Retrospective analysis of the clinical characteristics and patient-reported outcomes in vulval lichen planus: Results from a single-center study
Abstract
Vulval lichen planus (VLP) is a rare, but often chronic, inflammatory disease whose symptoms include genital pain, discomfort, and dyspareunia. The clinical manifestations include erythema, erosions, and scarring. The aim of this study was to longitudinally investigate patient-reported outcomes and clinical findings in patients with VLP. Patients (>18 years) with histologically confirmed VLP were included in the retrospective analysis. Patient demographics, clinical features, symptomatology, quality of life, management, clinical outcomes, and comorbidities associated with VLP were analyzed. Twenty-four patients were identified with a mean (standard deviation [SD]) follow-up time of 19.3 (13.8) months. Classical VLP with glazed erythema was found in seven (29.2%) patients, erosive VLP was present in 15 (62.5%) patients, and hypertrophic VLP in two (8.3%). Seven patients had additional cutaneous involvement, while six patients had both vulval and oral mucosal involvement. The labia minora was the most frequently affected anatomical site (83.3%), followed by the clitoris (58.3%). Scarring lesions were found in 62.5% (n = 15) of patients. All study participants received treatment with potent and/or superpotent topical corticosteroids but 50% required systemic therapy (acitretin, corticosteroids, or hydroxychloroquine). Five (20.8%) patients underwent surgery due to adhesions and scarring resulting from VLP. One patient was diagnosed with a vulval squamous cell carcinoma during long-term follow-up. The mean (SD) Dermatology Life Quality Index score was 8.4 (5.5) at presentation and 8.9 (6.8) at the end of follow-up. In conclusion, VLP was associated with moderate quality of life impairments which persisted despite treatment, suggesting that current treatments for VLP are inadequate.
1 INTRODUCTION
Vulval lichen planus (VLP) is a rare disease with a broad spectrum of clinical presentation, ranging from diffuse erythema to severe erosions or hyperkeratotic plaques, and may be accompanied by scarring and loss of the normal vulval architecture.1-3 The incidence of VLP is unknown,4 but is estimated at 1/4000 women. The disease may be restricted to the vulva or also affect the vagina, oral mucosa, and/or the skin. Vulvovaginal-gingival syndrome is a severe variant of VLP in which erosions develop on the vulval, vaginal, and gingival mucosal surfaces.5 A biopsy should be considered to confirm that diagnosis3 and exclude other dermatoses including mucous membrane pemphigoid (MMP), bullous pemphigoid (BP), pemphigus vulgaris (PV), and lichen sclerosus. MMP, BP, and PV are autoimmune blistering diseases. MMP is clinically characterized by erosions and erythema, whereas the clinical hallmarks of BP are blisters and/or eczema or an urticarial rash on the trunk, but may be accompanied by blisters or erosions in the mouth or vulva. PV manifests clinically with erosions in the oral cavity and/or on the trunk, and may also affect the vulva. Vulval lichen sclerosus (VLS) typically shows porcelain-white papules and plaques, and may often be associated with erosions, fissures, introital narrowing, and scarring. VLP and VLS are both immunologically-mediated diseases of the genitalia, sharing overlaying clinical features, and biopsies of VLP/VLS may be difficult to distinguish.6 Cases of an overlap of VLP and VLS have been described, leading to the discussion of whether VLP and VLS are a continuum, rather than independent entities.7, 8 Patients with VLP should undergo gynecological assessment to exclude vaginal involvement. The major aims of treatment are symptomatic relief and the prevention and/or limitation of scarring.9 Whilst the application of potent/superpotent topical steroids remains the mainstay of treatment,9 topical calcineurin inhibitors can be considered.10 Systemic treatments, including corticosteroids, retinoids, hydroxychloroquine, and methotrexate, are usually used for treatment-resistant and erosive variants of VLP.9, 11 Regular follow-up is recommended to monitor disease activity and to allow early detection of malignant transformation.9 To date, longitudinal data on patient-reported outcomes, such as the quality of life as well as treatment outcomes and clinical manifestations, remain scant.12, 13 Thus, the aim of this retrospective single-center cohort study was to longitudinally characterize the quality of life, clinical presentation, and treatment outcomes in patients with VLP.
2 METHODS
2.1 Study population and definition of eligible cases
The retrospective cohort study encompassed biopsy-proven VLP between January 2017 and December 2020 managed in the dermatological referral outpatient clinic of University of Lübeck, Germany. The patients were diagnosed with VLP according to consensus clinicopathological diagnostic criteria: glazed erythema, erosions, hyperkeratotic borders/plaques, Wickham striae in surrounding skin, vaginal inflammation, pain/burning sensation, and typical histological features (band-like lymphohistiocytic infiltrate along the dermoepidermal junction, basal layer degeneration).3 The study was approved by the institutional ethical committee (21–008) and performed in accordance with the Declaration of Helsinki.
2.2 Definition of covariates
The medical records of patients were systematically reviewed and the following variables were retrieved: clinical features; Dermatology Life Quality Index (DLQI)14 scores at the onset of the disease and the last recorded follow-up; and treatment modalities as well as comorbidities. The electronic case records were screened for the presence of the following signs and/or symptoms at initial presentation based on the clinical diagnostic criteria of VLP: glazed erythema, erosions, hyperkeratotic borders/plaques, and pain/burning sensation.3, 15 The printed DLQI questionnaire was handed out to the patients at baseline and at the regular follow-up visits at the outpatient department.
2.3 Statistical analysis
All continuous parameters were expressed as mean values (standard deviation [SD]). Percentages of different patient groups were compared by χ2-test. Normally distributed continuous variables were compared using Student’s t-test. Data found to be non-normally distributed were analyzed using the Mann–Whitney U-test for independent subgroups and the Wilcoxon test for dependent subgroups. To identify predicting factors of morphological features and therapeutic modalities, a logistic regression model was used to calculate odds ratios (OR) and 95% confidence intervals (CI). SPSS version 25 software (IBM Corp.), was utilized to conduct all statistical analyses.
3 RESULTS
3.1 Demographic and clinical features
The present study included 24 female patients with VLP (Table 1). The mean (SD) and median (range) age of study participants was 60.9 (13.3) and 63.0 (30.0–85.0) years, respectively. The study population was followed for a mean (SD) duration of 19.3 (13.8) months, thus contributing a follow-up of 38.7 person-years. Seven (29.2%) patients were suffering from classic VLP with glazed erythema; erosive VLP was present in 15 (62.5%) patients; and hypertrophic VLP in two (8.3%). The labia minora was the most frequently implicated anatomical site (n = 20; 83.3%), followed by the clitoris (n = 14; 58.3%), vaginal introitus (n = 8; 33.3%), and labia majora (n = 6; 25.0%). Twenty (83.3%) patients presented with glazed erythema, whereas 14 (58.3%) had erosions, and two (8.3%) patients displayed hyperkeratotic borders. Fifteen (62.5%) patients developed scarring lesions during the course of the disease. Vulvovaginal-gingival syndrome was found in six patients. Seven patients had cutaneous lichenoid eruption. In fact, skin involvement preceded the development of genital lesions in five patients by a median (range) latency of 4.5 (0.5–15) years. In one patient, cutaneous eruption followed the genital disease by 1.0 year, whilst in the remaining patient genital and extragenital lesions emerged simultaneously.
| Patients, n | 24 |
| Age at diagnosis; years | |
| Mean (SD) | 60.9 (13.3) |
| Median (range) | 63.0 (30.0–85.0) |
| Disease phenotype, n (%) | |
| Classic vulval lichen planus (glazed erythema ± Wickham striae) | 7 (29.2%) |
| Erosive vulval lichen planus (well-demarcated erosions ± Wickham striae) | 15 (62.5%) |
| Hypertrophic vulval lichen planus (hyperkeratotic white border to erythematous areas) | 2 (8.3%) |
| Anatomical site of genital lesions, n (%) | |
| Labia minora | 20 (83.3%) |
| Clitoris | 14 (58.3%) |
| Vaginal introitus | 8 (33.3%) |
| Labia majora | 6 (25.0%) |
| Scarring of genital lesions, n (%) | 15 (62.5%) |
| Clinical variants, n | |
| Vulvovaginal-gingival syndrome | 6 |
| Cutaneous involvement | 7 |
| Vulva restricted | 11 |
| Management, n (%) | |
| Topical treatment | 24 (100.0%) |
| Systemic treatment | 12 (50.0%) |
| Surgical treatment | 5 (20.8%) |
- Abbreviation: SD, standard deviation.
3.2 Symptomatology and quality of life
Ten (41.7%) patients reported a prominent burning sensation at their initial presentation. The mean (SD) DLQI score was 8.4 (5.5) at initial presentation and 8.9 (6.8) at the end of follow-up. The DLQI did not show any significant improvement despite treatment (p = 0.342).
3.3 Management
All study participants were treated with topical therapy, ranging from potent and/or super-potent topical corticosteroids (n = 24; 100%) to pimecrolimus/tacrolimus (n = 13; 54.2%). While eight (33.3%) patients were treated with topical corticosteroids alone, 10 (41.7%) and six (25.0%) patients were prescribed a combination therapy of two and three of the aforementioned ointments, respectively. Twelve (50.0%) patients required systemic therapy, including acitretin (n = 7, 29.2%), systemic corticosteroids (n = 5, 20.8%), or hydroxychloroquine (n = 4, 16.7%). Four patients (16.7%) received sequential treatment with systemic agents given a lack of response. Five (20.8%) patients underwent surgical intervention due to vulval adhesions and stenosis (Table 1).
3.4 Outcomes
One 80-year-old patient developed stage 1A vulval squamous cell carcinoma (SCC), 17 months after the diagnosis of VLP. Histological findings showed no human papillomavirus (HPV) presence. Overall, our study participants cumulatively contributed 39.4 person-years of follow-up. The incidence rate of vulval SCC in our cohort was 25.9 (95% CI, 1.30–127.8) per 1000 person-years. When reviewing the literature, the incidence rate of vulvar SCC in the German population in the corresponding age category is 0.18/1000 person-year.16 Taken together, VLP was associated with a significantly increased incidence rate ratio of 143.9 (95% CI, 1.03–21 690.0; p = 0.037). In addition, two (8.3%) patients presented with vulval intraepithelial neoplasia (VIN).
3.5 Comorbidities
Hypertension was present in 12 (50.0%) patients, whereas diabetes mellitus, hypothyroidism, and hyperlipidemia were associated with VLP in five (20.8%), five (20.8%), and four (16.7%) patients (Table 2). Hepatitis B and C serology was negative in all of the patients (n = 20, 83.3%) tested.
| Comorbidities, n (%) | |
|---|---|
| Hypertension | 12 (50%) |
| Diabetes mellitus | 5 (20.8%) |
| Hypothyroidism | 5 (20.8%) |
| Hyperlipidemia | 4 (16.7%) |
| Asthma | 2 (8.3%) |
| Malignancies* | 2 (8.3%) |
| Ischemic heart disease | 1 (4.2%) |
| Depression | 1 (4.2%) |
- *Excluding cases with vulvar SCC and VIN.
- Abbreviations: SCC, squamous cell carcinoma; VIN, vaginal intraepithelial neoplasia.
3.6 Predictors of morphological features
Table 3 demonstrates a logistic regression analysis aiming to identify predictors of cutaneous involvement, coexisting vulval and oral mucosal involvement, and systemic treatments. Older age (≥63.0 years) was associated with a decreased likelihood of cutaneous involvement (odds ratio [OR] = 0.29; 95% CI, 0.14–0.61; p = 0.002). The anatomical site, the treatment as well as SCC/VIN had no association with the cutaneous involvement, oral involvement, and need for systemic treatment.
| Cutaneous involvement, OR (95% CI) [p-value] | Oral involvement, OR (95% CI) [p-value] | Systemic treatment, OR (95% CI) [p-value] | |
|---|---|---|---|
| Age ≥63.0 years | 0.29 (0.14–0.61) [0.002] | 0.71 (0.14–3.58) [0.682] | 0.51 (0.10–2.59) [0.414] |
| Oral involvement | 0.22 (0.03–1.49) [0.106] | NA | 1.40 (0.28–7.02) [0.682] |
| Cutaneous involvement | NA | 0.22 (0.03–1.49) [0.106] | 0.67 (0.11–3.93) [0.653] |
| Anatomical site | |||
| Labia minora | 0.88 (0.73–1.05) [0.364] | 1.18 (0.94–1.49) [0.217] | 1.22 (0.93–1.62) [0.138] |
| Labia majora | 1.50 (0.20–11.54) [0.696] | 0.60 (0.09–3.99) [0.595] | 2.57 (0.36–18.33) [0.338] |
| Clitoris | 1.20 (0.17–8.66) [0.856] | 0.33 (0.05–2.26) [0.215] | 0.45 (0.08–2.67) [0.375] |
| Vaginal introitus | 2.20 (0.32–14.98) [0.416] | 1.25 (0.21–7.41) [0.806] | 0.45 (0.08–2.67) [0.375] |
| Management | |||
| Systemic treatment | 0.67 (0.11–3.93) [0.653] | 1.40 (0.28–7.02) [0.682] | NA |
| Surgical intervention | 0.40 (0.04–4.24) [0.437] | 0.32 (0.05–2.22) [0.237] | 2.50 (0.36–17.32) [0.346] |
| SCC/VIN | 1.25 (0.10–16.51) [0.865] | 0.38 (0.03–4.81) [0.439] | 0.46 (0.04–5.81) [0.537] |
Note
- Bold text indicates statistical significance.
- Abbreviations: CI, confidence interval; OR, odds ratio; NA, not applicable; SCC, squamous cell carcinoma; VIN, vaginal intraepithelial neoplasia.
4 DISCUSSION
Our study demonstrated that VLP was associated with moderate impairments in quality of life, which largely persisted despite treatment. In addition, 41.7% of patients reported painful burning sensations as a presenting symptom. These data underscore the negative impact of VLP on quality of life. The rate of vulval scarring reached 62.5%, in line with literature reporting scarring rates of up to 95%.17 In this cohort, one patient with erosive VLP developed a HPV-independent vulval SCC. Of note, a recent study showed no association of lichen planus with HPV-independent vulval SCC.18 However, longstanding erosive lesions on mucosal sites, especially in patients who carry sexually acquired and oncogenic HPV, are at higher risk of malignant transformation.19 Long-term follow-up is mandatory for patients with VLP to monitor disease activity and to exclude an SCC at an early timepoint.9 Warning flags are chronic erosive lesions, ulcers with thickened edges, or enlarging nodules. The pathomechanism driving the association of VLP with SCC is yet to be established. However, we might assume that chronic and persistent inflammation in vulvovaginal tissues, as a result of the activity of VLP, may eventually contribute to the development of carcinogenesis and neoplasia,20 via inducing proneoplastic mutations, resistance to apoptosis, and environmental changes such as stimulation of angiogenesis.20-22
This retrospective analysis showed that two out of 24 patients had a history of cancer (cervix and thyroid). Superpotent topical corticosteroids were the most widely administrated treatment, followed by topical calcineurin inhibitors. Systemic treatments including corticosteroids, retinoids, and hydroxychloroquine were used for persistent and treatment-refractory VLP.
There are very few controlled trials examining the existing treatments of VLP, making its management a clinical challenge. Apremilast, a selective inhibitor of the enzyme phosphodiesterase 4, is under investigation in female genital erosive lichen planus (NCT03656666). Given the poor treatment response to standard therapy and the high scarring rate despite treatment in VLP, there is a pressing need for the development of new treatment strategies and to develop adequate treatment algorithms to achieve disease control and improve quality of life in these patients.
Limitations of the current study include the relatively small number of patients identified and its retrospective nature. It is also worth noting that due to the lack a control group, the relative risk of VIN was compared to that in the general population, thus may have resulted in some degree of selection bias, given that the patients were attending a tertiary referral center.
In conclusion, the current retrospective cohort study revealed that in more than half of patients with VLP present with concomitant oral lesions, the labia minora is the most frequently involved anatomical structure, and the glazed erythema is the most frequent manifestation. Half of the study participants were managed by systemic drugs and 20% underwent surgical intervention. Patients with VLP experience a moderate impairment in quality of life which does not considerably improve under treatment. The current study increases the awareness of the chronic course of VLP and its enormous impact on quality of life. Our findings suggest that the current treatment is insufficient to minimize the disease’s burden. Further research is required to estimate the utility of different therapeutic modalities utilized to manage this disease.
ACKNOWLEDGMENTS
Open Access funding enabled and organized by Projekt DEAL.
CONFLICT OF INTEREST
None declared.
