Article Vulve

European Journal of Obstetrics and Gynecology 292 (2024) 210–238
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.journals.elsevier.com/european-journal-of-obstetrics-and-gynecology-and-
reproductive-biology
Expert Opinion
British Gynaecological Cancer Society (BGCS) vulval cancer guidelines: An

update on recommendations for practice 2023
Jo Morrison a, *, Peter Baldwin b, Louise Hanna c, Adrian Andreou d, Lynn Buckley e, f,
Lisa Durrant g, Katharine Edey h, Asma Faruqi i, Christina Fotopoulou i, j, Raji Ganesan k,
Kathryn Hillaby l, Alexandra Taylor m
a
Department of Gynaecological Oncology, GRACE Centre, Musgrove Park Hospital, Somerset NHS Foundation Trust, Taunton TA1 5DA, UK
b
Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
c
Department of Oncology, Velindre Cancer Centre, Whitchurch, Cardiff CF14 2TL, UK
d
Department of Radiology, Royal United Hospitals Bath NHS Foundation Trust, Combe Park, Bath BA1 3NG, UK
e
Department of Gynae-Oncology, Castle Hill Hospital, Hull University Teaching Hospitals NHS Trust, East Yorkshire HU16 5JQ, UK
f
Perci Health Ltd, 1 Vincent Square, London SW1P 2PN, UK
g
Radiotherapy Department, Beacon Centre, Musgrove Park Hospital, Somerset NHS Foundation Trust, Taunton TA1 5DA, UK
h
Centre for Women’s Health Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter EX2 5DW, UK
i
Department of Cellular Pathology, The Royal London Hospital, Barts Health NHS Trust, London E1 2ES, UK
j
Gynaecologic Oncology, Imperial College London Faculty of Medicine, London SW7 2DD, UK
k
Department of Cellular Pathology, Birmingham Women’s Hospital, Birmingham B15 2TG, UK
l
Department Gynaecological Oncology, Cheltenham General Hospital, Gloucestershire, Hospitals NHS Foundation Trust, GL53 7AN, UK
m
The Royal Marsden NHS Foundation Trust, Fulham Road, London SW3 6JJ, UK
A R T I C L E I N F O
Keywords:
Vulval cancer
Vulvar cancer
Vulval/vulvar intraepithelial neoplasia
Lichen sclerosus
High grade intraepithelial lesion
Human papiloma virus
National guideline
Introduction Controlled Trials (CENTRAL, The Cochrane Library April 2022, Issue 4),
MEDLINE and EMBASE up to April 2022, with top up searches up to July
Grades of recommendations 2023, registers of clinical trials, abstracts of scientific meetings, refer
ence lists of included studies and contacted experts in the field.
Recommendations are graded as per the Royal College of Obstetri This guideline is for healthcare professionals who care for women,
cians and Gynaecologists document. Clinical Governance Advice No. 1: non-binary and trans people with vulval cancer and related conditions.
Guidance for the Development of RCOG Green-top Guidelines, available Within this document we use the terms woman and women’s health.
on the RCOG website at: However, it is important to acknowledge that it is not only women for
https://www.rcog.org.uk/en/guidelines-research-services/gu whom it is necessary to access women’s health and reproductive services
idelines/clinical-governance-advice-1a/. See Supplementary Table 1 in order to maintain their gynaecological health and reproductive
and Supplementary Table 2 for details. wellbeing. Gynaecological and obstetric services and delivery of care
Evidence was searched in the Cochrane Central Register of must therefore be appropriate, inclusive and sensitive to the needs of
* Corresponding author.
E-mail address: [email protected] (J. Morrison).
URL: https://www.percihealth.com/ (L. Buckley).
https://doi.org/10.1016/j.ejogrb.2023.11.013
Received 3 November 2023; Accepted 10 November 2023
Available online 15 November 2023
0301-2115/© 2023 Elsevier B.V. All rights reserved.
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J. Morrison et al. European Journal of Obstetrics & Gynecology and Reproductive Biology 292 (2024) 210–238
those individuals whose gender identity does not align with the sex they the past decade [6,7]. It is likely to be decades before the effects of HPV
were assigned at birth. vaccination on reducing vulval cancer are known; nevertheless, it is
The purpose of this guideline update is to collate evidence and pro anticipated that a decrease will occur, as HPV16 is the most common
pose evidence-based guidelines for the management and diagnosis of viral subtype associated with vulval cancer. Unfortunately, this is likely
adult patients with vulval carcinoma treated in the UK. Malignant to be less dramatic than for other HPV-related malignancies, as vulval
melanoma may present via similar routes and will be discussed. The dermatoses account for a large proportion of vulval cancers.
reader is referred to the Ano-uro-genital Mucosal Melanoma Guideline Globally, there were 45,240 new vulval cancers in 2020, with an age-
[1] for more detailed recommendations. The management of vulval standardised incidence rate of 0.85/100,000 females [8]. Incidence
sarcoma is outside of the scope of this guideline. 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/
Guideline development process 100,000) and Middle Africa (0.85/100,000).
The guideline development process is detailed below: Prevention, screening, presentation and diagnosis
• Chair, officers, council and guidelines committee (GC) nominated a Prevention and treatment of pre-disposing conditions
lead for each guideline topic;
• Lead then identified a team called the guideline team (GT) to develop For a summary of recommendations on prevention and screening,
the 1st draft; please see Table 1. The most common type of vulval cancer is squamous
• 1st draft was submitted to the GC; cell carcinoma (VSCC). This may be HPV-independent, developing on a
• GC approved draft and recommended changes; background of vulval dermatoses (lichen sclerosus and lichen planus)
• Changes were accepted by the GT who produced the guidelines; and differentiated vulval intraepithelial neoplasia (dVIN), or it may
• 2nd draft was then submitted to council members and officers; HPV-dependent with a background of usual type vulval intraepithelial
• Council and officers approved 2nd draft and recommended changes; neoplasia (uVIN), more commonly referred to as a high grade squamous
• Changes were then accepted by GC and GT; intraepithelial lesion (HSIL) outside of the UK. Please see below for a
• 3rd draft was sent to national and international peer review; description of pathological classification systems. The combination of
• GC and GT then made changes based on peer review comments; the two may increase the risk as the risk of developing VSCC in women
• 4th draft was sent back to council for approval; with VIN and LS was 19 % in one Dutch cohort study over 10 years [4].
• 4th draft was sent to BGCS members for feedback;
• GC and GT then made changes based on members’ feedback; HPV-related squamous cell carcinoma
• 5th draft was sent to public consultation including patient support
groups; HPV vaccination. The majority of HPV-related VSCC is caused by HPV16
• GC and GT then made changes based on non-members’ feedback; [7]. HPV vaccination will likely provide significant protection to those
• Final draft approved by council and officers. vaccinated prior to HPV exposure. However, since the natural history of
developing VIN and vulval carcinoma is often decades from original
Background and epidemiology exposure, the effects of HPV vaccination programmes are likely to take
many years to become apparent. HPV vaccination has already had a
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 Table 1
female cancer and 4th most common gynaecological cancer, with a Recommendations for prevention and screening.
crude incidence rate of 3.9/100 000 [2]. The incidence in the UK is Recommendation Grade of
highest in females over 90 years of age. The incidence of vulval cancer recommendation
has increased by 17 % since the early 1990s, mainly due to an increase in
HPV vaccination is likely to reduce the incidence of uVIN Grade C
incidence of over 50 % in those under 60 years [3], and projected to rise and HPV-related vulval SCC in the future.
by another 5 % over the next 15–20 years [2]. While most vulval cancer Imiquimod, cidofovir, surgical excision and laser ablation Grade A
is still diagnosed in women aged over 70 years, age standardized rates are treatment options for high grade VIN with similar
have increased by over 100 % within the 50–59 cohort between 1993 efficacy. However, cidofovir is currently unlicensed for
use in uVIN.
and 1995 and 2016–2018. This increase in incidence in younger cohorts Good control of lichen planus and lichen sclerosus with Grade C
is most likely due to an increase in human papilloma virus (HPV)-related maintenance ultra-potent topical steroids improves
VIN within those groups [3]. However, Dutch Registry data demonstrate symptoms and may reduce the incidence of developing
an almost two-fold rise in incidence of lichen sclerosus between 1991 SCC.
There is currently no proven screening test to prevent Grade D
and 2011, so the rise may not be solely HPV-related [4].
vulval cancer.
Approximately 90 % of vulval cancers are squamous cell carcinomas, Women with multi-focal HPV related disease should be Grade D
with the main risk factors for disease being infection with high-risk HPV followed up with colposcopy of the lower genital tract
and inflammation due to vulval dermatoses, such as lichen sclerosus and and digital ano-rectal examination with prompt referral
lichen planus. The remaining 10 % are made up of primary vulval should symptoms of anal cancer develop.
Women with multicentric HPV-related disease should be Grade D
melanoma, basal cell carcinoma, Bartholin’s gland carcinoma, adeno offered HIV testing.
carcinoma, and rarely, sarcoma. Women with high grade uVIN should be followed up with Grade D
In 2017–19 there were 469 vulval cancer-related deaths per year in careful clinical inspection ±vulvoscopy.
the UK, representing less than 1 % of all cancer-related deaths in females Women with uncomplicated lichen sclerosus or lichen Grade C
planus can be followed up in primary care and once
that year. The mortality rate increases with age with the majority of
symptoms are controlled and confident of self-
deaths occurring in women over 70 years of age. However, mortality management, 12-monthly review is suggested.
rates overall have reduced by 38 % since the 1970s [2], and in the over Women with lichen sclerosus who develop new focal Grade C
70s deaths have reduced by 30 % since the early 1990s [5]. lesions should be referred to secondary care via a Cancer
The increased incidence of squamous cell vulval cancer is mirrored Wait Pathway if these do not start to respond to nightly
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significant effect on rates of genital warts and cervical intraepithelial imiquimod demonstrated very low recurrence rates of uVIN [21]. In one
neoplasia in vaccinated populations Bergman et al., 2019 [9]. However, small observational study, smoking reduced the response rates to imi
the time to development from exposure is much shorter for benign warts quimod, although this association was not seen in a much larger RCT
than for usual type vulval high-grade intraepithelial neoplasia (uVIN), [22,23].
the pre-malignant lesion for HPV-related VSCC therefore, these benefits Complete response rates after 6 months were similar for a 16-week
will take longer to realise. course of imiquimod and cidofovir (imiquimod 45 % and cidofovir
Prophylactic vaccination against HPV6, 11, 16 and 18 has been 46 %; RR 1.00, 95 % CI 0.73 to 1.37; moderate-certainty evidence). A
shown to result in a substantial decrease in the development of pre follow up study found that responses for complete responders were
invasive vulval lesions and it is anticipated that the relative proportions maintained after 18 months, especially in the cidofovir group (94 % for
of HPV- and non-HPV-associated malignancy may alter as vaccine cidofovir (95 % CI 78.2 to 98.5) versus 71.6 % for imiquimod (95 % CI
coverage increases and with the use of vaccines protecting against 52.0 to 84.3)) [24]. Side effects, mainly headache, fatigue and discon
additional HPV types [10]. Evidence on the effect of population-level tinuation due to pain, were slightly more common with imiquimod than
HPV-vaccination on rates of uVIN are expected shortly from a cidofovir. Topical cidofovir is currently not licenced for use in uVIN in
Cochrane review of observational studies [11]. However, in the US, rates the UK.
of uVIN in adolescent females (aged 15–19 years) have declined by 21 % The same Cochrane review looked at evidence for surgical treatment
per since the introduction of HPV vaccination [12]. This is on the of uVIN and found low-quality evidence from the better studies where
background of an increase in HPV-associated vulval cancer by 1.2 % per data were adjusted for confounders [20]. There was little to no differ
year, especially in women aged 50–59 years (2.6 %) and 60–69 years ence in the risk of VIN recurrence between surgical excision and laser
(2.4 %) [13]. vaporisation (51 % (37/70) of women overall, at a median of
Studies are ongoing to determine whether HPV-vaccination 14 months). Recurrence was, unsurprisingly, more common in those
following diagnosis of uVIN can reduce the risk of recurrence or with multifocal uVIN (66 % versus 34 %). There was only very low-
development of SCC. Studies looking at the effect of HPV vaccination on certainty evidence for other treatments including photodynamic ther
development of CIN in those already exposed to HPV did not suggest a apy, Cavitron ultrasonic surgical aspiration and loop electrosurgical
significant benefit overall in the incidence of CIN2+ [14]). In contrast, excision. There are no published data to support the use of plasmajet.
retrospective subgroup analysis of a randomised control trial (RCT) of In the small surgical studies included in the Cochrane review, vulval
HPV vaccination demonstrated a 46.2 % reduction in incidence of cancer occurred in 11 women (15.1 %) overall at a median of
further HPV-related disease (95 % confidence interval (CI) 22.5 % to 71.5 months (9to259months). They concluded that if cancer is suspected
63.2 %) in those vaccinated prior to initial treatment for HPV-related despite a biopsy showing uVIN only, ‘surgical excision remains the
disease, compared to the unvaccinated cohort [15]. Other studies sug treatment of choice’. However, if an occult cancer was not suspected,
gest that HPV vaccination after treatment for CIN may reduce the risk of treatment of uVIN can be individualised, taking into account women’s
recurrence and other HPV-related disease [16] and RCTs to look at this preferences and the site and extent of disease, using a combination
specifically are on-going. A systematic review of HPV-vaccination in approach to optimise outcomes, which can include conservative treat
patients treated for HPV-related disease included 16 studies with 21,472 ment and close follow up with vulvoscopy in selected patients. It should
participants randomised to HPV vaccination at the time of surgical be emphasised that the volume of data in this area, as with much of the
treatment versus surgical treatment alone [17]. Whilst the rates of vulval field, is limited. The 2016 American College of Obstetricians and
recurrence of CIN2+ and anal intraepithelial neoplasia (AIN) were lower Gynecologists guidelines note that recurrence rates are lower, but still
(odds ratio (OR) for CIN2+ 0.31 (95 % CI 0.14 to 0.72; 5 prospective high, if margins are clear (R0 – defined as a 1 mm free margin on
studies; 18,077 participants) and AIN (13.6 % unvaccinated versus microscopic examination) and recommend drawing excision margins of
30.7 % vaccinated; P = 0.005;1 study; 202 participants [18], no dif 0.5–1 cm around lesions [25]. However, these guidelines pre-date recent
ferences were observed in rates of ano-genital warts (OR 1.04, 95 % CI recommendations of more conservative margins with invasive vulval
0.65 to 1.65; 2 studies; 656 participants) or VIN/VaIN (OR 0.81, 95 % CI squamous cell cancer and malignant melanoma, and note that this “may
0.42 to 1.55; 2 studies; 740 participants). There is not sufficient evidence be altered to avoid injury to the clitoris, urethra, anus, or other critical
to support HPV vaccination for secondary prevention. structures”. If margins are involved by uVIN, in the absence of invasion
within the lesion, options include observation, re-excision or consider
Treatment of uVIN. A systematic review of the natural history of high- ation of imiquimod treatment, taking into account the patient’s wishes,
grade VIN (both uVIN and dVIN) found 97 articles including a total of general condition and anatomy.
3,322 women. There was an occult cancer rate of 3.2 % in those with A more recent RCT demonstrated non-inferiority of imiquimod
suspected high-grade VIN and 3.3 % went on to develop VSCC during versus surgery for treatment of uVIN [26]. Complete clinical response
follow up [19]. Of 88 women with untreated high-grade VIN, 9 % went rates were seen in 37/46 patients (80 %) in the imiquimod group
on to develop VSCC over 12 to 96 months. However, they concluded that compared with 41/52 patients (79 %) after one surgical intervention
the progression rate to VSCC is likely to be over-estimated. (difference in proportion –0⋅016, 95 % CI –0⋅15 to 0⋅18; p = 0⋅0056). No
A Cochrane review of intervention for treatment of uVIN examined one treated per protocol imiquimod group developed invasive cancer
effects of imiquimod, cidofovir, indole-3 carbinol and surgery [20]. during the study.
They found that topical imiquimod, an immune modulator, was more A systematic review of HPV vaccination for the treatment of VIN and
effective than placebo in achieving a response (complete or partial) to vaginal intra-epithelial neoplasia (VaIN) found only seven studies that
treatment 5–6 months after randomisation (risk ratio (RR) 11.95, 95 % fit their inclusion criteria. All were case series and at high risk of bias, so
confidence interval (CI) 3.21 to 44.51; high-certainty evidence). A the evidence was of very low quality and very uncertain [27].
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). Squamous cell carcinoma on a background of lichen sclerosus (LS)/lichen
Persistent responses after 12 months were present in just over a third of planus (LP)
women. Only one study reported vulval cancer rates at 12 months follow Lichen sclerosus is associated with an increased lifetime risk of
up (1/24 and 2/23 in imiquimod and placebo groups, respectively). developing vulval cancer, with estimates of the risk varying between 2.2
Adverse events were more common with imiquimod than placebo (RR and 6.6 % depending on the series [4,28]). A recent systematic review
7.77, 95 % CI 1.61 to 37.36; high-certainty evidence). One very small, looked at the incidence of developing vulval cancer in women with
long-term follow-up study of those with complete response to vulvovaginal LS and LP [29]. They found 14 studies on vulval LS, which
Ce document PDF a été édité via Icecream PDF Editor. included 14,030 women without a previous diagnosis of vulval
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neoplasia. During follow-up 2.2 % (range 0 % to 2.7 %) went on to genital tract and perianal area with timely cervical screening. Where
develop vulval cancer,1.2 % dVIN, and 0.4 % uVIN. For those with LP, anal/peri-anal intraepithelial neoplasia is identified a multi-disciplinary
there were eight studies of 14,268 women; 0.3 % went on to develop approach to follow up and management may be required. There are no
vulval cancer, 2.5 % dVIN. Vulval cancer was preceded by dVIN in published data to support virtual/remote/patient-initiated follow up
around half (52 %) of women in one study and the risk of dVIN pro and use of patient-performed digital photography remain unproven.
gressing to invasive disease was 18.1 %, albeit based on only 11 women The risk of recurrent disease is high, particularly in the first two years
with dVIN [28,30]. However, these data are not based on population- [42]. Follow-up regimens should reflect this fact, and increased sur
level data, and lichen sclerosus is frequently under-diagnosed, so these veillance is suggested in the first two years, particularly for those with
data are likely to be at high risk of bias and over-estimate the risk. multifocal disease. The optimum follow-up regime remains to be
Data from non-randomised studies suggest that good control of LS/ defined, but, in the absence of a robust evidence base, six-monthly
LP with ultra-potent topical steroids (such as Clobetasol 17- propionate follow up for two years and annual follow up to five years is sug
0.05 %) and maintenance treatment when asymptomatic (e.g., 1-2x gested, as a minimum. Patients with unifocal, treated disease may be
weekly) may reduce the risk of progression to SCC [28,29,31,32]. discharged at that time, with instructions to return if new lesions or
There are yet no RCT level data to support this, although control of symptoms develop. Patients with multifocal or recurrent disease may
active LS/LP should be recommended to improve symptoms, reduce require more long-term follow-up. Human immunodeficiency virus
scarring and may reduce the risk of developing malignancy. Often (HIV) testing should be offered as per the 2020 recommendations from
women are fearful of using ‘too much’ steroid cream and they should be the British HIV Association, British Association of Sexual Health and HIV
reassured that appropriate usage (less than 30 g tube of ultra-potent British Infection Society [43].
steroid ointment/cream, such as Dermovate (clobetasol propionate The effectiveness of anal screening in this population has not been
0.05 %), over a 3-month period) is unlikely to be harmful and may be of proven and most data on anoscopy and anal cytology is limited to higher
benefit, both to scarring/vulval appearance as well as longer term risk of risk populations (HIV-positive (HIV + ) men who have sex with men
cancer. For the same reasons, women should be advised to avoid irri (MSM)), reviewed in [44]. An expert review group of American Society
tants that can exacerbate LS/LP, e.g., detergents, such as soap, synthetic Colposcopists and Cervical Pathologists and the International Anal
underwear, plastic pads, wipes or topical cream/oils. Neoplasia Society examined the data and made recommendations on
anal HPV infection, anal intraepithelial neoplasia (AIN) and anal cancer
Mucosal malignant melanoma in women. They did not find data to support routine anal cytology or
Unlike cutaneous melanomas, vulval mucosal melanomas are not anoscopy in women with uVIN or vulval cancer, although noting that
related to ultraviolet light exposure. A small minority may be related to they were at higher risk than the general population [45]. They rec
c-kit mutations, which are more common than in cutaneous melanoma ommended screening for anal cancer with digital ano-rectal examina
[33]. tion and assessment if anal cancer symptoms developed, such as pain or
bleeding. They noted that routine screening and treatment of AIN2/3
Screening was not proven to be effective in reducing anal cancer in this population.
There are currently no proven screening tests for vulval carcinoma. Presentation
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- For recommendations on presentation and diagnosis, see Fig. 1 and
year series for uVIN [34]). Some studies have demonstrated a Table 2. Most vulval carcinomas will present with a specific lesion. The
2.6––6.6 % overall risk for those with lichen sclerosus/lichen planus risk of cancer in the presence of a ‘suspicious vulval lesion’, was 12.8 %
[28,35], which is increased significantly when associated with VIN [4]. in a recent study of women referred to a secondary care ‘rapid access
A recent systematic review found 31 studies looking at association of clinic’ with vulval symptoms [40]. This risk of invasion was higher if the
VSCC and lichen sclerosus and lichen planus. Due to the heterogeneity of lesion was symptomatic (pain and/or bleeding). Women with general
populations and study designs, a narrative synthesis was performed; it is ized vulval irritation without a visible lesion on careful examination
very challenging to give and accurate indication of risk [36]). They were extremely unlikely to have a cancer diagnosis.
found the absolute risk of developing VSCC in patients with lichen Women with clinical features highly suspicious of vulval cancer, for
sclerosus ranged from 0.0 % (95 % CI 0.0 to 5.52) to 21.88 % (95 % CI example a fungating lesion ± palpable groin nodes, should be referred to
9.28 to 39.97) and was 1.16 % (95 % CI 0.1 to 4.1) with lichen planus a cancer centre without the need to await biopsy results. Punch biopsies
[36]. The incidence of VSCC per 1000 person-years for those with a may not adequately sample the lesion, especially if it is large and/or
diagnosis of lichen sclerosus ranged from 1.16 (95 % CI 0.03 to 6.44) to deep, and delay for diagnostic biopsy is not warranted.
13.67 (95 % CI 5.50 to 28.17) [36]. In contrast, studies have demon Vulval melanoma is rare, presents as a vulval lesion, which may or
strated dVIN, which arises on a background of lichen sclerosus, has a not be pigmented and may or may not develop in the background of
very high risk of progression to cancer compared to uVIN and should melanocytic dysplasia. Symptoms may include altered vulvo-vaginal
ideally be surgically excised (relative risk (RR) of progression: dVIN pigmentation, itching or bleeding. Alternatively, an asymptomatic
RR = 38.5 (9.8–150.8); uVIN = 0.065 (0.03–0.15) [37,38]. Current lesion is noted, which may occur as an irregularly outlined pigmented or
guidelines from the British Association of Dermatologists recommend non-pigmented macule, papule, patch or nodule with or without ulcer
annual review in primary care in those with lichen sclerosus, following ation. Some lesions will be found on clinical examination after noticing
review at 3-months to check response to initial treatment and a 6-month groin lymph node(s) enlargement.
follow up to check compliance and understanding of self-management Basal cell carcinoma of the vulva tends to present with a discrete
[39]. Importantly, patients should be aware of the small risk of devel vulval lesion or classical raised, rolled-edge ulcer, without a background
oping vulval cancer and report new lesions to their GP, especially if dermatosis or evidence of uVIN.
these symptomatic. Recent data suggest that the risk of vulval cancer in Bartholin’s gland carcinoma is rare and may present with a mass in
the presence of a lesion is around 13 % and presence of a suspicious the vulva/lower vagina over the area of the Bartholin’s gland. These
vulval lesion should prompt rapid ‘Cancer Wait Time’ referral to sec lesions are often painful and may be mis-diagnosed as a Bartholin’s cyst
ondary care [40,41]. or abscess. The diagnosis should be suspected and excluded in those
Women with uVIN should receive follow up with formal vulvoscopy. aged over 40 years presenting with a ‘Bartholin’s abscess’, since inad
These women are at increased risk of multi-centric disease, so it is vertent Bartholin’s gland ‘excision’ or marsupialisation can delay diag
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Fig. 1. Flowchart demonstrating investigation of suspicious vulval lesion. LSA = lichen sclerosus atrophicus; LP = lichen planus; VIN = vulval intraepithelial
neoplasia; uVIN = usual-type VIN; dVIN = differentiated VIN; D/C = discharge.
Diagnosis At a minimum, a detailed diagram of the vulva is required, indicating

each biopsy site is mandatory. Use of a schematic diagram, which can be
Incisional biopsy (punch or wedge biopsy) ideally including the edge annotated is encouraged (e.g., https://www.nva.org/what-is-vulvody
of a lesion, where there is a transition from normal to abnormal tissues. nia/vulvar-anatomy/). Ideally, vulvoscopic ‘before and after’ biopsy
Biopsies should avoid a central ulcer, since this may not be diagnostic. photos should ideally also be taken where possible (with a scale indi
Biopsies should be of adequate depth to allow differentiation between cation). This will help to localize the lesion for the treating gynaeco
superficially invasive and those with invasion >1 mm, since this will logical oncologist and assist pre-planning of more definitive treatment.
inform subsequent management. General Medical Council and local guidance on the capture and storage
Excision biopsy should be avoided, where possible, since this can of images should be followed. If more than one lesion is present, each
limit options for more conservative treatment with wide local excision individual biopsy should be sampled separately, sent in separate pots
and sentinel node biopsy. This is especially the case if the lesion is small, and carefully labelled, so that lesion site can be identified at a later date.
as the vulva can heal well and the original site being hard to determine
at the time of more definitive treatment. However, there may be ex
ceptions to this, for instance in someone who is very elderly or frail it Pre-operative investigations
may be acceptable to excise a small, symptomatic lesion under local
anaesthetic for palliation and planning of subsequent treatment. This For recommendation on pre-operative investigations, see Table 3.
should ideally be performed by the gynaecological oncologist who will
perform subsequent treatment. Histological confirmation is required Squamous cell carcinoma (SCC)
prior to consideration and planning more radical treatment. Squamous cell carcinoma most commonly spreads via inguino-
Ce document PDF a été édité via Icecream PDF Editor. femoral (groin) lymph nodes and rarely presents at distant sites, if
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Table 2 further investigated with USS-guided fine needle aspiration (FNA) or

Recommendations for presentation and diagnosis. core biopsy, where node positivity would change management.
Recommendation Grade of Where tumour encroaches on median structures (urethra, vagina,
recommendation anus, rectum), imaging should not be limited to just the groin nodes, due
Women with suspicious vulval lesions should be referred Grade C to the increased risk of pelvic nodal drainage, and further evaluation of
to a rapid access clinic for urgent assessment, as per the pelvic nodes with cross-sectional imaging is advised.
NICE guidelines [40,41]. Cross-sectional imaging (with computerised tomography of chest,
Women highly likely to have vulval cancer on clinical Grade D abdomen and pelvis (CT CAP), magnetic resonance imaging (MRI) or
grounds should be referred to a gynaecological cancer
centre without waiting for biopsy results.
single-photon emission computed tomography (SPECT-CT)) can also be
Clear documentation of clinical exam size of lesion, Grade D used to assess the groin nodes and has the benefit of also allowing
distance to the midline/clitoris/anus/vagina/urethra assessment of pelvic nodes, which is recommended before undertaking
and palpation of lymph nodes is mandatory. Imaging, lymphadenectomy.
with indication of biopsy sites and/or clinical drawing
Staging with full body, cross-sectional imaging (CT CAP) should be
is essential for further treatment planning.
Suspicious vulval lesions should ideally be sampled with a Grade D considered for all those with suspected or diagnosed with Stage III or
punch or wedge biopsy and excisional biopsy avoided greater disease, as the presence of distant metastatic disease will influ
until a diagnosis is made. ence the extent of loco-regional treatment options. CT is also suggested
Biopsies should include the edge of a lesion to ascertain Grade D for those with locally extensive disease who are not fit for radical
the background condition.
At a minimum, a detailed diagram, indicating lesion and Grade D
treatment, to aid discussion and planning of treatment options.
biopsy sites, should be drawn. Due to its high soft tissue resolution, MRI should be considered for
Ideally, clinical photographs, before and after biopsy Grade D tumours with equivocal or clear involvement of midline structures, if
should be taken, with an indication of scale. this will direct surgical management [47].
Biopsies from separate lesions should be sent in separate Grade D
Positron emission tomography (PET-CT) is not recommended for the
pots and clearly labelled.
All cases vulval cancer should have the diagnosis Grade D routine staging of vulval cancer. PET-CT has limited value in detecting
confirmed by a specialist multi-disciplinary team lymph node metastases less than 5 mm and in necrotic nodes, and in
(MDT) prior to planning radical treatment. flammatory nodes can be false positive. Sensitivities ranging from 50 %
to 100 % and specificities ranging from 67 % to 100 % have been re
ported in 18F-FDG PET-CT’s evaluation of inguinal lymph nodes [48].
Table 3 There may however be a role for PET-CT if radical surgery is proposed to
Recommendations for pre-operative imaging. help to detect pelvic nodal and more distant metastases.
Recommendation Grade of
recommendation Melanoma
Vulval melanoma commonly presents with a more locally advanced
Gross nodal involvement should be excluded by clinical Grade D
examination and appropriate imaging / radiologic lesion than cutaneous melanoma, since the area is difficult to visualise.
staging. The risk of metastatic disease (both lymphatic and haematogenous
If sentinel lymph node biopsy is considered, imaging of Grade D spread) is high. Recommended imaging at diagnosis would include CT
the groins (Ultrasound, MRI or CT) is mandatory to CAP and also CT or MRI head, since systemic disease and intra-cranial
identify potential lymph node metastases. Ultrasound
has better specificity and sensitivity in studies, but is
lesions are not uncommon. Please see the Ano-uro-genital Mucosal
operator dependent. Melanoma Full Guideline for further details [1].
FNA or core biopsy can be used to evaluate suspicious Grade D
nodes when this would alter primary treatment, e.g., Basal cell carcinoma
SLN biopsy. Removal of involved lymph nodes should
Distant disease spread is rare and no specific imaging is required,
be considered standard of care.
Further staging with CT/PET-CT is recommended in the Grade D unless there is clinical suspicion of nodal disease.
presence of proven metastatic disease (i.e. positive
lymph nodes) and/or in advanced disease prior to Bartholin’s gland carcinoma
radical treatment/surgery. Bartholin’s gland carcinoma may present with more advanced dis
No additional imaging is required in the pre-operative Grade D
assessment of BCC lesions, unless there is a clinical
ease, since they arise deep to the surface of the skin and are less clinically
suspicion of nodal disease. obvious. Pre-operative imaging with CT CAP is therefore recommended,
Melanoma and Bartholin’s cancers should be assessed Grade D since these lesions are not suitable for a SLN approach and there is an
with combination imaging (MRI and CT) to provide increased risk of locoregional spread at diagnosis. MRI pelvis may help
information on the extent of local disease and
to delineate the local degree of involvement.
metastatic disease. PET-CT may be appropriate in
selected cases.
Paget’s disease of the vulva
See below for discussion of management of Paget’s disease of the
regional nodes are negative. Imaging is poor at excluding microscopic vulva, including pre-operative investigations.
groin node metastases; hence groin node surgery is recommended for
those with greater than FIGO Stage IA SCC. Pathology
Prior to sentinel lymph node (SLN) biopsy (SLNB), clinical exami
nation and imaging of the groins are required to identify metastatic For a summary of pathological subtypes, please see Table 4.
disease, since obvious groin node involvement would be a contraindi
cation to SLNB. Precursor lesions
Ultrasound (USS) has a good accuracy in assessing groin nodes,
however, it is operator- and equipment-dependant. In a meta-analysis of Vulvar intraepithelial neoplasia, HPV-associated
ultrasound assessment of groin nodes in patient with vulval cancer, HPV-associated neoplasia is the term used in the fifth edition of WHO
pooled sensitivity of 85 %; specificity of 86 %; positive predictive value classification of tumours of the female genital tract [49]. Acceptable
(PPV) of 65 % and NPV of 92 % were recorded [46]. Those with sus terms for describing vulval intraepithelial neoplasia (VIN) include: low-
picious groin
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Table 4 uVIN and lichen simplex chronicus [58].

Pathology of vulval malignancies and their precursor lesions.
Pathological subtype Precursor lesion(s) Pathology of squamous cell carcinoma
Vulval squamous cell carcinoma (VSCC) HPV-associated vulval intraepithelial
neoplasia (VIN);HPV-independent Types of squamous cell carcinomas
vulval intraepithelial neoplasia Invasive squamous cell carcinomas constitute 90 % of vulvar cancers.
(dVIN and p53-wild type precursors) Two pathogenetic pathways exist and correlate with the precursor le
Bartholin’s gland carcinoma (squamous HPV-associated VIN in some SCCs sions: an HPV-associated pathway which is associated with younger age,
cell carcinoma (SCC), adenocarcinoma,
adenoid cystic carcinoma or transitional
HPV infection and smoking, and an HPV-independent p53 mutated
cell carcinoma) pathway that is associated with older age of onset and lichen sclerosus.
Vulval malignant melanoma There is increasing awareness of an HPV-independent, p53 wild-type
Invasive Paget’s disease (adenocarcinoma) Vulval Paget’s disease (VPD) pathway often associated with verrucous carcinomas.
(adneocarcinoma in situ)
Basal cell carcinoma
Macroscopic features of importance
Documentation of specimen size allows correlation between clinical
squamous intraepithelial lesion (VIN2 or HSIL); high-grade squamous appearances of the specimen. Measurement of the tumour and distance
intraepithelial lesion (VIN3 or HSIL); VIN2 or 3 of usual type [50]. from resection margins is important, as size is included in FIGO and
The terms low-grade squamous intraepithelial lesion (LSIL) and TNM staging [59–61].
high-grade squamous intraepithelial lesion (HSIL) are not widely used in
the UK and the use of the alternative terms low-grade VIN (or VIN 1) and Microscopic features of importance
high-grade VIN can be used, with sub-categorisation of the latter as VIN
2 or VIN 3. High grade VIN is characterized by cytological atypia Grade. Squamous carcinomas of the vulva are no longer graded [60].
extending beyond the middle third of the epithelium usually accompa This is because the HPV status has far more prognostic significance than
nied by mitotic activity and lack of maturation of the squamous cells the grade. There is no agreed grading system for adenocarcinoma of the
with or without associated stigmata of HPV infection such as vulva.
koilocytosis.
Depth of invasion. This is an independent prognostic factor which, in
Vulvar intraepithelial neoplasia, HPV-independent conjunction with tumour size, helps distinguish between FIGO stage IA
Vulvar intraepithelial neoplasia, HPV-independent, also acceptably and stage IB tumours. Reference to the vulval cancer dataset of the Royal
described as differentiated VIN (dVIN), is an HPV-independent lesion College of Pathologists is recommended for further details [60]. In the
that is often seen in older women on a background of lichen sclerosus. It updated 2021 FIGO staging system there was a recommendation to
is characterised by basal cell atypia and abnormal keratinocyte differ change how depth of invasion is measured. Depth of invasion is now
entiation. Differentiated VIN is typically associated with TP53 “measured from the basement membrane of the deepest, adjacent,
mutations. dysplastic, tumour-free rete ridge (or nearest dysplastic rete peg) to the
There has been increased awareness of p53 wild type, HPV inde deepest point of invasion”. This method is associated with less inter-
pendent precursors of vulvar squamous cell carcinomas. Differentiated observer variation and early retrospective data suggest that down
exophytic vulvar intraepithelial lesion (DEVIL) and vulvar acanthosis staging that occurred as a result of the new measurement guidelines was
with altered differentiation (VAAD) are characterized by exophytic not associated with increased nodal recurrence [62,63]. This has been
growth, acanthotic or verruciform architecture, and an absence of sig implemented in the UK since January 2022. Other guidelines groups,
nificant nuclear atypia [51]. Recently, there has been a proposal to including ESGO, have not adopted the updated FIGO 2021 system, due
combine these entities under the term HPV-independent, p53-wild-type concerns about low quality and sparsity of evidence to guide clinical
verruciform acanthotic vulval intraepithelial neoplasia (HPVi(p53wt) decisions about nodal staging [64]. See https://www.rcpath.org/
vaVIN) [52]. There is some support for using the term vulval aberrant G070-Dataset-for-histopathological-reporting-of-vulval-carcinomas.
maturation (VAM) as an umbrella term for lesions that arise in lichenoid pdf.
dermatitis and lack the atypia needed to diagnose dVIN. These lesions
have an unquantifiable risk of subsequent dVIN [53]. Lymphovascular and/or perineural invasion (PNI). Both factors are asso
ciated with higher risk of recurrence. Presence of malignant cells in the
Ancillary imunohistochemistry in vulvar intraepithelial neoplasia layers of the nerve sheath is associated with a worse prognosis [65].
Although the distinction between HPV-associated and HPV-
independent VIN is typically straightforward, morphological overlap Margin clearance. This is discussed below.
between the two can exist [54,55] and create diagnostic difficulty.
Immunohistochemistry for p16, a cyclin dependent kinase inhibitor
Preoneoplastic and non-neoplastic disease. The presence of lichen scle
that accumulates in transforming HPV infection, is mandatory on all
rosus and/or differentiated VIN at excision margins are associated with
index biopsies with a diagnosis of VIN. Block positive staining is a sur
increased risk of local recurrence [66,67].
rogate marker of HPV aetiology and allows accurate distinction between
HPV-assocIated and HPV-independent VIN.
p16 status. It is increasingly recognised that HPV-associated squamous
Diffuse strong p53 staining of the basal layer with suprabasilar
carcinomas have better outcomes than HPV-independent cancers. Block
extension has been described in ~85 % of cases of dVIN. [56] Complete
positive p16 staining by immunohistochemistry is a surrogate marker of
loss of staining (null pattern) has also been described [57]. In contrast,
HPV aetiology and p16 staining is recommended on all vulval squamous
normal (wild-type) p53 staining is identified as staining of variable in
cell carcinomas [68,69]. Documentation of the HPV status of the tumour
tensity. The different patterns may be difficult to interpret in small bi
is strongly recommended (whether HPV-associated or HPV-
opsy specimens where ‘normal’ epithelium is not available for
independent) [49].
assessment. p53 staining is recommended for all cases of VIN, especially
when p16 shows non block (mosaic) staining.
The utility of CK17 immunohistochemistry in the diagnosis of dVIN
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diffuse expression favouring dVIN over
216
Spread origin is seen. In the majority of cases, disease is confined to the

epithelium but in up to 20 % of cases there is invasion into the under
Lymph node metastasis lying stroma. The risk of progression to invasive disease or metastasis
The number of involved lymph nodes, the size of the largest meta following treatment for non-invasive VPD is low [77].
static deposit and the presence or absence of extracapsular spread The lesion is characterised by an apparently well demarcated,
should be recorded. Nodal deposits greater than 2 mm in size have been painful and erythematous eczematoid lesion, usually on the labia
shown to correlate with poorer survival. In sentinel nodes, it is impor majora. Histologically, there is a population of large round cells with
tant to document the exact size of nodal metastases (including the pale cytoplasm and nuclei with prominent nucleoli distributed
presence of isolated tumour cells) as this will have a direct bearing on throughout the epithelium as single cells or clusters. The tumour cells
subsequent management options [70,71]. express cytokeratin 7, carcinoembryonic antigen and apocrine cell
marker GCDFP15, which may help to distinguish VPD from other intra-
Sentinel lymph nodes (SLN) epidermal neoplasms such as malignant melanoma in situ and VIN. The
A sentinel node can be defined as any lymph node receiving drainage borders of the lesions seen clinically correlate poorly with the histo
directly from the primary tumour. The indications and evidence for logical extent of the disease, which may account for the high rate of
sentinel lymph node biopsy are discussed below [72]. Intraoperative recurrence after primary surgery.
frozen sectioning of lymph nodes may lead to tissue loss and therefore Data on the pathogenesis of VPD are limited. Androgen receptors
examination of paraffin-embedded tissue is recommended. All nodal may be detected in >50 % of VPD cases and represent a potential
tissue is sampled. The technique is described in detail in the British therapeutic target. Overexpression of HER2/neu (ERBB2) is present in at
Association of Gynaecological Pathologists document on protocols for least one third of VPD lesions. HER2 positivity may confer a poorer
processing of sentinel lymph nodes. (https://www.thebagp.org/down prognosis with respect to invasion, recurrence and nodal metastasis but
load/bagp-sentinel-node-protocol/) [60]. further study is needed to establish the precise biological significance of
this marker [78].
Definitions of nodal involvement. The size of the metastases in the lymph
node affects the stage. These are defined as per those for FIGO cervical
staging [73]: Pathology of vulval melanoma
Macrometastasis: >2 mm pN1;
Micrometastasis: >0.2 mm to ≤2 mm pN1 mi; Primary vulval melanoma is uncommon compared with those at
ITC – isolated tumour cells – microscopic clusters and single ultraviolet light exposed sites (with a ratio of sun exposed skin to vulva
cells ≤ 0.2 mm pN0(i+). melanoma of 71:1) and is typically diagnosed at older age. Up to 40 % of
Macroscopic handing of SLN is important. The lymph node and women present with regional or distant metastasis. Compared with
adherent fat must be examined. Lymph nodes up to 2 mm are embedded other cutaneous and non-gynaecological mucosal melanomas, the
whole. Lymph nodes 2–4 mm in size are bisected and both halves sub prognosis is relatively poor (five-year survival is 58 % for vulval mela
mitted. Nodes that are 4 mm or more in largest dimension should be noma compared with up to 81 % for cutaneous disease). Lesions are
sliced at 2 mm intervals. Diagrammatic representation is available in the typically asymmetric, with irregular borders and uneven pigmentation
British Association of Gynaecological Pathologists document on pro and there may be surface ulceration. Up to 25 % may be amelanotic.
tocols for processing of sentinel lymph nodes. (https://www.thebagp. Adverse prognostic factors are advanced clinical stage, Breslow thick
org/download/bagp-sentinel-node-protocol/) A block index must be ness greater than 1 mm, vertical growth phase, ulceration and mitotic
maintained. index over 1 per mm2. Microsatellite lesions and perineural invasion are
associated with increased local recurrence [79,80].
An understanding of molecular alterations within melanoma has led
Rationale of ultrastaging. When the initial H&E staining of the SLN does
to expansion of treatment options and increased survival. Vulvo-vaginal
not identify metastatic disease, enhanced pathological assessment or
melanoma appears to be different from both cutaneous melanoma and
ultrastaging should be performed. The false negative rate of examination
those from other mucosal sites. BRAF mutations are present in 26 % of
of a single H&E slide ranges from 5 to 58.3 % [74], the higher figure due
vulvo-vaginal melanomas, lower than in other sites, whereas cKIT mu
to the additional detection of micrometastases with ultrastaging [75].
tations are found in 22 % of vulvo-vaginal melanomas compared with
The recommended protocol involves cutting four sections at 200 µm
8.8 % in other mucosal melanomas. PD-L1 (56 %) and PD1 (75 %) are
intervals through the block and staining one section each with H&E
among the most frequent markers expressed, highlighting the potential
and pancytokeratin stain (AE1/AE3 antibody) [76]. Two additional
use of immunotherapy targeted at this pathway [81].
sections are retained at each level in case there is a problem with H&E or
IHC staining. This interval should ensure that a large percentage of
micrometastases are identified. Treatment of primary disease
Extracapsular spread Surgery

Tumour extension outside the lymph node is an independent pre
dictor of poorer survival and is included in the FIGO and TNM staging Management of primary site
systems [61].
Vulval squamous cell carcinoma (VSCC). Surgery with curative intent is
the mainstay of treatment for all locally limited vulval carcinomas. In
Pathology of vulval Paget’s disease and invasive adenocarcinoma of the FIGO stage IV tumours radical surgery is unlikely to be appropriate and
vulva surgery is limited to palliation of symptoms. For details of FIGO staging
system please see Table 5 [61]. For surgical treatment recommendations
Vulval Paget’s disease (VPD) is an uncommon, intra-epithelial see Table 6 and Fig. 2.
adenocarcinoma, which arises most commonly on the vulva, usually in Modern management of vulval cancer is dictated by the size and site
postmenopausal Caucasian women. Most lesions arise from a pluripo of the cancer and individualised to the patient. Historically, these tu
tent epidermal stem cell within the interfollicular epidermis or folliculo- mours were managed by en-bloc radical excision of the entire vulva and
apocrine-sebacous unit. Occasionally origin from an underling skin the IFLN, but evidence demonstrated no benefit for this technique over
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of anorectal radical local excision, with separate incisions for the groin
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Table 5 diagrams drawn for the patient to ensure adequate consent is achieved.
Adapted from International Federation of Gynecology and Obstetrics (FIGO Patients should be warned about the effects on sexual function following
2021) revised staging system [85]. surgery, especially if the clitoral area is involved. Showing patients
Stage Description images of outcomes of surgery of previous patients can be useful to
Stage I Tumour confined to the vulva
inform the consent process, as is commonly done in breast cancer.
Stage IA Lesions ≤ 2 cm in size, confined to the vulva or perineum and The aim of surgery for the primary tumour is removal of the cancer
with stromal invasion ≤ 1 mm. No nodal metastasis with clearance at all microscopic margins, including the deep margin
Stage IB Lesions > 2 cm in size or with stromal invasion > 1 mm (R0). Historically, a 1–2 cm macroscopic tumour-free margin was rec
confined to the vulva or perineum. No nodal metastasis
ommended on the basis of very limited retrospective data. More recent
Stage II Tumour of any size with extension to adjacent perineal structures (lower
1/3urethra; lower 1/3 vagina; anus) studies have shown that margins should be clear of disease, but that
with negative nodes large negative margins are not required in node-negative patients
Stage Tumour of any size with extension to adjacent perineal structures(lower 1/ treated with surgery alone [86–90]. Another contemporary series did
III 3 urethra; lower 1/3 vagina; anus), or with any number of with positive not show an association with margin status unless margins were <2 mm
regional (inguino-femoral)
lymph nodes
[91]. A systematic review of prognostic factors in vulval cancer found a
Stage Tumour of any size with extension to adjacent perineal 4 % annual local recurrence rate and that pathological margins <8 mm
IIIA structures (lower 1/3 urethra; lower 1/3 vagina; anus), or were not associated with an increased risk [92]. Vulval recurrence is
regional lymph node metastasis ≤ 5 mm more often a new primary tumour within an area of field change as
Stage Regional lymph node metastases > 5 mm
indicated by the presence of lichen sclerosus or VIN at the margins
IIIB
Stage Regional lymph node metastases with extracapsular spread [67,93].
IIIC The planned excision margins should be marked out with a ruler and
Stage Tumor of any size fixed to bone, or fixed, ulcerated lymph marker pen prior to commencing surgery. Care should be taken that this
IV node metastases, or distant metastases is in the natural state, i.e., the tissue is not stretched prior to marking.
Tumor of any size fixed to bone, or fixed, ulcerated lymph
Consideration should also be given to Langer lines to achieve optimal
node metastases, or distant metastases
Tumor of any size fixed to bone, or fixed, ulcerated lymph healing and cosmesis. To facilitate pathological examination, the
node metastases, or distant metastases excised skin specimen should be secured in a way that allows accurate
Tumour of any size fixed to bone, or fixed or ulcerated regional lymph orientation by the pathologist (e.g., marker suture and pinned to cork
node metastases, or distant metastases
board).
Stage Tumour of any size fixed to bone, or fixed or ulcerated
IVA regional lymph node metastases In tumours which arise in a background of dVIN or Paget’s disease,
Stage Any distant metastases including pelvic lymph nodes consideration should be given to excising the whole of the abnormal
IVB area. Recurrence rates if margins are involved with dVIN are high
[34,94].
Table 6 Stage IA VSCC. Small tumours can be managed by excision, ensuring

Recommendations for surgical treatment of primary site of VSCC. margins are achieved all around the primary tumour, as described
Recommendation Grade of above. For most tumours primary closure can be achieved, but for
recommendation posterior lesions, or larger lateral lesions, consideration should be given
The excised skin specimen should be secured in a way that Grade D to reconstructive surgery (described below) to allow the defect to be
allows accurate orientation by the pathologist (e.g., more easily closed, and vaginal function maintained. This is especially
marker suture and pinned to cork board). the case in women with re-occurrence of VSCC where there may be less
Excision should be planned with macroscopic clearance of Grade C tissue available for closure.
tumour with the goal of achieving clear margins (R0) on
pathological assessment.
Optimal radicality (margins) of the excision is unclear. It Grade D Stage IB VSCC. The management of these is determined by the location
is acceptable (and often desirable) to limit radicality to of the tumour. If the tumour is lateral of the midline, defined by the edge
preserve structure and function (e.g., preservation of of the tumour lying more than 1 cm from midline structures, such as
clitoris, anus and urethra)
Excision margins should be extended superficially to Grade D
urethra, clitoris and anus, a radical wide local excision should be un
include adjacent differentiated VIN and/or lichen dertaken, which can subsequently be tailored for best approximation of
sclerosus to reduce risk of local recurrence the tissues and cosmesis. If the tumour is peri-clitoral, an anterior vul
Discrete multi-focal disease may be managed with Grade D vectomy may be required, or if the tumour is close to the midline, sur
multiple wide local excision. Vulvectomy may be
gery will often involve the contralateral side of the vulva to ensure an
required for those with multifocal invasion arising on a
background of vulvar dermatosis adequate margin is achieved, and the defect can be closed without
If VSCC extends to the pathological excision margins, re- Grade D tension. Patients should be counselled about the risk of losing clitoris/
excision is the treatment of choice. clitoral sensation and the impact on sexual function. Where the lesion is
Some patients require access to reconstructive techniques Grade D close to the urethra consideration should be given to removing the distal
at the time of vulval surgery.
Joint pre-operative planning with gynaecological Grade D
1–2 cm of the urethra to achieve an adequate margin, which does not
oncology and reconstructive surgeons, including an usually compromise urinary continence.
examination under anaesthetic should be considered for Lesions in the posterior part of the vulva are best managed with a
those with large lesions. posterior vulvectomy, with care being taken to ensure the anal sphincter
is not compromised, and that an adequate margin can be achieved on the
anal margin. These incisions are difficult to close with primary closure,
lymphadenectomy, which is far less mutilating to women and carries a
so consideration of reconstructive techniques should be made and
far lower rate of morbidity and mortality [82,83]. Rates of recurrence in
involvement of the rectal surgery and stoma team may also be required.
the skin bridge between the positive lymph node and the primary
Multi-focal disease may be managed with separate wide local exci
tumour are low [82].The exception to this is in the presence of large
sions. Caution is advised in large tumours or those demonstrating
and/or fixed nodes where recurrence in the skin bridge is higher and
multifocal invasion arising on the background of a vulval dermatosis
there may still be a role for en-bloc resection [84].
where radical vulvectomy should be considered. The principles of such
Treatment
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218
Fig. 2. Management of primary lesion. VSCC = vulval squamous cell carcinoma; DOI = depth of invasion; WLE = wide local excision; CT = Computerised to
mography scan; SLNB = sentinel lymph node biopsy; IFLND = inguino-femoral lymph node dissection.
surgery are to remove the tumour with microscopically-free margins Stage IV VSCC. Surgery rarely has a role in advanced disease. Palliative
(R0), encompassing the clitoris, both sides of the vulva, and the peri procedures may be considered to ease discomfort, which is otherwise
neum. The vagina is transected to achieve this, and care is taken to difficult to control. In cases of fistulation of the tumour to bowel or
ensure the urethral and anal margins are taken without compromise to bladder, de-functioning stomas and/ or urinary diversions or nephros
the sphincters. A plane from the mons pubis down to the perineum at the tomies can be considered.
level of fascia lata is developed, and the involved skin removed.
Principles of reconstructions are considered below and may involve Surgical management of other vulval cancers
primary closure or more complex reconstructive techniques [95]. Non-squamous carcinoma can be classified in to four main
However, healing by secondary intent, as was used historically, can categories:
achieve good results and may be appropriate in patients unfit for more
complex interventions. • Bartholin’s gland carcinoma (may be squamous, adenocarcinoma,
transitional cell carcinoma or adenoid cystic carcinoma);
Stage II VSCC. The principles of adequacy of surgical margins are • Adenocarcinomas arising from non-mammary Paget’s disease;
maintained with these tumours, and excision of the distal urethra and • Basal cell carcinoma;
vagina should be considered. Where the tumour involves the anus, pri • Malignant melanoma.
mary treatment with definitive chemoradiation should be considered in
an effort to preserve function. Alternatively, downstaging with chemo For treatment recommendations of non-squamous cancer, see
radiation in a neoadjuvant fashion may allow subsequent surgical Table 7.
excision without loss of faecal continence (see relevant sections below
for further details) [96–101]. However, for some women, surgical Carcinoma of the Bartholin’s gland. These rare tumours make up
excision may require formation of a colostomy, either as a temporary approximately 5 % of vulval malignancies. There are less than 300 cases
measure to aid wound healing after reconstructive techniques, or in the reported literature [102], so evidence for management is based on
following surgery to remove the anus and lower rectum. case series or extrapolated from management of squamous cancers of the
vulva.
Stage III VSCC. Management of the primary tumour is the same for these These tumours arise from the Bartholin glands or their ducts, and
as for earlier stages, removal of the groin lymph nodes is described later. classification is based on Honan’s criteria. The tumour must be: in the
Ce document PDF a été édité via Icecream PDF Editor. correct position; deep in the labium majora; have normal overlying skin;
219
Table 7 excision, with ipsilateral IFLND and where indicated, radiotherapy to

Recommendations for treatment of rare vulval malignancies. the vulval and regional lymph nodes. Post-operative radiotherapy
Recommendation Grade of reduced the local recurrence rate from 27 % to 7 %. See below for dis
recommendation cussion of recommended adjuvant treatment options.
Bartholin’s carcinoma
Patients with Bartholin’s gland carcinoma may need Grade D Adenoid cystic carcinoma of the vulva
multi-modal treatment and full body imaging with CT Background. Adenoid cystic carcinoma of the vulva is a very rare
CAP is recommended prior to surgery, as disease is
tumour that arises from Bartholin and Skene glands. It is found more
more likely to present at an advanced stage.
Adenoid cystic carcinoma of the vulva commonly in the salivary glands. There are no RCTs to guide manage
Adequate surgical excision is key to survival Grade D ment and treatment is based on case reports and series. Patients with
In patients with involved resection margins, postoperative Grade D adenoid cystic carcinoma of the vulva should be referred to a specialist
radiotherapy can reduce the risk of recurrence MDT.
Distant metastases appear to be relativley common and Grade D
data to support adjuvant systemic therapies are very
Adenoid cystic carcinoma accounts for approximately 10 % of all
limited Bartholin’s gland malignancies, while Bartholin’s gland carcinoma is
Vulval Paget’s Disease responsible for 0.1–5.0 % of all vulval carcinomas and 0.001 % of female
Investigations to exclude a co-existing malignancy, e.g., of Grade D malignancies. The mean age at diagnosis is 49 years (range 25–80 years)
the breast, gynaecological, urological and colorectal
[106].
tracts, are only required if there are symptoms
concerning for other malignancies. Pathological features. Histologically, adenoid cystic carcinoma is
Surgery should aim to remove invasive visible disease Grade C typically composed of rounded islands of uniform malignant epithelial
with macroscopically clear margins. Microscopic cells with a cribrifom pattern [107]. Pure adenoid cystic carcinomas of
involvement of the margins is common and re-excision the vulva appear unrelated to HPV infection [108]. A recent study
may not be of benefit.
Imiquimod may be of benefit and reduce the need for Grade C
showed NFIB gene rearrangements in six out of nine vulval adenoid
surgery, if invasive disease is excluded. cystic carcinomas, with two showing a MYB-NFIB fusion pattern [109].
Radiotherapy or photodynamic therapy have been used in Grade C Spread. Adenoid cystic carcinomas of the vulva are typically slow
VPD, but the certainty of this evidence is very low and growing tumours. They have a propensity for perineural invasion, which
should be considered with caution.
may account for symptoms of itching or burning [110]. Spread to lymph
Vulval malignant melanoma
Patients should be treated with close collaboration of the Grade D nodes is less common than for the more common types of vulval cancer
gynae-oncology and melanoma MDTs. [111]. There is a tendency for local recurrence and distant metastatic
Surgery should aim to achieve an R0 resection (no Grade C spread. The most common site of distant metastasis is to the lungs,
microscopic disease within < 1 mm of margins) with however, metastases to bone, liver and brain have also been reported
the least radicality.
[112].
Sentinel node dissection may help to guide adjuvant Grade D
immunotherapy and should be considered after Clinical features. Symptoms of adenoid cystic carcinoma are typi
discussion with the Melanoma MDT. cally of a vulval lump in the posterior part of the vulva, which may
Metastatic regional nodal disease may be considered for Grade D bleed. Other symptoms include pain, dyspareunia, pruritis and
removal as treatment may improve quality of life, but
discharge from an abscess [106]. The overlying skin may be intact or
without evidence of survival benefit.
ulcerated [110]. Due to its rarity and initial clinical similarity with
benign cysts it can be misdiagnosed, even as endometriosis, leading to
and there should be some normal gland present. The glands and their delays in treatment [113,114]. In one series, seven out of 14 patients
ducts are comprised of several different cell types: the lining epithelium below the age of 42 years had adenoid cystic vulval tumours diagnosed
changes from stratified squamous at the vulval surface to transitional in association with pregnancy [115].
epithelium in the terminal ducts. There can therefore be a variety of Treatment. There is no consensus on optimal surgical treatment,
histological types of Bartholin gland carcinomas including: adenocar although the cornerstone of treatment is complete surgical removal
cinoma; squamous carcinoma; transitional cell carcinoma and adenoid [112]. Wide local excision and radical vulvectomy, with or without
cystic carcinoma (see below). lymph node removal have all been reported, with recurrence in 68.9 %
Because the tumours develop deep in the vulva, surgical manage for wide local excision, compared with 42.9 % for radical vulvectomy
ment involves extensive dissection into the ischio-rectal fossa and [116]. Although radical vulvectomy can reduce local recurrence
potentially the anal sphincter. Surgery may require plastic reconstruc compared with more simple procedures, it has no impact on rates of
tion. There are no current data regarding the use of sentinel node biopsy, distant metastases [110].
hence inguinofemoral lymphadenectomy is recommended for the For patients with positive resection margins, adjuvant radiotherapy
management of the groins. may reduce the incidence of local recurrence [115,117]. A literature
Carcinoma of the Bartholin’s gland is more commonly associated review identified 16 patients who received adjuvant radiotherapy; of the
with metastatic disease at presentation with 60 % presenting with stage ten patients with positive resection margins, none had a local recur
III/IV disease in a recent case series [103]. Due to anatomical con rence, but six developed distant metastases [110]. There are fewer re
straints, patients may require multiple treatment modalities or consid ports of primary radiotherapy or chemoradiotherapy, although one case
eration of primary chemoradiotherapy. As with other VSCC, a staging CT report of a patient who developed multiple local and distant recurrences,
should be undertaken before treatment planning (see above for further in whom radiotherapy achieved complete local control, concluded that
details). adenoid cystic carcinoma of the vulva is radiosensitive [118]. A retro
Treatment is based on previous experience of more common vulval spective review of ten patients with primary Bartholin’s gland carci
carcinomas and case series, rather than randomized-control trial data. A noma, including two with adenoid cystic carcinoma, treated with
review of 14 cases, from 1955 to 1980, recommended treatment by radiotherapy or chemoradiotherapy with cisplatin reported three- and
radical vulvectomy and inguinal-femoral lymphadenectomy (IFLND), five-year survival rates or 71.5 % and 66 %, respectively [119].
similar to other vulval carcinomas [104]. Another series of 36 patients Due to the rarity of adenoid cystic carcinoma of the vulva, there is a
was based on 30 years’ clinical experience [105]. Nine patients had lack of data from clinical trials of palliative systemic anti-cancer ther
stage I disease, 14 stage II, ten stage III, and two stage IV. The five-year apy. There are reports of: stable disease after cyclophosphamide,
survival rate was 84 %. Recommended treatment was wide local doxorubicin and cisplatin in one patient with lung metastases [116];
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stable disease after doxorubicin and cisplatin in one patient with pul of imiquimod on non-invasive VPD and demonstrated good response
monary metastases; stable disease in a patient who received tamoxifen rates. These were summarised in a review article that concluded imi
[110]; and progressive disease in another patient who received both quimod seemed to be effective [77]. However, they also noted that
cyclophosphamide, doxorubicin and cisplatin, and ifosfamide single treatment schedules differ greatly between the studies and there is a
agent for recurrent disease [120]. More recently, a phase 2 study of the significant risk of publication bias. In the studies included in their
multityrosine kinase inhibitor dovitinib in 34 evaluable patients with narrative review, 64 women with VPD were treated with imiquimod
recurrent or metastatic adenoid cystic carcinoma showed a 6 % partial cream. Eight women were reported to have residual disease after
response rate with 65 % having stable disease at over four months. Sixty- treatment and 43 (67 %) had a complete response, and a further 13
three percent of patients had grade 3–4 toxicity, mostly fatigue and (21 %) had a partial response [77]. Another systematic review of imi
anorexia, and 94 % required dose modification [121]. Further studies quimod in VPD identified case reports and case series evidence from 63
are required. patients [129]. The recurrence rate for those with a complete response
Prognosis. The progression-free interval and overall survival are re (two of 35 women (5.7 %)) was an order of magnitude lower than in
ported as 47 % and 71 % at five years; 38 % and 50 % at 10 years [115]. studies of surgery, when surgical margins were clear. In the Paget Trial,
Basal cell carcinoma. Basal cell carcinomas (BCC) are rare (~5% of a multi-centre prospective observational clinical study from the
vulval cancers), normally behave in a locally invasive manner and only Netherlands [130], 24 women with VPD were treated with 3-weekly 5 %
metastasise to lymph nodes if very large and invasive [122]. Local imiquimod for 16 weeks. The majority (83 %) responded to treatment by
excision is recommended, with macroscopic clearance; recurrence is the end of the course, with over half (52 %) having a complete response.
associated with involved margins. Surgery should be performed with the Side effects of fatigue (67–71 %) and headache (17–46 %) were common
aim to achieve margins free of microscopic disease (R0). In a retro and one third of patients reduced treatment to twice a week, and 3/24
spective series of 45 patients, the mean age of presentation was 76 years discontinued treatment. Of the 12 patients with a complete response,
and most died of other causes [122]. Groin node surgery is not recom two relapsed with 12 months of treatment and overall, six patients had
mended unless there is clinical evidence of nodal disease. recurrence after a median of 31 months (14–46months). Whilst response
For patients with multiple basal cell carcinomas (e.g., in Gorlin’s rates are encouraging from these small studies, the data should be
syndrome) the surgical management should take in to account the interpreted with caution as follow-up periods in the available studies are
symptoms and tumour burden and be managed in conjunction with short, side-effects common and recurrence rates were not based on the
dermatology and plastic surgery. gold standard of histology.
Vulval Paget’s Disease. Vulval Paget’s Disease (VPD) is a rare disease Small case series have examined the use of radiotherapy and
with only few case series presented in the literature. Invasive VPD rep photodynamic therapy for treatment of VPD. Clinical responses have
resents 1–2 % of all vulval cancer. However, the literature very poorly been reported and are summarised in a narrative review [77]. However,
differentiates non-invasive VPD, invasive VPD, vulval adenocarcinoma the certainty of the evidence is very low and risk of reporting bias is very
and VPD with underlying malignancy, so the proportional incidence is high. In patients with extra-mammary Paget’s disease refractory to, or
difficult to estimate. VPD may be asymptomatic or present with itching, unable to tolerate, imiquimod, an observational study in three women
burning and irritation. VPD classically presents as an erythematous (two with VPD) of a 1:1 mixture of fluorouracil, 5 %, cream and calci
plaque with white scaling, called “cake-icing scaling”. However, it can potriene, 0.005 %, cream demonstrated palliation in all three patients
present with a variety of colours with nodules or plaque-like disease at and histological response in two, although no complete responses [131].
presentation. As with melanoma in situ, the risk of recurrence or development of
Patients with VPD may have an increased risk of an underlying invasive disease is high (~70 % in one series [128] and, with lack of data
malignancy and one study estimated a standardized incidence ratio of to guide recommendations, long-term follow up in a specialist pre-
1.39 (95 % CI 1.11 to 1.73) [123]. The risks are lower than with malignant vulval disease clinic is suggested [132].
Mammary Paget’s Disease and somewhat uncertain due to lack of age Malignant melanoma. Malignant melanoma is the second most
standardisation in studies and whether an underlying invasive ano- common vulval malignancy after squamous cell carcinoma, representing
genital adenocarcinoma is considered to be an associated malignancy, 7–10 % of all vulval cancers. Relapse rates are high and correlate with
or not. However, underlying urological, colorectal, uterine and breast the depth of invasion (Breslow thickness) [133]. Forty-four patients
cancers have been reported. In one longitudinal study of 89 patients from the South West of England, with the median age of 71 years, had an
with VPD, 41 (46.1 %) were diagnosed with 53 synchronous or meta overall median survival of 32.5 months (95 % CI 17.8 to 46.5 months)
chronous cancers and seven (7.9 %) had invasive vulvar cancer with and median recurrence-free survival 12.6 months (95 % CI 7.7 to
≥1 mm depth of invasion [124]. Cystoscopy, colonoscopy, hysterosco 17.4 months) [134]. An international study of vulval cancer, VULvar
py, CT and breast examination have therefore been recommended at CANcer, involved 100 international centers [135]. Of the 1727 patients
diagnosis [125]. However, more recent data from the Dutch pathology included, 42 were diagnosed with vulval melanoma (2.4 %). During a
registry suggests that routine screening for secondary malignancies mean follow up period of 44.1 months the recurrence rate was 50 %. The
could be safely omitted for those patients with primary cutaneous VPD mean overall survival for vulval melanomas was 45.9±4 months and the
as defined by immunohistochemistry [126]. 5-year overall survival rate was 78.6 %. Tumour size was the only sig
Treatment for VPD consists mainly of surgery ± lymphadenectomy, nificant prognostic factor for local recurrence (P = 0.003). Width of
if there is evidence of ≥1 mm depth of invasion [127]. The updated resection margins, lymphadenectomy rate or adjuvant treatment were
Cochrane review of treatment of VPD in 2019 noted that there was an not associated with recurrence or overall survival. Distant recurrence
absence of evidence in treatment of VPD and that good quality studies was related to The American Joint Committee on Cancer (AJCC) staging
were required [127]. Recurrent VPD is common (60–70 %) and is as system, which includes prognostic factors important for cutaneous
frequent in those with microscopically clear margins compared to those melanoma (including tumor thickness, tumor ulceration, status of
with involved margins [128]. Further excision may not reduce the risk of regional lymph nodes, site of distant metastasis, and serum lactate de
recurrence and alternatives, including imiquimod or watchful waiting, hydrogenase). Younger age was associated with an improved overall
should be strongly considered, if invasion is excluded. There are no data survival (P < 0.001). Vulval melanoma treatment recommendations are
regarding the safety or effectiveness of sentinel lymph node biopsy in covered by the recent Ano-uro-genital Mucosal Melanoma Full Guide
VPD with evidence of invasion ≥1 mm and at present lymphadenec line, which should be consulted for more detailed evidence and rec
tomy, whether ipsilateral or bilateral, depending on position, would be ommendations [1].
recommended. All vulval melanoma should be discussed in both the gynaecology
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pathways to enable effective communication between teams, particu reproducible lymphatic drainage with lymphatic flow from posterior to
larly with regards to potential trial allocation. anterior. The lymphatics do not cross the labio-crural folds but decussate
Currently there is no evidence that survival of gynaecological mel in the mons pubis [144]. Tumour spread in the lymphatics is embolic in
anoma has improved over the last 40 years [136]. However, novel early-stage disease, with ‘midline’ tumours having the potential to drain
immunotherapy agents are starting to show to improved survival in to both groin fields. The consistently low rate (<1%) risk of lymph node
cutaneous melanomas and should be considered. Patients therefore metastasis for tumours of ≤1 mm depth of invasion [145] means that for
should be tested at least for c-KIT and BRAF mutations, although rare in this limited group, surgical assessment of the inguinal nodes can safely
vulvo-vaginal melanomas [33,137]. be omitted. IFLND should also be omitted for basal cell and verrucous
Inguino-femoral lymphadenectomy/lymph node dissection (IFLND) subtypes. For recommendations on lymph node management and initial
has not been shown to improve survival. SLNB has been used in vulval management flowchart see Table 8, Table 9, Table 10 and Fig. 2.
melanoma and may influence treatment choices. Recent NICE guidance Formal IFLND is associated with high-rates of complications,
suggests a role for immunotherapy (Nivolumab) in improving including wound breakdown and lymphoedema [75]. SLNB should be
recurrence-free survival for patients with node-positive surgically the standard of care, where indicated, as it is both accurate and asso
resected melanoma [138]. Surgical resection of involved regional nodes ciated with reduced morbidity [75,146]. Sentinel node(s) can be iden
may be considered for palliation and improve quality of life, although tified with vital or fluorescent dyes and radioisotopes [147]. The use of
groin node surgery is not without significant morbidity [139]. vital dye alone is not recommended due to lower detection rates [72].
Surgical management should consist of a wide local excision to The use of combinations of radiocolloid and vital (blue) dye is associated
achieve margins free of microscopic disease by >1 mm (R0) in the least with high detection rates and low groin recurrence rates (<3%) when
radical fashion. There is no evidence that more radical surgery is used to assess unifocal, small (T2, <4 cm) primary tumours
beneficial [135]. If margins are microscopically involved (R1), further [148,149,75]. False negative rates were around 9 % in a meta-analysis
salvage surgery is normally recommended. If this is not possible, or is which included multiple smaller studies [149]. The technique is asso
declined, options involve: ciated with reduced sensitivity and higher false negative rates for larger
tumours [150] and formal IFLND should therefore be standard of care
• Watch and wait, treating recurrences as identified and appropriate at for this group (T3, >4 cm).
the time; Fluorescent detection with indocyanine green fluorescence (ICG)
• Adjuvant radiotherapy with the aim of reducing local recurrence; provides a potential alternative to the use of blue dye. When used in
• Systemic therapy. isolation, ICG may outperform blue dye, but body habitus may limit the
utility of this approach [151,152]. Use in combination with isotope
Where appropriate, patients should be encouraged to participate in appears to provide comparable accuracy to the combination of isotope
clinical trials. and blue dye [153]. As with other methods of SLNB, there is a learning
curve associated with the technique [154]. The optimum protocol for
Management of inguinal lymph nodes ICG use remains to be defined, But it is likely to follow the same prin
ciples as injection of other tracers, with intradermal injection at four
Background. For recommendations for management of inguinal and sites around the tumour prior to node dissection. If using more than one
pelvic lymph nodes, see Table 8. In keeping with squamous cell carci tracer, it is recommended that the same operator injects all tracers used
nomas at other sites, the presence of lymph node metastases in VSCC is to improve correlation.
of crucial prognostic importance [140,141]. The FIGO staging was Case selection and appropriate training are of paramount impor
updated in 2009 to reflect the impact of size and number of lymph node tance. Recommended criteria for the use of SLNB in early vulval cancer
metastasis on outcome [142]. Imaging modalities including ultrasound, are listed in Table 9. The European Society of Gynaecological Oncology
MRI and CT/PET-CT have been advocated for pre-operative staging, but (ESGO) guidelines [72] recommend a minimum throughput to maintain
both sensitivities and specificities for these techniques remain subopti competency in this technique. The exact number of cases required is a
mal [142,143]. In light of the poor survival associated with groin node subject of debate. A centralised database of procedures could help with
recurrence, surgery has retained its central role in the detection of quality control on a national basis and would be highly valuable. This
lymph node metastasis. Anatomical studies have demonstrated should be centrally funded and co-ordinated, with all cases uploaded by
local centres. This could be modelled around other databases in gy
naecology in the UK, e.g., https://bsug.org.uk/pages/information/bsug
Table 8
-audit-database/103.
Recommendations for management of IFLN.
Preoperative lymphoscintigraphy is currently employed by most
Recommendation Grade of centres and is advised to enable the preoperative identification of the
recommendation
number and location of sentinel nodes. For tumours that are truly
Treatment to the groin(s) is required where the depth of Grade C midline, bilateral drainage should occur. Where only unilateral drainage
the primary tumour is > 1 mm (>FIGO IA; pT1a)
Sentinel lymph node biopsy (SLNB) is the treatment of Grade B
choice for small (<4 cm), unifocal tumours without
clinical or radiological evidence of lymph node Table 9
metastasis at presentation, providing representative Criteria for performing sentinel lymph node biopsy (SLNB).
injection and pathological analysis is possible, and the
Criteria Comment
tumour does not involve the urethra, vagina or anus
For tumours ≥ 4 cm and/or multifocal disease, Grade C Unifocal disease False negative rate higher for multifocal
inguinofemoral lymphadenectomy (IFLND) via disease
separate groin incisions is recommended Depth of invasion > 1 mm Low risk LN metastasis if ≤ 1 mm
IFLND should include removal of the deep femoral nodes Grade D Tumour < 4 cm in vivo ≥4 cm associated with higher false
Preservation of the saphenous vein may reduce the risk of Grade D negative rate
post-operative complications and is recommended Representative peri-lesional injection is Risk of false negative if non-
where feasible possible representative injection
Patients with advanced or recurrent disease require Expert opinion (✓) Tumour should not involve urethra, anus Representative injection not possible
individualised, multimodal management and the or vagina
optimal choice and order of treatment modalities No clinical or radiological evidence of USS ± Cross sectional imaging
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Table 10 Management of the positive SLN. Where disease is identified in the SLN,
Recommendations for sentinel lymph node biopsy (SLNB). additional treatment to the groins should occur as there is a significant
Recommendation Grade of risk of disease (8–35 %) in other nodes within the lymphatic basin
recommendation [70,75].
Sentinel node dissection is recommended for small (<4 Grade B GROINSS-VII was a prospective phase-II single-arm treatment trial,
cm), unifocal tumours without clinical or radiological including patients with early-stage vulvar cancer (diameter < 4 cm) who
evidence of lymph node metastasis at presentation had surgical treatment (wide local excision with SLN biopsy) [71]. Of
providing representative injection is possible and the the 1213 participants with negative SLN, 31 developed isolated groin
tumour does not involve the urethra, vagina or anus.
There is a clear learning curve for SLNB and the technique Expert opinion (✓)
recurrence (2.7 % at 2 years, 95 % CI 1.7 to 3.6). If the SLN was involved
should be performed by clinicians/centres with (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy).
appropriate levels of training and expertise to maintain The trial design was amended, after the incidence of groin recurrences
practice. exceeded their stopping rule, so that those with SLN metastases >2 mm
The use of radioisotope is mandatory for SLNB. Vital or Grade B
underwent standard of care (ipsilateral IFLND); patients with SLN
fluorescent dyes may be used in addition to radioactive
tracer. micrometastases (≤2 mm including isolated tumour cells) continued to
Preoperative lymphoscintigraphy is recommended to Grade C receive inguinofemoral radiotherapy. Positive SLN were found in 21 %
enable the identification, location and number of of participants. In patients with SLN micrometastases, 126 of 160 par
sentinel nodes. ticipants received inguinofemoral radiotherapy; the ipsilateral isolated
When a sentinel lymph node (SLN) is not found (method Expert opinion (✓)
failure) inguinofemoral lymphadenectomy (IFLND)
groin recurrence rate was 1.6 % after 2 years’ follow-up. For the 162
should be recommended. participants with >2 mm metastases in the SLN, the isolated groin
For tumours involving the midline, bilateral SLNB should Expert opinion (✓) recurrence rate was 22 % in those who treated with radiotherapy, and
be performed. The identification of a unilateral SLN in 6.9 % in those who underwent ipsilateral inguinofemoral lymphade
such tumours should be regarded as ‘method failure’
nectomy ± RT after 2 years’ follow-up (P = 0.011). Lymphoedema was
and IFLND of the contralateral groin (no sentinel found)
is recommended. uncommon in those who had SLNB alone (4.1 % at 12 months) and less
Pathological assessment of the SN should include Grade C common in those treated with SLN and radiotherapy compared with
ultrastaging if the initial sections are negative. ipsilateral IFLND ± radiotherapy (10.7 % versus 22.9 % at 12 months).
Ultrastaging should include serial step sectioning every Radiotherapy is therefore a better option than completion IFLND for
200 µm with the use of immunohistochemistry where
those with micrometastases in SLN. The ongoing GROINSS-V III study is
the H&E sections are negative.
When macrometastic disease is identified in the SLN, Grade C investigating concurrent chemotherapy and radiotherapy dose escala
IFLND for the groin affected by metastatic disease is the tion for the involved groin as an alternative to IFLND ± RT in case of
current treatment of choice, with the addition of macrometastasis in the SLN [159],
radiotherapy as subsequently required.
The management of the unaffected groin in patients with bilateral
For patients with micrometastic disease or ITC detected in Grade C
the SLN, further treatment with radiotherapy alone drainage but unilateral positive SLN is a matter of debate. Early retro
(without surgery) is effective and associated with fewer spective studies provided conflicting results. Three studies observed
complications than IFLND contralateral non-sentinel positive node rates of 0 % (0/28), 5.3 % (1/
Where bilateral drainage is demonstrated, but metastatic Grade C 19) and 0 % (0/62), respectively [160–162]. However, another small,
disease is only identified in one groin, the incidence of
single institution study found this rate to be much higher (22 %; 4/18)
contralateral metastasis is low and further treatment
may be limited to the affected groin, but evidence for [163]. Prospective data from the GROINS-V trial group provides reas
this is limited. surance that omitting further treatment to the non-positive contralateral
groin may be safe, providing bilateral drainage has been identified for
true midline tumours. The authors report on 244 of the 366 patients with
is identified for midline tumours, inguinofemoral lymphadenectomy a unilateral positive node who received either IFL or no treatment to the
should be performed for the groin in which the technique has failed. contralateral groin. The incidence of a non-sentinel, contralateral
The utility of SLNB in cases of recurrent cancer remains to be defined. metastasis was 2.9 % (7/244; 95 % CI 1.4 to 5.8 %). This rate is com
The technique appears feasible in this setting [155], but detection rates parable to the risk of groin recurrence after identification of a unilateral,
appear lower and lymphatic drainage may be unusual following previ negative SLN. The majority of non-sentinel contralateral recurrences
ous surgery. Further investigation of the safety and efficacy of the occurred in tumours of >3 cm and contralateral treatment would seem
technique in this setting is required. wiser for those with bilateral draining primary tumours > 3 cm where
the ipsilateral node is positive [164].
Pathological assessment of the SLN. Intraoperative evaluation and/or
frozen sectioning of the sentinel lymph node (SLN) is controversial. Follow up after SLNB. The optimal follow-up protocol for detecting groin
There is an increased risk of missing micrometastases on final pathology recurrence in cases of negative SLNB is yet to be established. Salvage
from the loss of tissue arising from processing for frozen- section treatment with inguinofemoral lymphadenectomy and radiotherapy
assessment [149,156]. A retrospective institutional study provides some may be effective in cases of lymph node recurrence following false
reassurance in this regard [157]. However, frozen section confirmation negative results at sentinel node dissection [165]. Recurrence risk is
of macrometastases would support proceeding to IFLND at the time of greatest in the first two years [165,166] and follow-up regimes should
initial surgery. If the initial sections are negative, the SLN should be be aimed at detecting metastases at an early stage during this period.
subject to ultrastaging, with serial sectioning (at 200 µm) and immu
Ultrasound is more effective at detecting lymph node metastasis than
nohistochemistry with epithelial marker (usually AE1/AE3) to detect clinical assessment, but data to support the cost-effectiveness of routine
macro- and especially micro-metastatic disease. Metastatic disease
ultrasound in these patients is limited [167].
found by ultrastaging in patients who are node negative by conventional
histology is associated with higher recurrence rates [158]. The use of
Inguino-femoral lymph node (groin) dissection. IFLND remains the pri
combination detection techniques with pathological ultrastaging is both
mary treatment modality for the groins for tumours ≥4 cm. IFLND
highly accurate and cost effective in the management of early-stage
should include the medial, deep femoral nodes as omission of this group
disease [149,156]. The pathological protocol for assessment of the
is associated with a higher risk of groin node recurrence [168]. There are
sentinel lymph node is discussed in detail above.
conflicting data to support the preservation of the great saphenous vein
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to reduce the risk of subsequent complications, particularly lymphoe The use of fibrin sealant does not reduce lymphoedema and may
dema, since in some studies differences did not reach statistical signif increase post-operative infection rates [190]. A small double-blind RCT
icance. However, since in many other series there was a statistically of 19 patients (38 IFLND), did not find any beneficial effect of using a
significant increased morbidity in the patients where the saphenous vein collagen-fibrin sealant patch [191]. Objective leg measurements over
was not preserved, we would advise to preserve the saphenous vein time revealed a prevalence of grade 1 lymphoedema of 44.4 % and 50 %
when and where possible [169,170]. There is no consistent evidence as in investigational and control arms, respectively (P = 0.744), and a third
to the impact of node count on prognosis in vulval cancer [171–174]. In (33.3 %) of patients in both arms had grade 2 and 3 lymphoedema in
early disease, spread in the lymphatics appears to be embolic and both arms (P = 1). These data suggest that lymphoedema is very com
separate incisions can be used for the vulval and inguinal dissections to mon and under-recorded in most studies. Transposition of the sartorius
reduce surgical morbidity [82,175]. For lateralized tumours >1 cm from muscle has been advocated, particularly where adjuvant groin radiation
midline, bilateral lymphadenectomy can be omitted in favour of ipsi is anticipated, but more recent data have suggested that the technique is
lateral lymphadenectomy, although for larger tumours the risk of not associated with any benefit in wound complication or lymphoedema
contralateral involvement rises [176]. Contralateral inguinofemoral rates [192]. See section below for management of lymphoedema.
lymphadenectomy should be performed when ipsilateral nodes show A small multicentre RCT of use of energy device, Ligasure™, for
metastatic disease [68]. For patients with positive nodes, the number dissection and lymphatic sealing during groin node dissection in 20
and size of lymph node metastases determines outcome [70,177–179]. patients (40 IFLND) found the incidence of one or more complications
Extracapsular spread of tumour is associated with particularly poor was 29 % after LigaSure™ versus 70 % after conventional IFLND (using
prognosis [177,178]. sharp dissection/diathermy) (risk difference 41 %, 95 % CI 19 to 62;
Where inguinofemoral lymph node metastases are identified at P < 0.001) [193]. Patient-reported outcomes of restriction of daily living
lymphadenectomy, adjuvant treatment with radiation is associated with activities and pain were similar with both treatment methods.
improved survival for cases with >5 mm deposits and/or the presence of
extracapsular lymph node involvement [180]. Limiting surgery to Recurrent disease after lymphadenectomy. The outcome following
debulking of involved groin nodes rather than formal IFLND can reduce inguinal recurrence after IFLND is historically regarded as poor [194].
the morbidity of dual modality treatment without adverse effect on Limited recent data suggests that long-term survival can be achieved
disease control [181,182]. Where imaging suggests negative pelvic with multimodality treatment (OS 50 % at 7 years; n = 30) [166].
nodes, adjuvant radiotherapy should include at least the ipsilateral groin Restaging with CT/PET CT is advised and combination treatment with
and the distal part of the iliac nodes with an upper limit at the level of surgery and post-operative chemoradiation (in radiotherapy naïve pa
the bifurcation of the common iliac artery [72]. Treatment to the ipsi tients) is typically employed. Individualised treatment in a multidisci
lateral pelvic nodes should be considered due to the high risk of pelvic plinary setting is essential for these complex patients.
node involvement in this group. Treatment with chemoradiation ap
pears superior to pelvic node dissection, as although pelvic recurrence Reconstructive surgery. Since the publication of the first RCOG guidelines
was lower in the surgically treated group, groin recurrence was higher, for the management of vulval cancer in 2006, there has been a ‘gradual
as radiotherapy (without concurrent chemotherapy) was omitted in this increase in the number of women having reconstructive or plastic sur
older study [183]. Where bulky pelvic nodal disease is identified, sur gery input’ [132]. The European Society of Gynaecological Oncology
gical debulking prior to radiotherapy was previously recommended to Vulvar cancer guidelines also advise ‘availability of reconstructive skills
improve nodal control [72]. Recent developments in radiotherapy mean for both early & late disease’ [72]. However, despite increasing use of
that it is now feasible to escalate the nodal dose with an integrated or reconstructive techniques in gynaecological oncology surgery, there is
sequential boost. Extrapolating data from the management of squamous very limited evidence in this field, both regarding when reconstructive
cell carcinoma of the cervix would suggest that surgery is not be surgery is needed, and which techniques to use. This section is therefore
required when such techniques are utilised [184]. based on personal experience, case reports and series, and extrapola
tions from other reconstructive surgery fields. Many women will have
Complications of lymphadenectomy. The high incidence of complications good results following primary closure with appropriate release tech
(particularly wound breakdown (34 %), lymphocyst formation and niques. Leaving wounds open to heal by secondary intention is also a
lymphoedema (25–45 %) following IFLND has been confirmed in recent valid option in some cases and can achieve good functional and cosmetic
studies [75,185]). A variety of strategies have been suggested in an results.
effort to reduce the rate of complications, but high-quality evidence to
support recommendations is lacking. A population-based cohort study Aims of reconstructive surgery. In the setting of vulval cancer, the pri
from Sweden demonstrated short-term complication rates of 21.8 %, mary aim of reconstructive surgery is to facilitate complete, curative
39.6 % and 54.2 % after vulval surgery only, vulval plus SLNB and vulval surgical resection of the disease with appropriate margins and preser
plus IFLND, respectively [186]. Preservation of the great saphenous vein vation of organ functions. Secondary aims are to enable wound healing
during lymphadenectomy may reduce the risk of cellulitis and lym by primary intention and to reduce morbidity due to scarring.
phoedema and is recommended [170]. Suction drainage is usually The anatomy of the vulva means that for small resections, direct
employed after IFLND, but the optimum management of wound closure is often possible. However, wider resections or repeated small
drainage is yet to be defined Pontre et al., 2018; Thomson et al., 2014 excisions can lead to tightness and scarring around the vaginal introitus
[187–188]. In an observational study, two regimens of suction drainage with dyspareunia, pain on passing urine or even discomfort on sitting
were compared: volume-controlled (removal once drainage ≤30 ml, and walking. Ultimately, tension of wound closure will reduce blood
after a minimum of 48 h and up to a maximum of 28 days following supply to the skin margins and therefore affect wound healing. Radio
surgery); versus short drainage (removal after five days following sur therapy reduces effective cell division and therefore reduces the skin’s
gery) [189]. They included 77 participants (139groins) for volume- ability to heal. Irradiated wounds may be particularly slow to heal, if
controlled drainage and 64 patients (112groins) for short drainage. closed under tension. Reconstructive surgery techniques can be used to
There was no difference in wound infection or wound breakdown rates, reduce tension on previously irradiated skin, or to introduce non-
but there were fewer lymphocysts in the volume-controlled cohort. irradiated tissue into the wound bed.
Overall, complication rates per groin wound were 46 % per groin after The reconstructive surgeon will employ a variety of techniques to
volume-controlled drainage versus 75 % after short drainage (RD 29 %, close a perineal wound, taking into account the disease pathology and
95 % CI 8 % to 49 %; P = 0.006). tissues to be excised; local anatomy; comorbidities; and patient
224
preferences. These techniques include split and full thickness skin grafts; Table 11
local & regional flaps; and free flaps. Similar techniques can also be used Reconstructive options for wound closure.
to release areas of tight, uncomfortable scar after excision and direct Graft and flaps Pros Cons
closure. The option of primary closure using release techniques is
Split skin graft Do not add bulk from Prone to contracture; effect
appropriate for the very large majority of resections and consideration underlying tissues, unlike on donor site
should be given to leaving wounds open to heal by secondary intention flaps
in selected cases. Dermal replacement Used with split skin grafts Still in development
to allow more pliable skin
Local flaps: Unilateral or bilateral; May be thicker than needed,
Surgical planning. rhomboid; lotus relatively simple requiring secondary
petal; local thinning; affected by
• The resecting surgeon should not be tempted to limit their surgical advancement previous radiotherapy; risk of
excision by the constraints of soft tissue closure. lymphoedema affecting
wound healing
Distant flaps: gracilis; Minimal tension; option to Bigger/thicker flap may
• Where reconstructive surgery is anticipated, there will ideally be a rectus abdominus; cover large and deeper cause issues and risk of
combined excision/reconstruction examination, either in clinic or anterolateral thigh defects; can be taken from devascularisation; effect on
flap skin outside of previous donor sites
under anaesthesia, to plan which tissues to excise and allow full pre-
radiotherapy/
operative counselling regarding reconstruction. lymphoedema area
Free flaps More tailored Higher risk of
• If the anal margin is involved by the disease, potential approaches reconstruction devascularisation; effect on
donor sites
are: primary treatment with chemoradiation, temporary or perma
nent stoma with excision of the required amount of anal margin; or
neo-adjuvant (chemo)radiotherapy with the aim of down-sizing the They may be useful if previous surgery, radiotherapy or lymphoe
disease and allowing preservation of the anus. dema have compromised local flap options.
• Free flaps: these are rarely used in the vulva because of the diverse
• Local flap reconstruction is possible after radiotherapy to the flap local options, but offer the possibility of a more tailored
field, but the length to breadth ratio of the flap may need to be reconstruction.
modified to avoid tip necrosis.
Vacuum-assisted closure (VAC)
• If excision margins are difficult to assess, frozen section should be Vacuum-assisted closure or VAC dressings, can be helpful in the
considered before planning flaps for reconstruction. management of vulval wounds, but the challenges of obtaining an
adequate seal due to local anatomy can limit their utility. VAC dressing
• After flap reconstruction, if lateral margins are incomplete then the may have a limited place in management of inguinal wounds that have
margin of the flap and an appropriate amount of native tissue can be opened up due to infection; a Cochrane review suggest that negative
excised. If the deep margin is involved, a thick flap may be lifted in a pressure dressings may decrease the time of wound healing of wounds
more superficial plane and replaced after excision of deeper tissues. by secondary intent, but data are limited and of very low certainty
However, a thin flap may need to be entirely excised with the un [195]. Data from another Cochrane review of negative pressure dress
derlying soft tissue to obtain a clear margin. For this reason, if there ings following primary closure, suggest that there may be a slight
is uncertainty about surgical margins, delayed flap reconstruction decrease in surgical site infections, but again the certainty of evidence is
with either dressings, direct closure or skin graft while pathology is very low [196].
obtained should be considered.
Radiotherapy
The complex three-dimensional anatomy and specialized skin of the Surgery is usually the treatment of choice for vulval cancer, but there
different regions of the vulva make for a reconstructive challenge. It is are indications for radiotherapy, with or without concomitant chemo
difficult to completely match excised vulval skin in terms of colour, therapy, in both the primary, adjuvant and recurrent settings. Table 12
texture, hair, secretions and thickness. However, the vulval region has a includes the recommendations for adjuvant and primary radiotherapy.
rich blood supply so local and regional flap options abound. See Table 11 The Royal College of Radiologists guidelines on Radiotherapy for Vulval
for a summary. Cancer are in draft and will provide more detail on radiotherapy target
volumes, dose fractionation regimens, treatment planning, concurrent
• Skin grafts: split or full thickness skin grafts are useful for skinning chemotherapy and care during treatment. Please refer to this document
vulvectomies where a local flap would be bulkier than the tissue for further details once published (currently out for consultation).
removed. Split skin grafts are more prone to contracture than full
thickness grafts. Full thickness graft donor sites are directly closed so Adjuvant radiation / chemoradiation therapy
a donor site with adequate laxity is needed. Following surgery for vulval cancer, up to 40 % patients develop
• Dermal replacement: this is a developing field, and may be of use in local recurrence with increasing incidence with time, although many are
the future as an adjunct to split skin grafting to allow for more pliable second primary tumours [92]. The aim of adjuvant treatment is to
skin. reduce the risk of disease recurrence but the benefits need to be balanced
• Local flaps: rhomboid flaps, lotus petal flaps and local advancement with the potential long-term consequences of radiotherapy.
flaps can be used unilaterally or bilaterally even in the face of prior Radiotherapy to the vulva is recommended in the post-operative
surgery or radiotherapy. Consider the impact of the donor site scar; setting, if the surgical resection margins are positive and further surgi
thickness of the flap (they may require secondary thinning); and cal excision is not possible [197]. Significant damage/ impairment of
potential for lymphoedema after lymph node dissection which may structures, such as anus, urethra, and clitoris should be considered when
affect wound healing. planning surgical re-excision and radiotherapy may therefore be the
• Distant flaps: gracilis, rectus abdominis and anterolateral thigh flaps preferred approach. A dose of 60–64 Gy (equivalent dose in 2 Gy frac
will reach the vulval wound without tension and offer more versa tions (EQD2)) should be considered with external beam radiotherapy or
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225
Table 12 [204,206,207].
Recommendations for adjuvant and primary radiotherapy. External beam radiotherapy should be delivered with intensity-
Recommendation Grade of modulated radiotherapy techniques (including volumetric modulated
recommendation arc therapy (VMAT)), which reduce dose to the organs at risk, as well as
Adjuvant (chemo)radiotherapy should ideally take place Grade B providing the option of dose escalation with an integrated boost to
within 6–8 weeks of surgery. involved nodes that should improve outcomes [208,209]. Treatment
Postoperative radiotherapy is to be considered when: should ideally be commenced within eight weeks of surgery and
- positive excision margins of the primary tumour, and Grade D completed within 105 days as overall treatment time impacts on out
further surgical excision not possible;
- pathological margins < 2 mm, where repeat excision is Grade D
comes [210].
not recommended, even though no consensus for the
threshold of pathological margin distance exists. Each Primary chemoradiotherapy
case should be individualised and discussed at MDT, Primary radiation therapy should be considered for patients deemed
taking into account patient factors (co-morbidities,
inoperable due to extent of tumour, when exenterative surgery with
previous treatment), location of close margins, and
need for groin/pelvic radiotherapy; permanent stoma formation would otherwise be required, and/or unfit
- following inguinofemoral lymphadenectomy, presence Grade B for anaesthesia. Early studies assessed the role of neoadjuvant chemo
of > 1 metastatic lymph node and/or the presence of radiotherapy prior to surgery, with the GOG completing two landmark
extracapsular lymph node involvement. multi-centre phase 2 trials; GOG 101 delivered 47.6 Gy with a split
- following SLNB: micrometastasis present
Definitive chemoradiation, generally weekly cisplatin Grade B
course schedule [211]; and followed by GOG 205 which delivered
with IMRT, is the treatment of choice in patients with 57.6 Gy without any treatment gaps. These studies reported higher
locally unresectable disease. complete clinical (64 % versus 48 %) and pathological response rates
Consideration needs to be given to enrolling patients into Grade D (50 % vs. 31 %) with the higher dose [212]. Of those who achieved a
clinical trials to explore primary chemoradiation (no
complete clinical response, 78 % had a pathological complete response.
surgery) alone for patients with earlier stages of locally
advanced vulval cancer to avoid exenterative surgery. With more advanced radiotherapy techniques enabling further dose
escalation, the treatment aim should now be to deliver definitive
treatment, with surgery reserved only for patients without a complete
pathological margins, post-operative vulval radiotherapy may be response. A case series using IMRT to escalate vulval dose to median
considered to reduce the frequency of local recurrences [199]. There is 66 Gy and involved nodes to 60.6 Gy and concurrent weekly cisplatin
no consensus for the threshold of pathological margin distance below chemotherapy had a complete clinical response rate of 88 %, compared
which adjuvant radiotherapy should be advised, although margins of to 63 % with median vulval dose of 59.4 Gy pre-operatively [213]. A
<2–3 mm have been associated with increased local recurrence rates large database study of >2000 patients showed that patients receiving
[200,201,72,91]. Additional factors for local recurrence include lym definitive chemoradiation to a dose above 55 Gy had equivalent survival
phovascular or perineural invasion, large tumour size, depth of invasion to those receiving surgery after RT [214]. The five-year survival was
>5 mm, and presence of LS/dVIN at the resection margin 50 % with chemoradiation compared to 27 % with radiotherapy alone in
[88,94,202–204]. In addition, a retrospective study of 360 patients with a National Cancer Database study of 1352 patients, with a significant
inguinal lymph node involvement reported that delivering radiotherapy survival benefit still present when propensity matched to account for age
to the vulva as well as the inguinal nodes reduced the incidence of local [215]. A recent multi-centre study of 52 patients delivering 64.8 Gy to
recurrence irrespective of margin status [205]. the primary tumour and concurrent capecitabine chemotherapy had a
The GROINS-V II study showed that patients with early-stage disease complete response rate of 62 % at 12 weeks, and persistent response at
and a sentinel node metastasis ≤2 mm can be treated with postoperative two years of 42 %, with five-year overall survival 52 % [216]. The acute
radiotherapy to the inguinal nodes using a dose of 50 Gy in 25–28 and long-term toxicity was acceptable, with grade 3 long term toxicity in
fractions as a less morbid option than inguinofemoral lymphadenectomy 21 % patients.
[71]. When there is a sentinel node metastasis >2 mm, patients should Staging investigations should include MRI and CT-PET scans to aid
undergo inguinofemoral lymphadenectomy which is then followed by radiotherapy planning. The target volume should include the primary
postoperative radiotherapy in case of 1 or more additional LN metastasis tumour, vulva, inguino-femoral and pelvic nodes depending on extent of
and/or extracapsular tumour spread. In this study the two-year isolated disease. Please refer to the new Royal College of Radiologists vulval
groin recurrence rate was unacceptably high (22 %) with radiotherapy cancer radiotherapy guidance once published (currently out for
alone using 50 Gy. However, toxicity of radiotherapy versus surgery in consultation).
this situation needs to be carefully considered on an individual patient IMRT techniques are recommended, with integrated or sequential
basis. The addition of concurrent chemotherapy with radiotherapy may boosts to escalate dose to macroscopic disease to at least 64 Gy (EQD2)
improve outcomes, and the ongoing GROINS-V III study is investigating to primary tumour. MRI-image guided brachytherapy may be consid
concurrent chemotherapy with radiotherapy dose escalation instead of ered as a boost for selected patients.
IFLND for a SLN macrometastasis. Treatment breaks should be avoided with treatment completed
Probably the most frequent indication for external beam radio within 50 days when possible. Careful management of acute toxicities is
therapy is for patients who have undergone surgical resection and in essential, with regular clinical review, expert skin care and adequate
whom the histological examination has demonstrated positive lymph analgesia. Assessment of response should be performed at 12 weeks
nodes. Trials conducted by the Gynaecological Oncology Group (GOG) following completion of treatment with clinical assessment and imaging.
in the 1980s and 1990s showed that adjuvant radiation therapy was of Biopsy should be performed if residual disease is suspected.
benefit if there were two or more lymph nodes involved, or if there were
one or more nodes with extracapsular spread [183]. A more recent Palliative radiotherapy
database study of 2779 patients with involved lymph nodes showed Palliative radiotherapy can provide symptomatic benefit when
adjuvant radiotherapy improved survival for patients with a single radical radiotherapy is not an option. Patients may have pain, bleeding,
involved node, as well as for those with two or more nodes, compared to ulceration and local invasion into bladder and/or or rectum. Palliative
no further treatment [206]. The addition of chemotherapy to radio radiation may alleviate distressing symptoms, but should be given as
therapy further improved outcomes, with five-year overall survival of relatively short courses. The most frequent schedules include 20 Gy in
49 % when two or more lymph nodes are involved compared to 29 % five fractions or 30 Gy in 10 fractions delivered over one or two weeks,
with radiotherapy
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adjuvant treatment and hypofractionated regimens to a smaller volume including 30–36 Gy
226
in six fractions over three to six weeks. In very frail patients who have The pooled reanalysis found that neoadjuvant therapy plus surgery led
active bleeding, a single fraction of 8 Gy or 10 Gy may be considered and to significantly better five-year overall survival (73 %) than definitive
this can be repeated if required. CRT (43 %) alone. However, no significant difference was found be
tween CRT (five-year overall survival 69 %) and CT (77 %, P = 0.11) in
Chemotherapy the neoadjuvant setting. In addition, patients showing a positive
See Table 12 for recommendations for adjuvant/neoadjuvant response to CT or CRT had a better five-year overall survival (67 % vs.
treatment. 20 %, P = 0.001). The authors concluded that NAC plus surgery can
potentially improve survival of patients with advanced vulval cancer.
Squamous cell carcinoma A Cochrane review [222] evaluating the effectiveness and safety of
Chemotherapy has been used in the management of vulval cancer at neoadjuvant and primary chemoradiation for women with locally
multiple points: in a neoadjuvant setting to reduce the extent of surgery; advanced primary vulval cancer compared to other primary modalities
and in the adjuvant setting with concomitant radiation, for node positive of treatment, such as primary surgery or primary radiation, failed to
disease. Chemotherapy treatment for recurrent and metastatic disease is demonstrate any significant difference in overall survival or treatment-
discussed below. The potential for using more targeted systemic thera related adverse events when chemoradiation (primary or neoadjuvant)
pies e.g., growth factor receptor inhibitors, biological agents and was compared with primary surgery. But there were only three publi
immunotherapy is also explored here. cations describing 141 patients, the largest of which (68 patients) was a
randomised controlled clinical trial which has only been published in
Neoadjuvant chemotherapy for invasive squamous cell carcinoma abstract form [223]. This publication had an imbalance in the distri
Systemic neoadjuvant therapy is reserved for vulval cancer patients bution of patients with inguinal node involvement (node positive pa
who are either too unwell to undergo radical curative surgery/radiation, tients made up 80 % of the primary CRT cohort compared with 62 % of
or for those whose large volume primary / nodal disease could be treated surgical patients) and it is not clear whether there was any statistical
with more conservative surgery / radiation, if adequately down-staged. adjustment for this very poor prognostic factor. There was also no
Publications in this setting are limited to small case series. Reports of stratification for, or details about, HPV status in the treated population,
response rates between 56 and 67 % to various cytotoxic combinations another important prognostic indicator.
in this setting date back to 1990 and include agents such as bleomycin,
vincristine, mitomycin C, methotrexate, lomustine, 5-flourouracil, Adjuvant chemotherapy
paclitaxel, carboplatin and cisplatin [101,217]. Reported long-term Adjuvant chemotherapy alone is not routinely undertaken in patients
survival was limited, e.g., 24 % still alive at 3 years [97]. More with vulval cancer. There is however increasing evidence for giving
recently infusional 5-FU with cisplatin has been evaluated as NACT for chemotherapy concomitantly with radiation in this setting. The evi
patients with locally advanced vulval cancer in small studies, with re dence for this is discussed above. Only 9.1 % patients in the largest
sponses ranging from 20 to 100 %. [99,100] A very small study of seven retrospective study of adjuvant therapies received chemotherapy
patients (and two with recurrent metastatic disease) were treated with following radiation therapy for node positive vulval cancer. The out
weekly paclitaxel (60 mg/m2) and carboplatin (AUC 2.7), however, the comes for these patients are not reported separately from the larger
study failed to show any response [218]. Another recent publication chemoradiation population where the addition of chemotherapy to ra
describes the use of platinum-based NACT or bleomycin alone in 32 and diation resulted in a non-significant reduction in the risk of death [206].
five patients, respectively [96]. Responses were documented in 30 pa
tients (81 %) and 27 proceeded to radical vulvectomy. Eleven women Targeted agents
(40 %) had residual tumour in IFLN and underwent post-operative Very little clinical work involving targeted biological agents has been
chemoradiation. At 49 months follow up 24/27 (88 %) of the surgical undertaken to date in vulval cancer. A recent review of all published
patients had no evidence of recurrence. Conversely, Raspagliesi et al evidence of the last two decades in the field [224], provided a
described the treatment of ten patients with cisplatin / paclitaxel ± comprehensive insight into the molecular biology of vulval SCC and
ifosfamide [219]. Nine patients subsequently underwent radical local possible associated molecular targeted therapies. Working groups are
excision or radical partial vulvectomy and bilateral inguino-femoral mainly focussing on aberrant cell cycle activity as a common pathway in
lymphadenectomy. The clinical response rate of all enrolled patients both HPV- and non-HPV- associated cancers. These aberrant cascades
was 80 %, whereas the pathological responses included one case with are characterized by an overexpression of p53, Rb and cyclin D1, sup
complete remission, two with persistent carcinoma in situ, and six porting development of targeted factors of those protein products and of
invasive cancer cases with tumour shrinkage of more than 50 %. The their downstream pathways. Further identified areas of interest are
authors concluded that based on the high response rates and manage extracellular regulators of cellular activity, such as EGFR, as well as
able toxicity, NACT with paclitaxel and cisplatin with or without ifos inhibitors of angiogenesis. HPV-independent vulval SCC is characterized
famide followed by surgery could be considered as a therapeutic option by actionable mutations, including PI3K, CDKN2A and PTEN as opposed
for locally advanced vulval cancer [99,211,219]. to HPV-associated disease where therapeutic vaccines targeting the E6
In analogy to the standard carboplatin and paclitaxel regimen given and E7 HPV oncogenes and immune-based therapies are under investi
in other gynaecological cancers, the group by Amant et al, reported their gation [224].
experience with 3-weekly paclitaxel-carboplatin chemotherapy for pa A single arm study of erlotinib examined two separate cohorts: 17
tients with locally advanced vulvar cancer demonstrating clinical re patients with locally advanced vulval lesions amenable to definitive
sponses that enabled patients to have subsequent surgery [220]. The surgery or chemoradiation; and 24 patients with metastatic disease (see
authors recommended that a prospective multicentre study should be metastatic section for outcomes of cohort 2) [225]. In the first cohort,
performed in a larger series of patients in order to compare neoadjuvant patients were only treated with erlotinib for between 28 and 42 days. Of
paclitaxel-carboplatin with chemoradiation, based on these preliminary these, 35 % (6/17) achieved a partial response and four of these six
results. patients had previously undertaken chemoradiation for prior vulval
A recent pooled analysis of published evidence addressing treatment cancer and were being treated for ‘in-field’ local recurrences. All these
of advanced vulval cancer by neoadjuvant or definitive chemotherapy patients had high EGFR expression on IHC, yet gene amplification, high
(CT) or chemoradiation (CRT) analysed the factors influencing patients’ trisomy or disomy were only found in 35 %; there were no identified
survival [221]. A total of 97 patients with stage III and IV disease were EGFR mutations [225].
included and re-evaluated, although results should be interpreted with There is an urgent need to reconsider vulval cancer diagnoses in the
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to significant light of their aetiology with prospective p16- and p53-status in all cases
227
for better management of any background lichen sclerosus and SLNB is not advisable.
improved prognostication. Additionally, translational research needs to The opinion of an experienced plastic surgeon may often be neces
explore the reasons for the poorer prognosis for non-HPV related vulval sary in order to assess options or local reconstruction and covering of
cancers and novel treatment strategies including biological targeted defects in more advanced local relapses, especially since multiple re
therapies. In HPV-associated vulval SCC, novel treatments that exploit sections may be undertaken over a number of years in patients who have
and/or enhance the host immune response merit further investigations slow patterns of recurrence. When the situation arises that further sur
in line with novel studies for cervical cancer. gery will lead to a risk of incontinence or a stoma formation, patients
may be considered for radical radiation treatment as outlined above.
Treatment of recurrent disease Similar discussions will take place regarding the need for “adjuvant
The management of recurrent disease can be challenging and may radiation therapy” after surgery for relapse and these will be similar to
require a multidisciplinary team approach. A number of factors need to the indications that are used in primary treatment.
be carefully considered, most notably the previous treatment(s) deliv
ered, the site(s) of disease and the performance status of the patient. The Radiotherapy. The indications for postoperative radiotherapy are com
treatment of recurrent disease may be associated with significant parable to those for the treatment of primary disease, even though no
morbidity and often impacts on bladder, bowel and sexual function. As randomised studies exist in this setting [72]. The addition of concomi
always, the patient should be central to treatment planning and a clear tant chemotherapy should be considered in the similar approach for
decision made as to whether intervention planned is with radical or primary disease.
palliative intent. Definitive chemoradiation is recommended when surgical treatment
Possible options include: is not possible or would result in a permanent stoma [212]. While sur
gical procedures may be repeated there is usually only one opportunity
• Further surgery to give high-dose radiation so the optimal timing of radical radiotherapy
• Radical radiation therapy with or without chemotherapy must therefore be carefully deliberated; in practice, this is most often
• Neoadjuvant chemotherapy followed by tailored therapy scheduled when the surgical options have been exhausted. External
• Palliative radiotherapy beam radiation utilising IMRT or VMAT is the standard approach. A dose
• Palliative chemotherapy to the primary site of 60–68 Gy is recommended; this may be achieved
• Novel approaches including immunotherapy by external beam alone or in combination with either an electron boost
• Best supportive care or an interstitial implant [209].
The techniques for radiotherapy for recurrence when used as salvage
See Table 13 for recommendations in recurrent disease management. will be broadly similar to those outlined above. Discussions may take
place as to whether the treatment field should simply encompass the
Vulval recurrence locally recurrent disease at the vulva or whether the inguinal/pelvic
nodes ought to be included. Ideally, the nodal basins will be irradiated,
Surgery. Vulval recurrences should be treated as primary tumours with especially as the majority of patients will have undergone at least uni
wide or radical local excision and inguinofemoral lymphadenectomy in lateral groin node dissection previously leading to altered lymphatic
case of depth of invasion of more than 1 mm and not previously per dynamics. However, this decision may well be influenced by the precise
formed groin dissection or after previous SLN alone in accordance also surgical history, including the presence of complications such as lym
with the ESGO guidelines [64]. Appropriate imaging with MRI and/or phoedema, and patient frailty/patient wishes. There may be a role for
CT (and PET CT when radical excision is a consideration) is advised to re-irradiation with either EBRT, stereotactic radiotherapy or brachy
exclude metastatic disease and determine extent of local disease. The use therapy for selected patients if no further surgery is feasible.
of repeat SLNB alongside radical excision of small recurrences/second Although isolated distant recurrence is rare, stereotactic radio
tumours is discussed above Data to support the safety/efficacy of SLNB therapy or surgery can be considered for patients with oligometastatic
in the setting of recurrent disease are very limited, based on one small disease.
retrospective study [205]. Prospective studies are ongoing to provide Palliative radiotherapy may be used for relapsed disease when sur
data on oncological safety but until more data are available, repeated gical options have been exhausted and the patient is not fit for high dose
external beam radiotherapy. Simple planning techniques may be used,
and doses between 20 Gy in five fractions up to 30 Gy in ten fractions are
Table 13
commonly used. A higher dose may be feasible using an IMRT approach
Recommendations for treatment of recurrent disease.
including 30–36 Gy in 6 fractions. In patients who have bleeding and are
Recommendation Grade of of poor performance status, a single fraction of 8 Gy or 10 Gy may be
recommendation
given which can be repeated.
Surgical re-excision of local and/ or IFLN relapse should Grade D
be considered in patients with relapsed disease
amenable to surgery, in analogy with the primary
Systemic therapies. Palliative chemotherapy is to be considered in pa
presentation of the disease. tients for whom further surgery or radiotherapy is not feasible (either
Imaging by CT (or PET-CT when appropriate) of the Grade D due to fitness or previous treatment) or for those who have distant
thorax/abdomen/pelvis is recommended prior to any metastatic disease. Treatment is given with the intention of palliating
treatment to tailor adequate approaches.
symptoms to try and improve the quality of life. The most commonly
SLNB can be considered for recurrent disease, if the new Grade D
focus of invasion meets criteria for primary SLNB. Data used cytotoxic drugs will include platinum agents, pyrimidines, taxanes
regarding the safety and efficacy of this approach is and mitomycin-c. Other drugs that may also be considered include
very limited gemcitabine and the vinca alkaloids [218]. There have been no rando
In patients not amenable to surgery, palliative Grade C mised trials, but the EORTC GCG reported that single-agent paclitaxel
chemotherapy, or radiotherapy, or combination of both
should be considered, depending on the previous
had modest activity in 31 patients with advanced, recurrent or meta
treatment modalities of the patient, the patient’s static vulvar carcinoma not amenable for locoregional treatment from
preferences and the patient’s fitness status. ten international institutions [226]. Overall response was 13.8 %, while
Systemic treatment may be considered in patients with Grade D at a median follow-up of 24 months, median PFS was 2.6 months (95 %
distant metastases, but published data are insufficient
confidence interval 2.04–4.21) [226].
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In patients who are fit, combination treatments can be considered. principles should be adopted throughout the patient’s pathway. It pro
There is no strong evidence in favour of any particular schedule but vides information on the psychosocial and psychosexual needs of
regimens such as cisplatin and capecitabine/5-fluorouracil, carboplatin women following diagnosis of vulval cancer and its subsequent treat
and paclitaxel, and mitomycin-c and 5 fluorouracil/capecitabine may be ments. It aims to guide/signpost the reader to agencies/services that
offered. These regimens will normally be given at three-weekly intervals provide appropriate intervention and support for the woman and her
up to a maximum of six cycles and with an interval assessment after family if needed. See Table 14 for recommendations.
three cycles to assess the response, in analogy to other gynaecological Patients should have access to personalised care including holistic
cancers. needs assessment, a care plan and health and wellbeing information in
Multiple very small retrospective series of patients are published line with the NHS Long Term Plan [233], similar strategies in the
involving a variety of cytotoxic agents and outcomes. No preferred devolved nations and Macmillan’s guidance on providing Personalised
regimens can be identified from the literature to date. National / in Care for People Living With Cancer [234].
ternational collaboration will be required to identify appropriate treat Determining appropriate strategies for supporting cancer survivor
ments for metastatic disease. Two studies utilised ‘biological’ agents. A ship should be based on three key elements: physical, psychosocial and
basket study for any gynaecological cancer was due to involve 32 pa psychosexual. Supporting cancer care has proven effective in improving
tients receiving durvalumab ± tremelimumab with stereotactic RT physical function, fatigue, anxiety and depression in other cancer types
(NCT03277482) [227]). This study was terminated after 16 patients [235]. The challenge remains to implement this effectively in vulval
were recruited due to no responses in non-irradiated lesions. Eleven cancer patients, where the disease is often multi-faceted. It is recognised
vulval cancer patients have received cisplatin with a p16-based vaccine that there are potential cost savings if survivors are effectively able to
as treatment for advanced / metastatic disease (NCT02526316 self-manage, reducing the overall burden on the healthcare system
[228,229]); results have not been published, although this study [236].
competed some time ago. Supportive care should also try to encompass preparation for treat
Immunotherapy agents, particularly checkpoint inhibitors, have ment (prehabilitation) which has been proposed to improve outcomes in
shown significant activity in squamous cell carcinomas including can gynaecological surgery [237], although a standardised, well-evidenced
cers of the cervix, skin and lung [230,231]. Pembrolizumab, a human programme does not yet exist [238].
ized monoclonal antibody targeting the programmed death 1 (PD-1) Both physiological and psychosocial factors can impact on quality of
pathway, demonstrated a complete clinical remission after 2 cycles in a life, and addressing possible and actual problems as they arise, may help
case study lung [231]. The phase 2 multicohort, open-label KEYNOTE- to reduce the negative impact experienced by gynaecological cancer
158 study enrolled women with advanced VSCC with prior treatment patients [239]. It is good practice to talk about symptoms that could be
failure to receive pembrolizumab 200 mg i.v. 3-weekly, for up to 35 attributed to cancer and the consequence of treatment, this should also
cycles [204]. Overall, the objective response rate (ORR) was 10.9 % be addressed at each follow-up appointment or through holistic needs
(95 % CI 5.6 % to 18.7 %), 9.5 % (95 % CI 4.2 % to 17.9 %) in 84 patients assessment (HNA). Since longer-term survivorship care is becoming
with PD-L1-positive VSCC, and 28.6 % (95 % CI 3.7 % to 71.0 %) in the increasingly important in the overall well-being of women treated for
seven patients with PD-L1-negative VSCC. Median PFS was 2.1 months vulval cancer, effort should be made to introduce nurse or allied health
(95 % CI 2.0 to 2.1 months) and OS 6.2 months (95 % CI 4.9 to practitioner (AHP)-led survivorship clinics to support holistic and indi
9.4 months). Treatment-related adverse events occurred in half of the vidualised approaches.
patients (50.5 %) and serious adverse events (grade 3–5) in 12 %). Two Women should have the opportunity to address symptoms attributed
of the 101 patients died from treatment-related hepatitis. Data for vulval
cancer are very limited, mainly as a result of the low incidence of the
Table 14
disease. Extrapolating data from the management of squamous cell Recommendations for supportive care.
cancer of the cervix, the addition of pembrolizumab in cases with PD-L1
Recommendation Grade of
expression with combined positive score (CPS) ≥ 1 and/or bevacizumab
recomendation
to platinum-based chemotherapy may be considered for selected pa
All patients should have a named keyworker to co-ordinate Grade D
tients in first line, although these drugs do not have specific approval for
treatment and their care pathway and be give contact
vulval cancer. details in a format they can understand
Other immunotherapeutic approaches are also likely to be rewarding Access to a CNS or equivalent and psycho-sexual counsellors Grade C
such as tumour infiltrating lymphocytes (TILs) which offer a further should be available as part of the multi-disciplinary team.
approach [232]. Immunotherapy approaches using vaccines and anti- Written information should be provided about treatment Grade D
choices and side effects including late effects.
viral therapy may also have a future role.
Recording of late side effects should be documented Expert opinion (✓)
Patients who develop lymphoedema should be referred to Grade D
Regional nodal recurrence. Treatment of IFLN recurrence is recom specialist lymphoedema service for assessment and
mended in analogy with a local recurrence where the preferred treat management
Patients with signs of radiation induced proctopathies or Grade D
ment option is radical excision followed by postoperative
enteropathies should have access to care from a team of
chemoradiation in radiotherapy-naive patients [72]. Re-staging with professionals who may include oncologists,
CT/PET-CT is recommended exclude distant metastatic disease prior to gastroenterologists, bowel surgeons, therapeutic
any local resection. In an analogous fashion to the treatment of primary radiographers, dieticians and specialist nurses.
disease, limiting surgery to debulking of large nodes prior to planned Patients with troublesome urinary symptoms after Expert opinion (✓)
treatment should have access to urology and specialist
chemoradiation may be considered to reduce morbidity without continence services for assessment, diagnosis and
affecting disease control [181,182]. Although historic data suggest IFLN conservative treatment.
recurrence is associated with a poor outcome [194], the use of multi Patients should be counselled regarding the increased risk Expert opinion (✓)
modal treatment can provide long term survival in up to 50 % of selected and symptoms of pelvic insufficiency fractures, early
menopause and infertility if appropriate, and the risk of
patients [166].
treatment related neuropathies.
Hormone replacement therapy for SCC vulval cancers is not Expert opinion (✓)
Supportive care contraindicated and should be assessed on an individual
basis. The overall evidence does not support or contradict
Although this section sits towards the end of the guideline, its HRT use in patient with melanoma, and advice should be
Ce document PDF a été édité via Icecream PDF Editor. individualised

229
to their cancer and its management before, during and after treatment. fe/side-effects-of-treatment-to-the-female-pelvic-area
They must have the opportunity to be prepared for the impact of pre
dictable symptoms and issues that may arise as a result of their vulval Psychosocial
cancer diagnosis and its subsequent treatments. Both physiological and
psychosocial factors can impact on quality of life, addressing possible The impact of cancer and treatment can affect quality of life, the
and actual problems as they arise may help to reduce the negative psychosocial needs of patients should be addressed throughout. A HNA
impact experienced by women. should be performed at pivotal points in the cancer pathway. Patients
Good quality information is available from both Macmillan and Eve should have the opportunity to explore ways of improving their quality
Appeal charities. The challenge is for providers to look to offer inno of life through appropriate support and signposting to living with and
vative ways of offering such services to those with vulval cancer. Pa beyond cancer services, and psychological services where available.
tients who experience late effects of their cancer treatment will require Patient resources: macmillan.org.uk/cancer-information-and-suppo
continuous and new information about how to best manage symptoms. rt/after-treatment.
Consideration should be given to online clinics, webinars and face-to-
face clinics delivered by CNSs and Cancer Support Workers. Lymphoedema
Patient resources: macmillan.org.uk/cancer-information-and-su
pport/vulval-cancer and eveappeal.org.uk/gynaecological-cancers/v Lymphoedema can affect lower limbs, lower abdomen and the
ulvar-cancer. pelvis/perineum after vulval cancer treatment. Risk of lymphoedema
after IFLND ranged from 17 to 50 % [254,255]. However, the lack of a
Psychosexual standardised definition of lymphoedema and its measurements make
true evaluation difficult [256]. The increasing use of SLNB rather than
Psychosexual issues following vulval cancer are common and diffi IFLND should reduce incidence [75]. Lymphoedema is significantly
culties include increased vaginal dryness, dyspareunia, reduced arousal worse in women who have both surgery and radiotherapy [257]. High
and desire, altered orgasm and sexual satisfaction, and reduced pleasure BMI, lack of physical activity and pre-existing lymphoedema may also
[240]. Women also experience psychological challenges around their increase risk [185].
sexuality in relation to altered body image, femininity fertility and loss Prophylactic information on reducing the risk of lymphoedema
of role [241]. A recent study showed sex and body image are major should be available to patients. Pre-surgical assessment, regular moni
concerns in patients diagnosed with vulval cancer, nearly one in three toring and early intervention may have some benefit in reducing the
women diagnosed were afraid to have sex [242]. Although treatments burden of lymphoedema in gynaecological cancer patients [258]. See
do not always result in higher risk of sexual dysfunction, especially macmillan.org.uk/Lymphoedema for patient resources. Patients should
minimally invasive approaches [243,244], the risk increases with be made aware of overt signs of lymphoedema; swelling, changes in
addition of radiotherapy, with up to 81 % patients reporting sexual sensation, aching, skin changes. Prophylactic monitoring with bioelec
difficulties including dyspareunia, vaginal stenosis, reduced desire and trical impedance analysis may be able to detect sub-clinical signs of
arousal [245]. The use of vaginal dilators or vibrators following radio lymphoedema [259].
therapy should be recommended to reduce the risk of stenosis [246]. Those patients who develop lymphoedema should be referred to
Factual information on possible changes to sexual function due to specialist lymphoedema services for assessment and management of this
surgery, radiotherapy and chemotherapy should be given to the patient condition. Management can include compression garments, manual
prior to treatment, to acknowledge that the subject of sexuality is open lymphatic drainage and pneumatic compression [260]. Patients should
should she need to seek further information, if difficulties occur [247]. be encouraged to maintain a healthy weight, keep active and undertake
Access to specialised psychosexual and psychosocial counselling ser daily skin care. Lymphaticovenular anastomosis (LVA) surgery may be
vices is recommended for women with vulval conditions including, but an option for those with early stage lymphoedema [261], especially in
not limited to vulval cancer. the presence of recurrent cellulitis. Evidence is growing that early
Sexual difficulties have multifaceted causes including physiological/ intervention with LVA may reduce the incidence of lymphoedema in
biological, psychological, interpersonal and socio-cultural factors, so a gynaecological cancers [262]. In a small, single centre study, immediate
joint approach to addressing problems should be adopted, having a lymphatic reconstruction in vulval cancer patients with inguinofemoral
multi-disciplinary approach to allow clinicians the safety to address this node dissection had a 17 % reduction in lower limb oedema [263].
topic and refer to on if the issues are beyond their comfort or expertise Currently, availability of LVA service is very limited [262,264].
[240,248].
Assessment and identification of sexual issues by clinicians can be Management of late effects of radiotherapy
done efficiently and easily with short validated tools using a style of
inquiry which starts by acknowledging how common sexual dysfunction Late effects, especially from radiotherapy are often permanent and
is amongst cancer survivors rather than asking direct questions [248]. progressive and can manifest many years after treatment completion.
Assessment tools/patient reported outcome measures (PROMS) can help Patients and primary care teams should be made aware that beyond the
to identify sexual difficulties, promote discussions and management of conventional follow up period they can be seen in a clinic to investigate
sexual issues [249–251]. late effects as well as potential recurrences. The following sections are
If sexual difficulties are present these should be addressed and where generic to patients treated with pelvic radiotherapy and are not specific
possible specific suggestions given, e.g., psychosexual education, use of to those treated for vulval cancer.
lubrication during intercourse or vaginal moisturiser [240,252,253]. Late side effects in gynaecological cancers are dependent on treat
Where available, patients with ongoing difficulties should be referred to ment modality and potentially pre-existing morbidities [265]. Conse
psychosexual services especially in women when sexual difficulties are quences of vulval cancer and its treatment and can include
persistent despite appropriate interventions and where there are high lymphoedema, effects on gastrointestinal and genitourinary systems,
levels of individual/couple distress, the woman has pre-existing sexual bone pain/insufficiency fractures and nerve damage.
problems and psychological vulnerability prior to diagnosis, or if there Professional resources: PRD Best Practice Pathway - PRDA
are dual sexual difficulties within the relationship.
Patient resources: Female pelvic side effects and your sex life | Gastrointestinal late effects
Macmillan Cancer Support. https://www.macmillan.org.uk/cancer-in Gastrointestinal (GI) effects from radiotherapy can include faecal
formation-and-support/treatment/coping-with-treatment/your-sex-li urgency, diarrhoea, leakage, rectal bleeding, malabsorption syndromes,
230
ileus/obstruction and small bacterial overgrowth. Data are not adequate counselled regarding the increased risk and symptoms of pelvic insuf
to define how many patients experience permanent GI changes post ficiency fractures. PIF occur under normal stresses on bones weakened
gynaecological cancer treatments [266]. There is limited evidence to by external beam radiotherapy. Recent meta-analyses of gynaecology
support the use of prophylactic dietary or pharmacotherapy in pelvic radiotherapy patients reported PIF rates of 7.8 % to 15.3 %
terventions to reduce GI toxicity from pelvic radiotherapy [267], treatment; developing 7 to 39 months post treatment, with the majority
although a recent systematic review and meta-analysis concluded biotic occurring within 2 years of treatment [284–286]. Pain is the main re
supplements may reduce acute GI toxicities [268]. ported symptom although up to 40 % may be asymptomatic [286].
At follow up it is important to ask if there are any new problems Pre-treatment screening for PIF risk factors including bone density
relating to bowel function. Validated tools can be used to assess symp measurements, fracture risk assessment tool, age >65 years, low BMI
toms include: EORTC PRT23 for radiation proctitis [269]; or ALERT B 20 kg/m2, history of fragility fracture, oral corticosteroid use and
[270]. European Organisation for Research and Treatment of Cancer is smoking history are probably warranted in post-menopausal gynaeco
currently developing a vulval cancer PROM [271]. logical cancer patients [284,287]. Interventions to prevent PIF such as
GI symptoms following pelvic cancer treatment are complex and calcium and vitamin D supplementation, bisphosphonate therapies, or
multifactorial. They should be managed in a sequential manner using a denosumab have little evidence but warrant further investigation
validated algorithm [266,272]. Initial management may involve simple [288,289]. Strategies to prevent fractures in these patients, such as the
lifestyle advice and medicines such as loperamide for diarrhoea and use of IMRT may benefit this population at significant risk of PIF but
dietary changes for constipation. A Cochrane review of non-surgical data is not conclusive [284,286].
options such as sucralfate for rectal bleeding look promising but the Patients should be made aware that pelvic pain, pain on weight
quality of evidence remains very low [273]. More complex and persis bearing and immobility are signs of PIF [286]. MRI images are useful to
tent problems warrant referral to specialist services e.g., gastroenter diagnose PIF and distinguish between bony metastases [290]. Conser
ology, colorectal, dieticians. A small study showed Sacral Nerve vative management involves rest, pain management and physiotherapy
Stimulation (SNS) can improve faecal incontinence following pelvic led exercise for stable fractures.
radiotherapy without increased complication rates [274]. Trials inves Professional resources: Endocrine late effects guidance for
tigating the use of hyperbaric oxygen treatment to treat chronic healthcare professionals | Macmillan Cancer Support.
gastrointestinal radiation damage do not provide sufficient data to be Patient resources: Bone health and looking after yourself | Macmillan
conclusive [275]. Cancer Support.
Professional resources: Managing lower gastrointestinal problems Pelvic radiotherapy damages oocytes at low doses, can lead to
after cancer treatment | Macmillan Cancer Support. uterine changes and induce the menopause. Early menopause increases
Patient resources: Bowel problems after pelvic radiotherapy - Cancer osteoporosis and cardiovascular disease [291]. Ovarian transposition in
treatment | Macmillan Cancer Support. pre-menopausal patients has been documented for colo-rectal cancers
and cervical cancers prior to pelvic radiotherapy, although data are
Urinary late effects lacking for vulval cancer patients and the majority of patients are post-
Gynaecological cancer patients have increased levels of urinary menopausal.
system disorders [276]. Stricture, contraction, obstruction, inflamma Systemic anti-cancer therapies and pelvic radiotherapy can cause
tion, impaired pelvic floor function and detrusor over-activity are po iatrogenic menopause and sudden onset of symptoms such as vasomotor
tential consequences of treatment. High grade (3and4) toxicities appear symptoms, mood changes, sleep disturbance and urinary dysfunction.
to be rare in vulval cancer patients 12 months after treatment [71] or at An individualised approach to managing radiation-induced meno
34 months [215], although longer-term data are lacking and radiation- pause is recommended depending on age, tumour type, stage, tumour
induced fibrosis, which can cause urinary dysfunction, can occur may hormone receptor status and presence/absence of uterus [292]. Most
years after treatment. vulval cancers are SCCs where systemic and topical HRT are not con
Improved delivery of radiotherapy treatments to spare structures of traindicated [292–294]. Evidence does not support or contradict the use
the urinary system may reduce late effects [277]. Evidence for phar of HRT in patients treated for vulval melanoma, although is unlikely to
macological interventions is lacking. be harmful.
Urinary incontinence is common, affecting up to 40 % of the UK Professional resources: Endocrine late effects guidance for
female population and becoming more prevalent with age and post- healthcare professionals | Macmillan Cancer Support and Fertility and
menopause [278]. It is therefore useful to establish a baseline for uri cancer | Macmillan Cancer Support.
nary function prior to any treatment [277] although there is no agreed
validated tool to use. Enquire directly about any new problems relating Patient resources: Late effects of pelvic radiotherapy | Macmillan
to bladder function at follow up visits. Cancer Support
Treatment for increased urinary frequency, urgency and stress in
continence can include coping strategies, absorbent containment prod Nervous tissue late effects
ucts, pelvic floor muscle re-education and bladder retraining [279].
Conservative pharmacotherapies and treatments such as anti- Radiation induced lumbosacral plexopathy (RILP) is an under-
muscarinics and bladder instillations may be preferable, as surgical in reported late effect of pelvic radiotherapy, it is a rare event but poten
terventions have high failure rates due to tissue ischaemia [280,281]. tially increasing with improved survival rates [295,296]. Patients
Patients may benefit from discussion at a urogynaecology MDT. Com should be informed of the increased risk of neuropathies, such as
plex problems such as fistulae, haematuria and radiation induced chemotherapy induced peripheral neuropathy and radiation induced
interstitial cystitis require intervention from urology specialists. Hy lumbosacral plexopathy. Defining and avoiding the lumbosacral plexus
perbaric oxygen therapy may have some benefits for late radiation during radiotherapy planning and delivery may reduce doses and late
cystitis [282]. consequences [297,298].
Patient resources: Managing bladder late effects | Macmillan Cancer Patients present with bilateral lower limb pain, numbness, weakness,
Support. paresis or paralysis [297]. MRI may be useful to rule out recurrence and
aid the diagnosis of RILP [299].
Endocrine late effects Neurological damage is irreversible and there are currently no
Pelvic radiotherapy significantly increases the risk of pelvic insuffi effective therapies, patients may benefit from supportive care.
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231
Follow up Table 15
Recommendations for follow up after a diagnosis of vulval cancer.
Follow up of VSCC Recommendation Grade of
recommendation
There are no clinical trial data to inform the optimum follow up VSCC
strategy in VSCC and strategies (Table 15) are therefore based on expert There is no proven regimen for follow up of VSCC. Grade D
opinion [300]). Background vulval dermatoses influence the risk of However, recurrence rates/new foci are common,
recurrence and should therefore be taken into account. VSCC arising on especially on a background of dVIN/ LSA.
Those with no recurrence of HPV-dependent VSCC or Grade D
a background of dVIN is more likely to recur than on a background of uVIN could be discharged to patient-initiated follow-up,
uVIN [66]. In one retrospective review overall VSCC recurrence rate was with access to rapid re-referral after five years.
22.6 %, although the local recurrence rate is proportional to the dura Those with recurrent disease, HPV-independent VSCC and Grade D
tion of follow-up, with an annual rate of approximately 4 %. The odds multi-focal disease may need life-long follow up.
All patients should be told to report new lesions and be Grade D
ratio (OR) of having a recurrence of VSCC associated with dVIN alone
seen urgently since interval cancers are not uncommon
was 3.85 (95 % CI 0.52 to 28.24) and higher when associated with dVIN and should be treated promptly.
in combination with lichen sclerosus/lichen planus (OR 4.3; 95 % CI Vulval malignant melanoma
0.84 to 21.92). The risk of VSCC recurrence when disease occurred of a see https://melanomafocus.com
background of uVIN was much less (OR 1.35; 95 % CI 0.20 to 9.01). Basal cell carcinoma
An initial follow up 3 months following surgery may be Grade D
Even in early-stage disease, local recurrences can occur a long time after appropriate to check healing and local recurrence. In
primary treatment, leading some to advocate life-long follow-up after a patients without Gorlin’s syndrome, further follow up is
diagnosis of vulval cancer [92]. However, those with unifocal, HPV- not required, if completely excised.
related disease are at lower risk and in absence of new areas of uVIN Vulval Paget’s disease
Patients with vulval Paget’s disease should have long- Grade D
developing during follow up, discharge to primary care, with emphasis
term follow-up.
on the need for rapid re-referral in the event of developing a new lesion,
may be considered after five years.
Follow up should include clinical examination of the vulva and None to declare. LB- Works for Perci Health Ltd, 1 Vincent Square,
groins with assessment for physical and psychological sequelae of London, SW1P 2PN and director of Buckley Consultants Ltd. KE- Royal
treatment. Loco-regional recurrence most commonly occurs in the first College of Obstetricians and Gynaecologists Workforce Fellow Jan 2022-
two years and follow-up regimes should reflect this. For uncomplicated Dec 2022. Paid for 8 h/week via her organisation. CF – Has received
early-stage disease, intervals of 3–6 months would be reasonable in the payments for participation on a Data Safety Monitoring Board or Advi
first two years, with 6–12 monthly follow up to 5 years. A recent study sory Board for Glaxo Smith Klein, Roche, Ethicon, Astra Zeneca MSD
suggested that three-monthly ultrasound of the groins for two years (Merck & Co., Inc). RG – Has received payments for lectures from Astra
following negative sentinel node dissection was cost-effective in the Zeneca, Oncoinvent and MSD. AT - Has received financial support to
detection of lymph node metastasis [167] (see above). For patients with attend meetings and for participation on a Data Safety Monitoring Board
underlying vulval dermatoses, or multifocal/recurrent cancer, more or Advisory Board from MSD.
frequent and prolonged follow-up (possibly life-long) may be required.
Patient discharged from regular review, should be aware of the need to Acknowledgements
report symptoms and new lesions at an early stage and should ideally
have rapid, direct access to specialist clinics for assessment. This guideline was performed without funding support from any
At the follow-up visit 10–12 weeks post-definitive (chemo)radiation, organisation; we are extremely grateful to all the authors, guideline
imaging with MRI scan ± CT/CT-PET is recommended to document subgroup team, national and international reviewers, who have given up
response to treatment. their time freely to contribute to this document. We thank Lucy Cogs
well, Marcia Hall, Nick Reed and Phil Rolland for their involvement in a
Follow up of basal cell carcinoma of the vulva previous version of this BGCS guideline. We thank Debbie Lewis for her
administrative support and Jo Platt, formerly of the Cochrane Gynae
Patients with basal cell carcinoma, if margins are clear following cological, Neuro-oncology and Orphan Cancer Review Group, for in
surgery, are unlikely to have recurrent disease and long term follow up is formation specialist support, designing and running the searches for the
not indicated. Patients with Gorlin’s syndrome are at risk of basal cell literature review. We are especially grateful to the international re
carcinoma across skin sites and so long-term follow up with a specialist viewers, Maaike Oonk, Amanda Tristram, Linn Wölber for their time,
dermatology team is more appropriate. care and expertise in reviewing this document.
Follow up of vulval Paget’s disease Appendix A. Supplementary data
As discussed above the risk of recurrence or development of invasive Supplementary data to this article can be found online at https://doi.
disease is high and, with lack of data to guide recommendations, long- org/10.1016/j.ejogrb.2023.11.013.
term follow up in a specialist vulval cancer clinic is suggested [132].
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to declare. PB - via
NoneIcecream PDF
to declare. LH -Editor.
None to declare. AA-
232
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European Journal of Obstetrics and Gynecology 292 (2024) 210–238

Contents lists available at ScienceDirect

European Journal of Obstetrics & Gynecology and

British Gynaecological Cancer Society (BGCS) vulval cancer guidelines: An

Diagnosis At a minimum, a detailed diagram of the vulva is required, indicating

Table 2 further investigated with USS-guided fine needle aspiration (FNA) or

Table 4 uVIN and lichen simplex chronicus [58].

Spread origin is seen. In the majority of cases, disease is confined to the

Extracapsular spread Surgery

Table 6 Stage IA VSCC. Small tumours can be managed by excision, ensuring

Table 7 excision, with ipsilateral IFLND and where indicated, radiotherapy to

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Follow up of vulval Paget’s disease Appendix A. Supplementary data

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