Long-term outcome of high-grade serous carcinoma established in risk-reducing salpingo-oophorectomy specimens in asymptomatic BRCA1/2 germline pathogenic variant carriers.

OBJECTIVE: The aim of this study was to describe the long-term outcome of asymptomatic BRCA1/2 germline pathogenic variant (GPV) carriers with high-grade serous carcinoma (HGSC) in their risk-reducing salpingo-oophorectomy (RRSO) specimen. METHODS: In a previously described cohort of asymptomatic BRCA1/2 GPV carriers derived from the Hereditary Breast and Ovarian cancer in the Netherlands (HEBON) study, women with HGSC at RRSO were identified. Main outcome was ten-year disease-free survival (DFS). Secondary outcomes were time to recurrence, ten-year disease-specific survival (DSS), ten-year overall survival (OS). Patient, disease and treatment characteristics associated with recurrence were described. RESULTS: The 28 included women with HGSC at RRSO were diagnosed at a median age of 55.3 years (range: 33.5-74.3). After staging, eighteen women had (FIGO) stage I, three stage II and five had stage III disease. Two women did not undergo surgical staging and were classified as unknown stage. After a median follow-up of 13.5 years (range: 9.1-24.7), six women with stage I (33%), one woman with stage II (33%), two women with stage III (40%) and none of the women with unknown stage developed a recurrence. Median time to recurrence was 6.9 years (range: 0.8-9.2 years). Ten-year DFS was 68%, ten-year DSS was 88% and ten-year OS was 82%. CONCLUSION: Most asymptomatic BRCA1/2 GPV carriers with HGSC at RRSO were diagnosed at an early stage. Nevertheless, after a median follow-up of 13.5 years, nine of the 28 women with HGSC at RRSO developed a recurrence after a median of 6.9 years.

Diagnosis and management of isolated serous tubal intraepithelial carcinoma: A qualitative focus group study.

OBJECTIVE: A Serous Tubal Intraepithelial Carcinoma (STIC) without concomitant invasive carcinoma is occasionally identified and associated with a high risk of subsequent peritoneal carcinomatosis. Management needs optimisation. This study explores professionals' opinions and clinical practices regarding the diagnosis, counselling, treatment and follow-up of isolated STIC to facilitate clinical decision making and optimise the direction of future research. A secondary aim is to assess international clinical guidelines. DESIGN: Focus group study. SETTING: Four online sessions. POPULATION: International panel (n = 12 countries) of gynaecologists, gynaecologic oncologists, pathologists and medical oncologists (n = 49). METHODS: A semi-structured interview guide was used. Two independent researchers analysed transcripts by open and axial coding. Results were organised in domains. Relevant (inter)national guidelines were screened for recommendations regarding isolated STIC. MAIN OUTCOME MEASURES: Professionals' opinions and clinical practices regarding isolated STIC management. RESULTS: Regarding pathology, most professionals identified the SEE-FIM protocol as standard of care for high-risk patients, whereas variation exists in the histopathological examination of fallopian tubes in the general population. Confirmation of STIC diagnosis by a specialised pathologist was recommended. Regarding work-up and follow-up after STIC diagnosis, there was variety and discordance. Data on outcomes is limited. As for treatment, chemotherapy and PARP inhibitors were not recommended by most. Eleven guidelines provided limited recommendations. CONCLUSIONS: We identified recommendations and highlighted knowledge gaps in the diagnosis and management of isolated STIC. Moreover, recommendations in clinical guidelines are limited. There is an agreed need for international collaboration for the prospective registration of isolated STIC.

Functional estrogen receptor signal transduction pathway activity and antihormonal therapy response in low-grade ovarian carcinoma.

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

Incidence of inguinofemoral lymph node metastases at the first local recurrence of vulvar cancer: a Dutch nationwide study.

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

Consensus based recommendations for the diagnosis of serous tubal intraepithelial carcinoma: an international Delphi study.

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

Vulvar squamous cell carcinoma in women 80 years and older: Treatment, survival and impact of comorbidities.

BACKGROUND: Despite being a disease of mainly older women, little is known about the clinical management of older women with vulvar squamous cell carcinoma (VSCC). We evaluated their daily clinical management compared with younger women, and established the prevalence of comorbidities and its impact on overall survival (OS). METHODS: All Dutch women diagnosed with VSCC from 2015 to 2020 (n = 2249) were selected from the Netherlands Cancer Registry. Women aged ≥80 years (n = 632, 28%) were defined as "older" patients, women <80 years were considered as "younger". Chi-square tests were performed to evaluate differences in treatment by age group and comorbidities. Differences in OS were evaluated using Kaplan-Meier Curves and log-rank test. RESULTS: The vast majority of both older (91%) and younger (99%) patients with FIGO IA VSCC received surgical treatment of the vulva. Older FIGO IB-IV VSCC patients were less likely to undergo groin surgery than younger patients (50% vs. 84%, p < 0.01). Performance of surgical treatment of the vulva and groin(s) was not associated with the number of comorbidities in older patients (p = 0.67 and p = 0.69). Older patients with ≥2 comorbidities did have poorer OS compared to women with one or no comorbidities (p < 0.01). CONCLUSION: The vast majority of older patients underwent vulvar/local surgery. Older patients less often received groin surgery compared to younger patients. The majority of older patients had at least one comorbidity, but this did not impact treatment choice. The poorer survival in older VSCC patients may therefore be due to death of competing risks instead of VSCC itself.

The most efficient and effective BRCA1/2 testing strategy in epithelial ovarian cancer: Tumor-First or Germline-First?

OBJECTIVE: Genetic testing in epithelial ovarian cancer (OC) is essential to identify a hereditary cause like a germline BRCA1/2 pathogenic variant (PV). An efficient strategy for genetic testing in OC is highly desired. We evaluated costs and effects of two strategies; (i) Tumor-First strategy, using a tumor DNA test as prescreen to germline testing, and (ii) Germline-First strategy, referring all patients to the clinical geneticist for germline testing. METHODS: Tumor-First and Germline-First were compared in two scenarios; using real-world uptake of testing and setting implementation to 100%. Decision analytic models were built to analyze genetic testing costs (including counseling) per OC patient and per family as well as BRCA1/2 detection probabilities. With a Markov model, the life years gained among female relatives with a germline BRCA1/2 PV was investigated. RESULTS: Focusing on real-world uptake, with the Tumor-First strategy more OC patients and relatives with a germline BRCA1/2 PV are detected (70% versus 49%), at lower genetic testing costs (€1898 versus €2502 per patient, and €2511 versus €2930 per family). Thereby, female relatives with a germline BRCA1/2 PV can live on average 0.54 life years longer with Tumor-First compared to Germline-First. Focusing on 100% uptake, the genetic testing costs per OC patient are substantially lower in the Tumor-First strategy (€2257 versus €4986). CONCLUSIONS: The Tumor-First strategy in OC patients is more effective in identifying germline BRCA1/2 PV at lower genetic testing costs per patient and per family. Optimal implementation of Tumor-First can further improve detection of heredity in OC patients.

Sexual functioning more than 15 years after premenopausal risk-reducing salpingo-oophorectomy.

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 1 to 3 years after a premenopausal oophorectomy. However, the long-term effects of premenopausal oophorectomy on sexual functioning are unknown. OBJECTIVE: This study aimed to study long-term sexual functioning in women at increased familial risk of breast or 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). Subgroup analyses were performed 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, 817 women with a high familial risk of breast or ovarian cancer from an ongoing cohort study were invited to participate in our study. Because of a large difference in age in the 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 to 70 years old at completion of the questionnaire (226 in the premenopausal group and 142 in the postmenopausal group). In 496 women with a premenopausal risk-reducing salpingo-oophorectomy, we compared the sexual functioning between women in the early premenopausal group (n=151) and women in 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 or no), and body image. RESULTS: Mean times since risk-reducing salpingo-oophorectomy were 20.6 years in the premenopausal group and 10.6 years in the postmenopausal group (P<.001). The mean age at questionnaire completion was 62.7 years in the premenopausal group, compared with 67.0 years in the postmenopausal group (P<.001). Compared with 48.9% of women in the postmenopausal group, 47.4% of women in the premenopausal group were still sexually active (P=.80). Current sexual pleasure scores were the same for women in the premenopausal group and women in the postmenopausal group (mean pleasure score, 8.6; P=.99). However, women in the premenopausal group more often reported substantial discomfort than women in the postmenopausal group (35.6% vs 20.9%; P=.04). After adjusting for confounders, premenopausal risk-reducing salpingo-oophorectomy was associated with substantially more discomfort during sexual intercourse than postmenopausal risk-reducing salpingo-oophorectomy (odds ratio, 3.1; 95% confidence interval, 1.04-9.4). Moreover, after 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 the age of 41 years reported similar pleasure and discomfort scores as women with a risk-reducing salpingo-oophorectomy between ages 41 and 45 years. CONCLUSION: More than 15 years after premenopausal risk-reducing salpingo-oophorectomy, the proportion of sexually active women was comparable with the proportion of sexually active 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.

Care after premenopausal risk-reducing salpingo-oophorectomy in high-risk women: Scoping review and international consensus recommendations.

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

TUBectomy with delayed oophorectomy as an alternative to risk-reducing salpingo-oophorectomy in high-risk women to assess the safety of prevention: the TUBA-WISP II study protocol.

BACKGROUND: Risk-reducing salpingectomy with delayed oophorectomy has gained interest for individuals at high risk for tubo-ovarian cancer as there is compelling evidence that especially high-grade serous carcinoma originates in the fallopian tubes. Two studies have demonstrated a positive effect of salpingectomy on menopause-related quality of life and sexual health compared with standard risk-reducing salpingo-oophorectomy. PRIMARY OBJECTIVE: To investigate whether salpingectomy with delayed oophorectomy is non-inferior to the current standard salpingo-oophorectomy for the prevention of tubo-ovarian cancer among individuals at high inherited risk. STUDY HYPOTHESIS: We hypothesize that postponement of oophorectomy after salpingectomy, to the age of 40-45 (BRCA1) or 45-50 (BRCA2) years, compared with the current standard salpingo-oophorectomy at age 35-40 (BRCA1) or 40-45 (BRCA2) years, is non-inferior in regard to tubo-ovarian cancer risk. TRIAL DESIGN: In this international prospective preference trial, participants will choose between the novel salpingectomy with delayed oophorectomy and the current standard salpingo-oophorectomy. Salpingectomy can be performed after the completion of childbearing and between the age of 25 and 40 (BRCA1), 25 and 45 (BRCA2), or 25 and 50 (BRIP1, RAD51C, and RAD51D pathogenic variant carriers) years. Subsequent oophorectomy is recommended at a maximum delay of 5 years beyond the upper limit of the current guideline age for salpingo-oophorectomy. The current National Comprehensive Cancer Network (NCCN) guideline age, which is also the recommended age for salpingo-oophorectomy within the study, is 35-40 years for BRCA1, 40-45 years for BRCA2, and 45-50 years for BRIP1, RAD51C, and RAD51D pathogenic variant carriers. MAJOR INCLUSION/EXCLUSION CRITERIA: Premenopausal individuals with a documented class IV or V germline pathogenic variant in the BRCA1, BRCA2, BRIP1, RAD51C, or RAD51D gene who have completed childbearing are eligible for participation. Participants may have a personal history of a non-ovarian malignancy. PRIMARY ENDPOINT: The primary outcome is the cumulative tubo-ovarian cancer incidence at the target age: 46 years for BRCA1 and 51 years for BRCA2 pathogenic variant carriers. SAMPLE SIZE: The sample size to ensure sufficient power to test non-inferiority of salpingectomy with delayed oophorectomy compared with salpingo-oophorectomy requires 1500 BRCA1 and 1500 BRCA2 pathogenic variant carriers. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Participant recruitment is expected to be completed at the end of 2026 (total recruitment period of 5 years). The primary outcome is expected to be available in 2036 (minimal follow-up period of 10 years). TRIAL REGISTRATION NUMBER: NCT04294927.

Can late lymphoscintigraphy be omitted in the sentinel node procedure in early-stage vulvar cancer?

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

First step in implementation of opportunistic salpingectomy for prevention of ovarian cancer: Current care and its determinants.

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

Probability of detecting germline BRCA1/2 pathogenic variants in histological subtypes of ovarian carcinoma. A meta-analysis.

BACKGROUND: Histology restricted genetic predisposition testing of ovarian carcinoma patients is a topic of debate as the prevalence of BRCA1/2 pathogenic variants (PVs) in various histological subtypes is ambiguous. Our primary aim was to investigate the proportion of germline BRCA1/2 PVs per histological subtype. Additionally, we evaluated (i) proportion of somatic BRCA1/2 PVs and (ii) proportion of germline PVs in other ovarian carcinoma risk genes. METHODS: PubMed, EMBASE and Web of Science were systematically searched and we included all studies reporting germline BRCA1/2 PVs per histological subtype. Pooled proportions were calculated using a random-effects meta-analysis model. Subsets of studies were used for secondary analyses. RESULTS: Twenty-eight studies were identified. The overall estimated proportion of germline BRCA1/2 PVs was 16.8% (95% CI 14.6 to 19.2). Presence differed substantially among patients with varying histological subtypes of OC; proportions being highest in high-grade serous (22.2%, 95% CI 19.6 to 25.0) and lowest in clear cell (3.0%, 95% CI 1.6 to 5.6) and mucinous (2.5%, 95% CI 0.6 to 9.6) carcinomas. Somatic BRCA1/2 PVs were present with total estimated proportion of 6.0% (95% CI 5.0 to 7.3), based on a smaller subset of studies. Germline PVs in BRIP1, RAD51C, RAD51D, PALB2, and ATM were present in approximately 3%, based on a subset of nine studies. CONCLUSION: Germline BRCA1/2 PVs are most frequently identified in high-grade serous ovarian carcinoma patients, but are also detected in patients having ovarian carcinomas of other histological subtypes. Limiting genetic predisposition testing to high-grade serous ovarian carcinoma patients will likely be insufficient to identify all patients with a germline PV.

The Paget Trial: topical 5% imiquimod cream for noninvasive vulvar Paget disease.

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.

Primary prevention of ovarian cancer: a patient decision aid for opportunistic salpingectomy.

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.

Cancer worry among BRCA1/2 pathogenic variant carriers choosing surgery to prevent tubal/ovarian cancer: course over time and associated factors.

OBJECTIVE: High cancer risks, as applicable to BRCA1 and BRCA2 pathogenic variant (PV) carriers, can induce significant cancer concerns. We examined the degree of cancer worry and the course of this worry among BRCA1/2-PV carriers undergoing surgery to prevent ovarian cancer, and identified factors associated with high cancer worry. METHODS: Cancer worry was evaluated as part of the multicentre, prospective TUBA-study (NCT02321228) in which BRCA1/2-PV carriers choose either novel risk-reducing salpingectomy with delayed oophorectomy or standard risk-reducing salpingo-oophorectomy. The Cancer Worry Scale was obtained before and 3 and 12 months after surgery. Cancer worry patterns were analysed using latent class growth analysis and associated factors were identified with regression analysis. RESULTS: Of all 577 BRCA1/2-PV carriers, 320 (57%) had high (≥ 14) cancer worry pre-surgery, and 54% had lower worry 12 months post-surgery than pre-surgery. Based on patterns over time, BRCA1/2-PV carriers could be classified into three groups: persistently low cancer worry (56%), persistently high cancer worry (6%), and fluctuating, mostly declining, cancer worry (37%). Factors associated with persistently high cancer concerns were age below 35 (BRCA1) or 40 (BRCA2), unemployment, previous breast cancer, lower education and a more recent BRCA1/2-PV diagnosis. CONCLUSIONS: Some degree of cancer worry is considered normal, and most BRCA1/2-PV carriers have declining cancer worry after gynaecological risk-reducing surgery. However, a subset of these BRCA1/2-PV carriers has persisting major cancer concerns up to 1 year after surgery. They should be identified and potentially offered additional support. CLINICAL TRIAL REGISTRATION: The TUBA-study is registered at ClinicalTrials.gov since December 11th, 2014. Registration number: NCT02321228.

Diagnostic accuracy of mutational analysis along the Müllerian tract to detect ovarian cancer.

OBJECTIVE: Ovarian cancer is known for its poor prognosis, which is mainly due to the lack of early symptoms and adequate screening options. In this study we evaluated whether mutational analysis in cervicovaginal and endometrial samples could assist in the detection of ovarian cancer. METHODS: In this prospective multicenter study, we included patients surgically treated for either (suspicion of) ovarian cancer or for a benign gynecological condition (control group). A cervicovaginal self-sample, a Papanicolaou (Pap) smear, a pipelle endometrial biopsy, and the surgical specimen were analyzed for (potentially) pathogenic variants in eight genes (ARID1A, CTNNB1, KRAS, MTOR, PIK3CA, POLE, PTEN, and TP53) using single-molecule molecular inversion probes. Sensitivity and specificity were calculated to assess diagnostic accuracy. RESULTS: Based on surgical histology, our dataset comprised 29 patients with ovarian cancer and 32 controls. In 83% of the patients with ovarian cancer, somatic (potentially) pathogenic variants could be detected in the final surgical specimen, of which 71% included at least a TP53 variant. In 52% of the ovarian cancer patients, such variants could be detected in either the self-sample, Pap smear, or pipelle. The Pap smear yielded the highest diagnostic accuracy with 26% sensitivity (95% CI 10% to 48%). Overall diagnostic accuracy was low and was not improved when including TP53 variants only. CONCLUSIONS: Mutational analysis in cervicovaginal and endometrial samples has limited accuracy in the detection of ovarian cancer. Future research with cytologic samples analyzed on methylation status or the vaginal microbiome may be relevant.

Oncologic outcomes after splenectomy during initial cytoreductive surgery in advanced epithelial ovarian cancer: a nationwide population-based cohort study.

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

Evaluation of a patient decision aid for BRCA1/2 pathogenic variant carriers choosing an ovarian cancer prevention strategy.

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 recommend 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 cancer worry were similar in both cohorts. CONCLUSIONS: The use of the patient decision aid for risk-reducing surgery is feasible, effective and highly appreciated among BRCA1/2-PV carriers facing the decision between salpingo-oophorectomy or salpingectomy with delayed oophorectomy.

Patients' and professionals' perspectives on implementation of opportunistic salpingectomy: a mixed-method study.

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