Mosaic RASopathies concept: different skin lesions, same systemic manifestations?

BACKGROUND: Cutaneous epidermal nevi are genotypically diverse mosaic disorders. Pathogenic hotspot variants in HRAS, KRAS, and less frequently, NRAS and BRAF may cause isolated keratinocytic epidermal nevi and sebaceous nevi or several different syndromes when associated with extracutaneous anomalies. Therefore, some authors suggest the concept of mosaic RASopathies to group these different disorders. METHODS: In this paper, we describe three new cases of syndromic epidermal nevi caused by mosaic HRAS variants: one associating an extensive keratinocytic epidermal nevus with hypomastia, another with extensive mucosal involvement and a third combining a small sebaceous nevus with seizures and intellectual deficiency. Moreover, we performed extensive literature of all cases of syndromic epidermal nevi and related disorders with confirmed pathogenic postzygotic variants in HRAS, KRAS, NRAS or BRAF. RESULTS: Most patients presented with bone, ophthalmological or neurological anomalies. Rhabdomyosarcoma, urothelial cell carcinoma and pubertas praecox are also repeatedly reported. KRAS pathogenic variants are involved in 50% of the cases, especially in sebaceous nevi, oculoectodermal syndrome and encephalocraniocutaneous lipomatosis. They are frequently associated with eye and brain anomalies. Pathogenic variants in HRAS are rather present in syndromic keratinocytic epidermal nevi and phacomatosis pigmentokeratotica. CONCLUSION: This review delineates genotype/phenotype correlations of syndromic epidermal nevi with somatic RAS and BRAF pathogenic variants and may help improve their follow-up.

Women with Cervical High-Risk Human Papillomavirus: Be Aware of Your Anus! The ANGY Cross-Sectional Clinical Study.

Anogenital human papillomaviruses (HPV) are highly prevalent in sexually active populations, with HR-HPV being associated with dysplasia and cancers. The consequences of cervical HPV infection are well-known, whereas those of the anus are less clear. The correlation of cervical and anal HPVs with the increasing number of anal cancers in women has not been studied yet. The objective of our prospective study was to determine whether cervical and anal HPV correlated in a cohort of women recruited in a university hospital in Switzerland. Recruitment was conducted in the gynecology clinic, the colposcopy clinic, and the HIV clinic. Cervical and anal HPV genotyping and cytology were performed. Overall, 275 patients were included (360 were initially planned), and among them, 102 (37%) had cervical HR-HPV. Patients with cervical HR-HPV compared to patients without cervical HR-HPV were significantly younger (39 vs. 44 yrs, p < 0.001), had earlier sexual intercourse (17.2 vs. 18.3 yrs, p < 0.01), had more sexual partners (2.9 vs. 2.2, p < 0.0001), more dysplastic cervical cytology findings (42% vs. 19%, p < 0.0001) and higher prevalence of anal HR-HPV (59% vs. 24%, p < 0.0001). Furthermore, the HR-HPV group reported more anal intercourse (44% vs. 29%, p < 0.015). Multivariate analysis retained anal HR-HPV as independent risk factor for cervical HR-HPV (OR3.3, CI 1.2−9.0, p = 0.02). The results of this study emphasize that it is of upmost importance to screen women for anal HR-HPV when diagnosing cervical HR-HPV.

[Human Papillomavirus: screening of cervical and anal cancers]. / Papillomavirus humain : dépistage des cancers du col et de l'anus.

Cervical cancer is preventable through primary and secondary prevention. Vaccination against the human papillomavirus (HPV), the virus necessary for the development of precancerous lesions, can prevent most of them. Screening by cytology for these precancerous (or cancerous) lesions can be replaced by screening for certain types of HPV, high risk (HR-HPV), causing cervical cancer. The presence of HR-HPV on the cervix should raise suspicion of concomitant infection in the anus, as both epithelia are highly susceptible. This attitude is dictated by the increase incidence in anal cancer in the population, which is also HPV-dependent and therefore also potentially preventable through vaccination and screening.

Le cancer du col utérin est évitable, au travers d'une politique de prévention primaire et secondaire. Une vaccination contre le papillomavirus humain (HPV), et plus particulièrement contre les HPV dits à haut risque (HR-HPV) qui induisent le développement des états précancéreux, permet ainsi d'éviter une majeure partie de ceux-ci. Un dépistage par cytologie à la recherche de ces lésions précancéreuses (ou cancéreuses) peut être supplanté par la recherche de la présence des HR-HPV. La présence de HR-HPV sur le col doit faire suspecter une infection concomitante au niveau de l'anus car les deux épithéliums y sont très sensibles. Cette attitude est dictée par l'augmentation des cancers de l'anus dans la population, cancer lui aussi dépendant du HPV, et donc aussi potentiellement évitable au travers de la vaccination et du dépistage.

Prevalence of anal dysplasia and HPV genotypes in gynecology patients: The ANGY cross-sectional prospective clinical study protocol.

BACKGROUND: Human Papillomaviruses (HPV) are highly prevalent in the sexually active populations, with a significant burden in terms of health and psychological cost in all class ages. High-risk (HR) HPV genotypes are associated with anogenital dysplasia and cancers, and anal HPV-induced cancer is increasingly observed in women. The interactions of HPV genotype's between the anus and the cervix, and the subsequent occurrence of dysplasia remains unclear. This clinical study set out to test the hypothesis that risk factors for anal HR-HPV and dysplasia may differ in women with or without cervical dysplasia or in HIV-positive women. METHODS: Cervical and anal HPV genotypes and cytology testing will be performed prospectively in a cohort of women recruited in a tertiary university hospital in Switzerland. Women will be allocated to three groups: 1) normal previous cervical smear; 2) high-grade cervical dysplasia (H-SIL) at previous cervical smear; 3) HIV+, independently of previous cervical smear result. General inclusion criteria comprised the followings: Female-Age > = 18 years; Satisfactory understanding of French; No objection to HIV testing. Specific inclusion criteria are: Group 1, no past or current gynecological dysplasia and HIV negative; Group 2, Gynecological dysplasia (H-SIL) or carcinoma in situ demonstrated by histology (vulvar, vaginal or cervical) and HIV negative; Group 3: HIV-positive (regardless of viremia or CD4 count) with or without gynecological dysplasia. General exclusion criteria are: Pregnancy; History of anal dysplasia/cancer; Status after pelvic radiotherapy; Absence of anus and anal canal. Estimated prevalences of anal dysplasia are: in group 1, 1% (0-2%); in group 2, 15% (5-27%), and in group 3, 30% (19-45%). With a 10% margin error, a sample size of 120 women per group is required to reach 90% power for detecting statistical significance (unilateral α error of 5%). DISCUSSION: The primary endpoint is the prevalence of anal and cervical dysplasia, and description of the respective HPV genotypes in each group. The results of this study could improve the standard of screening of cervical and anal dysplasia in women through evidence of concomitant presence of HPV's and/or dysplasia in anus or cervix to support vaccination for instance. Beginning of recruitment started in September 2016. Results should be presented in end of 2022. Preliminary analysis for first 100 patients reveals that the mean age of the population is 39.6 (± 10.9) years with mean age of first sexual intercourse of 18.5 (± 3.9) years. In this cohort, 12% are vaccinated and 38% having had anal intercourse. Overall, 43% of the studied population had cervical HR-HPV in the studied population, and 53% had normal cytology. Anal LR HPV and HR HP were found in 27.6% and 38.4% of all patients respectively. Eighty percent had normal anal cytology. Groups 1,2 and 3 had a significant difference in terms of age, gestity, parity, age of first sexual intercourse, systematic use of condom, number of cervical LR HPV and HR HPV and abnormal cervical cytologies. TRIAL REGISTRATION: The study was approved by the institutional review board-CER-VD#2015-00200-on the 29th of June 2016 and is registered on the Swiss National Clinical Trials Portal (SNCTP), SNCTP000002567, Registered 29 June 2016, https://www.kofam.ch/en/snctp-portal/study/40742/.

Is women's sexual function impaired by an abnormal pap smear?

OBJECTIVE: Although the stressful psychological impact on women of an abnormal Pap smear is well documented, little research has been undertaken on its sexual impact. Our objective was to assess the impact of an abnormal Pap smear on the sexual function of affected women. METHODS: A prospective study compared the sexual function of 48 women with an abnormal Pap smear (case group) with that of 48 women with a normal Pap smear (control group). Sexual function was assessed using the Female Sexual Function Index and the Hospital Anxiety Depression Scale. The questionnaires were mailed to the participants. RESULTS: Surprisingly, the risk of sexual dysfunction was comparable between women with and without an abnormal Pap smear (odds ratio [OR] 0.7; p = 0.4). The OR remained statistically non-significant after adjustment for risk factors. Multivariable analysis showed that only older age at first intercourse, depression and anxiety were identified as factors significantly associated with sexual dysfunction. CONCLUSION: Contrary to our clinical experience, female sexual function is not impaired by an abnormal Pap smear. Further research is needed to better understand how sexuality in women with abnormal Pap smears may be affected.

HIV testing in termination of pregnancy and colposcopy services: a scoping review.

BACKGROUND: Women and girls are relatively under-represented across the HIV treatment cascade. Two conditions unique to women, pregnancy and cervical cancer/dysplasia, share a common acquisition mode with HIV. This scoping review aimed to explore HIV testing practices in voluntary termination of pregnancy (TOP) and colposcopy services. METHODS: The scoping review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. We searched articles published up to 20 December 2020 using three electronic databases (PubMed/Medline, Embase, Google Scholar) and including the keywords "HIV Testing", "Abortion, Induced", "Colposcopy", "HIV screen*" and "termination of pregnancy". RESULTS: A total of 1496 articles were identified, of which 55 met the inclusion criteria. We included studies providing background HIV prevalence in addition to prevalence in the study population and studies of women seeking TOP rather than presenting with TOP complications. This limited our review to high-income, low HIV prevalence settings. We observed two study phases: studies pre-antiretroviral therapy (ART) using unlinked anonymous testing data and examining HIV risk factors associated with positive HIV tests and studies post-ART using routine testing data and exploring HIV testing uptake. HIV prevalence was estimated at >0.2% in most TOP settings and >1% (range 1.7%-11.4%) in colposcopy services. Many TOP providers did not have local HIV testing policies and HIV testing was not mentioned in many specialist guidelines. Testing uptake was 49%-96% in TOP and 23%-75% in colposcopy services. CONCLUSION: Given the estimated HIV prevalence of >0.1% among women attending TOP and colposcopy services, HIV testing would be economically feasible to perform in high-income settings. Explicit testing policies are frequently lacking in these two settings, both at the local level and in specialist guidelines. Offering HIV testing regardless of risk factors could normalise testing, reduce late HIV presentation and create an opportunity for preventive counselling.

Predictive Factors Involved in Postpartum Regressions of Cytological/Histological Cervical High-Grade Dysplasia Diagnosed during Pregnancy.

OBJECTIVE: The aim of this study was to describe the evolution of high-grade cervical dysplasia during pregnancy and the postpartum period and to determine factors associated with dysplasia regression. METHODS: Pregnant patients diagnosed with high-grade lesions were identified in our tertiary hospital center. High-grade lesions were defined either cytologically, by high squamous intraepithelial lesion/atypical squamous cells being unable to exclude HSIL (HSIL/ASC-H), or histologically, with cervical intraepithelial neoplasia (CIN) 2+ (all CIN 2 and CIN 3) during pregnancy. Postpartum regression was defined cytologically or histologically by at least a one-degree reduction in severity from the antepartum diagnosis. A logistic regression model was applied to determine independent predictive factors for high-grade cervical dysplasia regression after delivery. RESULTS: Between January 2000 and October 2017, 79 patients fulfilled the inclusion criteria and were analyzed. High-grade cervical lesions were diagnosed by cytology in 87% of cases (69/79) and confirmed by histology in 45% of those (31/69). The overall regression rate in our cohort was 43% (34/79). Univariate analysis revealed that parity (p = 0.04), diabetes (p = 0.04) and third trimester cytology (p = 0.009) were associated with dysplasia regression. Nulliparity (OR = 4.35; 95%CI = (1.03-18.42); p= 0.046) was identified by multivariate analysis as an independent predictive factor of high-grade dysplasia regression. The presence of HSIL on third-trimester cervical cytology (OR = 0.17; 95%CI = (0.04-0.72); p = 0.016) was identified as an independent predictive factor of high-grade dysplasia persistence at postpartum. CONCLUSION: Our regression rate was high, at 43%, for high-grade cervical lesions postpartum. Parity status may have an impact on dysplasia regression during pregnancy. A cervical cytology should be performed at the third trimester to identify patients at risk of CIN persistence after delivery. However, larger cohorts are required to confirm these results.

Safety and Efficacy of an Atraumatic Uterine Cervical Traction Device: A Pilot Study.

Introduction: Alignment of the uterine cervix with the vaginal canal is often required during insertion of an intrauterine contraceptive device (IUD). Currently available instruments are traumatic tenacula, which can cause pain and bleeding and represent an obstacle for certain patients to pursue their medical follow-up. A novel investigational cervical vacuum tenaculum, enables atraumatic traction of the cervix using a semi-circular suction pad, designed to conform to the anatomical shape of the external cervical os. Suction is generated by manually pulling out a sliding tube in a vacuum chamber. Methods: We performed a single arm non-comparative pilot study to assess the safety and efficacy of the cervical vacuum tenaculum in 13 women receiving an IUD. Data on procedural efficacy, safety, patient-reported pain scores at specific time points during IUD insertion procedure and patient satisfaction were collected prospectively. Results: Insertion of IUD was successful with use of the study device in 7 of the 13 enrolled patients (54%). No bleeding or only limited ecchymosis were caused by the device. No adverse events were reported. Participants reported very little pain (mean Visual Analog Scale <10) when applying the device. Participants who achieved IUD insertion with the device reported strong overall satisfaction with the procedure. Conclusions: The suction-based atraumatic tenaculum can be used to manipulate the cervix during IUD insertion with satisfactory efficacy and safety. The results of this pilot study support further studies of this device in larger populations comparing with standard single-tooth tenaculum. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT04441333.

[Is there still a space for the vaginal examination in the gynecological consultation ?] / Y a-t-il encore une place pour l'examen vaginal en consultation gynécologique ?

The vaginal examination is too often part of the routine in periodic gynecological consultations. However, its performance as a screening examination for gynecological diseases such as cancers and infections is poor when performed in the asymptomatic patient. It is appropriate for cervical cancer screening every 3 years from the age of 21. Moreover, the intrusive nature of the vaginal examination, which is sometimes experienced as traumatic by patients, encourages the targeting of indications for its practice. Fear of this examination may also result in avoidance of care. The gynecological consultation is a privileged setting for screening for sexual risk taking or domestic violence, but also for exploring overall sexual health and promoting women's health.

L'examen vaginal est trop souvent ancré dans la routine des consultations périodiques en gynécologie. Or, sa performance comme examen de dépistage des maladies gynécologiques telles que cancers et infections est mauvaise lorsqu'il est effectué chez la patiente asymptomatique. Il est justifié tous les 3 ans à partir de 21 ans dans le cadre du dépistage du cancer du col utérin. De plus, le caractère intrusif de l'examen vaginal parfois vécu comme traumatisant par les patientes incite à cibler les indications à sa pratique. La crainte de cet examen peut en outre se manifester par un évitement des soins. La consultation gynécologique est un espace privilégié pour dépister des prises de risque sur le plan sexuel ou des violences domestiques, mais aussi pour l'exploration de la santé sexuelle globale et la promotion de la santé des femmes.

Vaginal Enterobius vermicularis diagnosed on liquid-based cytology during Papanicolaou test cervical cancer screening: A report of two cases and a review of the literature.

Enterobiasis is one of the most common human parasitic infections. It is considered an intestinal parasite, but cases of extra-intestinal affections exist, notably infections of the female genital tract. Enterobius vermicularis (EV) eggs (or ova) have been found in the cervical smears of two patients in our institute during the last 16 years. No gynaecological or gastrointestinal symptoms were reported, and there was no known intestinal infection in these two cases. A review of the available literature revealed rare cases of vaginal enterobiasis, with a wide range of clinical presentations, many patients being asymptomatic. The diagnosis may sometimes be difficult, mainly because of the lack of clinical suspicion. However, cytological identification of EV in cervico-vaginal smears is important, especially when considering the risk of ascending infections of the genital tract associated with severe complications.

Impact of HPV vaccination with Gardasil® in Switzerland.

BACKGROUND: Gardasil®, a quadrivalent vaccine targeting low-risk (6, 11) and high-risk (16, 18) human papillomaviruses (HPV), has been offered to 11-14 year-old schoolgirls in Switzerland since 2008. To evaluate its success and its potential impact on cervical cancer screening, HPV genotypes were examined in 18-year-old girls five years later (sub-study 1) and in outpatients participating to cervical cancer screening before and after vaccine implementation (sub-study 2). METHODS: For sub-study 1, 3726 females aged 18 in 2013 were invited to fill a questionnaire on personal demographics and HPV risk factors and to provide a self-collected cervicovaginal sample for HPV genotyping and Chlamydia trachomatis PCR. Personal data were evaluated by univariable and multivariable statistics. In sub-study 2, the proportion of the vaccine-type HPV among anogenital HPV was examined with archived genotyping data of 8039 outpatients participating to cervical cancer screening from 1999 till 2015. The yearly evolution of this proportion was evaluated by segmented logistic regression. RESULTS: 690 (18.5%) women participated to sub-study 1 and 327 (8.8%) provided a self-collected sample. Prevalence of Chlamydia trachomatis (4.6%) and demographics confirmed that the subjects were representative of sexually-active Swiss young women. Vaccine (five-year coverage: 77.5%) was preferentially accepted by contraceptive-pill users (P = 0.001) and samples were mainly provided by sexually-active subjects (P < 0.001). The proportion (4%) of the vaccine-type HPV in this population was lower than in sub-study 2 outpatients (n = 849, <26 years old) in the pre-vaccine era (25.7%). The proportion of the high-risk vaccine-type HPV decreased significantly (59%, P = 0.0048) in the outpatients during the post-vaccine era, yet this decrease was restricted to those aged less than 26 years (n = 673, P < 0.0001). CONCLUSIONS: The low proportion of vaccine-type HPV in 18-year-old females and its rapid decrease in young women participating to cervical cancer screening extend the success of HPV vaccination to Switzerland. Our data suggest that cervical cancer screening is now entering a stage of reduced proportion of HPV16 and/or 18 in samples reported positive by cytology. In view of the high likelihood of reduced clinical specificity of cytology, primary screening modalities involving HPV testing and cytology should now be re-evaluated in Switzerland.

Adolescents' contraception continuation in Switzerland: a prospective observational study.

BACKGROUND: Securing the adherence over time to contraception by adolescent girls is a challenge. Until now little was known about this topic in Switzerland. The aim of our study was to determine contraceptive continuation rates among adolescents in this country and assess possible predictive factors for discontinuation. METHODS: A prospective observational cohort study of 12- to 19-year-old girls starting contraception was performed. Patients were interviewed again after 1 year by phone, email or postal mail. RESULTS: A total of 204 patients were included, of whom 85.8% chose a combined oestrogen-progestogen pill. The answer rate 1 year later was 71%. Among these, continuation of the initially prescribed contraceptive method was observed in 73.1%. Factors statistically affecting the continuation rate were the initial contraceptive method, the place of residence and sexual activity after 1 year. Classification of contraceptive methods in decreasing order of continuation rate was the following: long acting reversible contraception (LARC) methods, oestrogen-progestogen pills, injections, progestogen pills, patches and rings. Major reasons reported for stopping the prescribed contraceptive method were ending sexual relations (54.3%), developing side effects (34.3%) or changing to another contraceptive method (22.9%). Neither age, nationality, smoking, occupation, nor the legal representative's knowledge of the contraception influenced adherence. CONCLUSION: Contraceptive continuation rate was high among the adolescent population studied. The only predictive factor of discontinuation was the contraceptive method. Our study also reveals that respecting teenagers' confidentiality is essential as it does not negatively impact the continuation rate. The significant impact of the type of contraception on continuation rates stresses the importance of individualised counselling.

Human papillomavirus (HPV) contamination of gynaecological equipment.

OBJECTIVE: The gynaecological environment can become contaminated by human papillomavirus (HPV) from healthcare workers' hands and gloves. This study aimed to assess the presence of HPV on frequently used equipment in gynaecological practice. METHODS: In this cross-sectional study, 179 samples were taken from fomites (glove box, lamp of a gynaecological chair, gel tubes for ultrasound, colposcope and speculum) in two university hospitals and in four gynaecological private practices. Samples were collected with phosphate-buffered saline-humidified polyester swabs according to a standardised pattern, and conducted twice per day for 2 days. The samples were analysed by a semiquantitative real-time PCR. Statistical analysis was performed using Pearson's χ(2) test and multivariate regression analysis. RESULTS: Thirty-two (18%) HPV-positive samples were found. When centres were compared, there was a higher risk of HPV contamination in gynaecological private practices compared with hospitals (OR 2.69, 95% CI 1.06 to 6.86). Overall, there was no difference in the risk of contamination with respect to the time of day (OR 1.79, 95% CI 0.68 to 4.69). When objects were compared, the colposcope had the highest risk of contamination (OR 3.02, 95% CI 0.86 to 10.57). CONCLUSIONS: Gynaecological equipment and surfaces are contaminated by HPV despite routine cleaning. While there is no evidence that contaminated surfaces carry infectious viruses, our results demonstrate the need for strategies to prevent HPV contamination. These strategies, based on health providers' education, should lead to well-established cleaning protocols, adapted to gynaecological rooms, aimed at eliminating HPV material.

[Human papillomavirus: what do young people really know about it?]. / Papillomavirus humain: que savent les jeunes?

It has been five years since the introduction of the HPV vaccination campagnes in Switzerland. Although a majority of young people age 16 to 20 have heard about the HPV, many false beliefs regarding this virus and its effects persist, and a lot of young people feel insufficiently informed about it. The surveyed population is conscious that the HPV is a sexually transmitted infection; however, more than 80% do not know that men can also be infected. Preventive information must be improved to target men too, in order that everybody understands that men, as well as women, are concerned by this infection. Medical consultations are the ideal setting to inform young people about the HPV.