British Gynaecological Cancer Society (BGCS) vulval cancer guidelines: An update on recommendations for practice 2023
2023; Elsevier BV; Volume: 292; Linguagem: Inglês
10.1016/j.ejogrb.2023.11.013
ISSN1872-7654
AutoresJo Morrison, Peter Baldwin, Louise Hanna, Adrian Andreou, Lynn Buckley, Lisa Durrant, Katharine Edey, Asma Faruqi, Christina Fotopoulou, Raji Ganesan, K. Hillaby, Alexandra Taylor,
Tópico(s)Clinical practice guidelines implementation
ResumoRecommendations are graded as per the Royal College of Obstetricians and Gynaecologists document. Clinical Governance Advice No. 1: Guidance for the Development of RCOG Green-top Guidelines, available on the RCOG website at: https://www.rcog.org.uk/en/guidelines-research-services/guidelines/clinical-governance-advice-1a/. See Supplementary Table 1 and Supplementary Table 2 for details. Evidence was searched in the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library April 2022, Issue 4), MEDLINE and EMBASE up to April 2022, with top up searches up to July 2023, registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. This guideline is for healthcare professionals who care for women, non-binary and trans people with vulval cancer and related conditions. Within this document we use the terms woman and women's health. However, it is important to acknowledge that it is not only women for whom it is necessary to access women's health and reproductive services in order to maintain their gynaecological health and reproductive wellbeing. Gynaecological and obstetric services and delivery of care must therefore be appropriate, inclusive and sensitive to the needs of those individuals whose gender identity does not align with the sex they were assigned at birth. The purpose of this guideline update is to collate evidence and propose evidence-based guidelines for the management and diagnosis of adult patients with vulval carcinoma treated in the UK. Malignant melanoma may present via similar routes and will be discussed. The reader is referred to the Ano-uro-genital Mucosal Melanoma Guideline [[1]Gore M, Bagwan I, Board R, Capper S, Coupland S, Lalondrelle S, et al. Ano-uro-genital Mucosal Melanoma. Full Guideline: Melanoma Focus; 2018 [Available from: https://melanomafocus.com/wp-content/uploads/2018/05/2_Full-Guideline-V.7.4-FINAL-29.5.18.pdf.Google Scholar] for more detailed recommendations. The management of vulval sarcoma is outside of the scope of this guideline. The guideline development process is detailed below:•Chair, officers, council and guidelines committee (GC) nominated a lead for each guideline topic;•Lead then identified a team called the guideline team (GT) to develop the 1st draft;•1st draft was submitted to the GC;•GC approved draft and recommended changes;•Changes were accepted by the GT who produced the guidelines;•2nd draft was then submitted to council members and officers;•Council and officers approved 2nd draft and recommended changes;•Changes were then accepted by GC and GT;•3rd draft was sent to national and international peer review;•GC and GT then made changes based on peer review comments;•4th draft was sent back to council for approval;•4th draft was sent to BGCS members for feedback;•GC and GT then made changes based on members' feedback;•5th draft was sent to public consultation including patient support groups;•GC and GT then made changes based on non-members' feedback;•Final draft approved by council and officers. Vulval cancer is a rare disease with ∼1400 new cases registered per year in the UK during (2016–18), representing less than 1 % of all new cancer cases registered in females. In the UK it is the 20th most common female cancer and 4th most common gynaecological cancer, with a crude incidence rate of 3.9/100 000 [[2]Cancer Research UK. Vulval Cancer Incidence [Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/vulval-cancer/incidence.Google Scholar]. The incidence in the UK is highest in females over 90 years of age. The incidence of vulval cancer has increased by 17 % since the early 1990s, mainly due to an increase in incidence of over 50 % in those under 60 years [[3]Lai J. Elleray R. Nordin A. Hirschowitz L. Rous B. Gildea C. et al.Vulval cancer incidence, mortality and survival in England: age-related trends.BJOG. 2014; 121 (discussion 39): 728-738Crossref PubMed Scopus (71) Google Scholar], and projected to rise by another 5 % over the next 15–20 years [[2]Cancer Research UK. Vulval Cancer Incidence [Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/vulval-cancer/incidence.Google Scholar]. While most vulval cancer is still diagnosed in women aged over 70 years, age standardized rates have increased by over 100 % within the 50–59 cohort between 1993 and 1995 and 2016–2018. This increase in incidence in younger cohorts is most likely due to an increase in human papilloma virus (HPV)-related VIN within those groups [[3]Lai J. Elleray R. Nordin A. Hirschowitz L. Rous B. Gildea C. et al.Vulval cancer incidence, mortality and survival in England: age-related trends.BJOG. 2014; 121 (discussion 39): 728-738Crossref PubMed Scopus (71) Google Scholar]. However, Dutch Registry data demonstrate an almost two-fold rise in incidence of lichen sclerosus between 1991 and 2011, so the rise may not be solely HPV-related [[4]Bleeker M. Visser P. Overbeek L. van Beurden M. Berkhof J. Lichen sclerosus: incidence and risk of vulvar squamous cell carcinoma.Cancer Epidemiol Biomark Prev. 2016; Crossref PubMed Scopus (36) Google Scholar]. Approximately 90 % of vulval cancers are squamous cell carcinomas, with the main risk factors for disease being infection with high-risk HPV and inflammation due to vulval dermatoses, such as lichen sclerosus and lichen planus. The remaining 10 % are made up of primary vulval melanoma, basal cell carcinoma, Bartholin's gland carcinoma, adenocarcinoma, and rarely, sarcoma. In 2017–19 there were 469 vulval cancer-related deaths per year in the UK, representing less than 1 % of all cancer-related deaths in females that year. The mortality rate increases with age with the majority of deaths occurring in women over 70 years of age. However, mortality rates overall have reduced by 38 % since the 1970s [[2]Cancer Research UK. Vulval Cancer Incidence [Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/vulval-cancer/incidence.Google Scholar], and in the over 70s deaths have reduced by 30 % since the early 1990s [[5]Cancer Research UK. Vulval Cancer Mortality Data [Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/vulval-cancer/mortality.Google Scholar]. The increased incidence of squamous cell vulval cancer is mirrored by data from Germany and Australia, where rates have nearly doubled in the past decade [6Buttmann-Schweiger N. Klug S.J. Luyten A. Holleczek B. Heitz F. du Bois A. et al.Incidence patterns and temporal trends of invasive nonmelanotic vulvar tumors in Germany 1999–2011. A population-based cancer registry analysis.PLoS One. 2015; 10: e0128073Crossref PubMed Scopus (53) Google Scholar, 7Pils S. Gensthaler L. Alemany L. Horvat R. de Sanjose S. Joura E.A. HPV prevalence in vulvar cancer in Austria.Wien Klin Wochenschr. 2017; 129: 805-809Crossref PubMed Scopus (3) Google Scholar]. It is likely to be decades before the effects of HPV vaccination on reducing vulval cancer are known; nevertheless, it is anticipated that a decrease will occur, as HPV16 is the most common viral subtype associated with vulval cancer. Unfortunately, this is likely to be less dramatic than for other HPV-related malignancies, as vulval dermatoses account for a large proportion of vulval cancers. Globally, there were 45,240 new vulval cancers in 2020, with an age-standardised incidence rate of 0.85/100,000 females [[8]Ferlay J, Ervik M, Lam F, Colombet M, L M, Piñeros M, et al. Global Cancer Observatory: Cancer Today Lyon, Frabce: International Agency for Research on Cancer; 2020 [Available from: https://gco.iarc.fr/today/data/factsheets/cancers/21-Vulva-fact-sheet.pdf.Google Scholar]. Incidence rates were highest in Western Europe, at 2.4 per 100,000, although age-standardised mortality is lower (0.49/100,000) than in Eastern (0.89/100,000) and Middle Africa (0.85/100,000). For a summary of recommendations on prevention and screening, please see Table 1. The most common type of vulval cancer is squamous cell carcinoma (VSCC). This may be HPV-independent, developing on a background of vulval dermatoses (lichen sclerosus and lichen planus) and differentiated vulval intraepithelial neoplasia (dVIN), or it may HPV-dependent with a background of usual type vulval intraepithelial neoplasia (uVIN), more commonly referred to as a high grade squamous intraepithelial lesion (HSIL) outside of the UK. Please see below for a description of pathological classification systems. The combination of the two may increase the risk as the risk of developing VSCC in women with VIN and LS was 19 % in one Dutch cohort study over 10 years [[4]Bleeker M. Visser P. Overbeek L. van Beurden M. Berkhof J. Lichen sclerosus: incidence and risk of vulvar squamous cell carcinoma.Cancer Epidemiol Biomark Prev. 2016; Crossref PubMed Scopus (36) Google Scholar].Table 1Recommendations for prevention and screening.RecommendationGrade of recommendationHPV vaccination is likely to reduce the incidence of uVIN and HPV-related vulval SCC in the future.Grade CImiquimod, cidofovir, surgical excision and laser ablation are treatment options for high grade VIN with similar efficacy. However, cidofovir is currently unlicensed for use in uVIN.Grade AGood control of lichen planus and lichen sclerosus with maintenance ultra-potent topical steroids improves symptoms and may reduce the incidence of developing SCC.Grade CThere is currently no proven screening test to prevent vulval cancer.Grade DWomen with multi-focal HPV related disease should be followed up with colposcopy of the lower genital tract and digital ano-rectal examination with prompt referral should symptoms of anal cancer develop.Grade DWomen with multicentric HPV-related disease should be offered HIV testing.Grade DWomen with high grade uVIN should be followed up with careful clinical inspection ±vulvoscopy.Grade DWomen with uncomplicated lichen sclerosus or lichen planus can be followed up in primary care and once symptoms are controlled and confident of self-management, 12-monthly review is suggested.Grade CWomen with lichen sclerosus who develop new focal lesions should be referred to secondary care via a Cancer Wait Pathway if these do not start to respond to nightly ultra-high potency steroids within 1–2 weeks.Grade C Open table in a new tab The majority of HPV-related VSCC is caused by HPV16 [[7]Pils S. Gensthaler L. Alemany L. Horvat R. de Sanjose S. Joura E.A. HPV prevalence in vulvar cancer in Austria.Wien Klin Wochenschr. 2017; 129: 805-809Crossref PubMed Scopus (3) Google Scholar]. HPV vaccination will likely provide significant protection to those vaccinated prior to HPV exposure. However, since the natural history of developing VIN and vulval carcinoma is often decades from original exposure, the effects of HPV vaccination programmes are likely to take many years to become apparent. HPV vaccination has already had a significant effect on rates of genital warts and cervical intraepithelial neoplasia in vaccinated populations Bergman et al., 2019 [[9]Bergman H. Buckley B. Villanueva G. Petkovic J. Garritty C. Lutje V. et al.Comparison of different human papillomavirus (HPV) vaccine types and dose schedules for prevention of HPV-related disease in males and females.Cochrane Database Syst Rev. 2019; 11 (CD013479)https://doi.org/10.1002/14651858.CD013479Crossref Scopus (89) Google Scholar]. However, the time to development from exposure is much shorter for benign warts than for usual type vulval high-grade intraepithelial neoplasia (uVIN), the pre-malignant lesion for HPV-related VSCC therefore, these benefits will take longer to realise. Prophylactic vaccination against HPV6, 11, 16 and 18 has been shown to result in a substantial decrease in the development of preinvasive vulval lesions and it is anticipated that the relative proportions of HPV- and non-HPV-associated malignancy may alter as vaccine coverage increases and with the use of vaccines protecting against additional HPV types [[10]Munoz N. Kjaer S.K. Sigurdsson K. Iversen O.E. Hernandez-Avila M. Wheeler C.M. et al.Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women.J Natl Cancer Inst. 2010; 102: 325-339Crossref PubMed Scopus (474) Google Scholar]. Evidence on the effect of population-level HPV-vaccination on rates of uVIN are expected shortly from a Cochrane review of observational studies [[11]Henschke N. Bergman H. Villanueva G. Loke Y.K. Golder S.P. Crosbie E.J. et al.Effects of human papillomavirus (HPV) vaccination programmes on community rates of HPV-related disease and harms from vaccination.Cochrane Database Syst Rev. 2022; 5Google Scholar]. However, in the US, rates of uVIN in adolescent females (aged 15–19 years) have declined by 21 % per since the introduction of HPV vaccination [[12]Mix J.M. Saraiya M. Senkomago V. Unger E.R. High-grade vulvar, vaginal, and anal precancers among U.S. Adolescents and Young Adults after human papillomavirus vaccine introduction.Am J Prev Med. 2022; 62: 95-99Abstract Full Text Full Text PDF PubMed Google Scholar]. This is on the background of an increase in HPV-associated vulval cancer by 1.2 % per year, especially in women aged 50–59 years (2.6 %) and 60–69 years (2.4 %) [[13]Mix J.M. Gopalani S.V. Simko S. Saraiya M. Trends in HPV- and non-HPV-associated vulvar cancer incidence, United States, 2001–2017.Prev Med. 2022; 164107302Crossref PubMed Scopus (4) Google Scholar]. Studies are ongoing to determine whether HPV-vaccination following diagnosis of uVIN can reduce the risk of recurrence or development of SCC. Studies looking at the effect of HPV vaccination on development of CIN in those already exposed to HPV did not suggest a significant benefit overall in the incidence of CIN2+ [[14]Arbyn M. Xu L. Simoens C. Martin-Hirsch P.P.L. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors.Cochrane Database Syst Rev. 2018; 5PubMed Google Scholar]). In contrast, retrospective subgroup analysis of a randomised control trial (RCT) of HPV vaccination demonstrated a 46.2 % reduction in incidence of further HPV-related disease (95 % confidence interval (CI) 22.5 % to 63.2 %) in those vaccinated prior to initial treatment for HPV-related disease, compared to the unvaccinated cohort [[15]Joura E.A. Garland S.M. Paavonen J. Ferris D.G. Perez G. Ault K.A. et al.Effect of the human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: retrospective pooled analysis of trial data.BMJ. 2012; 344: e1401Crossref PubMed Scopus (246) Google Scholar]. Other studies suggest that HPV vaccination after treatment for CIN may reduce the risk of recurrence and other HPV-related disease [[16]Ghelardi A. Parazzini F. Martella F. Pieralli A. Bay P. Tonetti A. et al.SPERANZA project: HPV vaccination after treatment for CIN2+.Gynecol Oncol. 2018; 151: 229-234Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] and RCTs to look at this specifically are on-going. A systematic review of HPV-vaccination in patients treated for HPV-related disease included 16 studies with 21,472 participants randomised to HPV vaccination at the time of surgical treatment versus surgical treatment alone [[17]Di Donato V. Caruso G. Bogani G. Cavallari E.N. Palaia G. Perniola G. et al.HPV vaccination after primary treatment of HPV-related disease across different organ sites: A multidisciplinary comprehensive review and meta-analysis.Vaccines (Basel). 2022; 10Google Scholar]. Whilst the rates of recurrence of CIN2+ and anal intraepithelial neoplasia (AIN) were lower (odds ratio (OR) for CIN2+ 0.31 (95 % CI 0.14 to 0.72; 5 prospective studies; 18,077 participants) and AIN (13.6 % unvaccinated versus 30.7 % vaccinated; P = 0.005;1 study; 202 participants [[18]Swedish K.A. Factor S.H. Goldstone S.E. Prevention of recurrent high-grade anal neoplasia with quadrivalent human papillomavirus vaccination of men who have sex with men: a nonconcurrent cohort study.Clin Infect Dis. 2012; 54: 891-898Crossref PubMed Scopus (157) Google Scholar], no differences were observed in rates of ano-genital warts (OR 1.04, 95 % CI 0.65 to 1.65; 2 studies; 656 participants) or VIN/VaIN (OR 0.81, 95 % CI 0.42 to 1.55; 2 studies; 740 participants). There is not sufficient evidence to support HPV vaccination for secondary prevention. A systematic review of the natural history of high-grade VIN (both uVIN and dVIN) found 97 articles including a total of 3,322 women. There was an occult cancer rate of 3.2 % in those with suspected high-grade VIN and 3.3 % went on to develop VSCC during follow up [[19]van Seters M. van Beurden M. de Craen A.J.M. Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients.Gynecol Oncol. 2005; 97: 645-651Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Of 88 women with untreated high-grade VIN, 9 % went on to develop VSCC over 12 to 96 months. However, they concluded that the progression rate to VSCC is likely to be over-estimated. A Cochrane review of intervention for treatment of uVIN examined effects of imiquimod, cidofovir, indole-3 carbinol and surgery [[20]Lawrie T.A. Nordin A. Chakrabarti M. Bryant A. Kaushik S. Pepas L. Medical and surgical interventions for the treatment of usual-type vulval intraepithelial neoplasia.Cochrane Database Syst Rev. 2016; 1: CD011837Google Scholar]. They found that topical imiquimod, an immune modulator, was more effective than placebo in achieving a response (complete or partial) to treatment 5–6 months after randomisation (risk ratio (RR) 11.95, 95 % confidence interval (CI) 3.21 to 44.51; high-certainty evidence). A complete response occurred in 58 % of women in the imiquimod groups and none in the placebo groups (RR 14.40, 95 % CI 2.97 to 69.80). Persistent responses after 12 months were present in just over a third of women. Only one study reported vulval cancer rates at 12 months follow up (1/24 and 2/23 in imiquimod and placebo groups, respectively). Adverse events were more common with imiquimod than placebo (RR 7.77, 95 % CI 1.61 to 37.36; high-certainty evidence). One very small, long-term follow-up study of those with complete response to imiquimod demonstrated very low recurrence rates of uVIN [[21]Terlou A. van Seters M. Ewing P.C. Aaronson N.K. Gundy C.M. Heijmans-Antonissen C. et al.Treatment of vulvar intraepithelial neoplasia with topical imiquimod: Seven years median follow-up of a randomized clinical trial.Gynecol Oncol. 2011; 121: 157-162Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar]. In one small observational study, smoking reduced the response rates to imiquimod, although this association was not seen in a much larger RCT [22Harvey G. Pontefract D. Hughes B.R. Brinkmann D. Christie C. Impact of smoking on imiquimod response in patients with vulval intraepithelial neoplasia.Clin Exp Dermatol. 2019; 44: e140-e144Crossref PubMed Scopus (3) Google Scholar, 23Tristram A. Hurt C.N. Madden T. Powell N. Man S. Hibbitts S. et al.Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT(3)VIN): a multicentre, open-label, randomised, phase 2 trial.Lancet Oncol. 2014; 15: 1361-1368Abstract Full Text Full Text PDF PubMed Google Scholar]. Complete response rates after 6 months were similar for a 16-week course of imiquimod and cidofovir (imiquimod 45 % and cidofovir 46 %; RR 1.00, 95 % CI 0.73 to 1.37; moderate-certainty evidence). A follow up study found that responses for complete responders were maintained after 18 months, especially in the cidofovir group (94 % for cidofovir (95 % CI 78.2 to 98.5) versus 71.6 % for imiquimod (95 % CI 52.0 to 84.3)) [[24]Hurt C.N. Jones S. Madden T.A. Fiander A. Nordin A.J. Naik R. et al.Recurrence of vulval intraepithelial neoplasia following treatment with cidofovir or imiquimod: results from a multicentre, randomised, phase II trial (RT3VIN).BJOG. 2018; 125: 1171-1177Crossref PubMed Scopus (2) Google Scholar]. Side effects, mainly headache, fatigue and discontinuation due to pain, were slightly more common with imiquimod than cidofovir. Topical cidofovir is currently not licenced for use in uVIN in the UK. The same Cochrane review looked at evidence for surgical treatment of uVIN and found low-quality evidence from the better studies where data were adjusted for confounders [[20]Lawrie T.A. Nordin A. Chakrabarti M. Bryant A. Kaushik S. Pepas L. Medical and surgical interventions for the treatment of usual-type vulval intraepithelial neoplasia.Cochrane Database Syst Rev. 2016; 1: CD011837Google Scholar]. There was little to no difference in the risk of VIN recurrence between surgical excision and laser vaporisation (51 % (37/70) of women overall, at a median of 14 months). Recurrence was, unsurprisingly, more common in those with multifocal uVIN (66 % versus 34 %). There was only very low-certainty evidence for other treatments including photodynamic therapy, Cavitron ultrasonic surgical aspiration and loop electrosurgical excision. There are no published data to support the use of plasmajet. In the small surgical studies included in the Cochrane review, vulval cancer occurred in 11 women (15.1 %) overall at a median of 71.5 months (9to259months). They concluded that if cancer is suspected despite a biopsy showing uVIN only, 'surgical excision remains the treatment of choice'. However, if an occult cancer was not suspected, treatment of uVIN can be individualised, taking into account women's preferences and the site and extent of disease, using a combination approach to optimise outcomes, which can include conservative treatment and close follow up with vulvoscopy in selected patients. It should be emphasised that the volume of data in this area, as with much of the vulval field, is limited. The 2016 American College of Obstetricians and Gynecologists guidelines note that recurrence rates are lower, but still high, if margins are clear (R0 – defined as a 1 mm free margin on microscopic examination) and recommend drawing excision margins of 0.5–1 cm around lesions [[25]Gynecologists CONACoOa Management of vulvar intraepithelial neoplasia.Obstet Gynecol. 2016; 128: e178-e182Crossref PubMed Scopus (42) Google Scholar]. However, these guidelines pre-date recent recommendations of more conservative margins with invasive vulval squamous cell cancer and malignant melanoma, and note that this "may be altered to avoid injury to the clitoris, urethra, anus, or other critical structures". If margins are involved by uVIN, in the absence of invasion within the lesion, options include observation, re-excision or consideration of imiquimod treatment, taking into account the patient's wishes, general condition and anatomy. A more recent RCT demonstrated non-inferiority of imiquimod versus surgery for treatment of uVIN [[26]Trutnovsky G. Reich O. Joura E.A. Holter M. Ciresa-König A. Widschwendter A. et al.Topical imiquimod versus surgery for vulvar intraepithelial neoplasia: a multicentre, randomised, phase 3, non-inferiority trial.Lancet. 2022; 399: 1790-1798Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Complete clinical response rates were seen in 37/46 patients (80 %) in the imiquimod group compared with 41/52 patients (79 %) after one surgical intervention (difference in proportion –0·016, 95 % CI –0·15 to 0·18; p = 0·0056). No one treated per protocol imiquimod group developed invasive cancer during the study. A systematic review of HPV vaccination for the treatment of VIN and vaginal intra-epithelial neoplasia (VaIN) found only seven studies that fit their inclusion criteria. All were case series and at high risk of bias, so the evidence was of very low quality and very uncertain [[27]Bryan S. Barbara C. Thomas J. Olaitan A. HPV vaccine in the treatment of usual type vulval and vaginal intraepithelial neoplasia: a systematic review.BMC Womens Health. 2019; 19: 3Crossref PubMed Scopus (9) Google Scholar]. Lichen sclerosus is associated with an increased lifetime risk of developing vulval cancer, with estimates of the risk varying between 2.2 and 6.6 % depending on the series [4Bleeker M. Visser P. Overbeek L. van Beurden M. Berkhof J. Lichen sclerosus: incidence and risk of vulvar squamous cell carcinoma.Cancer Epidemiol Biomark Prev. 2016; Crossref PubMed Scopus (36) Google Scholar, 28Cooper S.M. Gao X.H. Powell J.J. Wojnarowska F. Does treatment of vulvar lichen sclerosus influence its prognosis?.Arch Dermatol. 2004; 140: 702-706Crossref PubMed Scopus (209) Google Scholar]). A recent systematic review looked at the incidence of developing vulval cancer in women with vulvovaginal LS and LP [[29]Vieira-Baptista P. Perez-Lopez F.R. Lopez-Baena M.T. Stockdale C.K. Preti M. Bornstein J. Risk of development of vulvar cancer in women with lichen sclerosus or lichen planus: a systematic review.J Low Genit Tract Dis. 2022; Crossref Scopus (10) Google Scholar]. They found 14 studies on vulval LS, which included 14,030 women without a previous diagnosis of vulval neoplasia. During follow-up 2.2 % (range 0 % to 2.7 %) went on to develop vulval cancer,1.2 % dVIN, and 0.4 % uVIN. For those with LP, there were eight studies of 14,268 women; 0.3 % went on to develop vulval cancer, 2.5 % dVIN. Vulval cancer was preceded by dVIN in around half (52 %) of women in one study and the risk of dVIN progressing to invasive disease was 18.1 %, albeit based on only 11 women with dVIN [28Cooper S.M. Gao X.H. Powell J.J. Wojnarowska F. Does treatment of vulvar lichen sclerosus influence its prognosis?.Arch Dermatol. 2004; 140: 702-706Crossref PubMed Scopus (209) Google Scholar, 30Meani R. Howard A. Veysey E. Incidence of vulval squamous cell carcinoma in women with vulval lichen sclerosus in an Australian tertiary referral centre.Australas J Dermatol. 2019; 60: 76-77Crossref PubMed Scopus (5) Google Scholar]. However, these data are not based on population-level data, and lichen sclerosus is frequently under-diagnosed, so these data are likely to be at high risk of bias and over-estimate the risk. Data from non-randomised studies suggest that good control of LS/LP with ultra-potent topical steroids (such as Clobetasol 17- propionate 0.05 %) and maintenance treatment when asymptomatic (e.g., 1-2x weekly) may reduce the risk of progression to SCC [28Cooper S.M. Gao X.H. Powell J.J. Wojnarowska F. Does treatment of vulvar lichen sclerosus influence its prognosis?.Arch Dermatol. 2004; 140: 702-706Crossref PubMed Scopus (209) Google Scholar, 29Vieira-Baptista P. Perez-Lopez F.R. Lopez-Baena M.T. Stockdale C.K. Preti M. Bornstein J. Risk of development of vulvar cancer in women with lichen sclerosus or lichen planus: a systematic review.J Low Genit Tract Dis. 2022; Crossref Scopus (10) Google Scholar, 31Renaud-Vilmer C. Cavelier-Balloy B. Porcher R. Dubertret L. Vulvar lichen sclerosus: effect of long-term topical application of a potent steroid on the course of the disease.Arch Dermatol. 2004; 140: 709-712Crossref PubMed Scopus (0) Google Scholar, 32Lee A. Bradford J. Fischer G. Long-term management of adult vulvar lichen sclerosus: a prospective cohort study of 507 women.JAMA Dermatol. 2015; 151: 1061-1067Crossref PubMed Scopus (230) Google Scholar]. There are yet no RCT level data to support this, although control of active LS/LP should be recommended to improve symptoms, reduce scarring and may reduce the risk of developing malignancy. Often women are fearful of using 'too much' steroid cream and they should be reassured that appropriate usage (less than 30 g tube of ultra-potent steroid ointment/cream, such as Dermovate (clobetasol propionate 0.05 %), over a 3-month period) is unlikely to be harmful and may be of benefit, both to scarring/vulval appearance as well as longer term risk of cancer. For the same reasons, women should be advised to avoid irritants that can exacerbate LS/LP, e.g., detergents, such as soap, synthetic underwear, plastic pads, wipes or topical cream/oils. Unlike cutaneous melanomas, vulval mucosal melanomas are not related to ultraviolet light exposure. A small minority may be related to c-kit mutations, which are more common than in cutaneous melanoma [[33]Johnson D.B. Pectasides E. Feld E. Ye F. Zhao S. Johnpulle R. et al.Sequencing treatment in BRAFV600 mutant melanoma: Anti-PD-1 before and After BRAF inhibition.J Immunother. 2017; 40: 31-35Crossref PubMed Scopus (33) Google Scholar]. There are currently no proven screening tests for vulval carcinoma. Those with known VIN and lichen sclerosus/lichen planus are at higher risk. Rates of progression to vulval carcinoma were 5.7 % in a 14-year series for uVIN [[34]van de Nieuwenhof H.P. Massuger L.F. van der Avoort I.A. Bekkers R.L. Casparie M. Abma W. et al.Vulvar squamous cell carcinoma development after diagnosis of VIN increases with age.Eur J Cancer. 2009; 45: 851-856Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar]). Some studies have demonstrated a 2.6––6.6 % overall risk for those with lichen sclerosus/lichen planus [28Cooper S.M. Gao X.H. Powell J.J. Wojnarowska F. Does treatment of vulvar lichen sclerosus influence its prognosis?.Arch Dermatol. 2004; 140: 702-706Crossref PubMed Scopus (209) Google Scholar, 35Maclean A.B. Jones R.W. Scurry J. Neill S. Vulvar cancer and the need for awareness of precursor lesions.J Low Genit Tract Dis. 2009; 13: 115-117Crossref PubMed Scopus (12) Google Scholar], which is increased significantly when associated with VIN [[4]Bleeker M. Visser P. Overbeek L. van Beurden M. Berkhof J. Li
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