrence of sepsis did not affect the oncologic and survival outcomes of advanced-stage EOC patients. [ABSTRACT FROM AUTHOR]

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Aim: Reliably diagnosing or safely excluding serous tubal intraepithelial carcinoma (STIC), a precursor lesion of tubo‐ovarian high‐grade serous carcinoma (HGSC), is crucial for individual patient care, for better understanding the oncogenesis of HGSC, and for safely investigating novel strategies to prevent tubo‐ovarian carcinoma. To optimize STIC diagnosis and increase its reproducibility, we set up a three‐round Delphi study. Methods and results: In round 1, an international expert panel of 34 gynecologic pathologists, from 11 countries, was assembled to provide input regarding STIC diagnosis, which was used to develop a set of statements. In round 2, the panel rated their level of agreement with those statements on a 9‐point Likert scale. In round 3, statements without previous consensus were rated again by the panel while anonymously disclosing the responses of the other panel members. Finally, each expert was asked to approve or disapprove the complete set of consensus statements. The panel indicated their level of agreement with 64 statements. A total of 27 statements (42%) reached consensus after three rounds. These statements reflect the entire diagnostic work‐up for pathologists, regarding processing and macroscopy (three statements); microscopy (eight statements); immunohistochemistry (nine statements); interpretation and reporting (four statements); and miscellaneous (three statements). The final set of consensus statements was approved by 85%. Conclusion: This study provides an overview of current clinical practice regarding STIC diagnosis amongst expert gynecopathologists. The experts' consensus statements form the basis for a set of recommendations, which may help towards more consistent STIC diagnosis. [ABSTRACT FROM AUTHOR]

Background: Advanced low‐grade ovarian carcinoma (LGOC) is difficult to treat. In several studies, high estrogen receptor (ER) protein expression was observed in patients with LGOC, which suggests that antihormonal therapy (AHT) is a treatment option. However, only a subgroup of patients respond to AHT, and this response cannot be adequately predicted by currently used immunohistochemistry (IHC). A possible explanation is that IHC only takes the ligand, but not the activity, of the whole signal transduction pathway (STP) into account. Therefore, in this study, the authors assessed whether functional STP activity can be an alternative tool to predict response to AHT in LGOC. Methods: Tumor tissue samples were obtained from patients with primary or recurrent LGOC who subsequently received AHT. Histoscores of ER and progesterone receptor (PR) were determined. In addition, STP activity of the ER STP and of six other STPs known to play a role in ovarian cancer was assessed and compared with the STP activity of healthy postmenopausal fallopian tube epithelium. Results: Patients who had normal ER STP activity had a progression‐free survival (PFS) of 16.1 months. This was significantly shorter in patients who had low and very high ER STP activity, with a median PFS of 6.0 and 2.1 months, respectively (p <.001). Unlike ER histoscores, PR histoscores were strongly correlated to the ER STP activity and thus to PFS. Conclusions: Aberrant low and very high functional ER STP activity and low PR histoscores in patients with LGOC indicate decreased response to AHT. ER IHC is not representative of functional ER STP activity and is not related to PFS. Patients who have low‐grade ovarian carcinoma with a functionally low or high active estrogen receptor signaling pathway have a decreased response to antihormonal therapy. Estrogen receptor immunohistochemistry does not have predictive value for antihormonal therapy response and is not representative of functional estrogen receptor signaling. [ABSTRACT FROM AUTHOR]

Background: Increasing numbers of BReast CAncer (BRCA) 1 or 2 pathogenic variant (PV) carriers, who have an inherited predisposition to breast and ovarian cancer, are being identified. Among these women, data regarding the effects of contraception on cancer risks are unclear and various guidelines provide various recommendations.Objective and Rationale: We aim to optimize counselling regarding contraception for BRCA1/2-PV carriers. Therefore, we performed a systematic review and meta-analysis. We investigated the risk ratio for developing breast cancer or ovarian cancer in BRCA1/2-PV carriers who have used any form of contraception versus non-users. Second, we analysed breast and ovarian cancer risk among BRCA1/2-PV carriers as influenced by the duration of contraceptive use and by the time since last use. In addition, we provide an overview of all relevant international guidelines regarding contraceptive use for BRCA1/2-PV carriers.Search Methods: A systematic search in the Medline database and Cochrane library identified studies describing breast and/or ovarian cancer risk in BRCA1/2-PV carriers as modified by contraception until June 2021. The search included medical subject headings, keywords and synonyms related to BRCA and contraceptives (any kind). PRISMA guidance was followed. Risk Of Bias In Non-randomized Studies of Interventions and Grading of Recommendations, Assessment, Development and Evaluations assessments were performed. Random-effects meta-analyses were used to estimate pooled effects for breast and ovarian cancer risk separately. Subgroup analyses were conducted for BRCA1 versus BRCA2 and for the various contraceptive methods.Outcomes: Results of the breast cancer risk with oral contraceptive pill (OCP) analysis depended on the outcome measure. Meta-analyses of seven studies with 7525 women revealed a hazard ratio (HR) of 1.55 (95% CI: 1.36-1.76) and of four studies including 9106 women resulted in an odds ratio (OR) of 1.06 (95% CI: 0.90-1.25), heterogeneity (I2) 0% and 52%, respectively. Breast cancer risk was still increased in ever-users compared with never-users >10 years after last OCP use. In contrast, ovarian cancer risk was decreased among OCP users: HR 0.62 (95% CI: 0.52-0.74) based on two studies including 10 981 women (I2: 0%), and OR 0.49 (95% CI: 0.38-0.63) based on eight studies including 10 390 women (I2: 64%). The protective effect vanished after cessation of use. Tubal ligation also protects against ovarian cancer: one study including 3319 women (I2: 0%): HR: 0.44 (95% CI: 0.26-0.74) and three studies with 7691 women (I2: 44%): OR: 0.74 (95% CI: 0.53-1.03). Data regarding other contraceptives were unavailable. No differences were observed between BRCA1 and BRCA2-PV carriers. The quality of evidence was either low or very low.Wider Implications: The OCP potentially increases breast cancer risk, while ovarian cancer risk decreases with either the OCP and tubal ligation in BRCA1/2-PV carriers. Counselling of BRCA1/2-PV carriers should be personalized; the genetic and non-genetic factors (like prior risk-reducing surgeries, prior breast cancer and age) and patients' preferences (reversibility, ease of use, reliability and effect on menstrual cycle) should be balanced. To further optimize counselling for high-risk women, future research should focus on other (commonly used) contraceptive methods and cancer risks in this specific population, and on the potential impact of changing formulations over time. [ABSTRACT FROM AUTHOR]

Introduction: Opportunistic salpingectomy (OS) refers to additional removal of the fallopian tubes during abdominal surgery performed for another medical indication, as prevention for ovarian cancer. As OS has been inconsistently implemented, its clinical practice varies worldwide. To reduce this variation, insight is required into current clinical practice and its determinants. Therefore, the study aim was to determine the implementation of counseling and performance of OS between 2015 and 2018, and its patient, surgical, physician, and hospital characteristics. Material and methods: Retrospective study using electronic medical records from six different Dutch hospitals: two academic, two large teaching, and two non‐teaching hospitals. Patients were considered eligible for OS if they underwent elective non‐obstetric abdominal surgery for a gynecological indication from January 2015 through December 2018. Primary outcomes were uptake of counseling and performance of OS. Multilevel multivariable logistic regression analyses were conducted to identify characteristics associated with OS. Results: A total of 3214 patients underwent elective non‐obstetric abdominal surgery for a gynecological indication and were eligible for OS. Counseling on OS increased significantly from 2.9% in 2015 to 29.4% in 2018. In this period, 440 patients were counseled on OS, of which 95.9% chose OS. Performance of OS increased significantly from 6.9% in 2015 to 44.5% in 2018. Counseling for and performance of OS were more likely in patients who had surgery by laparoscopic approach, were counseled by a gynecological resident, or had more than three contact moments before surgery. Additionally, OS was less likely in patients who had vaginal surgery. Conclusions: Although the uptake of OS increased from 2015 to 2018, the majority of patients who were eligible for OS were not counseled and did not undergo OS. Its clinical practice varies on patient, surgery, and physician characteristics. Therefore, an implementation strategy tailored to associated determinants is recommended. [ABSTRACT FROM AUTHOR]

Introduction: In the Netherlands, the sentinel lymph node procedure protocol consists of preoperative lymphoscintigraphy combined with intraoperative blue dye for identifying sentinel lymph nodes in early vulvar squamous cell carcinoma. This study aimed at investigating the role of early and late lymphoscintigraphy. Material and methods: From January 2015 to January 2019, early and late lymphoscintigraphies of 52 women were retrospectively analyzed. Lymphoscintigraphy was performed 30 minutes (early) and 2.5–4 hours (late) after vulvar injection of 99mTc‐labeled nanocolloid. We calculated the concordance correlation coefficient (CCC) between number of sentinel lymph nodes detected on both images using the Lins concordance coefficient and correlated with clinicopathological data. Results: Thirty‐four women had a midline tumor and 18 had a lateral tumor. Detection rates with early and late scintigraphy were 88.5% and 98.1%, respectively. Median number of detected nodes was 1.0 (0–7) and 2.0 (0–7). Good statistical correlation between number of sentinel lymph nodes detected on early and late imaging was found (CCC = 0.76) in most patients. In 18 women (35%) a mismatch occurred: a higher number of nodes was detected on late imaging. In 11 of 18 women re‐injection was performed because no sentinel lymph nodes were visualized on early images. Late imaging and intraoperative detection showed a good statistical correlation (CCC = 0.61). One woman showed an isolated groin recurrence despite negative sentinel lymph nodes. Conclusions: This study showed good statistical correlations between early and late scintigraphy in most patients. However, in 35% of women late scintigraphy detected more nodes. In case of poor visualization after the first scintigraphy, re‐injection should be considered. Late scintigraphy is probably helpful in confirming successful re‐injection and in showing deviating lymph flow in women with failed mapping after the first injection and successful re‐injection. Because missing metastatic sentinel lymph nodes often leads to a poor prognosis, we prefer optimal correlations between imaging and intraoperative identification. Hence, late scintigraphy cannot be safely omitted. [ABSTRACT FROM AUTHOR]

Universal tumor DNA testing in epithelial ovarian cancer patients can function not only as an efficient prescreen for hereditary cancer testing, but may also guide treatment choices. This innovation, introduced as Tumor-First workflow, offers great opportunities, but ensuring optimal multidisciplinary collaboration is a challenge. We investigated factors that were relevant and important for large-scale implementation. In three multidisciplinary online focus groups, healthcare professionals (gynecologic oncologists, pathologists, clinical geneticists, and clinical laboratory specialists) were interviewed on factors critical for the implementation of the Tumor-First workflow. Recordings were transcribed for analysis in Atlas.ti according to the framework of Flottorp that categorizes seven implementation domains. Healthcare professionals from all disciplines endorse implementation of the Tumor-First workflow, but more detailed standardization and advice regarding the logistics of the workflow were needed. Healthcare professionals explored ways to stay informed about the different phases of the workflow and the results. They emphasized the importance of including all epithelial ovarian cancer patients in the workflow and monitoring this inclusion. Overall, healthcare professionals would appreciate supporting material for the implementation of the Tumor-First workflow in the daily work routine. Focus group discussions have revealed factors for developing a tailored implementation strategy for the Tumor-First workflow in order to optimize care for epithelial ovarian cancer patients. Future innovations affecting multidisciplinary oncology teams including clinical geneticists can benefit from the lessons learned. [ABSTRACT FROM AUTHOR]

Introduction: Germline BRCA1/2-associated epithelial ovarian cancer has been associated with better progression-free survival and overall survival than sporadic epithelial ovarian cancer, but conclusive data are lacking. Methods: We matched 389 BRCA1-associated and 123 BRCA2-associated epithelial ovarian cancer patients 1:1 to sporadic epithelial ovarian cancer patients on year of birth, year of diagnosis, and FIGO stage (< = IIA/> = IIB). Germline DNA test was performed before or after epithelial ovarian cancer diagnosis. All patients received chemotherapy. We used Cox proportional hazards models to estimate the associations between mutation status (BRCA1 or BRCA2 versus sporadic) and progression-free survival and overall survival. To investigate whether DNA testing after epithelial ovarian cancer diagnosis resulted in survival bias, we performed additional analyses limited to BRCA1/2-associated epithelial ovarian cancer patients with a DNA test result before cancer diagnosis (n = 73 BRCA1; n = 9 BRCA2) and their matched sporadic controls. Results: The median follow-up was 4.4 years (range 0.1–30.1). During the first three years after epithelial ovarian cancer diagnosis, progression-free survival was better for BRCA1 (HR 0.88, 95% CI 0.74–1.04) and BRCA2 (HR 0.58, 95% CI 0.41–0.81) patients than for sporadic patients. Overall survival was better during the first six years after epithelial ovarian cancer for BRCA1 (HR 0.7, 95% CI 0.58–0.84) and BRCA2 (HR 0.41, 95% CI 0.29–0.59) patients. After surviving these years, survival benefits disappeared or were in favor of the sporadic patients. Conclusion: For epithelial ovarian cancer patients who received chemotherapy, we confirmed survival benefit for BRCA1 and BRCA2 germline pathogenic variant carriers. This may indicate higher sensitivity to chemotherapy, both in first line treatment and in the recurrent setting. The observed benefit appears to be limited to a relatively short period after epithelial ovarian cancer diagnosis. [ABSTRACT FROM AUTHOR]

Background: Standard groin treatment in recurrent vulvar cancer consists of uni- or bilateral inguinofemoral lymphadenectomy (IFL), whereas in the primary setting women with selected unifocal tumours will undergo a sentinel lymph node (SLN) procedure. The SLN procedure results in fewer short and long-term sequelae compared to IFL, but some concerns must first be considered. Lymph drainage of the vulvar region can be affected by a previous surgery, which might reduce the number of detectable SLN nodes (feasibility) but increase the chance of encountering aberrant lymph drainage patterns such as bilateral SLNs in lateral tumours or SLNs at unexpected locations. Therefore, the SLN procedure potentially carries a higher risk of groin recurrence if a tumour positive node is not retrieved, but may also improve outcomes for women with aberrant drainage patterns. Since the relative benefits and drawbacks of the SLN procedure are still unclear we will investigate the safety of the SLN procedure in women with a first recurrent vulvar cancer. In a simultaneously started registration study we prospectively gather information on women with a first recurrence of vulvar cancer ineligible for the SLN procedure.Method: In this prospective multicentre observational study all women with a first recurrence of vulvar cancer will be asked to consent to the collection of information on their diagnostics, treatment and outcome, and to complete quality of life and lymph oedema questionnaires. Women with unifocal tumours smaller than 4 cm and unsuspicious groin nodes will be offered the SLN procedure, with follow-up every 3 months together with imaging at 6 and 12 months when the SLN is tumour negative. The primary outcome is groin recurrence within 2 years of initial surgery. A total of 150 women with negative SLNs will be required to demonstrate safety, a stopping rule will apply and an extensive statistical analysis has been designed.Discussion: Should the SLN procedure prove feasible and safe in recurrent vulvar cancer, it will be available for implementation in clinics worldwide. The inclusion of women ineligible for the SLN procedure in the current prospective study will help to bridge knowledge gaps and define future research questions.Trial Registration: Medical Ethical Committee approval number NL70149.078.19 (trial protocol version 2.0, date March 2nd, 2020). Affiliation: Erasmus Medical Centre. Dutch trial register NL8467 . Date of registration 19.03.2020. [ABSTRACT FROM AUTHOR]

Our understanding of the oncogenesis of high-grade serous cancer of the ovary and its precursor lesions, such as serous tubal intraepithelial carcinoma (STIC), has significantly increased over the last decades. Adequate and reproducible diagnosis of these precursor lesions is important. Diagnosing STIC can have prognostic consequences and is an absolute requirement for safely offering alternative risk reducing strategies, such as risk reducing salpingectomy with delayed oophorectomy. However, diagnosing STIC is a challenging task, possessing only moderate reproducibility. In this review and meta-analysis, we look at how pathologists come to a diagnosis of STIC. We performed a literature search identifying 39 studies on risk reducing salpingo-oophorectomy in women with a known BRCA1/2 PV, collectively reporting on 6833 patients. We found a pooled estimated proportion of STIC of 2.8% (95% CI, 2.0–3.7). We focused on reported grossing protocols, morphological criteria, level of pathologist training, and the use of immunohistochemistry. The most commonly mentioned morphological characteristics of STIC are (1) loss of cell polarity, (2) nuclear pleomorphism, (3) high nuclear to cytoplasmic ratio, (4) mitotic activity, (5) pseudostratification, and (6) prominent nucleoli. The difference in reported incidence of STIC between studies who totally embedded all specimens and those who did not was 3.2% (95% CI, 2.3–4.2) versus 1.7% (95% CI, 0.0–6.2) (p 0.24). We provide an overview of diagnostic features and present a framework for arriving at an adequate diagnosis, consisting of the use of the SEE-FIM grossing protocol, evaluation by a subspecialized gynecopathologist, rational use of immunohistochemical staining, and obtaining a second opinion from a colleague. [ABSTRACT FROM AUTHOR]

Introduction: Epithelial ovarian cancer (EOC) patients undergoing splenectomy during cytoreductive surgery represent a small subgroup of patients. Splenic metastases or technical reasons due to extensive upper abdominal disease may require a splenectomy. It has been hypothesized that as the spleen's antitumor immunologic functions may inhibit cancer growth, splenectomy may promote the growth of residual disease as observed in other cancer types of murine studies. The few studies assessing the impact of splenectomy on the oncologic outcomes of advanced stage EOC patients have reported inconsistent results. It remains unclear whether splenectomy during cytoreductive surgery is justified to achieve complete cytoreduction. The aim of this study was to assess the impact of a splenectomy on perioperative outcomes and survival of advanced stage EOC patients. Material and methods: In this nationwide population‐based study, all consecutive patients diagnosed with FIGO stage IIIC and IV EOC between 1 January 2008 and 31 December 2015 were identified from the Netherlands Cancer Registry. Patients who underwent cytoreductive surgery combined with platinum‐based chemotherapy as primary treatment were selected. Differences in clinicopathologic characteristics between splenectomy and non‐splenectomy patients were assessed. Progression‐free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier survival curves and log‐rank tests. Cox proportional hazards models were used to adjust for covariates that influence survival. Results: A total of 3911 patients were identified: 99 splenectomy and 3812 non‐splenectomy patients. Splenectomy patients were more likely to undergo extensive surgery or surgical reintervention, to receive intraperitoneal chemotherapy, intraoperative and postoperative blood transfusion, to experience postoperative infections, and to be admitted to an intensive care unit (all p < 0.002). No significant differences in PFS or OS were observed between splenectomy vs non‐splenectomy patients after adjusting for covariates. Conclusions: Although advanced stage EOC patients who undergo splenectomy during cytoreductive surgery have less favorable perioperative outcomes, no adverse impact of splenectomy on the survival of advanced stage EOC patients was observed. Splenectomy during cytoreductive surgery seems to be justified to achieve complete cytoreduction in advanced stage EOC patients. [ABSTRACT FROM AUTHOR]

Background: To prevent ovarian cancer, several international societies have issued guidelines which recommend to discuss opportunistic salpingectomy with women undergoing pelvic surgery after completion of childbearing. The opportunistic salpingectomy refers to the additional removal of Fallopian tubes during pelvic surgery for another indication to reduce the risk of developing ovarian cancer. These recommendations emphasize the importance of counselling on benefits and risks of opportunistic salpingectomy but offer no guidance on their implementation in daily practice. The lack of a tailored implementation strategy has resulted in a wide variation in current practice. To reduce this practice variation, we identified influencing factors on implementing opportunistic salpingectomy from patients' and professionals' perspectives.Methods: We conducted a mixed-method study between 2019 and 2020 throughout the Netherlands. In a qualitative phase, we conducted interviews with gynecologic patients (N = 11) and their professionals (N = 20) to explore barriers and facilitators, using an interview guide. In the quantitative phase, we quantified these barriers and facilitators among patients who underwent a hysterectomy or sterilization and were counselled on the opportunistic salpingectomy (N = 77), and members of the Dutch Society of Obstetrics and Gynecology (N = 204), using questionnaires. For both phases, barriers and facilitators were classified into the following domains: innovation, patient, healthcare professional, social setting, organization, and economic and political context.Results: For patients, main barriers were lack of knowledge about: the existence of the opportunistic salpingectomy (45%), size of the surgery (44%) and its associated possible disadvantages (37%). In addition, patients attributed their reluctance to concerns about the removal of healthy organs (46%). For professionals, main barriers were: patients' lack of knowledge of the size of surgery (85%) and its associated possible disadvantages (77%), the gap in evidence on long term risks and benefits (43%), the lack of feasibility in certain patients and during vaginal surgery (66%). Both patients (41%) and professionals (67%) identified the need for counselling material as facilitator.Conclusion: To reduce the variety in care regarding opportunistic salpingectomy, consensus and uniform counselling is needed. Including the opportunistic salpingectomy in gynecological guidelines and a decision aid for counselling could serve as tools to facilitate implementation. [ABSTRACT FROM AUTHOR]

Background/Aim: Differentiated vulvar intraepithelial neoplasia (dVIN) and lichen sclerosus (LS) can give rise to vulvar squamous cell carcinoma (VSCC), but genetic evidence is currently still limited. We aimed to determine genetic abnormalities in VSCC and backtrack these abnormalities in the dVIN and LS lesions. Materials and Methods: DNA from VSCC and patient-matched dVIN and LS samples of twelve patients was collected. Highresolution genome-wide copy number analysis was performed and subsequently, we sequenced TP53. Results: Copy number alterations were identified in all VSCC samples. One dVIN lesion presented with three copy number alterations that were preserved in the paired VSCC sample. Targeted sequencing of TP53 identified mutations in five VSCCs. All five mutations were traced back in the dVIN (n=5) or the LS (n=1) with frequencies ranging from 3-19%. Conclusion: Our data provide genetic evidence for a clonal relationship between VSCC and dVIN or LS. [ABSTRACT FROM AUTHOR]

Background: Women with epithelial ovarian cancer (OC) have a higher chance to benefit from poly (ADP-ribose) polymerase inhibitor (PARPi) therapy if their tumor has a somatic or hereditary BRCA1/2 pathogenic variant. Current guidelines advise BRCA1/2 genetic predisposition testing for all OC patients, though this does not detect somatic variants. We assessed the feasibility of a workflow for universal tumor DNA BRCA1/2 testing of all newly diagnosed OC patients as a prescreen for PARPi treatment and cancer predisposition testing.Methods: Formalin-fixed paraffin-embedded tissue was obtained from OC patients in seven hospitals immediately after diagnosis or primary surgery. DNA was extracted, and universal tumor BRCA1/2 testing was then performed in a single site. Diagnostic yield, uptake, referral rates for genetic predisposition testing, and experiences of patients and gynecologists were evaluated.Results: Tumor BRCA1/2 testing was performed for 315 (77.6%) of the 406 eligible OC samples, of which 305 (96.8%) were successful. In 51 of these patients, pathogenic variants were detected (16.7%). Most patients (88.2%) went on to have a genetic predisposition test. BRCA1/2 pathogenic variants were shown to be hereditary in 56.8% and somatic in 43.2% of patients. Participating gynecologists and patients were overwhelmingly positive about the workflow.Conclusions: Universal tumor BRCA1/2 testing in all newly diagnosed OC patients is feasible, effective, and appreciated by patients and gynecologists. Because many variants cannot be detected in DNA from blood, testing tumor DNA as the first step can double the identification rate of patients who stand to benefit most from PARP inhibitors. [ABSTRACT FROM AUTHOR]

Objective: To explore current practice and influencing factors on adoption of the opportunistic salpingectomy (OS), particularly regarding the decision making, to eventually enhance the development and implementation of clear guidelines. Methods: This nationwide cross-sectional survey study was conducted in all hospitals in the Netherlands. An anonymous online survey was sent to gynecologists with special interest in gynecological oncology, gynecological endoscopy or urogynecology and all Dutch gynecology trainees. The survey mainly focused on current practice regarding OS and identification of influencing factors on the level of innovation, organization, healthcare professional and individual patient. Results: The response rate was 348 out of 597 gynecologists (58.3%) and 142 out of 340 trainees (41.8%). Current practice of discussing and performing the OS varied widely, with ovarian cancer (OC) risk reduction as most important supportive factor on innovation level. Supportive factors on the level of organization and healthcare provider were; working in a non-training hospital, knowledge of current literature and extensive work experience (in years and annual number of hysterectomies). On individual patient level, a vaginal approach of hysterectomy, negative family history for OC and the presence of firm adhesions were suppressive factors for the OS. Conclusion: In this study we evaluated the current practice regarding the opportunistic salpingectomy in the Netherlands and identified influencing factors on different levels to raise awareness and attribute to development of a targeted implementation strategy, on both national and international level. [ABSTRACT FROM AUTHOR]

Abstract: Background: BRCA1/2 mutation carriers’ choice between risk‐reducing salpingo‐oophorectomy (RRSO) and salpingectomy with delayed oophorectomy is very complex. Aim was to develop a patient decision aid that combines evidence with patient preferences to facilitate decision making. Design: Systematic development of a patient decision aid in an iterative process of prototype development, alpha testing by patients and clinicians and revisions using International Patient Decision Aid Standards (IPDAS) quality criteria. Information was based on the available literature and current guidelines. A multidisciplinary steering group supervised the process. Setting and participants: Pre‐menopausal BRCA1/2 mutation carriers choosing between RRSO and salpingectomy with delayed oophorectomy in Family Cancer Clinics in the Netherlands. Main outcome measures: IPDAS quality criteria, relevance, usability, clarity. Results: The patient decision aid underwent four rounds of alpha testing and revisions. Finally, two paper decision aids were developed: one for BRCA1 and one for BRCA2. They both contained a general introduction, three chapters and a step‐by‐step plan containing a personal value clarification worksheet. During alpha testing, risk communication and information about premature menopause and hormone therapy were the most revised items. The patient decision aids fulfil 37 of 43 (86%) IPDAS criteria for content and development process. Discussion and conclusions: Both BRCA1/2 mutation carriers and professionals are willing to use or offer the developed patient decision aids for risk‐reducing surgery. The patient decision aids have been found clear, balanced and comprehensible. Future testing among patients facing the decision should point out its effectiveness in improving decision making. [ABSTRACT FROM AUTHOR]

Background: Risk-reducing salpingo-oophorectomy (RRSO) is recommended for BRCA1/2 mutation carriers because of their increased risk of ovarian carcinoma. Despite RRSO, metachronous peritoneal carcinomatosis occasionally is diagnosed.Methods: The literature was searched for BRCA1/2 mutation carriers with peritoneal carcinomatosis after risk-reducing surgery. The authors were asked for additional data. Clinical and histopathological data were descriptively analyzed. Cases were compared with a single-institution control cohort.Results: Of 36 cases, 86.1% concerned BRCA1 mutation carriers. The median age of the patients was 52 years (range, 30-71 years) at the time of risk-reducing surgery and 60 years (range, 37-75 years) at the time of diagnosis of peritoneal carcinomatosis. The median interval between the 2 events was 54.5 months (range, 11-292 months). Peritoneal carcinomatosis was mostly high-grade serous carcinoma. Histopathological details of the RRSO specimens were retrieved in 8 cases; 5 (62.5%) were found to have serous tubal intraepithelial carcinoma and 1 had epithelial atypia. Cases were older (P = .025) at the time of risk-reducing surgery and harbored more serous tubal intraepithelial carcinomas (P<.001) compared with women from the control cohort.Conclusions: Metachronous peritoneal carcinomatosis after risk-reducing surgery occurs predominantly in BRCA1 mutation carriers, usually within 5 years. Data have suggested that surgery at a younger age lowers the rates of peritoneal carcinomatosis. These data can be used in the gynecologic counseling of BRCA1/2 mutation carriers. RRSO should include complete salpingectomy. Detailed histopathological examination of specimens removed during RRSO is essential. Cancer 2018;124:952-9. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Introduction: Inguinofemoral lymphadenectomy (IFL) is performed in the treatment for vulvar cancer. One or more complications after IFL is reported in up to 85% of the patients. This review presents an overview of surgical techniques and peri- and post-operative care that has been studied in order to reduce the morbidity associated with IFL in vulvar cancer patients. Areas covered: Current knowledge on post-operative complications after different surgical techniques and peri- and post-operative protocols were discussed. A systematic literature review was conducted using MEDLINE, EMBASE and the Cochrane library on 20 February 2017. In order to be eligible for inclusion, studies must report the associated post-operative morbidity per surgical technique, or peri- or post-operative care given after IFL in vulvar cancer patients. Expert commentary: After the implementation of several new surgical techniques, the morbidity after IFL decreased but remains high and clinically meaningful. More research is needed on surgical techniques and peri-or post-operative care to further reduce the complication rates after IFL in vulvar cancer patients. [ABSTRACT FROM AUTHOR]

Background: It is unknown whether a history of breast cancer (BC) affects the outcome of BRCA1/2-associated epithelial ovarian cancer (EOC). This was investigated in the current analysis.Methods: We included 386 BRCA1/2-associated EOC patients diagnosed between 1980 and 2015. Progression-free survival (PFS), progression-free interval (PFI), overall survival (OS) and ovarian cancer-specific survival (OCSS) were compared between EOC patients with and without previous BC.Results: BRCA-associated EOC patients with, vs without, a BC history had a significantly worse PFS and PFI (multivariate hazard ratio (HRmult) 1.47; 95% confidence interval (CI) 1.03-2.08 and HRmult 1.43; 95% CI 1.01-2.03), and a non-significantly worse OS (HRmult 1.15; 95% CI 0.84-1.57) and OCSS (HRmult 1.18; 95% CI 0.85-1.62). Ovarian cancer-specific survival was significantly worse for the subgroup treated with adjuvant chemotherapy for BC (HRmult 1.99; 95% CI 1.21-3.31).Conclusions: Our results suggest that BRCA1/2-associated EOC patients with a previous BC have a worse outcome than EOC patients without BC, especially when treated with adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Risk-reducing salpingo-oophorectomy (RRSO) around the age of 40 is currently recommended to BRCA1/2 mutation carriers. This procedure decreases the elevated ovarian cancer risk by 80-96% but it initiates premature menopause as well. The latter is associated with short-term and long-term morbidity, potentially affecting quality of life (QoL). Based on recent insights into the Fallopian tube as possible site of origin of serous ovarian carcinomas, an alternative preventive strategy has been put forward: early risk-reducing salpingectomy (RRS) and delayed oophorectomy (RRO). However, efficacy and safety of this alternative strategy have to be investigated. Methods: A multicentre non-randomised trial in 11 Dutch centres for hereditary cancer will be conducted. Eligible patients are premenopausal BRCA1/2 mutation carriers after completing childbearing without (a history of) ovarian carcinoma. Participants choose between standard RRSO at age 35-40 (BRCA1) or 40-45 (BRCA2) and the alternative strategy (RRS upon completion of childbearing and RRO at age 40-45 (BRCA1) or 45-50 (BRCA2)). Women who opt for RRS but do not want to postpone RRO beyond the currently recommended age are included as well. Primary outcome measure is menopause-related QoL. Secondary outcome measures are ovarian/breast cancer incidence, surgery-related morbidity, histopathology, cardiovascular risk factors and diseases, and cost-effectiveness. Mixed model data analysis will be performed. Discussion: The exact role of the Fallopian tube in ovarian carcinogenesis is still unclear. It is not expected that further fundamental research will elucidate this role in the near future. Therefore, this clinical trial is essential to investigate RRS with delayed RRO as alternative risk-reducing strategy in order to improve QoL. [ABSTRACT FROM AUTHOR]

Background: Risk-reducing salpingo-oophorectomy (RRSO) around the age of 40 is currently recommended to BRCA1/2 mutation carriers. This procedure decreases the elevated ovarian cancer risk by 80–96 % but it initiates premature menopause as well. The latter is associated with short-term and long-term morbidity, potentially affecting quality of life (QoL). Based on recent insights into the Fallopian tube as possible site of origin of serous ovarian carcinomas, an alternative preventive strategy has been put forward: early risk-reducing salpingectomy (RRS) and delayed oophorectomy (RRO). However, efficacy and safety of this alternative strategy have to be investigated. Methods: A multicentre non-randomised trial in 11 Dutch centres for hereditary cancer will be conducted. Eligible patients are premenopausal BRCA1/2 mutation carriers after completing childbearing without (a history of) ovarian carcinoma. Participants choose between standard RRSO at age 35–40 (BRCA1) or 40–45 (BRCA2) and the alternative strategy (RRS upon completion of childbearing and RRO at age 40–45 (BRCA1) or 45–50 (BRCA2)). Women who opt for RRS but do not want to postpone RRO beyond the currently recommended age are included as well. Primary outcome measure is menopause-related QoL. Secondary outcome measures are ovarian/breast cancer incidence, surgery-related morbidity, histopathology, cardiovascular risk factors and diseases, and cost-effectiveness. Mixed model data analysis will be performed. Discussion: The exact role of the Fallopian tube in ovarian carcinogenesis is still unclear. It is not expected that further fundamental research will elucidate this role in the near future. Therefore, this clinical trial is essential to investigate RRS with delayed RRO as alternative risk-reducing strategy in order to improve QoL. [ABSTRACT FROM AUTHOR]

Genital psoriasis is a neglected manifestation of psoriasis, although it affects numerous patients and has major effects on (sexual) quality of life ((S)QoL). We aimed to assess the value of specialised care for patients with genital psoriasis. Patients were treated for at least one year at a specialised research outpatient clinic with extensive attention for genital lesions and (S)QoL. The genital lesions were treated according to a stepwise algorithm. First follow-up was planned after 6 weeks; subsequent follow-up visits were scheduled every 3 months. At every visit, psoriasis severity and (S)QoL were measured with validated tools. Differences in scores between visits were analysed by a mixed model for repeated measures. Forty-two patients were included (M:F = 25:17). All objective and subjective genital psoriasis severity and QoL parameters improved significantly within the first follow-up period of approximately 6 weeks. In female patients, (S) QoL also significantly improved. In conclusion, genital psoriasis can relatively easy be treated within limited time exposure, resulting in significant improvement of QoL. Prompt and simple adjustments in the provided care are enough to accomplish this. [ABSTRACT FROM AUTHOR]

Cervical screening programs for detecting cancer and precancer have dramatically reduced the incidence and mortality rates of cervical cancer since the 1960s. The efficacy of the screening programs depends on participation and the accuracy of the screening tests. Unfortunately, the participation rates are suboptimal; more than half the women with cervical cancer have not or have only sporadically been screened. Increasing participation is the best way of maximizing the program's benefit. Furthermore, cytology screening lacks high sensitivity for high-grade cervical intraepithelial neoplasia (≥CIN2). High-risk human papillomavirus (hrHPV) screening is more sensitive in the detection of cervical intraepithelial neoplasia than cytology screening, but less specific, so that additional triage testing is still mandatory. The aim of this article is to reflect on the efficacy of current cervical cancer screening and on promising future screening strategies with primary hrHPV testing and additional triage strategies for hrHPV-positive screening results. [ABSTRACT FROM AUTHOR]

It is well known that the genital skin may be affected by psoriasis. However, little is known about the prevalence and clinical appearance of genital psoriasis, and genital skin is often neglected in the treatment of psoriatic patients. We performed an extensive systematic literature search for evidence-based data on genital psoriasis with respect to epidemiology, aetiology, clinical and histopathological presentation, diagnosis and treatment. Three bibliographical databases (PubMed, EMBASE and the Cochrane Library) were used as data sources. Fifty-nine articles on genital psoriasis were included. The results show that psoriasis frequently affects the genital skin, but that evidence-based data with respect to the efficacy and safety of treatments for genital psoriasis are extremely limited. An advised treatment paradigm for genital psoriasis, based on the levels of evidence, is: first-line: (weak) topical corticosteroids; second-line: vitamin D preparations or tar-based treatments. [ABSTRACT FROM AUTHOR]

Intratumoral hypoxia has been associated with poor prognosis in several solid tumors. The aim of this study was to determine whether the hypoxia-associated markers glucose transporter (GLUT)-1 and carbonic anhydrase (CA)-IX expression and preoperative hemoglobin (Hb) levels correlate with presence of inguinofemoral or distant metastases, and disease-free survival (DSS) in vulvar squamous cell carcinoma (SCC) patients. Vulvar SCC (n=103) were reviewed for histopathological characteristics by an expert gynecopathologist and stained for GLUT-1 and CA-IX. Clinical data and preoperative Hb levels were obtained from medical records. No significant correlations were observed between GLUT-1 or CA-IX expression patterns and preoperative Hb levels, presence of inguinofemoral or distant metastases and DSS. However, anemic patients (Hb<11.2 g/dL) had significantly more inguinofemoral metastases and lower Hb level was an independent prognostic factor for a worse DSS (p<0.001). The number of comorbidic conditions was inversely correlated with preoperative Hb level. Preoperative Hb levels are associated with poor DSS for vulvar SCC patients, whereas tumor hypoxia reflected by GLUT-1 and CA-IX expression does not have a predictive value. Because preoperative Hb levels inversely correlated with the number of comorbidic conditions and not with GLUT-1 or CA-IX expression, it is most likely that preoperative Hb levels represent overall physical condition. [ABSTRACT FROM AUTHOR]

Lichen sclerosus (LS) is a chronic skin disorder mostly seen on the female anogenital skin. The aim of this study was to evaluate the quality of life (QoL) and sexuality in female patients with LS and to compare their scores with healthy controls. In addition, we wanted to find factors associated with impaired sexual functioning in patients with LS. Members of the Dutch LS foundation and support group were asked to fill in three questionnaires: the Dermatology Quality of Life Index, Female Sexual Function Index (FSFI) and Female Sexual Distress Scale (FSDS). 215 of 368 patients returned their questionnaire (58.4%). Their scores were compared to a control group which consisted of 61 women of similar age ( p = 0.472) without a skin disorder. Of all domains of QoL, LS interfered most with sexual functioning. Patients significantly scored lower on all subscales of the FSFI (desire ( p = 0.016), arousal ( p < 0.001), lubrication ( p < 0.001), orgasm ( p < 0.001), satisfaction ( p < 0.001) and pain ( p < 0.001), indicating worse sexual functioning. These problems with sexual functioning brought about significant sexual distress ( p < 0.001). Patients who experienced more influence on their QoL had more sexual difficulties, leading to more sexual distress independent of their age. [ABSTRACT FROM AUTHOR]

van de Nieuwenhof H P, Hebeda K M, Bulten J, Otte-Holler I, Massuger L F A G, de Hullu J A & van Kempen L C L T (2010) Histopathology 57, 351-362 Specific intraepithelial localization of mast cells in differentiated vulvar intraepithelial neoplasia and its possible contribution to vulvar squamous cell carcinoma development Aims: The aetiology of vulvar squamous cell carcinomas (SCC) that are not causally associated with high-risk human papillomavirus remains largely elusive. The aim of this study was to analyse the inflammatory response in its presumed precursor lesions, lichen sclerosus (LS) and differentiated vulvar intraepithelial neoplasia (dVIN), and provide evidence that dVIN is a likely precursor of vulvar SCC. Methods and results: Immunohistochemical analyses for CD4+, CD8+, CD20+, CD68+, S100+ and tryptase-positive immune cells were performed and quantified in LS ( n = 7), dVIN ( n = 19), SCC ( n = 11), and normal vulvar tissue ( n = 8). The subepithelial inflammatory response in dVIN and SCC was comparable, but absent in LS. Abundant intraepithelial mast cells were observed in dVIN only, and confirmed by electron microscopy, toluidine blue staining and cKIT expression. Adjacent keratinocytes displayed increased proliferation as determined by MIB-1 positivity. Electron microscopy revealed intraepithelial mast cell degranulation. Intraepithelial mast cells were not or infrequently observed in vulvar hyperplasia ( n = 13), condylomata acuminata ( n = 5), keratinocytic intraepidermal neoplasia of sun-exposed skin ( n = 15), epidermal hyperplasia of head and neck ( n = 12), and psoriasis ( n = 3). Conclusions: These data indicate that dVIN can be recognized by intraepithelial mast cells and that they might promote the progression of dVIN to SCC. [ABSTRACT FROM AUTHOR]

Immunosuppressive therapy in renal transplant recipients (RTRs) is associated with an increased risk for the development of (pre)malignancies involving the skin and the female lower genital tract. We assessed whether yearly cervical screening was performed and evaluated the development of skin cancer and gynaecological (pre)malignancies in RTRs. Female RTRs ( n = 224), transplanted between 1991 and 1995, were analysed retrospectively. Sociodemographic patient characteristics, frequency and results of cervical smears and prevalence of cutaneous, cervical, vaginal or vulvar (pre)malignancies were investigated and compared with that in the general population. A mean of 0.2 cervical smears per patient per year was found to have been performed in RTRs, which is significantly less than the recommended screening ratio of 1.0 for female RTRs ( P < 0.001). The risk for RTRs to develop malignancies of the female lower genital tract was increased: twofold to sixfold for cervical intraepithelial neoplasia, threefold for cervical carcinoma and 50-fold for vulvar carcinoma. Cervical screening is not performed in accordance with the advised yearly intervals, and the risk for RTRs to develop vulvar and cervical (pre)malignancies is increased. More attention should be paid to the vulvar and cervical surveillance of RTRs by both medical specialists and general physicians. [ABSTRACT FROM AUTHOR]

Two pathways leading to vulvar squamous cell carcinoma (SCC) exist. The expression of proliferation- and cell-cycle-related biomarkers and the presence of high-risk (hr) HPV might be helpful to distinguish the premalignancies in both pathways. Seventy-five differentiated vulvar intra-epithelial neoplasia (VIN)-lesions with adjacent SCC and 45 usual VIN-lesions (32 solitary and 13 with adjacent SCC) were selected, and tested for hr-HPV DNA, using a broad-spectrum HPV detection/genotyping assay (SPF [ABSTRACT FROM AUTHOR]

Simple Summary: All cells have a complex internal network of 'communication chains' called signal transduction pathways (STPs). Through interaction of different proteins in STPs, they are partly responsible for the behavior of a cell. In our study, we investigated the activity of six STPs in 85 women with advanced stage high-grade serous ovarian cancer (HGSC). To investigate the relation between and differences in survival and STP activity, women with a short disease-free survival (below 12 months) and a long disease-free survival (above 24 months) were included. We found no differences in mean STP activity between short-term survivors (52 women) and long-term survivors (33 women). However, when we analyzed postmenopausal women, we found that both disease-free and overall survival were related to estrogen receptor (ER) pathway signaling. This indicates that a better survival outcome was related to a more active ER pathway in this subgroup. High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, has a high mortality rate. Although there are some factors associated with survival, such as stage of disease, there are remarkable differences in survival among women diagnosed with advanced stage disease. In this study, we investigate possible relations between survival and signal transduction pathway (STP) activity. We assessed the functional activity of the androgen receptor (AR), estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor beta (TGF-β) and canonical wingless-type MMTV integration site (Wnt) pathway in 85 primary tumor samples of patients with FIGO stage IIIC to IVB HGSC and disease-free survival (DFS) below 12 (n = 52) or over 24 months (n = 33). There were no significant differences in median pathway activity between patients with a short and long DFS. In univariate Cox proportional hazards analysis, ER pathway activity was related to a favorable DFS and overall survival (OS) in postmenopausal women (p = 0.033 and p = 0.041, respectively), but not in premenopausal women. We divided the postmenopausal group into subgroups based on ER pathway activity quartiles. Survival analysis revealed that postmenopausal women in the lowest ER quartile had a shorter DFS and OS (log-rank p = 0.006 and p < 0.001, respectively). Furthermore, we were able to form subgroups of patients based on an inverse relation between ER and PI3K pathway activity. In conclusion, in postmenopausal patients with advanced stage HGSC, a poorer survival outcome was associated with low functional ER pathway activity. [ABSTRACT FROM AUTHOR]