Vulval intraepithelial neoplasia in immunosuppressed women: The management outcome and recommendations from a multi-disciplinary service

Introduction

The human papillomavirus (HPV) is a common viral sexually transmitted infections (STI) worldwide. ¹ It is an important global health concern, and in women, persistent infections with high risk HPV subtypes can lead to pre-malignant and malignant changes of the vulval skin (high-grade intraepithelial lesions, HSIL), the cervix and the remaining anogenital tract. ² The burden of HPV is even higher in those living with HIV. ³ Here, the concept of ‘epidemiologic synergy’ ⁴ has been described, whereby HIV may promote the progression of co-infected STIs making them more recalcitrant to treatment, while the presence of STIs may increase the acquisition of HIV.^3,4

Immunosuppressed women are at higher risk of developing multifocal vulval intraepithelial neoplasias (VIN), whereby pre-malignant changes of the vulval epithelium can affect multiple sites, in comparison to immunocompetent controls. ⁵ Furthermore, immunosuppressed women with high risk HPV may have a greater probability of multicentric disease due to a ‘field effect’, ⁶ defined by the co-existence of HPV associated diseases of the lower genital tract (LGT)) upon infection of one site.^5,7 In addition, immunosuppression may be associated with poorer treatment outcomes, particularly for those with HSIL. ⁵

As of 2022, 94,397 people were living with HIV in England, 98% achieving viral suppression as a result of access to specialist care. ⁸ Our tertiary, multi-disciplinary vulval clinic serves the largest HIV cohort in the country. The primary aim of this retrospective review was to determine the burden of VIN in immunosuppressed women in our cohort. The secondary aim was to determine whether immunosuppression was associated with worse treatment outcomes for VIN, including the rate of recurrence and the rate of progression to squamous cell carcinoma (SCC) after first-line VIN treatment.

Methods

104 biopsy proven adult women with VIN were identified from a histological database in our hospital from 1st April 2013 to 31st March 2023. Patient demographic data, disease and treatment outcomes were collated from electronic medical records. Medical photography, where available, was used to more accurately map the vulval lesions in quadrants. Complete response (CR) was defined as being clinically and/or pathologically clear of disease at 3 month follow-up. Recurrence was defined as lesions reappearing in the same quadrant after achieving CR. Data were analysed performed using IBM SPSS Statistics v.29.

Results

During the 10-years study period, 31 women (30%) with biopsy proven VIN were immunosuppressed. The total number of HSIL biopsied in this cohort was 47. The immunosuppression was due to HIV (n = 9), diabetes (n = 5), active malignancy within 3 years of diagnosis (n = 10), immunosuppressive medications (n = 3), solid organ transplant (n = 2) and haematologic disease (n = 1). The demographics of the cohort are summarized in Table 1. The mean age of immunosuppressed women was 54 years [range 20–94 years] compared to 57 years [24–93] in the immunocompetent controls. There was no difference in the prevalence of smoking, or co-existing lichen sclerosus or lichen planus between the groups. However, immunosuppressed women were more likely to present with multifocal disease (p = 0.003) and have a history of prior HPV infection (p = 0.008) and a greater burden of multicentric disease, with co-existing AIN (p = 0.02) and CIN (p = 0.031) (Table 1).

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Table 1.

“Patient and disease characteristics of immunosuppressed and immunocompetent women in the study cohort”.

	Immunosuppressed (n = 31)	Immunocompetent (n = 72)	p value
Mean age at diagnosis (years) [range]	54 [20–94]	57 [24–93]	0.157
Ever smoked (%)	16 (59.3)*	29 (55.8)^	0.813
Lichen sclerosus (%)	1 (3.4)**	11 (17.5)^^	0.01
Lichen planus (%)	1 (3.4)**	5 (7.9)^^	0.662
Previous HPV (%)	20 (66.7)***	26 (36.6)^^^	0.008
Multifocal disease	(57.4)	(29.8)	0.003
Associated active AIN (%)	8 (25.8)	5 (6.9)	0.02
Associated active CIN (%)	9 (29.0)***	11 (15.3)^^^	0.031
Mean follow-up duration in months [range]	70 [11–132]	59 [3-130]	0.205
Death due to disease (n, %)	0 (0.0)	3 (4.2)	0.315

First line treatment offered for the immunosuppressed group included topical imiquimod (36.2%), surgery (29.8%), CO₂ laser (19.1%) or a combination (8.5%) of these modalities. Figure 1 depicts an individual with HIV and multifocal VIN during their treatment visits, highlighting the need for multi-modality treatment in this cohort. The CR rate from first line treatment was 54.8% and 75.6% respectively in the immunosuppressed and control group (p = 0.073). On multivariate analysis (adjusting for age, HPV status, multifocal disease, previous CIN), there was no difference in the rate of recurrence (23.4% vs 22.1%, p = 0.088) or progression to SCC (14.9% vs 16.3%, p = 0.232) between the cohorts. Having multifocal disease, however, remained a significant risk factor for both a higher recurrence rate after treatment, and a greater risk of progression to SCC. There was no death due to disease observed in those immunosuppressed.OPEN IN VIEWER

Discussion

Almost a third of women living with VIN were immunosuppressed in this study, compared to 24.1% in a previous large VIN series. ⁹ This may reflect the complexity of referrals we receive in our specialist vulval service. On univariate analysis, immunosuppressed women had a higher burden of multifocal VIN, in keeping with prior studies. ⁵ They also had a higher probability of co-existing CIN and AIN at the time of VIN diagnosis, adding to our recognition of multicentric HPV disease.^6,7

On multivariate analysis immunosuppression alone was not associated with worse treatment outcome, although having multifocal disease remained significant. Two similar studies have tested the treatment outcome of immunosuppressed women with VIN to date. In a cohort of 90 women with VIN of whom 75% were living with HIV, having multifocal or multicentric HPV disease was associated with worse disease recurrence and poorer prognosis. ⁵ Similarly a cohort of 107 women revealed a lower recurrence-free survival and progression-free survival in those who were living with HIV. However, on multivariate analysis, having multifocal or multicentric disease remained a significant factor. ¹⁰

Our immunosuppressed group had similar treatment outcomes to the control group, with no difference in disease recurrence or rate of progression to SCC after VIN treatment. We may attribute these favourable results to our management strategy, in comparison to previous studies. Firstly, high-risk women and those with multifocal disease are identified early and remain on four to six monthly monitoring under Dermatologists, Gynaecologists and Genitourinary Medicine specialists in a multidisciplinary clinic. This is an adaptation to a treatment algorithm proposed by Bradbury et al. for immunosuppressed women with VIN. A flaw to this model, however, was the lack of stratification around multifocal and multicentric HPV disease. ¹⁰

Secondly, for women with multifocal VIN, both surgical interventions and non-surgical or multi-modality treatment options are offered as first or second-line. This is based on the understanding that the multicentric HPV disease may complicate their treatment response as in our cohort. ¹⁰ Therefore in conjunction with surgery, ¹⁰ other skin preserving modalities including topical imiquimod, CO₂ laser and PlasmaJet are frequently utilised to manage multicentric disease, as in the case study demonstrated. The latter is an argon energy device which is particularly useful for treating functionally important sites near the urethra or perianal skin where surgery is not amenable. ¹¹

The strengths of this study included the identification and inclusion of biopsy proven disease only, that were photomapped to improve the reporting of recurrence. The study was limited by its small numbers which did not allow for sub-group analyses to further predict treatment outcomes in those who were immunosuppressed.

Despite this, our immunosuppressed women living with VIN showed treatment outcome non-inferior to those who were immunocompetent. Revised guidance is recommended for similar multi-disciplinary clinics managing such complex women. Long term, close surveillance with active treatment of HPV is important and any burden of multifocal and multicentricity should be identified early to facilitate successful treatment outcomes.