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PURPOSE The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). METHODS GROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS From December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (≤ 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL ( P = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL. CONCLUSION Inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL.

OBJECTIVE: To compare the effect of tibolone to conjugated estrogens with medroxyprogesterone-acetate (CEE + MPA) on breast density, as a predictor for breast cancer risk, in women with a high risk of breast and ovarian cancer. METHODS: Women aged 30-50 (N = 114) who had undergone risk-reducing salpingo-oophorectomy (RRSO) were randomized to tibolone or CEE + MPA. RESULTS: Breast density decreased 46% after RRSO in untreated women, 39% after treatment with tibolone, and 17% after treatment with CEE + MPA; the decrease in breast density after CEE + MPA was significantly different compared with that of untreated women (P = 0.017). CONCLUSIONS: A decline in breast density is seen after premenopausal RRSO despite the use of both CEE + MPA or tibolone, although lower breast density is seen after tibolone use.

Objective. Risk-reducing surgery is advised to BRCA1/2 pathogenic variant (PV) carriers around the age of 40 years to reduce ovarian cancer risk. In the TUBA-study, a multicenter preference study (NCT02321228), BRCA1/2-PV carriers are offered a choice: the standard strategy of risk-reducing salpingo-oophorectomy or the novel strategy of risk-reducing salpingectomy with delayed oophorectomy. We evaluated feasibility and effectiveness of a patient decision aid for this choice. Methods. Premenopausal BRCA1/2-PV carriers were counselled for risk-reducing surgical options in the TUBA study; the first cohort was counselled without and the second cohort with decision aid. Evaluation was performed using digital questionnaires for participating women and their healthcare professionals. Outcome measures included actual choice, feasibility (usage and experiences) and effectiveness (knowledge, cancer worry, decisional conflict, decisional regret and self-estimated influence on decision). Results. 283 women were counselled without and 282 women with decision aid. The novel strategy was chosen less frequently in women without compared with women with decision aid (67% vs 78%, p = 0.004). The decision aid was graded with an 8 out of 10 by both women and professionals, and 78% of the women would rec-ommend this decision aid to others. Users of the decision aid reported increased knowledge about the options and increased insight in personal values. Knowledge on cancer risk, decisional conflict, decisional regret and can-cer worry were similar in both cohorts. Conclusions. The use of the patient decision aid for risk-reducing surgery is feasible, effective and highly ap-preciated among BRCA1/2-PV carriers facing the decision between salpingo-oophorectomy or salpingectomy with delayed oophorectomy. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Objective. To evaluate feasibility of chemoradiation as alternative for extensive surgery in patients with locally advanced vulvar cancer and to report on locoregional control, toxicity and survival. Methods. In a multicenter, prospective phase II trial patients with locally advanced vulvar cancer were treated with locoregional radiotherapy combined with sensitizing chemotherapy (capecitabine). Treatment feasibility, percentage locoregional control, survival and toxicity were evaluated. Results. 52 patients with mainly T2/T3 disease were treated according to the study protocol in 10 centers in the Netherlands from 2007 to 2019. Full dose radiotherapy (tumor dose of 64.8Gy) was delivered in 92% and full dose capecitabine in 69% of patients. Most prevalent acute >_ grade 3 toxicities were regarding skin/ mucosa and pain (54% and 37%). Late >_grade 3 toxicity was reported for skin/mucosa (10%), fibrosis (4%), GI incontinence (4%) and stress fracture or osteoradionecrosis (4%). Twelve weeks after treatment, local clinical complete response (cCR) and regional control (RC) rates were 62% and 75%, respectively. After 2 years, local cCR persisted in 22 patients (42%) and RC was 58%. Thirty patients (58%) had no evidence of disease at end of follow-up (median 35 months). In 9 patients (17%) extensive surgery with stoma formation was needed. Progression free survival was 58%, 51% and 45% and overall survival was 76%, 66%, 52% at 1,2, and 5 years. Conclusions. Definitive capecitabine-based chemoradiation as alternative for extensive surgery is feasible in locally advanced vulvar cancer and results in considerable locoregional control with acceptable survival rates with manageable acute and late toxicity. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Background BRCA1/2 mutation carriers are generally exposed to early menopause due to risk-reducing salpingo-oophorectomy (RRSO) around the age of 40 years. This risk-reducing intervention is based on a 10–40% life-time risk of ovarian cancer in this population. Although effective, premature and acute menopause induces non-cancer related morbidity in both the short and long term. Little is known about the impact of RRSO on the cardiovascular system. Methods This cross-sectional study explored the relationship between time since RRSO and signs of subclinical atherosclerosis, as measured by carotid intima-media thickness (CIMT) and pulse wave velocity (PWV), in 165 BRCA1/2 mutation carriers. All participants, aged 40 to 63 years, underwent RRSO before the age of 45 years, and at least 5 years ago. Cardiovascular risk factors were assessed by questionnaires and a single screening visit. Data were analyzed using linear regression models. Results Mean CIMT was 692.7 μm (SD 87.0), and mean central PWV 6.40 m/s (SD 1.42). After adjustment for age and several relevant cardiovascular risk factors, time since RRSO was not associated with CIMT (β=0.68 μm; 95% CI –4.02, 5.38) and PWV (β=44 mm/s; 95% CI –32, 120). Compared to women of a reference group from the general population, lower systolic blood pressure [mean difference 12 mmHg; 95% confidence interval (CI) 10, 14] was found in BRCA1/2 mutation carriers. Conclusions We found that, in BRCA1/2 mutation carriers, at 5 to 24 years follow-up, time since RRSO is not related to development of subclinical atherosclerosis. However, the follow-up period in these relatively young women might have been too short.

Background In epithelial ovarian cancer (EOC), 15-20% of the tumors do not respond to first-line chemotherapy (paclitaxel with platinum-based therapy), and in recurrences this number increases. Our aim is to determine the feasibility of cell proliferation assays of tumor cells isolated from malignant ascites to predict in vitro chemotherapy sensitivity, and to correlate these results with clinical outcome. Materials and methods Ascites was collected from twenty women with advanced EOC. Cell samples were enriched for tumor cells and EOC origin was confirmed by intracellular staining of CK7, surface staining of CA125 and EpCAM, and HE4 gene expression. In vitro sensitivity to chemotherapy was determined in cell proliferation assays using intracellular ATP content as an indirect measure of cell number. In vitro drug response was quantified by calculation of the drug concentration at which cell growth was inhibited with 50%. Clinical outcome was determined using post-treatment CA125 level. Results Cell samples of twenty patients were collected, of which three samples that failed to proliferate were excluded in the analysis (15%). Three other samples were excluded, because clinical outcome could not be determined correctly. In twelve of the fourteen remaining cases (86%) in vitro drug sensitivity and clinical outcome corresponded, while in two samples (14%) there was no correspondence. Conclusions Our study demonstrates the feasibility of drug sensitivity tests using tumor cells isolated from ascites of advanced EOC patients. Larger observational studies are required to confirm the correlation between the in vitro sensitivity and clinical outcome.

Contains fulltext : 244550.pdf (Publisher’s version ) (Open Access) 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

Background The discovery of the Fallopian tube epithelium as origin of high grade serous ovarian cancer has brought a new option for ovarian cancer prevention. As the Fallopian tubes have no known function after completion of childbearing, they can be removed to reduce the life-time risk of ovarian cancer. Although the lifetime risk in the general population does not justify preventive surgery in itself, salpingectomy can be performed during abdominal surgery for other indications, also known as an opportunistic salpingectomy. The popularity of opportunistic salpingectomy is increasing globally, however substantial variation between gynecologists and hospitals in their advice on the opportunistic salpingectomy occurs due to remaining uncertainty of evidence. As a result, whether or not a woman is able to make her own decision depends on the hospital or gynecologist she visits. We aim to lower this practice variation by providing standardized and unbiased counseling material. Objective(s) To develop and test a patient decision aid for an opportunistic salpingectomy in women undergoing either pelvic gynecological surgery with the intention to retain the ovaries or opting for sterilization. Study Design We followed a systematic development process based on the International Patient Choice Aid Standard (IPDAS). Data were collected between June 2019 and June 2020, using both qualitative and quantitative methods. The development process which took place in collaboration with patients and healthcare professionals, was overseen by a multidisciplinary steering group, and was divided in four phases; 1. Assessment of decisional needs using individual telephone interviews and questionnaires; 2. Development of content and format based on decisional needs, current literature and guidelines; 3. Alpha-testing and first revision round; and 4. Alpha-testing and second revision round. Results An outline of the patient decision aid was developed based on decisional needs, current literature and guidelines. It became clear that the decision aid should consist of two separate paths: one with information specifically for salpingectomy in addition to abdominal surgery and one for salpingectomy as a sterilization method. Both paths contain information on the anatomy and function of ovaries and Fallopian tubes, the risk reduction of ovarian cancer and the potential benefits and risks of opportunistic salpingectomy. The sterilization path also contains information on the various sterilization methods and the risk of unwanted pregnancy. The patient decision aid was developed as an online tool that includes information chapters, a knowledge quiz, consideration statements, and a summary detailing patient’s preference and considerations. Adjustments were made following alpha-testing round one. The improved patient decision aid was subjected to usability tests (alpha-testing round two), in which it scored an ‘excellent’ in patient testing and a ‘good’ in tests with gynecologists. Furthermore, our patient decision aid met the requirements of 45 out of 49 applicable items from the International Patient Decision Aid Standards criteria. Conclusion In collaboration with patients and healthcare professionals, a patient decision aid was developed on opportunistic salpingectomy and salpingectomy as a sterilization method. Both patients and gynecologists thought it a usable aid which supports patients in making an informed decision whether to undergo an opportunistic salpingectomy, and supports the counseling process by gynecologists.

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 &lt, 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.

Item does not contain fulltext IMPORTANCE: Most women with a BRCA1/2 pathogenic variant undergo premature menopause with potential short- and long-term morbidity due to the current method of ovarian carcinoma prevention: risk-reducing salpingo-oophorectomy (RRSO). Because the fallopian tubes play a key role in ovarian cancer pathogenesis, salpingectomy with delayed oophorectomy may be a novel risk-reducing strategy with benefits of delaying menopause. OBJECTIVE: To compare menopause-related quality of life after risk-reducing salpingectomy (RRS) with delayed oophorectomy with RRSO in carriers of the BRCA1/2 pathogenic variant. DESIGN, SETTING, AND PARTICIPANTS: A multicenter nonrandomized controlled preference trial (TUBA study), with patient recruitment between January 16, 2015, and November 7, 2019, and follow-up at 3 and 12 months after surgery was conducted in all Dutch university hospitals and a few large general hospitals. In the Netherlands, RRSO is predominantly performed in these hospitals. Patients at the clinical genetics or gynecology department between the ages of 25 and 40 years (BRCA1) or 25 to 45 years (BRCA2) who were premenopausal, had completed childbearing, and were undergoing no current treatment for cancer were eligible. INTERVENTIONS: Risk-reducing salpingo-oophorectomy at currently recommended age or RRS after completed childbearing with delayed oophorectomy. After RRSO was performed, hormone replacement therapy was recommended for women without contraindications. MAIN OUTCOMES AND MEASURES: Menopause-related quality of life as assessed by the Greene Climacteric Scale, with a higher scale sum (range, 0-63) representing more climacteric symptoms. Secondary outcomes were health-related quality of life, sexual functioning and distress, cancer worry, decisional regret, and surgical outcomes. RESULTS: A total of 577 women (mean [SD] age, 37.2 [3.5] years) were enrolled: 297 (51.5%) were pathogenic BRCA1 variant carriers and 280 (48.5%) were BRCA2 pathogenic variant carriers. At the time of analysis, 394 patients had undergone RRS and 154 had undergone RRSO. Without hormone replacement therapy, the adjusted mean increase from the baseline score on the Greene Climacteric Scale was 6.7 (95% CI, 5.0-8.4; P

Objective. To identify clinicopathological characteristics, treatment patterns, clinical outcomes and prognostic factors in patients with vulvar melanoma (VM). Materials & methods. This retrospective multicentre cohort study included 198 women with VM treated in eight cancer centres in the Netherlands and UK between 1990 and 2017. Clinicopathological features, treatment, recurrence, and survival data were collected. Overall and recurrence-free survival was estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariable Cox regression analysis. Results. The majority of patients (75.8%) had localized disease at diagnosis. VM was significantly associated with high-riskclinicopathological features, including age, tumour thickness, ulceration, positive resection margins and involved lymph nodes. Overall survival was 48% (95% CI 40?56%) and 31% (95% CI 23?39%) after 2 and 5 years respectively and did not improve in patients diagnosed after 2010 compared to patients diagnosed between 1990 and 2009. Recurrence occurred in 66.7% of patients, of which two-third was non-local. In multivariable analysis, age and tumour size were independent prognostic factors for worse survival. Prognostic factors for recurrence were tumour size and tumour type. Only the minority of patients were treated with immuno- or targeted therapy. Conclusion. Our results show that even clinically early-stage VM is an aggressive disease associated with poor clinical outcome due to distant metastases. Further investigation into the genomic landscape and the immune microenvironment in VM may pave the way to novel therapies to improve clinical outcomes in these aggressive tumours. Clinical trials with immunotherapy or targeted therapy in patients with high-risk, advanced or metastatic disease are highly needed.Objective. To identify clinicopathological characteristics, treatment patterns, clinical outcomes and prognostic factors in patients with vulvar melanoma (VM).Materials & methods. This retrospective multicentre cohort study included 198 women with VM treated in eight cancer centres in the Netherlands and UK between 1990 and 2017. Clinicopathological features, treatment, recurrence, and survival data were collected. Overall and recurrence-free survival was estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariable Cox regression analysis.Results. The majority of patients (75.8%) had localized disease at diagnosis. VM was significantly associated with high-riskclinicopathological features, including age, tumour thickness, ulceration, positive resection margins and involved lymph nodes. Overall survival was 48% (95% CI 40-56%) and 31% (95% CI 23-39%) after 2 and 5 years respectively and did not improve in patients diagnosed after 2010 compared to patients diagnosed between 1990 and 2009. Recurrence occurred in 66.7% of patients, of which two-third was non-local. In multivariable analysis, age and tumour size were independent prognostic factors for worse survival. Prognostic factors for recurrence were tumour size and tumour type. Only the minority of patients were treated with immuno-or targeted therapy.Conclusion. Our results show that even clinically early-stage VM is an aggressive disease associated with poor clinical outcome due to distant metastases. Further investigation into the genomic landscape and the immune microenvironment in VM may pave the way to novel therapies to improve clinical outcomes in these aggressive tumours. Clinical trials with immunotherapy or targeted therapy in patients with high-risk, advanced or metastatic disease are highly needed. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Background BRCA1/2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) at 35 to 45 years of age. RRSO substantially decreases ovarian cancer risk, but at the cost of immediate menopause. Knowledge about the potential adverse effects of premenopausal RRSO, such as increased risk of cardiovascular disease, osteoporosis, cognitive dysfunction, and reduced health-related quality of life (HRQoL), is limited. Objective The aim of this study is to assess the long-term health effects of premenopausal RRSO on cardiovascular disease, bone health, cognitive functioning, urological complaints, sexual functioning, and HRQoL in women with high familial risk of breast or ovarian cancer. Methods We will conduct a multicenter cross-sectional study with prospective follow-up, nested in a nationwide cohort of women at high familial risk of breast or ovarian cancer. A total of 500 women who have undergone RRSO before 45 years of age, with a follow-up period of at least 10 years, will be compared with 250 women (frequency matched on current age) who have not undergone RRSO or who have undergone RRSO at over 55 years of age. Participants will complete an online questionnaire on lifestyle, medical history, cardiovascular risk factors, osteoporosis, cognitive function, urological complaints, and HRQoL. A full cardiovascular assessment and assessment of bone mineral density will be performed. Blood samples will be obtained for marker analysis. Cognitive functioning will be assessed objectively with an online neuropsychological test battery. Results This study was approved by the institutional review board in July 2018. In February 2019, we included our first participant. As of November 2020, we had enrolled 364 participants in our study. Conclusions Knowledge from this study will contribute to counseling women with a high familial risk of breast/ovarian cancer about the long-term health effects of premenopausal RRSO. The results can also be used to offer health recommendations after RRSO. Trial Registration ClinicalTrials.gov NCT03835793; https://clinicaltrials.gov/ct2/show/NCT03835793. International Registered Report Identifier (IRRID) DERR1-10.2196/24414

Introduction/Background Invasive Cervical Cancer (ICC) develops from Cervical Intraepithelial Neoplasia (CIN) and persistence of high-risk HPV (HR-HPV) infection represents the main risk factor for evolution of CIN into ICC. Prevention of the disease is based on two screening methods: Papanicolau Smear (Pap-test) and HPV test; the latter with higher sensitivity and lower specificity. HR-HPV positive test detects earlier than Pap-test high-grade CIN (CIN 2–3) at colposcopy-guided biopsy, but the subsequent conization often reveals the absence of an high-grade CIN. The objective of the present study is to assess the incidence of persistency of high-grade CIN at conization after a positive biopsy. Secondly we aimed to investigate the role of HPV genotypes in the evolution of the lesion, in order to better triage women at time of colposcopy. Methodology A prospective study was conducted at Local Health Unit Toscana Centro and Careggi University Hospital (Florence, Italy) between January 2016 and February 2017 involving 308 women undergoing conization for high-grade CIN at cervical biopsy. All recruited patients underwent HPV testing prior conization. Biopsy and cone specimen data were recorded for each patient. Results Only in half of the patients there was a persistency of high-grade CIN. Histology discrepancy between biopsy and cone was observed in 181 out of the 308 recruited patients (58.7%; p Conclusion Approximately a third of patients with high-grade CIN at biopsy detected with Paptest and HPV screening underwent overtreatment with conization. Absent or LR HPV infection at time of conization were identified as predictors of regression. HPV test before conization could triage patients with high-grade CIN at cervical biopsy towards conisation or further follow-up with colposcopy. Disclosures The authors declare that there is no conflict of interest.

We investigated signal transduction pathway (STP) activity in high-grade serous ovarian carcinoma (HGSC) in relation to progression-free survival (PFS) and overall survival (OS). We made use of signal transduction pathway activity analysis (STA analysis), a novel method to quantify functional STP activity. Activity of the following pathways was measured: androgen receptor (AR), estrogen receptor (ER), phosphoinositide 3-kinase (PI3K), Hedgehog (Hh), Notch, nuclear factor-kappa B (NF-&kappa, B), transforming growth factor beta (TGF-&beta, ), and Wnt. We selected HGSC samples from publicly available datasets of ovarian cancer tissue, and used repeated k-means clustering to identify pathway activity clusters. PFS and OS of the clusters were analyzed. We used a subset of publicly available dataset GSE9891 (n = 140), where repeated k-means clustering based on PI3K and NF-&kappa, B pathway activity in HGSC samples resulted in two stable clusters. The cluster with low PI3K and high NF-&kappa, B pathway activity (n = 72) had a more favorable prognosis for both PFS (p = 0.004) and OS (p = 0.001) compared to the high-PI3K and low-NF-&kappa, B pathway activity cluster (n = 68). The low PI3K and high NF-&kappa, B pathway activity of the favorable prognosis cluster may indicate a more active immune response, while the high PI3K and low NF-&kappa, B pathway activity of the unfavorable prognosis cluster may indicate high cell division.

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

Vulvar Paget disease is a rare skin disorder, considered an in situ adenocarcinoma. It is characterized by intraepithelial Paget cells, of which the origin is unclear. About 75% of cases have a cutaneous origin; the other 25% originate from an intestinal or urological malignancy. We report the first case of retrograde pagetoid spread from a rectal adenocarcinoma to the vulva and cervix. A 66-year-old woman presented with postmenopausal bleeding and a history of Crohn disease. Gynecological workup revealed vulvar and endocervical lesions consisting of Paget cells and adenocarcinoma, respectively. A rectal adenocarcinoma with in situ adenocarcinoma was diagnosed. The surgical specimen demonstrated Paget cells in the squamous epithelium of the anus and vulva. Immunohistochemistry demonstrated an intestinal phenotype of these cells. Genetic testing revealed the same TP53 mutation in tumor cells of the rectal adenocarcinoma and vulvar and endocervical lesions, demonstrating that the Paget cells originated from the same intestinal tumor.

Background: Inguinofemoral lymphadenectomy (IFL) is part of the surgical treatment of different malignancies of the genital tract and/or the lower limb including vulvar carcinoma, penile carcinoma and melanoma. IFL is associated with morbidity in up to 85% of the patients. The aims of this MAMBO-IC study (Morbidity And Measurement of the Body) are to study the feasibility of using LigaSure for IFL and to assess the differences in the incidence of short-term complications using LigaSure versus conventional IFL randomized within each individual patient.Methods: In this multicenter randomized controlled trial (RCT), women diagnosed with squamous cell carcinoma of the vulva with an indication for bilateral IFL were included. It was randomly assigned for which groin the LigaSure was used; the other groin was treated with conventional IFL (sharp/diathermia). We estimated the incidence of >= 1 complication(s) per groin using logistic regression and compared this between the two surgical methods, adjusting for possible confounders.Results: We included 40 groins of 20 patients. The estimated incidence of >= 1 complication(s) was 29% after LigaSure versus 70% after conventional IFL (risk difference 41% (95% CI 19-62), p Conclusions: This RCT shows that LigaSure for IFL is feasible and associated with significantly less short-term surgical complications compared to conventional IFL. Further studies with a larger sample size are needed to validate our findings. ISRCTN15057626.

Vulvar squamous cell carcinoma (VSCC) originates from the progression of either a high-grade squamous intraepithelial lesion (HSIL) or differentiated-type vulvar intraepithelial neoplasia (dVIN), often in a background of lichen sclerosus (LS). The mechanisms leading to the progression of these premalignant lesions to VSCC are elusive. This study aims to identify pathogenic mutations implicated in VSCC development. Using next-generation sequencing, 38 HSIL, 19 dVIN, 20 LS, of which 10 were solitary lesions and 10 with adjacent VSCC, and 10 VSCC adjacent to LS, were screened for hotspot mutations in 50 genes covered by the Ion AmpliSeq Cancer Hotspot Panel v2 Kit (Thermo Fisher Scientific). Pathogenic mutations of TP53 were the most common genetic alterations identified in 53% and 24% of dVIN and HSIL cases, respectively, followed by CDKN2A (p16) mutated in 42% and 0% of dVIN and HSIL, respectively. Seven (70%) and three (30%) of 10 cases of VSCC associated with LS carried TP53 and CDKN2A mutations, respectively, whereas neither solitary LS nor LS associated with VSCC cases harbored mutations in these genes. It appears that TP53 mutations are early events during VSCC carcinogenesis, being present in both HSIL and dVIN lesions. Our preliminary data do not support a genetic background for the notion of LS as the VSCC premalignant lesion.

Objective Uterine serous carcinoma (USC) is presumed to arise from endometrial intra-epithelial carcinoma (EIC), whereas tubo-ovarian high-grade serous carcinomas have similar precursor lesions in the Fallopian tube, i.e. serous tubal intra-epithelial carcinoma (STIC). The presence of Fallopian tube abnormalities and their clonal relationship to the concurrent USC was investigated. Methods In this multicenter study, all patients treated for USC between 1992 and 2017 were retrospectively identified. Histopathological diagnosis of USC, EIC and STIC was revised by an expert pathologist. Additionally, all Fallopian tube sections were immunohistochemically stained (p53 and Ki-67). Fallopian tube abnormalities were classified as either p53 signature, serous tubal intra-epithelial lesion (STIL) or STIC. The USCs and Fallopian tube abnormalities were analyzed by targeted next-generation sequencing. Results In 168 included patients, Fallopian tube abnormalities were found in 27.4% (46/168): p53-signatures in 17.9% (30/168), STILs in 3.0% (5/168) and STICs in 6.5% (11/168). In subgroup analysis, STICs were found in 9.5% (11/115) of patients with at least one section of the fimbriated end embedded. Next-generation sequencing showed identical TP53-mutations in the STIC and corresponding USC. Conclusions In conclusion, the presence of Fallopian tube abnormalities was shown in a high percentage of patients with USC, representing either true precursor lesions or metastasized disease.

Synchronous primary endometrial and ovarian cancers (SEOs) represent 10% of all endometrial and ovarian cancers and are assumed to develop as independent entities. We investigated the clonal relationship between endometrial and ovarian carcinomas in a large cohort classified as SEOs or metastatic disease (MD). The molecular profiles were compared to The Cancer Genome Atlas (TCGA) data to explore primary origin. Subsequently, the molecular profiles were correlated with clinical outcome. To this extent, a retrospective multicenter study was performed comparing patients with SEOs (n = 50), endometrial cancer with synchronous ovarian metastasis (n = 19) and ovarian cancer with synchronous endometrial metastasis (n = 20). Targeted next‐generation sequencing was used, and a clonality index was calculated. Subsequently, cases were classified as POLE mutated, mismatch repair deficient (MMR‐D), TP53‐wild‐type or TP53‐mutated. In 92% of SEOs (46/50), the endometrial and concurrent ovarian carcinoma shared at least one somatic mutation, with a clonality index above 0.95, supporting a clonal origin. The SEO molecular profiles showed striking similarities with the TCGA endometrial carcinoma set. SEOs behaved distinctly different from metastatic disease, with a superior outcome compared to endometrial MD cases (p, What's new? When primary endometrial and ovarian tumors are found simultaneously in the same patient, it has been assumed that they are separate cancers that developed independently. However, in this study, the authors found that these tumors share a clonal origin 92% of the time. They also found that these “synchronous” cancers tend to have a favorable prognosis, with far better outcomes than metastatic disease. Some subgroups, including TP53 mutations and extra‐utero‐ovarian disease, were independent predictors for poor clinical outcome, which may impact adjuvant treatment planning.

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. High-resolution 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.

Introduction: The majority of advanced stage high-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, recurs within the first 24 months despite complete remission after initial treatment. Yet there are remarkable differences in disease-free (DFS) and overall survival (OS). We hypothesize that differences in signal transduction pathway (STP) activity may relate to survival and may also improve targeted therapy selection. We investigate the STP activity in relation to survival in patients diagnosed with advanced stage HGSC, as well as identify STPs that may be targeted in alternative treatment strategies. Methods: We included 85 HGSC patients (DFS 24 months, n=33) who achieved complete remission after treatment with debulking surgery and chemotherapy. Total mRNA was extracted, and RT-qPCR was performed to determine expression levels of pathway-specific target genes in primary HGSC samples taken prior to start of chemotherapy. OncoSignal pathway assays were used to quantitatively measure functional STP activity of the androgen and estrogen receptor (ER), PI3K, Hedgehog, TGF-β and Wnt pathways. Survival analysis in relation to STP activity was performed by means of Cox regression analysis and differences between groups were analyzed with Mann-Whitney U tests. Results: Differences in PI3K, Hedgehog and TGF-β pathway activity were observed across the HGSC cohort, suggesting unique tumor activation patterns. Median STP activity was not discernably different between the short and long DFS groups. Significantly higher ER pathway activity was found in premenopausal women (n=16) compared to postmenopausal women (n=67) (p=0.002). Cox regression analysis in postmenopausal women (n=67) showed that ER pathway activity was positively associated with DFS (HR=0.943, p=0.033) and OS (HR=0.930, p=0.041) in univariate analysis. None of the pathways were significantly related to DFS or OS in premenopausal women (n=16). Conclusion: We observed a positive association between ER pathway activity and survival in postmenopausal women but not in premenopausal women. Also, differences in activation levels of the other STPs were observed in individual patients. STP analysis may be used to aid targeted therapy selection, such as anti-hormonal therapy, in HGSC patients. Citation Format: Phyllis van der Ploeg, Laura van Lieshout, Yvonne Wesseling-Rozendaal, Anja van de Stolpe, Diederick Keizer, Steven Bosch, Marjolein Lentjes-Beer, Caroline Vos, Joanne de Hullu, Ruud Bekkers, Jurgen Piek. Characterization of high-grade serous ovarian carcinoma by measuring functional signal transduction pathway activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 741.

e17541 Background: High-grade serous carcinoma (HGSC) is the most common subtype of epithelial ovarian and tubal cancer. It has a high mortality rate, even after successful first-line treatment with debulking surgery and chemotherapy. Although therapeutic options for targeted therapy are rapidly expanding, identification of patients who respond to these therapies remains a challenge. In recognition of the importance of the functional phenotype of cancer cells, Verhaegh et al. (Cancer Res 2014) developed assays to measure functional activity of signal transduction pathways (STPs) based on mRNA expression levels of pathway-specific target genes. In this study, we aimed to identify HGSCs with STP activity with potential clinical target by comparing their activity assessment with STP activity in normal Fallopian tube epithelium (FTE), the tissue of origin of most HGSCs. Methods: We included 67 primary tumor samples taken prior to start of chemotherapy of postmenopausal patients diagnosed with advanced stage HGSC and 8 morphologically normal FTE samples of healthy postmenopausal women. Using OncoSignal pathway assays, we assessed functional pathway activity of the androgen receptor (AR), estrogen receptor (ER), PI3K, Hedgehog, TGF-𝛽 and Wnt pathways. Differences in STP activity between groups were compared with Mann-Whitney U tests. Cut-off value for aberrant STP activity was defined as two standard deviations above the mean value of STP activity measured in FTE samples. Results: In the HGSC group we observed lower median ER (p < 0.001) and Wnt (p = 0.046) pathway activity and higher median PI3K (p = 0.025) and TGF-𝛽 pathway (p = 0.030) activity as compared to the normal FTE group. In individual HGSC samples, aberrant activity was identified for the AR (n = 14), PI3K (n = 16), Hedgehog (n = 4), TGF-𝛽 (n = 36) and Wnt (n = 10) pathways. Frequently observed combinations of aberrant STP activity were AR/TGF-𝛽 (n = 8), TGF-𝛽/Wnt (n = 6) and PI3K/Hedgehog (n = 3). In total, we identified at least one STP with potential clinical target in 52 of the 67 HGSC samples. Conclusions: Our analysis enabled the identification of STP activity with potential clinical target in 78% of the analyzed HGSC samples. Differentiation between normal and aberrant STP activity could have clinical utility in the selection of HGSC patients for targeted therapy.

Contains fulltext : 174767.pdf (Publisher’s version ) (Open Access) 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.

Contains fulltext : 169711.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Female renal transplant recipients (RTRs) have increased risk for developing human papillomavirus (HPV)-related (pre)malignancies of the lower genital tract. Annual cervical screening is advised for RTRs, but the participation rate is low. The aim of this study is to investigate whether HPV self-sampling is suitable for gynecological screening of RTRs to increase participation rate. METHODS: A large cohort of 253 RTRs was investigated for the prevalence of HPV. All participants received a device for a cervicovaginal self-sample. Questionnaires were sent to assess the experience with this device. High-risk (hrHPV) presence was determined with the SPF10-LiPA25 system and GP5+/6+ PCR. HrHPV-positive patients underwent gynecological examination. RESULTS: More than 90% of the patients rated their experience with the self-sample device as good to excellent, and 77% preferred self-sampling over a physician taken sample. Approximately thirty-five of 217 women tested hrHPV positive with SPF10- LiPA25, and 22 tested positive with the GP5+/6+ PCR. Eleven hrHPV-positive patients had clinically relevant gynecological abnormalities, and they all tested positive with GP5+/6+ PCR. CONCLUSIONS: Self-sampling is clinically applicable in a gynecological screening and is preferred by female RTRs. Therefore, self-sampling could be implemented with the aim to increase the participation rate of female RTRs in yearly gynecological screening.

The presence of a germline BRCA1/2 mutation improves options for tailored risk-reducing strategies and treatment in both breast and ovarian cancer patients and their relatives. Currently, referral for germline BRCA1/2 mutation testing of women with epithelial ovarian cancer (EOC) varies widely, based on different criteria, such as age of onset, family history of breast and/or ovarian cancer and histological type of EOC. The overall probability of a germline BRCA1/2 mutation in women with EOC is above 10%, and a substantial part of the germline BRCA1/2 mutation carriers is missed when applying these criteria for referral. Therefore, we strongly recommend referral of all women with EOC for genetic counselling and DNA analysis. (C) 2016 Elsevier Ltd. All rights reserved.

Vulvar cancer accounts for only 5% of all gynecologic cancers with an incidence rate of 2.4 per 100,000 women. The most common histological type of vulvar cancer is vulvar squamous cell carcinoma (VSCC). There are two different types of VSCC with their own associated premalignant lesions. The most common type occurs in elderly women and leads to mostly differentiated keratinizing VSCC in a background of lichen sclerosus and often differentiated vulvar intraepithelial neoplasia. The second type of VSCC consists of mainly nonkeratinizing carcinomas, primarily affecting younger women, and is associated with high-grade squamous intraepithelial lesions. The diagnosis VSCC should be confirmed histologically, preferably by a punch biopsy. The method of treatment for VSCC depends on the extent of the disease. In general, surgery is the first choice of treatment in patients with primary VSCC. The inguinofemoral lymph node status at initial diagnosis reflected in stage is of critical prognostic importance for patients with VSCC. The treatment of VSCC consists of radical local excision of the tumor combined with the sentinel node procedure in patients with early-stage unifocal tumors of less than 4 cm and without clinically suspicious groin lymph nodes. In case of a metastatic sentinel node, a larger or multifocal tumor, or clinically suspicious lymph nodes, an inguinofemoral lymphadenectomy is indicated. There is a limited role for primary radio- and/or chemotherapy. Overall survival for early-stage VSCC patients is good with 75% at 5 years.

Aims The depth of invasion is an important prognostic factor for patients with vulvar squamous cell carcinoma (SCC). The threshold of 1 mm distinguishes between FIGO stages IA and >= IB disease and guides the need for groin surgery. Therefore, high interobserver agreement is crucial. The conventional and the alternative method are described to measure the depth of invasion. The aims of this study were to assess interobserver agreement for classifying the depth of invasion using both methods and to identify pitfalls. Methods and results Fifty slides of vulvar SCC with a depth of invasion approximately 1 mm were selected, digitally scanned and independently assessed by 10 pathologists working in a referral or oncology centre and four pathologists in training. The depth of invasion was measured using both the conventional and alternative method in each slide and categorised into 1 mm. The percentage of agreement and Light's kappa for multi-rater agreement were calculated, and 95% confidence intervals were calculated by bootstrapping (1000 runs). The agreement using the conventional method was moderate (kappa = 0.57, 95% confidence interval = 0.45-0.68). The percentage of agreement among the participating pathologists using the conventional method was 85.0% versus 89.4% using the alternative method. Six pitfalls were identified: disagreement concerning which invasive nest is deepest, recognition of invasive growth and where it starts, curved surface, carcinoma situated on the edge of the tissue block, ulceration and different measurement methods. Conclusions Pathologists reached only moderate agreement in determining the depth of invasion in vulvar SCC, without a notable difference between the two measurement methods.

Contains fulltext : 153955.pdf (Publisher’s version ) (Closed access) Depth of invasion is an important prognostic factor for patients with vulvar squamous cell carcinoma. The aim of this study was to identify the most optimal method of measuring the depth of invasion in relation to the individual outcome in patients with vulvar squamous cell carcinoma. Data of 175 consecutive patients with a primary vulvar squamous cell carcinoma with known lymph node status, treated in the Radboud University Medical Center, the Netherlands (2000-2010), were stored in a database. At pathology review of 148 (85%) cases, depth of invasion was measured using the conventional and alternative methods. Clinical and pathological characteristics of patients with a change in FIGO stage were compared with those without a change in stage. In 148 vulvar squamous cell carcinoma patients, the median depth of invasion was shown to be decreased from 5.5 mm (range 1.1-20) using the conventional method to 3.6 mm (range 0.2-20) using the alternative method (P

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.

A considerable number of mucinous ovarian tumors are metastatic from other primary tumors, mainly from the gastrointestinal tract, and primary malignant mucinous ovarian tumors are considered rare. Mucinous ovarian tumors occurring within the clinical syndrome of pseudomyxoma peritonei are assumed to almost always originate from the appendix. We describe a patient with a low-grade mucinous tumor involving the ovary in coexistence with pseudomyxoma peritonei, who underwent appendectomy 25 yr earlier. The tumor originated from a rare cystic gastrointestinal duplication found in the mesenteric fat showing adenomatous changes. This illustrates that even in absence of the appendix, mucinous ovarian tumors occurring with pseudomyoma peritonei rarely arise from the ovary.

Contains fulltext : 153902.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To identify influencing factors of BRCA1/2 mutation carriers and their professionals for risk-reducing salpingectomy (RRS) with delayed oophorectomy (RRO) as a substitute for risk-reducing salpingo-oophorectomy (RRSO) and for study participation on this concept. METHODS: A qualitative study was performed by four focus group interviews with 39 BRCA1/2 mutation carriers and semi-structured in-depth interviews with 23 professionals in the field of hereditary cancer. We used a theoretical framework of determinants of innovation within healthcare organizations to classify influencing factors (barriers and facilitators). RESULTS: Among BRCA1/2 mutation carriers, main barriers for RRS with delayed RRO were seriousness of ovarian cancer, family history, and previous breast cancer. Among professionals, delay of risk-reducing effect of oophorectomy on breast cancer risk and a second operation were recognized as main barriers. Both BRCA1/2 mutation carriers and professionals found uncertainty about the effect of RRS with delayed RRO and ease of the decision to undergo RRSO important barriers. The main facilitator mentioned by both was longer maintenance of ovarian function thereby delaying negative effects of early surgical menopause. For study participation, BRCA1/2 mutation carriers mentioned a randomized study design as the main barrier, whereas professionals identified two facilitators, namely willingness of BRCA1/2 mutation carriers for study participation and uniform counseling. Furthermore, most BRCA1/2 mutation carriers and professionals were willing to consider participation in a future non-randomized study. CONCLUSIONS: We identified several barriers and facilitators for RRS with delayed RRO, and for study participation which can be addressed to optimize the design and implementation of a non-randomized study.

Item does not contain fulltext BACKGROUND: In patients treated for early-stage squamous cell vulvar carcinoma local recurrence is reported in up to 40% after ten years. Knowledge on prognostic factors related to local recurrences should be helpful to select high risk patients and/or to develop strategies to prevent local recurrences. OBJECTIVE: This systematic review aims to evaluate the current knowledge on the incidence of local recurrences in vulvar carcinoma related to clinicopathologic and cell biologic variables. DATA SOURCES: Relevant studies were identified by an extensive online electronic search in July 2017. STUDY ELIGIBILITY CRITERIA: Studies reporting prognostic factors specific for local recurrences of vulvar carcinoma were included. STUDY APPRAISAL AND SYNTHESIS METHODS: Two review authors independently performed data selection, extraction and assessment of study quality. The risk difference was calculated for each prognostic factor when described in two or more studies. RESULTS: Twenty-two studies were included; most of all were retrospective and mainly reported pathologic prognostic factors. Our review indicates an estimated annual local recurrence rate of 4% without plateauing. The prognostic relevance for local recurrence of vulvar carcinoma of all analyzed variables remains equivocal, including pathologic tumor free margin distance

With the recent introduction of Poly(ADP‐ribose) polymerase inhibitors, a promising novel therapy has become available for ovarian carcinoma (OC) patients with inactivating BRCA1 or BRCA2 mutations in their tumor. To select patients who may benefit from these treatments, assessment of the mutation status of BRCA1 and BRCA2 in the tumor is required. For reliable evaluation of germline and somatic mutations in these genes in DNA derived from formalin‐fixed, paraffin‐embedded (FFPE) tissue, we have developed a single‐molecule molecular inversion probe (smMIP)‐based targeted next‐generation sequencing (NGS) approach. Our smMIP‐based NGS approach provides analysis of both strands of the open reading frame of BRCA1 and BRCA2, enabling the discrimination between real variants and formalin‐induced artefacts. The single molecule tag enables compilation of unique reads leading to a high analytical sensitivity and enabling assessment of the reliability of mutation‐negative results. Multiplex ligation‐dependent probe amplification (MLPA) and Methylation‐specific multiplex ligation‐dependent probe amplification (MS‐MLPA) were used to detect exon deletions of BRCA1 and methylation of the BRCA1 promoter, respectively. Here, we show that this combined approach allows the rapid and reliable detection of both germline and somatic aberrations affecting BRCA1 and BRCA2 in DNA derived from FFPE OCs, enabling improved hereditary cancer risk assessment and clinical treatment of ovarian cancer patients.

Item does not contain fulltext Vulvar squamous cell carcinoma, its precursor lesions (usual and differentiated vulvar intraepithelial neoplasia) and lichen sclerosus are rare diseases that may have a large impact on the lives of affected women and their partners. Proper identification is vital, but the lesions are sometimes difficult to diagnose because of their rarity and variety of symptoms. High quality of care and proper treatment is important in order to minimize the morbidity and mortality caused by these lesions. This review gives an outline of the latest insights regarding the current evidence in this area and unresolved issues. Additionally, it highlights the improvements that should be made in order to optimize prevention and identification of (pre-)malignant vulvar lesions and to increase the quality of care for these patients.

Contains fulltext : 170501.pdf (Publisher’s version ) (Closed access) AIM: There is limited knowledge in the field of glandular vulvar malignancies. The aim of this study is to describe the incidence and survival of women with glandular vulvar malignancies. METHODS: We searched PALGA, a nation-wide database registering all histo- and cytopathology in the Netherlands, for all cases of glandular vulvar malignancies between 2000 and 2015. Additional data were retrieved via the Netherlands Cancer Registry. Incidence rates were calculated per 1,000,000 women per year. Five-year net survival rates were calculated. RESULTS: We identified 197 patients with a glandular vulvar malignancy. Of these patients 55% had a primary malignancy while 45% had secondary malignancies: expansion of another tumour in 17% and metastases or recurrences of another malignancy in 28%. There is a great variety of different diagnoses of primary vulvar malignancies: 11 different types were identified. We found an overall incidence rate of glandular vulvar malignancies of 0.9-2.5 per 1,000,000 women per year. Five-year net survival for patients with a primary malignancy was 68.5%. Most of the secondary vulvar malignancies originated from (ano-)rectal malignancies. CONCLUSION: Glandular vulvar malignancies are extremely rare and primary tumours are slightly more common. Overall survival of patients with primary glandular vulvar malignancies is comparable to patients with a vulvar squamous cell carcinoma, with five-year survival around 70%. The great variety in diagnoses combined with the low incidence should lead to routine pathologic revision and treatment in specialised gynaecologic oncology centres.

Contains fulltext : 125202.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Epithelial ovarian cancer in women 40 years or younger is rare; diagnosis at this age justifies referral for genetic testing. We evaluated clinical data, family history, and risk of identifying BRCA1/2 mutations in women with early-onset epithelial ovarian cancer. MATERIALS/METHODS: Women 40 years or younger with epithelial ovarian cancer tested for BRCA1/2 mutation at our department of human genetics between 1996 and 2012 were included. The rate of BRCA1/2 mutation was obtained; carriers were compared to noncarriers regarding clinical data. RESULTS: Ten (19%) of 52 women had a BRCA1/2 mutation. This mutation was detected in 67% of women with and in 9% of the women without first-degree relatives with breast and/or ovarian cancer (P < 0.001; Fisher exact test). The median age at diagnosis was lower in the noncarriers compared to the carriers (30 vs 38 years; P = 0.014). Among the BRCA1/2 mutation carriers, 60% had serous tumors, 80% had moderately to poorly differentiated tumors, and 70% had International Federation of Gynecology and Obstetrics stage III/IV compared to 55%, 43%, and 45%, respectively, in the noncarriers. CONCLUSIONS: The risk of finding a BRCA1/2 mutation in women 40 years or younger is comparable to women of all ages with epithelial ovarian cancer. Prior probability of finding a BRCA1/2 mutation in these young women is largely determined by their family history, which can help caregivers in informing ahead of genetic counseling and testing.

Contains fulltext : 171109.pdf (Publisher’s version ) (Open Access) 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.

Contains fulltext : 110221.pdf (Publisher’s version ) (Closed access) Patients with double primary cancer (DPC) of the ovary and endometrium are considered to have a better prognosis than patients with only epithelial ovarian cancer (EOC). The aim of this study was to clarify the difference in prognosis by comparing clinicopathologic characteristics and survival. From the population-based database of the nationwide Netherlands Cancer Registry, women diagnosed between 1996 and 2006 with EOC were identified. Within this database of all EOC patients in 11 hospitals, the DPC patients were identified. Differences in characteristics between EOC-only and DPC patients were tested using Pearson chi tests and t-tests. Differences in overall survival were analyzed by Kaplan-Meier survival analyses and log-rank tests. Multivariable Cox regression analyses were performed to study the factors that influence survival. Among 1105 EOC patients, 29 (2.6%) DPC patients were identified. DPC patients were more often premenopausal (P

Contains fulltext : 110066.pdf (Publisher’s version ) (Open Access) OBJECTIVE: A precursor lesion for ovarian carcinoma, tubal intraepithelial carcinoma (TIC), has been identified in BRCA-mutation carriers undergoing prophylactic bilateral salpingo-oophorectomy (pBSO). Other lesions were also identified in fallopian tubes, but different terminology, interpretation, and lack of knowledge of normal epithelium, have hampered to unravel their possible role in carcinogenesis. The aim of this study is to classify tubal epithelial lesions in BRCA-mutation carriers and controls to enable comparison of prevalence, area of localization, and possible malignant potential. METHODS: Two hundred twenty-six BRCA1/2-mutation carriers were included; ovaries and fallopian tubes, embedded completely, were reviewed. Controls included 105 women who underwent BSO for non-malignant reasons. Tubal epithelial lesions included the following categories: hyperplasia, minor epithelial atypia, TIC, and invasive carcinoma. RESULTS: Tubal neoplasia was identified in 7.1% (invasive carcinoma, 0.9%; TIC, 6.2%) of BRCA-mutation carriers compared to none in controls (p=0.004, Fisher's exact test). Hyperplasia and minor epithelial atypia were identified in 41.6% BRCA-mutation carriers and compared to 58.1% in controls (p=0.005, Pearson's chi square). Invasive carcinoma and TIC showed preference for the fimbrial ends (p=0.027, Pearson's chi square), while hyperplasia and minor epithelial atypia displayed more variation in localization. CONCLUSIONS: Invasive tubal carcinoma and TIC were limited to BRCA-mutation carriers, whereas hyperplasia and minor epithelial atypia were commonly found in both BRCA-mutation carriers and controls. It is suggested that hyperplasia and minor atypia represent variations of normal tubal epithelium instead of premalignant lesions. Furthermore, total salpingectomy is strongly recommended as most but not all TIC occurred in the fimbriae. 01 oktober 2012

Item does not contain fulltext OBJECTIVE: Serum cancer antigen (CA) 125 is the only biomarker used frequently in women with or at risk for ovarian cancer. However, the same reference level is used before and after (prophylactic) bilateral salpingo-oophorectomy (BSO). We evaluated the effect of BSO on CA125 level in BRCA mutation carriers and tested which factors interact with the change in CA125 level. METHODS: All women who participated in the Nijmegen gynecological screening program and underwent prophylactic BSO were included. Information was obtained on age, smoking, menopausal state, previous hysterectomy and breast cancer, histopathological examination of the adnexa, hormone therapy use, and CA125 level before and after surgical operation. Ovarian volume was calculated. The logarithmic-transformed CA125 levels were used in a linear mixed model to study the relative change in CA125 level and possible interaction. RESULTS: In 60 women, a relative decrease of 18% in CA125 level after BSO was found (P < 0.01). The median serum CA125 level was 10.15 U/mL before and 8.36 U/mL after BSO. Menopausal state interacted with CA125 before and after the surgical operation (P < 0.01). In addition, ovarian volume did not explain the difference in CA125 level (P = 0.94). CONCLUSIONS: BRCA mutation carriers show a relative decrease in CA125 level after BSO. Menopausal state interacts with CA125. Ovarian volume was excluded as a confounder. Possibly, the hormonal effect of ovaries plays a role in the CA125 level. Our study suggests that not the reference level of 35 U/mL but a lower level, as already suggested for postmenopausal women, should be applied to women after a salpingo-oophorectomy.

Background Ovarian cancer has the highest mortality rate of all gynaecological malignancies with an overall five-year survival rate of 30% to 40%. In the past two decades it has become apparent and more commonly accepted that a majority of ovarian cancers originate in the fallopian tube epithelium and not from the ovary itself. This paradigm shift introduced new possibilities for ovarian cancer prevention. Salpingectomy during a hysterectomy for benign gynaecological indications (also known as opportunistic salpingectomy) might reduce the overall incidence of ovarian cancer. Aside from efficacy, safety is of utmost importance, especially due to the preventive nature of opportunistic salpingectomy. Most important are safety in the form of surgical adverse events and postoperative hormonal status. Therefore, we compared the benefits and risks of hysterectomy with opportunistic salpingectomy to hysterectomy without opportunistic salpingectomy. Objectives To assess the effect and safety of hysterectomy with opportunistic salpingectomy versus hysterectomy without salpingectomy for ovarian cancer prevention in women undergoing hysterectomy for benign gynaecological indications; outcomes of interest include the incidence of epithelial ovarian cancer, surgery-related adverse events and postoperative ovarian reserve. Search methods The Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two clinical trial registers were searched in January 2019 together with reference checking and contact with study authors. Selection criteria We intended to include both randomised controlled trials (RCTs) and non-RCTs that compared ovarian cancer incidence after hysterectomy with opportunistic salpingectomy to hysterectomy without opportunistic salpingectomy in women undergoing hysterectomy for benign gynaecological indications. For assessment of surgical and hormonal safety, we included RCTs that compared hysterectomy with opportunistic salpingectomy to hysterectomy without opportunistic salpingectomy in women undergoing hysterectomy for benign gynaecological indications. Data collection and analysis We used standard methodological procedures recommended by Cochrane. The primary review outcomes were ovarian cancer incidence, intraoperative and short-term postoperative complication rate and postoperative hormonal status. Secondary outcomes were total surgical time, estimated blood loss, conversion rate to open surgery (applicable only to laparoscopic and vaginal approaches), duration of hospital admission, menopause-related symptoms and quality of life. Main results We included seven RCTs (350 women analysed). The evidence was of very low to low quality: the main limitations being a low number of included women and surgery-related adverse events, substantial loss to follow-up and a large variety in outcome measures and timing of measurements.No studies reported ovarian cancer incidence after hysterectomy with opportunistic salpingectomy compared to hysterectomy without opportunistic salpingectomy in women undergoing hysterectomy for benign gynaecological indications. For surgery-related adverse events, there were insufficient data to assess whether there was any difference in both intraoperative (odds ratio (OR) 0.66, 95% confidence interval (CI) 0.11 to 3.94; 5 studies, 286 participants; very low-quality evidence) and short-term postoperative (OR 0.13, 95% CI 0.01 to 2.14; 3 studies, 152 participants; very low-quality evidence) complication rates between hysterectomy with opportunistic salpingectomy and hysterectomy without opportunistic salpingectomy because the number of surgery-related adverse events was very low. For postoperative hormonal status, the results were compatible with no difference, or with a reduction in anti-Mullerian hormone (AMH) that would not be clinically relevant (mean difference (MD) -0.94, 95% CI -1.89 to 0.01; I2 = 0%; 5 studies, 283 participants; low-quality evidence). A reduction in AMH would be unfavourable, but due to wide CIs, the postoperative change in AMH can still vary from a substantial decrease to even a slight increase. Authors' conclusions There were no eligible studies reporting on one of our primary outcomes - the incidence of ovarian cancer specifically after hysterectomy with or without opportunistic salpingectomy. However, outside the scope of this review there is a growing body of evidence for the effectiveness of opportunistic salpingectomy itself during other interventions or as a sterilisation technique, strongly suggesting a protective effect. In our meta-analyses, we found insufficient data to assess whether there was any difference in surgical adverse events, with a very low number of events in women undergoing hysterectomy with and without opportunistic salpingectomy. For postoperative hormonal status we found no evidence of a difference between the groups. The maximum difference in time to menopause, calculated from the lower limit of the 95% CI and the natural average AMH decline, would be approximately 20 months, which we consider to be not clinically relevant. However, the results should be interpreted with caution and even more so in very young women for whom a difference in postoperative hormonal status is potentially more clinically relevant. Therefore, there is a need for research on the long-term effects of opportunistic salpingectomy during hysterectomy, particularly in younger women, as results are currently limited to six months postoperatively. This limit is especially important as AMH, the most frequently used marker for ovarian reserve, recovers over the course of several months following an initial sharp decline after surgery. In light of the available evidence, addition of opportunistic salpingectomy should be discussed with each woman undergoing a hysterectomy for benign indication, with provision of a clear overview of benefits and risks.

Contains fulltext : 95926.pdf (Publisher’s version ) (Open Access) 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.

Item does not contain fulltext Lichen sclerosus is considered to be the precursor lesion of vulvar squamous cell carcinoma, of which only 2-5% progress to squamous cell carcinoma. Differentiated vulvar intraepithelial neoplasia (VIN) has been proposed to be the direct precursor lesion, but this is a recently recognized, and a difficult to diagnose, entity, which may easily be mistaken for a benign dermatosis. The aim of this study was to test the hypothesis that of all lesions that have been diagnosed as lichen sclerosus in the past, a part might currently be diagnosed as differentiated VIN, and to identify histopathological differences between lichen sclerosus lesions with and without progression to vulvar squamous cell carcinoma. All lichen sclerosus slides were revised by two expert gynecopathologists and histopathological characteristics were documented. After revision of lichen sclerosus biopsies without progression (n = 61), 58 were reclassified as lichen sclerosus. Revision of lichen sclerosus biopsies with progression yielded concordant diagnoses in 18 of 60 cases (30%). Of 60 lesions, 25 (42%) were reclassified as differentiated VIN. The median time from differentiated VIN to vulvar squamous cell carcinoma was shorter (28 months) than that from lichen sclerosus to vulvar squamous cell carcinoma (84 months) (P < 0.001). Lichen sclerosus that progressed to squamous cell carcinoma, but did not meet the criteria for differentiated VIN, more often showed parakeratosis (P = 0.004), dyskeratosis (P < 0.001), hyperplasia (P = 0.048) and basal cellular atypia (P = 0.009) compared with lichen sclerosus without progression. In conclusion, differentiated VIN diagnosis has been frequently missed and is associated with rapid progression to squamous cell carcinoma. Patients with lichen sclerosus with dyskeratosis and parakeratosis, hyperplasia and/or basal cellular atypia should be kept under close surveillance as these lesions also tend to progress to squamous cell carcinoma.

Item does not contain fulltext Uterine papillary serous carcinoma (UPSC) is an aggressive variant of endometrial cancer. Owing to its rarity, most clinicians are unfamiliar with the clinical aspects and management of UPSC. Furthermore, little prospective evidence exists regarding how best to treat this subset of patients. In anticipation of prospective clinical trials, this article summarizes the latest results of various clinical management options in the different substages of UPSC, with a special focus on the effects of cytoreductive surgery, comprehensive surgical staging and different adjuvant treatment options in relation to recurrence rate and survival outcome.

Contains fulltext : 88355.pdf (Publisher’s version ) (Open Access) The molecular pathogenesis of human papilloma virus-unrelated vulvar squamous cell carcinoma is not well known. Whether malignant progression of lichen sclerosus and differentiated vulvar intraepithelial neoplasia to vulvar squamous cell carcinoma could be accompanied by altered DNA content has not been studied extensively. DNA content in isolated nuclei of microdissected normal vulvar epithelium (n = 2), lichen sclerosus (n = 9), differentiated vulvar intraepithelial neoplasia (n = 13), and squamous cell carcinoma (n = 17) from 22 patients was measured via DNA image cytometry. For additional analysis, 6 differentiated vulvar intraepithelial neoplasia lesions were selected, bringing the number of patients to 28. p53 expression was determined by immunohistochemistry on consecutive tissue sections. Thirty-eight percent (5/13) of differentiated vulvar intraepithelial neoplasia lesions and 65% (11/17) of squamous cell carcinomas were DNA aneuploid or tetraploid. In lesions that contained differentiated vulvar intraepithelial neoplasia and adjacent squamous cell carcinoma, the ploidy status of differentiated vulvar intraepithelial neoplasia did not exceed that of squamous cell carcinoma. We observed a strong correlation between high p53 expression and DNA aneuploidy. This relation was also present at the level of a single nucleus, measured by sequential image cytometry of p53 immunohistochemistry followed by DNA image cytometry on formalin-fixed tissue sections. Similarly, we found p53-positive nonproliferating cells with increased DNA content in the superficial compartment of 6 additional solitary differentiated vulvar intraepithelial neoplasia lesions that were not associated with squamous cell carcinoma, indicating ascending aneuploid cells from the basal compartment. DNA ploidy measurements suggest that differentiated vulvar intraepithelial neoplasia has a higher malignant potential than lichen sclerosus and thus is a more likely precursor of squamous cell carcinoma. Furthermore, high p53 expression correlates with increased DNA content and aneuploidy; but it requires further research to unveil a possible causal relation. 01 oktober 2010

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.

Contains fulltext : 87234.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To compare the treatment and follow-up of patients with lichen sclerosus (LS) at the departments of Gynaecology and Dermatology at the Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands, to evaluate the need for a multidisciplinary vulvar clinic. MATERIALS AND METHODS: Treatment and follow-up data of all women with histologically proven (between January 1995 and January 2001) anogenital LS visiting the outpatient clinics of the departments of Obstetrics & Gynaecology and Dermatology were collected (last date of follow-up: January 2008). RESULTS: Eighty-four patients with LS were included in this study, 10 patients (12%) of which were treated by both specialties. At the Gynaecology department, LS patients more often received surgical treatment, topical estrogens, and lidocaine ointment, whereas at the Dermatology department, local class 2/3 corticosteroids were more often prescribed. Follow-up frequencies were similar in both specialties and took place at 3 to 4 visits in the first year and at least once a year afterward. One patient developed vulvar squamous cell carcinoma. This patient had withdrawn from follow-up and had her condition diagnosed with carcinoma 74 months after the LS had been diagnosed. CONCLUSIONS: Although no hospital guidelines existed, management of patients with LS agreed with current recommendations in the literature, although differences in secondary and supportive therapy existed owing to differences in expertise. The relatively high percentage of patients treated by both specialties with a high frequency of visits emphasizes the need for a multidisciplinary clinic for vulvar disease. 01 april 2010 6 p.