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• BRCA1/2 mutation carriers have a relatively healthy cardiovascular risk profile. • No association between premature menopause and subclinical atherosclerosis. • Premature surgical menopause does not increase carotid intima-media thickness. • Pulse wave velocity is not related to time since preventive salpingo-oophorectomy. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Background: Vulvar Paget disease (VPD) is a rare skin disorder that is considered premalignant.Objective: To assess the clinical course, treatment schedules, and effect of invasion and treatment on recurrence and survival in patients with VPD.Methods: Data on women with VPD were retrieved from the medical files and pathology reports in all Dutch tertiary university medical centers. Disease-free survival and 5-year disease-specific survival were estimated by using Kaplan-Meier curves.Results: Data on 113 patients whose VPD was diagnosed between 1991 and 2016 were analyzed; 77% had noninvasive VPD. Most of the women (65%) underwent a surgical procedure. Recurrences were reported in 40%. Of the women with noninvasive VPD, 8% developed invasion. There were no disease-specific deaths reported in the women with noninvasive VPD. The 5-year disease-specific survival rate was greater than 98% in noninvasive and microinvasive VPD, but significantly worse in invasive VPD (50% [P < .0005]).Limitations: The main limitations of this study are its retrospective character and the fact that original pathology samples were not available for reassessment.Conclusions: VPD is extremely rare, and the recurrence rates are high. Most patients have noninvasive VPD, which does not affect survival and should be considered a chronic disorder with limited invasive potential. In cases of invasive disease, survival decreases significantly. [ABSTRACT FROM AUTHOR]

Abstract Introduction The recommended pathological resection margin (8 mm) for vulvar squamous cell carcinoma (SCC) is broader than for SCC located elsewhere, and does not depend on tumor grade or lesion size. Our aim is to evaluate the resection margin in vulvar SCC in relation to local recurrence, and to determine the impact of other prognostic factors. Materials and methods Data of all surgically treated patients at the Gynecological Oncology Center South with vulvar SCC, FIGO IB-IIIC, between 2005 and 2015 were analysed retrospectively. The relation between the pathological resection margin and other clinicopathological factors with the risk of local recurrence was analysed. Results In this cohort of 167 patients, the tumor was radically removed in 87% of the patients. Yet, in 57% the pathological resection margin was <8 mm. Including re-excisions, the median closest margin was 7.0 mm. There was no significant difference in the risk of local recurrence for a resection margin <8 mm or ≥8 mm (25.0% (n = 20) and 22.2% (n = 16)), nor in the median resection margin of patients with or without local recurrence (6.5 mm and 7.0 mm). Lichen sclerosus was the only significant risk factor for local recurrence. Conclusion A pathological resection margin <8 mm was not related to an increased risk of local recurrence. The most important predictor of local recurrence was the presence of lichen sclerosus. A resection margin <8 mm in vulvar SCC can therefore be accepted, especially in tumors located close to clitoris, urethra or anus. [ABSTRACT FROM AUTHOR]

Background: Women with a BRCA1/2 pathogenic variant are advised to undergo premenopausal risk-reducing salpingo-oophorectomy after completion of childbearing, to reduce their risk of ovarian cancer. Several studies reported less sexual pleasure one to three years after a premenopausal oophorectomy. However, the long-term effects of a premenopausal oophorectomy on sexual functioning are unknown.Objective: Our aim was to study long-term sexual functioning in women at increased familial risk of breast/ovarian cancer who underwent a risk-reducing salpingo-oophorectomy either before the age of 46 years (premenopausal group), or after the age of 54 years (postmenopausal group). We performed subgroup analyses in the premenopausal group, comparing early (before the age of 41 years) and later (at ages 41-45 years) premenopausal risk-reducing salpingo-oophorectomy.Study Design: Between 2018 and 2021, we invited 817 women with a high familial risk of breast/ovarian cancer from an ongoing cohort study to participate in our study. Due to a large difference in age at study between the premenopausal and postmenopausal salpingo-oophorectomy groups, we restricted the comparison of sexual functioning between the groups to 368 women who were 60-70 years old at completion of the questionnaire (premenopausal group, n=226, postmenopausal group, n=142). In 496 women with a premenopausal risk-reducing salpingo-oophorectomy we compared sexual functioning between women in the early premenopausal group (n=151) and the later premenopausal group (n=345). Differences between groups were analyzed using multiple regression analyses adjusting for current age, breast cancer history, use of hormone replacement therapy, body mass index, chronic medication use (yes/no) and body image.Results: Mean time since risk-reducing salpingo-oophorectomy was 20.6 years in the premenopausal group and 10.6 years in the postmenopausal group (p-value <.001). In the premenopausal group, mean age at questionnaire completion was 62.7 years, versus 67.0 years in the postmenopausal group (p<.001). In the premenopausal group, 47.4% was still sexually active, compared to 48.9% of the postmenopausal group (p-value: .80). Current sexual pleasure scores were the same for women in the premenopausal group and the postmenopausal group (mean pleasure score 8.6, p-value .99). However, women in the premenopausal group more often reported substantial discomfort than women in the postmenopausal group (35.6% compared with 20.9%, p-value .04). After adjusting for confounders, premenopausal risk-reducing salpingo-oophorectomy was associated with substantially more discomfort during sexual intercourse, compared to postmenopausal risk-reducing salpingo-oophorectomy (odds ratio 3.1, 95% confidence interval 1.04; 9.4). Moreover, following premenopausal risk-reducing salpingo-oophorectomy, more severe complaints of vaginal dryness were observed (odds ratio 2.6, 95% confidence interval 1.4; 4.7). Women with a risk-reducing salpingo-oophorectomy before age 41 reported similar pleasure and discomfort scores as women with a risk-reducing salpingo-oophorectomy between ages 41 and 45.Conclusion: More than 15 years after premenopausal risk-reducing salpingo-oophorectomy, the proportion of sexually active women was comparable to that among women with a postmenopausal risk-reducing salpingo-oophorectomy. However, after a premenopausal risk-reducing salpingo-oophorectomy, women experienced more vaginal dryness and more often had substantial sexual discomfort during sexual intercourse. This did not lead to less pleasure with sexual activity. [ABSTRACT FROM AUTHOR]

Background: Vulvar Paget disease is an extremely rare skin disorder, which is most common in postmenopausal women. Most vulvar Paget disease cases are noninvasive; however, it may be invasive or associated with an underlying vulvar or distant adenocarcinoma. The current treatment of choice for noninvasive vulvar Paget disease is wide local excision, which is challenging because of extensive intraepithelial spread and may cause severe morbidity. Recurrence rates are high, ranging from 15% to 70%, which emphasizes the need for new treatment options. Imiquimod, a topical immune response modifier, has been shown to be effective in a few studies and case reports, and is a promising new treatment modality.Objective: To prospectively investigate the efficacy, safety, and effect on quality of life of a standardized treatment schedule with 5% imiquimod cream in patients with noninvasive vulvar Paget disease.Study Design: The Paget Trial is a multicenter prospective observational clinical study including 7 tertiary referral hospitals in the Netherlands. A total of 24 patients with noninvasive vulvar Paget disease were treated with topical 5% imiquimod cream 3 times a week for 16 weeks. The primary efficacy outcome was the reduction in lesion size at 12 weeks after the end of treatment. Secondary outcomes were safety, clinical response after 1 year, and quality of life. Safety was assessed by evaluation of adverse events and tolerability of treatment. Quality of life was investigated with 3 questionnaires taken before, during, and after treatment.Results: Data were available for 23 patients, 82.6% of whom responded to therapy. A complete response was reported in 12 patients (52.2%), and 7 patients (30.4%) had a partial response. A histologic complete response was observed in 10 of the 12 patients with a complete response. Patients experienced side effects such as fatigue (66.7%-70.9%) and headaches (16.7%-45.8%), and almost 80% needed painkillers during treatment. Eight patients (34.8%) adjusted the treatment protocol to 2 applications a week, and 3 patients (13.0%) stopped treatment because of side effects after 4 to 11 weeks. Treatment improved quality of life, whereas a slight, temporary negative impact was observed during treatment. Two patients with a complete response developed a recurrence within 1 year after treatment. Follow-up showed 6 patients with a noninvasive recurrence after a median of 31 months (14-46 months) after the end of treatment.Conclusion: Topical 5% imiquimod cream can be an effective and safe treatment alternative for noninvasive vulvar Paget disease, particularly when compared with treatment with surgical excision. [ABSTRACT FROM AUTHOR]

Background: The discovery of the fallopian tube epithelium as the origin of high-grade serous ovarian cancer has brought a new option for ovarian cancer prevention. The fallopian tubes have no known function after completion of childbearing and can be removed to reduce the lifetime 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 worldwide; however, the variation between gynecologists and hospitals in their advice on opportunistic salpingectomy occurs because of the remaining uncertainty of evidence. Therefore, whether a woman can make her own decision depends on the hospital or gynecologist she visits. We aimed to lower this practice variation by providing standardized and unbiased counseling material.Objective: We aimed to develop and test a patient decision aid for opportunistic salpingectomy in women undergoing pelvic gynecologic surgery to either retain the ovaries or opt for sterilization.Study Design: We followed a systematic development process based on the International Patient Decision Aid Standards. Data were collected between June 2019 and June 2020, using both qualitative and quantitative methods. The development process that occurred in collaboration with patients and healthcare professionals was overseen by a multidisciplinary steering group and was divided into 4 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 the first revision round; and (4) alpha testing and the second revision round.Results: An outline of the patient decision aid was developed on the basis of decisional needs, current literature, and guidelines. It became clear that the decision aid should consist of 2 separate paths: one with information specifically for salpingectomy in addition to abdominal surgery and one for salpingectomy as a sterilization method. Both paths contained information on the anatomy and function of ovaries and fallopian tubes, risk reduction of ovarian cancer, and potential benefits and risks of opportunistic salpingectomy. Moreover, the sterilization path contains information on various sterilization methods and risks 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 the patient's preferences and considerations. Adjustments were made following alpha testing round 1. The improved patient decision aid was subjected to usability tests (alpha testing round 2), in which it scored an "excellent" in tests with patients and a "good" in tests with gynecologists. Furthermore, our patient decision aid met the requirements of 45 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 believed it is a useful tool that supports patients in making an informed decision whether to undergo an opportunistic salpingectomy and supports the counseling process by gynecologists. [ABSTRACT FROM AUTHOR]

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.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.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.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. [ABSTRACT FROM AUTHOR]

Summary: 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. [Copyright &y& Elsevier]

The article presents a study which aims to fine tune the role of high-risk human papilloma virus (HPV) infection in vulvar squamous cell carcinoma development in connection with clinical prognosis. Results of the study show that usual vulvar intraepithelial neoplasia-associated squamous cell carcinomas was having high p16 expression along with the 24 of 25 squamous cell carcinomas. It is concluded that HPV's high risk has been usually associated with the usual vulvar intraepithelial neoplasia.

We report a patient with vulvar lichen sclerosus, Langerhans cell histiocytosis (LCH), and later vulvar cancer. In LCH, high amounts of non functional Langerhans cells are present in the affected tissue, making it possible that LCH may have contributed to vulvar cancer development in this patient. [Copyright &y& Elsevier]

Objective: The objective of the study was to quantify vessel type and density in lichen sclerosus (LS) to find a marker for its malignant potential. Study Design: Quantitative analysis was performed on paraffin-embedded tissue samples of 28 patients with LS (7 adjacent to vulvar squamous cell carcinoma, 21 solitary) and immunohistochemical staining for CD34 (vascular and lymphangiogenic lymph endothelial cells), D2-40 (lymphatic-specific marker), and α-SMA (pericyte marker). Electron microscopy was performed on fresh tissue. Results: No significant differences in vessel density or other vessel parameters could be demonstrated between the 2 groups. In hyalinized lesions, vessel diameter, and α-SMA positivity was reduced compared with nonhyalinized lesions. Electron microscopy revealed detachment of pericytes from vascular endothelial cells and increased thickening of basement membrane, whereas endothelial cell function did not appear strongly impaired. Conclusion: Malignant potential of LS cannot be predicted by vessel characteristics. Hyalinization in LS is associated with pericyte detachment from the basal lamina of vascular endothelial cells. [Copyright &y& Elsevier]

A patient was referred to our vulvar outpatient clinic because of a vaginal ulceration that persisted for 3 years and that had been unresponsive to any prescribed therapy. After a possible association was found with nicorandil therapy, this medication was stopped. Thereafter, the ulceration fully healed within 6 months. [Copyright &y& Elsevier]