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Contains fulltext : 249915.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To evaluate the incidence of pulmonary metastases in the preoperative work-up of patients with primary vulvar squamous cell carcinoma (SCC). DESIGN: Retrospective cohort study. SETTING: Tertiary referral centre. POPULATION: Patients treated for primary vulvar SCC from 2000 to 2018. METHODS: The pre-operative chest imaging of 452 consecutively treated patients was documented with a minimal follow-up period of 2 years. MEAN OUTCOME MEASURES: Incidence of pulmonary metastases, frequency of chest imaging and subsequent coincidental findings. RESULTS: In total, 80.8% of patients underwent pre-operative chest imaging. Seven patients (1.9%), with a median tumour size of 80 mm, presented with pulmonary metastases. None of the patients with early stage disease and tumour size

STUDY QUESTION What is the effect of salpingectomy for ectopic pregnancy or hydrosalpinx at a young age on ovarian cancer risk compared to no salpingectomy for any reason? SUMMARY ANSWER We found no significant reduction in ovarian cancer risk after salpingectomy for ectopic pregnancy or hydrosalpinx. WHAT IS KNOWN ALREADY Salpingectomy may reduce ovarian cancer incidence, although the lag-time between intervention and therapeutic effect remains to be elucidated. STUDY DESIGN, SIZE, DURATION This nationwide population-based database study uses the Dutch pathology database to identify all women who underwent salpingectomy for ectopic pregnancy or hydrosalpinx between January 1990 and December 2012 and compared ovarian cancer incidence to a control group of women who had a benign dermal nevus removed, matched for age at the time and year of procedure. PARTICIPANTS/MATERIALS, SETTING, METHODS After selection and manual control of intervention and control group, ovarian cancer incidence was recorded. Hazard ratios (HRs) with 95% CI for the development of ovarian cancer were calculated with Cox regression analyses, both unadjusted and adjusted for age. Subgroup analyses were performed to investigate lag-time between intervention and protective effect. MAIN RESULTS AND THE ROLE OF CHANCE In all, 18 961 women were included in the intervention group; 17 106 women had a unilateral salpingectomy and 1855 had a bilateral salpingectomy. The control group consisted of 23 686 women. With 14 ovarian cancer cases in the intervention group, the incidence rate (IR) of ovarian cancer was 5.4 (95% CI 3.1–8.9) per 100 000 person-years. In the control group, there were 24 ovarian cancer cases, resulting in an IR of 7.1 (95% CI 4.7–10.5) per 100 000 person-years (P = 0.34). The age-adjusted HR for ovarian cancer was 0.76 (95% CI 0.39–1.47) after salpingectomy. Unilateral salpingectomy resulted in an age-adjusted HR of 0.81 (95% CI 0.41–1.59) and bilateral salpingectomy resulted in an age-adjusted HR of 0.43 (95% CI 0.06–3.16) based on one case. None of our subgroup analysis for lag-time resulted in a significant difference in ovarian cancer incidence between intervention and control group. The difference in ovarian cancer incidence appeared largest in women with at least 8 years of follow-up (P = 0.08). LIMITATIONS, REASONS FOR CAUTION Due to the young population, ovarian cancer incidence is low, even at the end of follow-up. Furthermore, due to the anonymous nature of the pathology registry, we were unable to adjust for confounding factors. WIDER IMPLICATIONS OF THE FINDINGS Although results did not reach statistical significance, they add to the available data on ovarian cancer incidence after salpingectomy. Our subgroup analysis suggests there may be no benefit in the first years following salpingectomy. STUDY FUNDING/COMPETING INTEREST(S) None. TRIAL REGISTRATION NUMBER N/A.

Contains fulltext : 218565.pdf (Publisher’s version ) (Open Access) The new Dutch guidelines on hereditary and familial ovarian carcinoma recommend genetic testing of all patients with epithelial ovarian cancer (EOC). With this study, we aimed to obtain insight into (1) the acceptance and timing of the offer of genetic counseling in women with EOC, (2) reasons for accepting or declining genetic counseling, and (3) psychological differences between women who did and did not have genetic counseling. A multicenter questionnaire survey was performed in patients with EOC in four Dutch oncology centers. The questionnaire addressed whether, how, and when genetic counseling was offered, women's arguments to accept or decline genetic counseling, and included the Cancer Worry Scale (CWS) and the Hospital Anxiety and Depression Scale (HADS). A total of 67 women completed the questionnaire, of which 43 had genetic counseling. Despite a wide variability in the timing of the offer of genetic counseling, 89% of the women were satisfied with the timing. No significant differences were found between the CWS and HADS scores for the timing of the offer of genetic counseling and whether or not women had genetic counseling. Taking the small sample size into account, the results tentatively suggest that genetic counseling may have limited impact on the psychosocial wellbeing of women with EOC. Therefore, we assume that implementation of the new guidelines offering genetic counseling to all patients with EOC will not cause considerable additional burden to these patients.

Introduction/Background* Risk-reducing salpingectomy (RRS) with delayed oophorectomy (DO) has gained interest for women at high risk for ovarian cancer in the last years. In the first place because of the increasing number of studies pointing towards the fallopian tube as tissue of origin. In the second place because two studies demonstrated the positive effect on menopause-related quality of life and sexual functioning compared to standard risk reducing salpingo-oophorectomy (RRSO). However, the strategy is not yet proven to be safe. In the current TUBA-WISP II study, we aim to investigate whether RRS with DO is non-inferior to the current standard RRSO regarding ovarian cancer risk. Methodology In this international prospective multicenter preference trial, women choose between the novel RRS with DO and the current standard RRSO. RRS can be performed after the completion of child bearing and until the age of 40 (BRCA1), 45 (BRCA2) or 50 (BRIP1, RAD51C and RAD51D pathogenic variant (PV) carriers). Subsequent DO is recommended at a maximum delay of five years beyond the upper limit of the current guideline age for RRSO. The current guideline age, which is also recommended for RRSO within the study, is 35-40 for BRCA1, 40-45 for BRCA2 and 45-50 for BRIP1, RAD51C, and RAD51D PV-carriers. The primary outcome measure is the cumulative ovarian cancer incidence at target age: 46 for BRCA1 and 51 for BRCA2-PV carriers. A total 1500 BRCA1 and 1500 BRCA2-PV carriers are needed to prove non-inferiority of RRS with DO compared to RRSO. Kaplan-Meier analysis with Inverse probability weighting will be used to estimate the cumulative incidence at the appropriate target age (46 or 51) per BRCA-type. Result(s)* Conclusion* As RRS with DO is proven to be beneficial in regard to menopause-related quality of life and sexual functioning, the current international study is investigating the non-inferiority to RRSO regarding ovarian cancer incidence. Trial registration NCT04294927

Introduction/Background* 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. However, there is limited knowledge on the impact of splenectomy on the long-term outcome of patients. Particularly, it has been hypothesized that as the antitumor immunologic functions of the spleen may inhibit cancer growth, splenectomy may promote the growth of residual disease during the postoperative period as observed in murine models of other cancer types [3-6]. The aim of this study was to assess the effect of a splenectomy during cytoreductive surgery on perioperative outcomes and survival of advanced stage EOC patients. Methodology In this nationwide population-based study, all consecutive patients diagnosed with FIGO stage IIIC and IV EOC between 01-01-2008 and 31-12-2015 were identified from the Netherlands Cancer Registry. Patients who underwent cytoreductive surgery combined with platinum-based chemotherapy as primary treatment were selected. Differences in clinicopathological 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. Result(s)* A total of 3,911 patients were identified, including 99 splenectomy and 3,812 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 Intensive Care Unit (all p *An additional 163 patients were excluded from the survival analysis with reference to figure 1, since these patients had unknown follow-up or survival data. *An additional 10 patients were excluded from the survival analysis with reference to figure 1, since these patients had unknown follow-up or survival data. Conclusion* While advanced stage EOC patients who undergo splenectomy during cytoreductive surgery have more extensive disease and undergo intensive treatment, no adverse effect of splenectomy on the survival was observed. Splenectomy during cytoreductive surgery is justified to achieve complete cytoreduction in advanced stage EOC patients.

Introduction/Background* Risk reducing salpingo-oophorectomy is an effective intervention to reduce the risk of high grade serous carcinoma (HGSC) in patients with a BRCA1/2 pathogenic variant (PV), but results in significant short and long-term health risks. New interventions, such as risk-reducing salpingectomy with delayed oophorectomy are promising. In this alternative approach, the detection of serous tubal intraepithelial carcinoma (STIC) as precursor to HGSC, has become more important. The detection of STIC indicates an increased risk for HGSC and would prompt for an immediate oophorectomy. Unfortunately, reproducibility of STIC diagnosis is only moderate, even among experienced gynecological pathologists. The aim of this pilot study is to develop and validate an AI algorithm for automated detection of potential STIC lesions in scanned H&E slides, to aid the pathologist in diagnosing STIC Methodology We collected and digitalised 60 cases of STIC and 65 control cases. STIC diagnosis was confirmed using p53 and Ki-67 immunohistochemical stainings (IHC). The dataset was split into 50 cases for training, five for validation and five for testing. We developed a Convolutional Neural Network and compared two appraoches: directly detecting STIC (one-step) or first detecting all epithelium and subsequently detecting STIC within epithelial regions (two-step). Additionaly, we evaluated whether we could improve the network by enriching the training data with hard negative examples. Result(s)* We found that the optimal configuration for detection of STIC was the two-step approach, with training set enrichment by hard negatives. This network reached an area under the receiver operating curve of 0.90 (figure 1). Visual inspection of cases in the test set showed concordance between the model output, p53 and Ki67 IHC, and pathologists‘ annotations (see example model output on H&E stained tissue in figure 2. Conclusion* We present a convolutional neural network that can succesfully detect STIC lesions in whole slide images. AI has the potential to aid the pathologist in the detection of STIC and assist in producing more accurate and consistent diagnosis. Additional performance and robustness is expected to be achieved by expansion of the dataset.

Introduction/Background* High cancer risks, as applicable to BRCA1 and BRCA2 pathogenic variant (PV) carriers, can induce significant cancer concerns. We examined the degree of cancer worry and the course of this worry among BRCA1/2-PV carriers opting for surgery to prevent ovarian cancer, and identified factors associated with high cancer worry. Methodology Cancer worry was evaluated as part of the multicentre, prospective TUBA-study (NCT02321228) in which BRCA1/2-PV carriers choose between the standard risk-reducing salpingo-oophorectomy or a novel strategy, risk-reducing salpingectomy with delayed oophorectomy. The Cancer Worry Scale was obtained before and three and twelve months after surgery. Cancer worry patterns were analysed using latent class growth analysis and factors associated with cancer worry were identified with regression analysis. Result(s)* Of all 577 BRCA1/2-PV carriers, 320 (55.5%) had high (≥14) cancer worry pre-surgery and 70.2% had higher cancer worry pre-surgery than post-surgery. Based on the course of cancer worry, BRCA1/2-PV carriers could be classified into three groups: persistently low cancer worry (56.4%), persistently high cancer worry (6.3%), and fluctuating cancer worry that mainly declined over time (37.3%). Factors associated with persistently high cancer concerns were: age below 35 (BRCA1) or 40 (BRCA2) years, unemployment, previous breast cancer diagnosis, lower education and more recent diagnosis with the BRCA-PV. Conclusion* High cancer worry is common among BRCA1/2-PV carriers and mainly declines after risk-reducing surgery. However, cancer worry remains high in 6% of the women and they should be identified and offered support. It should be realized that in this group, surgery does not reduce cancer concerns.

Objective Optimizing the counselling of women ≤40 years with epithelial ovarian cancer (EOC) by investigating the role of young age and tumour characteristics on overall survival (OS). Methods A retrospective population-based study was done using data of EOC patients diagnosed between 1990 and 2014 registered in the Netherlands Cancer Registry. Descriptive statistics were performed to analyse clinical and tumour characteristics. Five- and 10-year OS rates were calculated using Kaplan Meier curves. To determine prognostic factors, univariable and multivariable survival analyses were performed. Results 1407 women ≤40 years and 29,022 women >40 years old were included. OS was higher for the younger women compared to older group (5-year survival of 65.6% vs. 32.7%, 10-year survival of 57.5% vs. 22.5%, respectively). The younger women had more often a mucinous (36.4%), well-differentiated (31.8%) tumour in early stage of disease (49.9%). Serous tumours (43.0%), high-grade (36.0%) and stage III (47.1%) were most frequently found in the older women. Histology, grade, stage, incidence year, and age group are independent prognostic factors for survival. OS of the young women for several combinations of tumour characteristics were calculated. Conclusions Age is an independent prognostic factor for OS in EOC patients. Counselling on prognosis could be more individualised in young EOC patients using the tumour characteristics histology, stage and grade.

Objectives Morbidity and mortality meetings (M&MMs) at surgical departments may improve when patients participate, leading to different learning points. A gynecological oncology department invited patients to join their M&MMs. The practical constraints and experiences important from the perspective of patients and their healthcare professionals were evaluated. Methods Semi-structured interviews were conducted with patients and professionals who attended M&MMs at a gynecological oncology department between 2016 and 2018. The interviews were transcribed and coded and thematic content analysis was performed. Results Eight patients and 17 healthcare professionals participated. Eleven themes related to interpersonal dynamics. The five shared themes are: patient–doctor relationship, language, openness of communication, learning and personal impact. All participants suggested maintaining the new practical design of the M&MMs. Conclusions Patients and healthcare professionals valued patient participation in the M&MMs. Patient participation is possible when professionals are open to discussing and learning from adverse events (AEs). In this setting, patients feel that they are taken seriously and gain a better understanding of the course of an AE. Practice Implications Involving patients in M&MMs led to new insights, better understanding, and improved processing of AEs. Collaborating with patients and using their feedback seems to be effective when developing innovations in healthcare.

Objective To identify clinicopathologic factors predictive of early relapse (i.e. a platinum-free interval (PFI) of ≤6 months) in advanced epithelial ovarian cancer (EOC) in first-line treatment, and to develop and internally validate risk prediction models for early relapse. Methods All consecutive patients diagnosed with advanced EOC between 01-01-2008 and 31-12-2015 were identified from the Netherlands Cancer Registry. Patients who underwent debulking and platinum-based chemotherapy as initial EOC treatment were selected. Two prediction models, a pretreatment and postoperative model, were developed. Candidate predictors of early relapse were fitted into multivariable logistic regression models. Model selection was performed using backward selection (p-value Results A total of 4,557 advanced EOC patients were identified, including 3,171 late or non-relapsers and 1,302 early relapsers. Early relapsers were more likely to have FIGO stage IV, mucinous or clear cell type EOC, ascites, >1 cm residual disease, and to have undergone interval debulking. The final pretreatment model demonstrated subpar model performance (AUC=0.65 [95%-CI 0.64–0.67]). The final postoperative model based on FIGO stage, histologic subtype, presence of ascites, type of debulking, and residual disease after debulking, demonstrated good model performance (AUC=0.72 [95%-CI 0.71–0.74]). Bootstrap validation revealed minimal optimism of the final postoperative model. Conclusion A good (postoperative) discriminative model has been developed and presented online that predicts the risk of early relapse in advanced EOC patients. Although external validation is still required, this prediction model can support treatment decision-making in daily clinical practice.

BACKGROUND Vulvar Paget disease (VPD) is extremely rare and thought to be associated with other malignancies. OBJECTIVES To evaluate the risk of developing breast, intestinal and urological malignancies in patients with VPD compared with the general population, and in particular to focus on the risk of malignancy in patients with cutaneous noninvasive VPD. METHODS Data on the oncological history of patients with any type of VPD between 2000 and 2015 were obtained from PALGA, a nationwide archive containing all pathology reports in the Netherlands. Follow-up data and a control group from the general population were obtained from the Netherlands Cancer Registry. After correction for age and calendar year at time of diagnosis, standardized incidence ratios (SIRs) for the first 3 years after VPD diagnosis were estimated with 95% confidence intervals (CIs). RESULTS We identified 199 patients with a first diagnosis of VPD [164 noninvasive, 35 (micro)invasive] between 2000 and 2015. The SIR of developing an associated malignancy in the first 3 years after diagnosis was 4·67 (95% CI 2·66-7·64). This was due mainly to the high incidence of intestinal malignancies among patients with secondary VPD. Subgroup analysis for cutaneous noninvasive VPD did not reveal a significantly increased risk for associated malignancies: SIR 2·08 (95% CI 0·76-4·62). CONCLUSIONS Of our patients with VPD, 76·9% were diagnosed with cutaneous noninvasive VPD, and this group has no increased risk for developing malignancies of the breast, intestine or urological tract. Our study suggests that routine screening for these malignancies in patients diagnosed with cutaneous noninvasive VPD may not be necessary.

Contains fulltext : 174161.pdf (Publisher’s version ) (Closed access) Female renal transplant recipients (RTRs) have an increased risk for developing human papillomavirus (HPV)-related (pre)malignant lesions of the genital tract. This study aims to assess the genital prevalence of HPV before and after renal transplantation (RT). In female patients who were counseled for RT at the Radboud University Medical Center Nijmegen, the Netherlands, gynecological examination was performed at first visit, and 1 and 2 years later. HPV self-sampling and questionnaires on sexual behavior were performed every 3 months. In 65 patients who underwent RT, the high-risk human papillomavirus (hrHPV) prevalence as assessed with the highly sensitive SPF10 -LiPA25 test increased significantly from 19% before to 31% after RT (p = 0.045). Based upon the clinically validated Cobas 4800 HPV test, the hrHPV prevalence increased from 10% before to 14% after RT (p = 0.31). During follow-up, no changes in sexual behavior were reported. Thirty-three patients who did not undergo RT showed a hrHPV prevalence of 21% at study entry and of 27% after 12 months with the sensitive test, and a stable prevalence of 16% with the clinically validated test. The results of this study indicate that activation of latent HPV infections may contribute to the increased risk of HPV-related (pre)malignant lesions in female RTRs.

Introduction/Background Introduction: GROINSS-V II investigated whether radiotherapy is a safe alternative for inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). Methodology Methods: In GROINSS-V II, a prospective multicentre phase II trial, patients were included with early-stage squamous cell carcinoma (SCC) of the vulva (diameter Results From December 2005 until October 2016, 1552 eligible patients were registered. SN-metastasis occurred in 324/1552 (21%) patients. After 54 months of inclusion the stopping-rule for SN-positive patients was activated; interim analysis showed an increased risk for groin recurrence in case of SN-metastasis >2 mm and/or extranodal extension (ENE). After amendment of the protocol only patients with SN-micrometastasis ≤2 mm received radiotherapy, while those with SN metastasis >2 mm underwent IFL (with radiotherapy if >1 metastasis or ENE). Final analysis after ≥2 years of follow-up revealed six isolated groin recurrences in 157 patients with a SN-micrometastasis (3.8%). Four could not be considered radiotherapy failures: two developed recurrence in the contralateral (SN-negative) groin, two refused radiotherapy. Twenty-eight patients did not get radiotherapy (2 recurrences;7.1%). Among 129 patients who received radiotherapy to the groin(s) only two isolated groin recurrences were diagnosed (1.6%: 95%CI:0–3.8%). The combination of radiotherapy with SN was associated with minimal toxicity: 5/118(4.2%) grade 3 toxicity, no grade 4 or 5 toxicity. In 38/1222 SN-negative patients (3.1%: 95%CI:2.1–4.1%) isolated groin recurrences were diagnosed with clear protocol violations in 6 patients: incomplete treatment of the groin (n=3); primary tumor >4cm (n=1); not all SNs visualized on the lymphoscintigram removed (n=2). After exclusion of these protocol violations an isolated groin recurrence rate of 2.6% (95%CI:1.7–3.5%) was observed. Conclusion Radiotherapy to the groins is a safe alternative for IFL in patients with SN metastasis ≤2 mm, with minimal toxicity. We further established the safety of omitting IFL in patients with SCC of the vulva 2 mm, radiotherapy with a total dose of 50Gy was no safe alternative for IFL; dose escalation and/or chemoradiation should be investigated in these patients. Disclosure Funded by Dutch Cancer Society.

Introduction/Background Local recurrences of vulvar squamous cell carcinoma (VSCC) are reported in up to 40% of patients. Knowledge of the risk of inguinofemoral lymph node metastases in local recurrences is necessary to optimally counsel patients with respect to treatment of the groins, and to explore alternative treatment regimens. The aim of our study is to determine the incidence and prognostic factors of lymph node metastases in women with a first local recurrence of VSCC. Methodology A nation-wide multicenter retrospective study was performed, including all patients with a first local recurrence of VSCC after primary surgical treatment with curative intent between 2000–2015. Interim analysis was conducted on the results of four out of eight participating gynecologic oncology centers (Academic Medical Center, Amsterdam; Erasmus Medical Center, Rotterdam; University Medical Center Groningen, Groningen and Radboud University Medical Center, Nijmegen). Results We retrieved 292 patients with a macro-invasive local recurrence of VSCC. The median follow-up after local recurrence was 61 months (range 2–208). The median interval time between the primary VSCC and the first local recurrence was 27 months (range 1–201) with a median age of 74 years (range 28–99). Positive inguinofemoral lymph nodes were present in 15.8% of the patients with a local recurrent VSCC. Significant differences for tumor size (median 25 mm vs 14 mm, p Conclusion Our study demonstrates an incidence rate of 15.8% of inguinofemoral lymph node metastases in women with a first local recurrence of VSCC. A larger tumor size and depth of invasion were significant prognostic factors for the presence of positive lymph nodes at the time of recurrent disease. More research is needed to accurately identify patients at high risk for lymph node metastases, in order to individualize treatment and follow-up. Disclosure Nothing to disclose

Introduction/Background The opportunistic salpingectomy (OS) during hysterectomy for prevention of ovarian cancer is under discussion for the general population. The effect on ovarian cancer risk, surgery-related adverse events and ovarian reserve have not been fully elucidated. We aim to evaluate benefits and potential harms of OS during hysterectomy for benign gynaecological complaints. Methodology We searched the Cochrane register of controlled trials, CENTRAL, MEDLINE and Embase from inception to January 2019. Regarding ovarian cancer incidence, both non-randomised trials (NRTs) and randomised controlled trials (RCTs) were eligible. For surgery-related adverse events and ovarian reserve, only RCTs were included. Two review authors independently screened and selected studies, extracted data and assessed risk of bias. Results We screened 3748 trials and identified zero NRTs and seven RCTs with 347 women in total. Five trials were at high risk of bias in at least one domain. No studies were available on ovarian cancer incidence. We found no statistically significant difference in intra-operative or post-operative adverse events or in ovarian reserve, based on post-operative AMH concentration after hysterectomy with or without OS (table 1). Duration of follow-up was limited to a maximum of 6 months. Conclusion There were no studies available on the effect of OS during hysterectomy on ovarian cancer incidence that met our inclusion criteria. We found no significant difference in surgery-related adverse event or ovarian reserve after hysterectomy with or without OS. To conclude; the OS seems to be a safe procedure both surgically and with regards to ovarian reserve, however the effect on ovarian cancer risk when performed during hysterectomy is not proven. Especially in young women, for whom an effect on ovarian reserve would be more clinically relevant, long term effects should be investigated. Disclosure Nothing to disclose.

Introduction/Background The disease-free survival (DFS) of high-grade serous cancer (HGSC) varies greatly, despite comparable clinicopathological features and treatment. It is our hypothesis that the difference in DFS is caused by differences in activity of tumour-driving signal transduction pathways. Methodology Using previously described Signal Transduction pathway Activity (STA) assays (table 1), signalling pathway activity scores for AR, ER, PI3K-FOXO, HH, NFkB, TGFβ, NOTCH and Wnt were derived from publicly available mRNA expression (Affymetrix) data of primary HGSC, with clinical annotation (GSE9891). K-means cluster analysis was performed on STA-scores of AR, ER, PI3K-FOXO, HH, NFkB, TGFB, NOTCH and Wnt pathway. However, as PI3K and NFkB scores were most discriminating in cluster formation, final clusters were based on these pathways alone. Results We selected 81 out of 140 sample data with a DFS 24 months. The remaining 59 samples with a DFS of 12–24 months were kept aside to be allocated to identified clusters by discriminant analysis in a later stage. Repeated K-means clustering resulted in two stable clusters; a low PI3K/high FOXO and high NFkB cluster (n=43) with a more favourable prognosis, and a high PI3K/low FOXO and low NFkB cluster (n=38) with a less favourable prognosis (log-rank=0.011, figure 1). The remaining samples (n=59) were then allocated resulting in a low PI3K and high NFkB cluster of 73 samples, and a high PI3K and low NFkB cluster of 67 samples (log-rank=0.036, figure 2). Conclusion We identified two signalling pathway activity clusters in HGSC with a difference in DFS. The low PI3K/high FOXO and high NFkB activity of the favourable prognosis cluster may indicate apoptosis, while the high PI3K/low FOXO and low NFkB activity of the unfavourable prognosis cluster may indicate high cell division. Elucidating underlying mechanisms of HGSC aids our understanding of the disease and provides possible new leads for targeted therapies. Disclosure LvL has nothing to disclose, AvdS is employed by Philips Research, RB has nothing to disclose, JdH has nothing to disclose, JP has nothing to disclose. Funding granted by the Ruby& Rose fund and Catharina research fund.

Objective: To determine the incidence of local recurrence of vulvar squamous cell carcinoma in relation to tumor- and/or precursor lesion free pathologic margins.Methods: Consecutive patients with primary vulvar squamous cell carcinoma surgically treated in two Dutch expert centers between 2000 and 2010 were included. All pathology slides were independently reviewed by two expert gynecopathologists, and local recurrence was defined as any recurrent disease located on the vulva. Time to first local recurrence was compared for different subgroups using univariable and multivariable Cox-regression analyses.Results: In total 287 patients with a median follow-up of 80months (range 0-204) were analyzed. The actuarial local recurrence rate ten years after treatment was 42.5%. Pathologic tumor free margin distance did not influence the risk on local recurrence (HR 1.03 (95% CI 0.99-1.06)), neither using a cutoff of eight, five, or three millimeters. Multivariable analyses showed a higher local recurrence rate in patients with dVIN and LS in the margin (HR 2.76 (95% CI 1.62-4.71)), in patients with dVIN in the margin (HR 2.14 (95% CI 1.11-4.12)), and a FIGO stage II or higher (HR 1.62 (95% CI 1.05-2.48)).Conclusions: Local recurrences frequently occur in patients with primary vulvar carcinoma and are associated with dVIN (with or without LS) in the pathologic margin rather than any tumor free margin distance. Our results should lead to increased awareness among physicians of an ongoing risk for local recurrence and need for life-long follow-up. Intensified follow-up and treatment protocols for patients with dVIN in the margin should be evaluated in future research. (C) 2019 Elsevier Inc. All rights reserved.

Contains fulltext : 171336.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To describe trends in incidence, treatment and survival of patients with basal cell carcinomas and melanomas of the vulva. Also to compare survival of vulvar and cutaneous melanoma patients. METHODS: All women with a vulvar malignancy between 1989 and 2012 were selected from the Dutch Cancer Registry (n=6436). Standardized incidence rates, estimated annual percentage change (EAPC) and 5-year relative survival rates were calculated for basal cell carcinomas (BCCs) and melanomas. Patients with vulvar melanomas were matched to women with cutaneous melanomas on period of diagnosis, age, Breslow thickness, tumour ulceration, lymph node status and distant metastases. Differences in survival were evaluated using Kaplan-Meier curves and the log rank test. RESULTS: 489 women were diagnosed with a BCC and 350 with a melanoma of the vulva. The EAPC in incidence for melanomas was 0.2% and 1.1% for BCCs. Eighty-six percent of patients with BCC underwent surgical treatment in 1989-2006 and 95% in 2005-2012. Forty-five percent with BCC and 79% with melanoma were treated in a referral centre. Five-year relative survival for BCCs was 100% and for melanomas survival increased from 37% (95%CI 28-47%) in 1989-1999 to 45% (95%CI: 37-54%) in 2000-2012. Five years after diagnosis survival of women with vulvar melanoma was 15% lower compared to matched cutaneous melanoma patients (p=0.002). CONCLUSION: No trends in age-adjusted incidence have been observed but more patients with BCC received surgical treatment over time. Having had vulvar BCC did not affect life expectancy. Well-known prognostic factors explained most of the differences in survival between cutaneous and vulvar melanoma patients, however a difference of 15% remained unexplained.

Item does not contain fulltext BRCA1/2 mutation carriers are at high risk of breast and ovarian cancer. The number of studies on non-cancer endpoints in BRCA1/2 mutation carriers is still limited. BRCA1/2 mutation carriers may be at higher cardiovascular risk due to early menopause after risk-reducing salpingo-oophorectomy and/or due to the potential cardiotoxic effects of breast cancer treatment (radiotherapy and chemotherapy). Moreover, BRCA genes have a role as a gatekeeper in cardiac function and structure, which may affect susceptibility to cardiac damage. Our goal is to review current knowledge of cardiovascular risk among BRCA1/2 mutation carriers.

Objective. In 2008 GROINSS-V-I, the largest validation trial on the sentinel node (SN) procedure in vulvar cancer, showed that application of the SN-procedure in patients with early-stage vulvar cancer is safe. The current study aimed to evaluate long-term follow-up of these patients regarding recurrences and survival. Methods. From2000 until 2006 GROINSS-V-I included 377 patientswith unifocal squamous cell carcinoma of the vulva (T1

Objective To determine the efficacy of the addition of an ultrasound of the groins in routine follow up of women with vulvar squamous cell carcinoma (SCC) after a negative sentinel lymph node (SLN). Design Prospective single‐centre study. Setting A tertiary expert oncology centre for the treatment of vulvar cancer. Population All women with vulvar SCC with a negative SLN, treated between 2006 and 2014. Methods We prospectively collected data of 139 women with vulvar SCC treated with an SLN procedure. We analysed data of 76 patients with a negative SLN. Three‐monthly follow‐up visits consisted of physical examination combined with an ultrasound of the groins by a radiologist. Main outcome measures The diagnostic value of ultrasound in the follow up of women with vulvar SCC with a negative SLN during the first 2 years after treatment. Results During a routine visit, two asymptomatic isolated groin recurrences were detected. Both patients were treated by inguinofemoral lymphadenectomy and adjuvant radiotherapy and are alive without evidence of disease 39 and 120 months after diagnosis. In total, 348 ultrasounds and 29 fine‐needle aspiration were performed. The sensitivity of ultrasound to detect a groin metastasis was 100% (95% CI 16–100%), and specificity was 92% (95% CI 89–95%). Conclusions Routine follow up including ultrasound of the groin led to early detection of asymptomatic isolated groin recurrences. Further research is necessary to determine the exact role of ultrasound in the follow up of patients with vulvar SCC with a negative SLN. Tweetable abstract Routine follow up including ultrasound of the groin led to early detection of asymptomatic isolated groin recurrences., Tweetable abstract Routine follow up including ultrasound of the groin led to early detection of asymptomatic isolated groin recurrences.

Objective. To describe clinical characteristics of Lynch syndrome associated ovarian cancer and the efficacy of surveillance in the early detection of these ovarian cancers.Methods. All Lynch syndrome associated ovarian cancer cases identified in either the Dutch Lynch syndrome registry (DLSR) between 1987 and 2016, and/or the cohort at the University Medical Center Groningen (UMCG) between 1993 and 2016 were included. Clinical data on age at diagnosis, mutation type, histological type, FIGO stage, treatment, follow-up and gynecological surveillance were collected.Results. A total of 46/798 (6%) women in the DLSR and 7/80 (9%) in the UMCG cohort were identified as LS associated ovarian cancer patients. The median age at ovarian cancer diagnosis was 46.0 years (range 20-75 years). The most frequently reported histological type was endometrioid adenocarcinoma (40%; n = 21) and serous carcinoma (36%; n = 19). Most tumors (87%; n = 46) were detected at an early stage (FIGO I/II). Forty-one of 53 (77%) patients were diagnosed with ovarian cancer before LS was diagnosed. In the other 12/53 (23%) women, ovarian cancer developed after starting annual gynecological surveillance for LS; three ovarian cancers were screen-detected in asymptomatic women. Overall survival was 83%.Conclusion. Ovarian cancer in women with LS has a wide age-range of onset, is usually diagnosed at an early stage with predominantly endometrioid type histology and a good overall survival. The early stage at diagnosis could not be attributed to annual gynecological surveillance. (C) 2018 Published by Elsevier Inc.

Contains fulltext : 154786.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The overall 5-year survival of patients with vulvar squamous cell carcinoma (SCC) is 70%. The clinical impression is that localization of SCC on the clitoris may lead to worse prognosis. The aim of this study is to assess the disease specific survival (DSS) in patients with clitoral SCC compared to patients with SCC without clitoral involvement. METHODS: All consecutive patients with primary vulvar SCC treated with surgery at the Department of Gynaecologic Oncology at the Radboud university medical centre (Radboudumc) between March 1988 and January 2012, were analysed. The clinical and histopathological characteristics and DSS rates of patients with (N = 72) and without clitoral SCC (N = 275) were compared. Furthermore, patients with clitoral involvement were compared to patients with perineal SCCs (N = 52) and other central SCCs without clitoral and/or perineal involvement (N = 117). RESULTS: Patients with clitoral SCC more often had larger and deeper invaded tumours, lymphovascular space involvement (LVSI), positive surgical margins and a higher percentage of positive lymph nodes. Kaplan-Meier survival analyses showed worse DSS in patients with a clitoral SCC compared to patients without clitoral involvement. Multivariable analysis showed that not clitoral involvement, but invasion depth, differentiation grade and lymph node status are independent prognostic factors. CONCLUSIONS: Patients with clitoral SCC have worse survival compared to patients without clitoral involvement. This is probably caused by unfavourable histopathological characteristics of the tumour rather than the localization itself. Prospective studies are needed to further assess the influence of localization of the vulvar SCC on prognosis.

Item does not contain fulltext OBJECTIVE: Inguinofemoral lymphadenectomy for patients with vulvar squamous cell carcinoma is associated with a high incidence of postoperative wound complications, which may be influenced by inguinal drain management. The aim of this nationwide prospective study (MAMBO: Morbidity And Measurement of the BOdy) was to assess the feasibility and the incidence of complications after volume-controlled versus short drainage. METHODS: The MAMBO study consisted of two observational studies in all eight oncology centers in the Netherlands, conducted between 2012 and 2016. In the first study, the drain was removed when the production was

Contains fulltext : 126182.pdf (Publisher’s version ) (Closed access) AIM: Previous studies showed an increase in incidence of vulvar intraepithelial neoplasia (VIN), the premalignant lesion of Vulvar Squamous Cell Carcinoma (VSCC). Furthermore, during the last decades treatment of VSCC became less radical. Considering these changes the aim of this study was to describe trends of incidence and survival of patients with VSCC in the Netherlands. METHODS: All patients with VSCC diagnosed between 1989 and 2010 (n=4614) were selected from the Netherlands Cancer Registry. Trends in age-adjusted incidence rates were evaluated by calculating the estimated annual percentage change (EAPC). Joinpoint regression analysis was used to detect changes in trends. Five-year relative survival rates were calculated for four time periods. RESULTS: The incidence of VSCC has increased since 2002 (EAPC 5.0; 95% confidence interval (CI): 2.7-7.7%). In women aged

Contains fulltext : 171122.pdf (Publisher’s version ) (Open Access) In this review, we provide an overview of the clinical aspects, histopathology, molecular genetics, and treatment options for Vulvar Paget's Disease (VPD), a rare skin disease, most commonly found in postmenopausal Caucasian women. The underlying cause of VPD remains not well understood. VPD is rarely associated with an underlying urogenital, gastrointestinal or vulvar carcinoma. In approximately 25% of the cases, VPD is invasive; in these cases, the prognosis is worse than in non-invasive cases. Recurrence rates in invasive VPD are high: 33% in cases with clear margins, and even higher when surgical margins are not clear, regardless of invasion. Historically, surgical excision has been the treatment of choice. Recent studies show that imiquimod cream may be an effective and safe alternative.

Contains fulltext : 171433.pdf (Publisher’s version ) (Open Access) Recurrent disease occurs in 12-37% of patients with vulvar squamous cell carcinoma (VSCC). Decisions about treatment of recurrent VSCC mainly depend on the location of the recurrence and previous treatment, resulting in individualized and consensus-based approaches. Most recurrences (40-80%) occur within 2 years after initial treatment. Currently, wide local excision is the treatment of choice for local recurrences. Isolated local recurrence of VSCC has a good prognosis, with reported 5-year survival rates of up to 60%. Groin recurrences and distant recurrences are less common and have an extremely poor prognosis. For groin recurrences, surgery with or without (chemo) radiotherapy is a treatment option, depending on prior treatment. For distant recurrences, there are only palliative treatment options. In this review, we give an overview of the available literature and discuss epidemiology, risk factors, and prognostic factors for the different types of recurrent VSCC and we describe treatment options and clinical outcome.

Contains fulltext : 171930.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Risk-reducing salpingo-oophorectomy (RRSO) is the only effective surgical strategy to reduce the increased risk of epithelial ovarian cancer in BRCA1/2 mutation carriers. Given the long-term health consequences of premature surgical menopause, we need insight in uptake and timing of RRSO to guide us in improving healthcare. METHODS: A single-center retrospective cohort study of BRCA1/2 mutation carriers diagnosed and counseled at the multidisciplinary Family Cancer Clinic of the Radboud university medical center in Nijmegen, The Netherlands, between 1999 and 2014. Descriptive statistics were used to analyze uptake and timing of RRSO. RESULTS: Data of 580 BRCA1/2 were analyzed. The uptake of RRSO among mutation carriers who are currently above the upper limit of the recommended age for RRSO, is 98.5% and 97.5% for BRCA1 and BRCA2 mutation carriers, respectively. The vast majority undergoes RRSO

BACKGROUND: Knowledge about quality of life and sexual health in patients with genital psoriasis is limited. OBJECTIVES: We studied quality of life and sexual function in a large group of patients with genital psoriasis by means of validated questionnaires. In addition, we evaluated whether sufficient attention is given by healthcare professionals to sexual problems in patients with psoriasis, as perceived by the patients. METHODS: A self-administered questionnaire was sent to 1579 members of the Dutch Psoriasis Association. Sociodemographic patient characteristics, medical data and scores of several validated questionnaires regarding quality of life (Dermatology Life Quality Index) and sexual health (Sexual Quality of Life Questionnaire for use in Men, International Index of Erectile Function, Female Sexual Distress Scale and Female Sexual Function Index) were collected and analysed. RESULTS: This study (n = 487) shows that psoriasis has a detrimental effect on quality of life and sexual health. Patients with genital lesions reported even significantly worse quality of life than patients without genital lesions (mean +/- SD quality of life scores 8.5 +/- 6.5 vs. 5.5 +/- 4.6, respectively, P < 0.0001). Sexual distress and dysfunction are particularly prominent in women (reported by 37.7% and 48.7% of the female patients, respectively). Sexual distress is especially high when genital skin is affected (mean +/- SD sexual distress score in patients with genital lesions 16.1 +/- 12.1 vs. 10.1 +/- 9.7 in patients without genital lesions, P = 0.001). The attention given to possible sexual problems in the psoriasis population by healthcare professionals is perceived as insufficient by patients. CONCLUSIONS: In addition to quality of life, sexual health is diminished in a considerable number of patients with psoriasis and particularly women with genital lesions have on average high levels of sexual distress. We underscore the need for physicians to pay attention to the impact of psoriasis on psychosocial and sexual health when treating patients for this skin disease.

BACKGROUND: Psoriatic lesions may involve nearly all sites of the body. Involvement of the genital skin is frequently classified as part of intertriginous psoriasis without special awareness and treatment for this presentation of the disease. Gaining knowledge about the frequency of the involvement of genital skin in these patients will improve the overall care for patients with psoriasis. OBJECTIVES: We studied the prevalence of genital psoriasis in the Netherlands and epidemiological characteristics of this specific presentation of the disease. Furthermore, we studied the relation between flexural and genital psoriasis. PATIENTS/METHODS: A self-administered questionnaire was sent to all 5300 members of the Dutch Psoriasis Society. Sociodemographic patient characteristics and disease-related data (such as localization of psoriatic lesions, involvement of the genitalia, age at onset of genital psoriasis and severity of genital psoriatic lesions) were collected and analysed. RESULTS: A response rate of 37% was achieved. Almost 46% of the responding patients with psoriasis, that is 16.5% of all potential responders (n = 5300), report genital involvement at some time during the course of their disease. The genitalia can become affected at any age. Many patients with current genital involvement (38%) do not have the flexural skin affected. CONCLUSIONS: A large part of patients with psoriasis suffer from genital psoriasis, which was not associated with flexural involvement in at least one third of them. More attention to the genital region is required in the current standard treatment of both male and female psoriatic patients at any age.

Contains fulltext : 70736.pdf (Publisher’s version ) (Closed access) PURPOSE: To assess the false-positive rate of breast cancer surveillance by magnetic resonance imaging (MRI) in BRCA mutation carriers and the impact of an abnormal mammography or breast MRI on the patients' decision for prophylactic mastectomy. PATIENTS AND METHODS: A total of 196 BRCA mutation carriers were included with a median follow-up of 2 years (range 1-9) with annual mammography and MRI. Preference for prophylactic mastectomy was registered at first surveillance after the mutation carriership was revealed. RESULTS: In all, 41% (81 of 196) of the women had at least one positive MRI or mammography. Malignancy was detected in 17 women: 11 at surveillance, 4 at an intended prophylactic mastectomy and 2 had an interval cancer. Imaging by mammography and MRI had a sensitivity of 71% and a specificity of 90%. The probability that a positive MRI result is false positive was 83%. In the group with a prior preference for mastectomy with and without a false-positive imaging, prophylactic mastectomy was carried out in 89% and 66%, respectively (P = 0.06), in the group with prior preference for surveillance these percentages were 15% and 11%, respectively (P = 0.47). CONCLUSION: Although the rate of false-positive MRI results is high, the impact on the choice for prophylactic mastectomy is limited and is determined by the woman's preference before the establishment of a BRCA mutation.

Contains fulltext : 51607.pdf (Publisher’s version ) (Closed access) BRCA1/2 mutation carriers are offered gynaecological screening with the intention to reduce mortality by detecting ovarian cancer at an early stage. We examined compliance and efficacy of gynaecological screening in BRCA1/2 mutation carriers. In this multicentre, observational, follow-up study we examined medical record data of a consecutive series of 888 BRCA1/2 mutation carriers who started annual screening with transvaginal ultrasonography and serum CA125 between 1993 and 2005. The women were annually screened for 75% of their total period of follow-up. Compliance decreased with longer follow-up. Five of the 10 incident cancers were interval tumours, diagnosed in women with a normal screening result within 3-10 months before diagnosis. No difference in stage distribution between incident screen-detected and interval tumours was found. Eight of the 10 incident cancers were stage III/IV (80%). Cancers diagnosed in unscreened family members had a similar stage distribution (77% in stage III/IV). The observed number of cases detected during screening was not significantly higher than expected (Standardized Incidence Ratio (SIR): 1.5, 95% confidence interval: 0.7-2.8). For the subgroup that was fully compliant to annual screening, a similar SIR was found (1.6, 95% confidence interval: 0.5-3.6). Despite annual gynaecological screening, a high proportion of ovarian cancers in BRCA1/2 carriers are interval cancers and the large majority of all cancers are diagnosed in advanced stages. Therefore, it is unlikely that annual screening will reduce mortality from ovarian cancer in BRCA1/2 mutation carriers.

Objectives. High morbidity of elective inguinofemoral lymphadenectomy in early stage vulvar cancer patients urges the need for defining a group of low-risk patients in whom inguinofemoral lymphadenectomy can be safely omitted. Aim of the study was to evaluate whether in addition to 'classic' clinicopathological factors determination of EGFR expression in vulvar cancer can be helpful in defining such a 'low-risk' group.Methods. Formalin-fixed paraffin-embedded tumor tissue samples of 197 surgically treated T1/2 patients were collected in a Tissue Micro Array (TMA). On this TMA, immumohistochemistry for EGFR was performed. Logistic regression analyses were performed including histopathological characteristics with the presence of nodal metastases as outcome. A predictive model was constructed, and absolute risks were calculated.Results. EGFR expression was present in 68% of the vulvar tumors and related to the presence of lymph node metastases (OR 2.12, 95% CI 1.09-4.10). Our predictive model with only clinicopathological factors was able to define a group of patients with a likelihood of absence of lymph node metastases of 13% (95% CI 5-36), which could be decreased to 6% (95% CI 0-29) after inclusion of EGFR expression (P=0.07).Conclusions. EGFR expression is present in the majority of vulvar tumors and is associated with groin node metastases in vulvar cancer. Current classic clinicopathological predictive factors for inguinofemoral lymph node metastases with or without EGFR analysis are not strong enough for identification of "sufficiently low" risk T1/2 vulvar cancer patients. Our predictive model approach however is excellent for evaluation of new cell biological parameters, associated with clinical outcome. (c) 2006 Published by Elsevier Inc.

The majority of patients with vulvar cancer have squamous cell carcinomas (SCC). The cornerstone of the treatment is surgery. Radical vulvectomy with "en bloc" inguinofemoral lymphadenectomy has led to a favorable prognosis but with impressive morbidity. Nowadays, treatment is more individualized with wide local excision with uni- or bilateral inguinofemoral lymphadenectomy via separate incisions as the standard treatment for early stage patients with SCC of the vulva with depth of invasion > 1 mm without suspicious groins. In case of more than one intranodal lymph node metastasis and/or extranodal growth, postoperative radiotherapy on the groins and pelvis is warranted. Until now there is a limited role for primary radiotherapy on the vulva and/or groins in early stage disease.The sentinel lymph node (SLN) procedure with the combined technique (preoperative lymphoscintigraphy with a radioactive tracer and intra-operative blue dye) is a promising staging technique for patients with early stage vulvar cancer. The safety of clinical implementation of the SLN procedure and the role of additional histopathological techniques of the SLNs need to be further investigated before its wide-scale application.Patients with advanced vulvar cancer are difficult to treat. One of the problems in patients with locally advanced vulvar cancer is the high incidence of concomitant bulky lymph nodes in the groin(s). Ultraradical surgery in case of resectable disease will lead to impressive morbidity because of the exenterative-type procedure. (Chemo)radiation with or without surgery should be regarded as the first choice for patients with locally advanced vulvar cancer only when primary surgery will necessitate performance of a stoma. Further studies are needed to determine the optimal combined modality treatment in these patients.Due to the fact that vulvar cancer is a rare disease, further clinical studies will only be possible, when international collaborative groups will join forces in order to perform clinical trials, in which different treatment options such as SLN procedure, primary radiotherapy on the groins and multimodality treatment for advanced disease will be investigated. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

Contains fulltext : 49535.pdf (Publisher’s version ) (Closed access) PURPOSE: To assess the occurrence of high-risk epithelial lesions in women of breast cancer families with and without a BRCA mutation. PATIENTS AND METHODS: Prospective study of women at very high risk of breast cancer undergoing prophylactic mastectomy (68 BRCA1 mutation carriers, 14 BRCA2 mutation carriers and 24 non-BRCA mutation carriers). RESULTS: The prevalence of high-risk lesions is equal in women with a BRCA1 or a BRCA2 mutation, but is higher in non-BRCA mutation carriers: all lesions 43% versus 71% (p=0.02), atypical lobular hyperplasia 26% versus 67% (p=0.001), atypical ductal hyperplasia 17% versus 42% (p=0.01), lobular carcinoma-in situ 15% versus 29% (p=0.10) and ductal carcinoma-in situ 9% versus 17% (p=0.25). The presence of high-risk lesions is related to absence of a BRCA mutation and to age over 40 years. CONCLUSION: Women with an autosomal dominant family history for breast cancer, with and without a BRCA mutation are prone to develop high-risk epithelial lesions, especially over 40 years.

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Background. In early stage vulvar cancer, the sentinel lymph node procedure with a radioactive tracer appears to be a promising new diagnostic tool to predict lymph node status. No detection failures have been published so far in vulvar cancer. We recently experienced failure in the detection of the sentinel lymph node in a patient with a positive lymph node.Case. A 75-year-old patient with a clinical T2N0M0 squamous cell carcinoma replacing the clitoris underwent a sentinel node procedure. A sentinel node was detected only at one groin. An exploration of the other groin showed a positive lymph node totally replaced by tumor.Conclusion. In the case we present, stasis of the lymph flow might be the leading cause of the failure of the sentinel lymph node procedure. (C) 2004 Elsevier Inc. All rights reserved.

Item does not contain fulltext PURPOSE OF REVIEW: The radical surgical approach in the treatment of vulvar cancer patients has led to a favourable prognosis for the majority of patients with early stage vulvar cancer. However, morbidity is impressive, leading to more individualized treatment. The authors have reviewed the most recent literature on the pros and cons of the modifications in treatment, including surgery and primary radiotherapy, for primary squamous cell carcinoma of the vulva and vulvar melanoma. RECENT FINDINGS: The sentinel lymph node procedure is a promising method of staging in patients with early stage squamous cell carcinoma of the vulva and possibly for patients with vulvar melanoma, but its safety still has to be proved. Less radical surgery has led to a higher local and regional recurrence rate. There may be a role for primary radiotherapy of the groin in a selected group of patients. SUMMARY: The authors have concluded that the individualization of treatment for vulvar cancer patients has led to a decrease in morbidity but an increase in recurrences. The increase in recurrences does not appear to compromise prognosis, probably because of the lack of power, based on the low incidence of vulvar cancer. The sentinel lymph node procedure and primary radiotherapy are promising methods to reduce the morbidity of treatment but their safety needs to be studied in randomized trials.

Item does not contain fulltext Vulvar cancer is a rare disease. Squamous-cell carcinomas account for 90% of vulvar cancers. The main mode of spread is lymphogenic to the inguinofemoral lymph nodes. Therefore, elective uni- or bilateral inguinofemoral lymphadenectomy is part of the standard treatment in combination with radical (wide) local excision of the vulvar tumour. Lymph drainage studies in relation to the biological behaviour of vulvar cancer are presented, as well as the anatomy and surgery of the groin. The sentinel lymph node procedure is a relatively new method of staging in vulvar cancer which may lead to the omission of inguinofemoral lymphadenectomy in those patients identified as not having inguinofemoral lymph node metastases. The accuracy of this technique appears to be high, but its safety still has to be proven. Moreover, the role of additional histopathological techniques for the examination of the sentinel lymph nodes needs to be established.

Contains fulltext : 133798.pdf (Publisher’s version ) (Closed access) BRCA1/2 mutation carriers have an elevated risk of developing breast and ovarian cancer at a relatively young age. Risk-reducing salpingo-oophorectomy is an established strategy to tremendously reduce the risk of ovarian cancer. It is recommended to perform this surgery at age 35-40 years (BRCA1) and at age 40-45 years (BRCA2) resulting in an early and abrupt menopause. BRCA1/2 mutation carriers are potentially at higher risk of cardiovascular diseases due to early surgical menopause, and cardiotoxic effects of adjuvant treatment for breast cancer. Furthermore, preliminary results of experimental studies suggest a possible causative function of the BRCA genes in cardiovascular risk. More research on cardiovascular health risks in BRCA1/2 mutation carriers is needed, especially in the field of cardio-oncology, requiring additional attention to potentially cumulative effects on cardiovascular risks in this specific group of women.

The sentinel lymph node procedure is a relatively new, minimally-invasive method for the assessment of nodal status in malignancies such as breast cancer, cutaneous melanoma and vulvar cancer. Although highly accurate, this new method is inevitably associated with a certain false-negative rate, possibly leading to worse survival in a small subset of patients. The clinical implementation of the sentinel lymph node procedure is therefore a matter of ongoing debate, especially among doctors. The aim of this study was to assess opinions on the acceptable false-negative rate of the sentinel lymph node procedure in patients with vulvar cancer, who in the past had undergone standard routine radical vulvectomy and complete inguinofemoral lymphadenectomy (and frequently experienced complications), and in gynecologists treating patients with vulvar cancer.Structured questionnaires were sent to both patients and gynecologists. The patients had been treated for vulvar cancer between 1985 and 7993, and were all in complete remission with a median follow-up of 118 months (range: 76-185). Questions to the patients dealt with experienced side-effects of the standard treatment and opinion on the acceptable false-negative rate of the sentinel lymph node procedure.The response rate among patients was 91% (1061117). Forty per cent of the patients experienced one or more infections in the legs (cellulitis) and 49% of the patients still experience either severe pain and/or severe lymphedema in the legs Sixty-six per cent of the patients preferred complete inguinofemoral lymphadenectomy in preference to a 5 % false-negative rate of the sentinel lymph node procedure of 5%. Their preference was not related to age or the side-effects they had experienced. The response rate among gynecologists was 80% (801100), of whom 60% were willing to accept a 5-20% false-negative rate of the sentinel lymph node procedure.While gynecologists may consider the sentinel lymph node procedure to be a promising diagnostic tool, the majority of vulvar cancer patients, who have undergone complete inguinofemoral lymphadenectomy in the past and have frequently experienced complications would not advise introduction of this technique because they do not want to take any risk of missing a lymph node metastasis.

In the majority of patients with early stage squamous cell cancer (SCC) of the vulva, an inguinofemoral lymphadenectomy is performed (in retrospect) for diagnostic reasons: exclusion of inguinofemoral lymph node metastases. The morbidity of this procedure, however, is significant. The aim of the present study was to evaluate noninvasive detection of inguinofemoral lymph node metastases by positron emission tomography (PET) using L-[1-C-11]-tyrosine (TYR) as tracer. In patients with SCC of the vulva, scheduled for resection of the primary tumor and uni- or bilateral inguinofemoral lymphadenectomy, results of preoperative palpation of the groins and TYR-PET imaging were compared with histopathology. PET imaging was performed using two different methods. In a first group (n = 16), nonattenuation corrected 'whole body' scans were performed, and in a second group (n = 9), attenuation corrected static emission scans. Sensitivity, specificity, accuracy, and positive and negative predictive value for palpation were 62%, 89%, 82%, 67%, and 87% per groin. Sensitivity, specificity, accuracy, and positive and negative predictive value for TYR-PET were calculated for the two methodologies separately and overall. There were no significant differences. Overall values were 53%, 95%, 94%, 33%, and 98% per lymph node and 75%, 62%, 65%, 41% and 88% per groin. Detection of inguinofemoral lymph node metastases by TYR-PET is not superior to palpation. Neither palpation nor TYR-PET is able to adequately predict or exclude presence of inguinofemoral lymph node metastases in patients with SCC of the vulva.

We report a patient with a bullous disorder which revealed both AL amyloidosis and a vulvar squamous cell carcinoma. Bullous amyloidosis is the rarest clinical manifestation of the amyloidoses, and is usually accompanied by systemic amyloid deposition with multiorgan involvement. This case illustrates that a localized disorder can trigger the diagnosis of a systemic disease.

Contains fulltext : 71028.pdf (Publisher’s version ) (Closed access) Over the period 1989-2003, the incidence of cervical adenocarcinoma (n=1615) was stable whereas that of cervical adenocarcinoma in situ (n=1884) significantly decreased (P=0.008), mainly caused by adenocarcinoma in situ lesions with a concurrent squamous dysplasia.

Item does not contain fulltext BACKGROUND: Recent studies suggested an improved overall survival (OS) for BRCA2- versus BRCA1-associated epithelial ovarian cancer (EOC), whereas the impact of chemotherapy is not yet clear. In a nationwide cohort, we examined the results of primary treatment, progression-free survival (PFS), treatment-free interval (TFI), and OS of BRCA1 versus BRCA2 EOC patients. METHODS: Two hundred and forty-five BRCA1- and 99 BRCA2-associated EOC patients were identified through all Dutch university hospitals. Analyses were carried out with the Pearson's Chi-square test, Kaplan-Meier, and Cox regression methods. RESULTS: BRCA1 patients were younger at EOC diagnosis than BRCA2 patients (51 versus 55 years; P < 0.001), without differences regarding histology, tumor grade, and International Federation of Gynecology and Obstetrics (FIGO) stage. Complete response rates after primary treatment, including chemotherapy, did not differ between BRCA1 (86%) and BRCA2 patients (90%). BRCA1 versus BRCA2 patients had a shorter PFS (median 2.2 versus 3.9 years, respectively; P = 0.006), TFI (median 1.7 versus 2.8 years; P = 0.009), and OS (median 6.0 versus 9.7 years; P = 0.04). Differences could not be explained by age at diagnosis, FIGO stage or type of treatment. CONCLUSIONS: PFS and OS were substantially longer in BRCA2- than in BRCA1-associated EOC patients. While response rates after primary treatment were similarly high in both groups, TFI, as surrogate for chemosensitivity, was significantly longer in BRCA2 patients.

Contains fulltext : 110767.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Taking a biopsy is a standard procedure to make the correct diagnosis in patients with suspicious premalignant vulvar lesions. The use of a less invasive diagnostic tool as triage instrument to determine whether biopsy is necessary may improve patient comfort especially in patients with chronic vulvar disorders that may warrant consecutive biopsies. This study was conducted to investigate whether vulvar brush cytology is feasible and may be used to detect (pre)malignant vulvar lesions. METHODS: A pilot study was performed with patients having clinically normal vulvar skin, lichen sclerosus (LS), usual or differentiated vulvar intraepithelial neoplasia or squamous cell carcinoma. A total of 65 smears were taken with the use of a vulvar brush and biopsies were performed for histopathological analysis. RESULTS: Out of 65 smears, 17 (26%) were discarded because of poor cellularity. A total of 28 of 29 (97%) smears with a histological proven (pre)malignancy had a smear classified as 'suspicious' or 'uncertain'. Cytology classified 11 smears as 'non-suspicious', of which 10 (91%) were indeed normal skin or LS. The accuracy, based on the presence of a lesion, for (pre)malignant lesions with the use of the brush showed a sensitivity of 97% and a negative predictive value of 88%. CONCLUSION: Vulvar brush cytology is feasible and may be a first step in the development of a triage instrument to determine whether subsequent biopsy of a clinically (pre)malignant lesion is necessary.

Item does not contain fulltext Renal transplantations (RTs) are performed routinely in many countries. After RT, the administration of lifelong immunosuppressive therapy is required. As a consequence, renal transplant recipients (RTRs) have a high risk to develop virus-associated (pre)malignancies, such as Human papillomavirus (HPV) related anogenital (pre)malignancies. It is known that the majority of the RTRs are infected with HPV and that these women have a 14-fold increased risk of cervical cancer, up to 50-fold of vulvar cancer and up to 100-fold of anal cancer. Often, treatment of these lesions requires concessions and may be suboptimal as radiation therapy and extensive surgery may damage the renal transplant. Therefore, prognosis may be compromised due to inadequately treated malignancies. Especially for these immunocompromised patients prevention is of utmost importance. Yearly cervical cancer screening for RTRs is advised, but appears to be executed poorly. For the future, optimizing screening and prevention of anogenital (pre)malignancies is an important issue for women after RT. This review gives a broad overview of all aspects regarding HPV-related (pre)malignancies of the female anogenital tract in RTRs.