Background
Lichen sclerosus (LS) is a chronic inflammatory dermatosis of unknown cause that most commonly affects the genitalia (vulvar and penile lichen sclerosus) but can occur at any skin site (extragenital lichen sclerosus). [1] Outdated terms for this conditions include lichen sclerosus et atrophicus, balanitis xerotica obliterans (glans penis presentation), and kraurosis vulvae (older description of vulvar presentation).
Although LS can occur in males or females of any age, it more commonly affects prepubertal or perimenopausal females or males between puberty and age 60 years. It is characterized by white, often atrophic, plaques associated with pruritus and pain that result in genital scarring and adhesion. Complications include pain, sexual or urinary dysfunction, reduced quality of life, and an increased risk (≤ 5%) of squamous cell carcinoma (SCC) with genital lichen sclerosus.
Guidelines for treatment of LS have been published by the British Association of Dermatologists (BAD), [2] the European Academy of Dermatology and Venereology (EADV), [3] and the EuroGuiDerm Centre for Guideline Development. [4]
Pathophysiology
In LS, inflammation and altered fibroblast function in the papillary dermis lead to fibrosis of the upper dermis. Genital skin and mucosa are affected most frequently, with only rare reports of oral presentations. It has been hypothesized that oral manifestations are underdiagnosed or misdiagnosed as oral lichen planus, or that environmental effects play a large role in disease expression.
Findings within LS tissue include the following:
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Increased glut-1 and decreased vascular endothelial growth factor (VEGF) expression - These suggest a role for hypoxia and ischemia [5]
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Higher expression of extracellular matrix (ECM) proteins and connective-tissue growth factor (CTGF) - Upregulation may induce accumulation of ECM proteins and maintain fibrosis in chronic vulval LS [6]
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Altered expression of isocitrate dehydrogenase enzymes and aberrant hydroxymethylation - These indicate an epigenetic background for the pathogenesis of vulval LS [7]
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Increased levels of Th1-specific cytokines, a dense T-cell infiltrate and enhanced BIC/miR-155 expression, and a microRNA involved in regulation of the immune response - These demonstrate an autoimmune phenotype in vulvar LS [8]
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Distinct expression patterns of tissue remodeling–associated genes in boys with congenital phimosis and LS [9]
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Decreased or absent epidermal expression of CD44 - This suggests that LS might result from epidermal damage of unknown origin, resulting in CD44-deficient dermal changes with hyaluronic acid accumulation [10]
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Increased incidence of autoantibodies to EMC protein 1 and to BP180 antigen, with increased circulation of NC16A domain–specific T cells [11]
Etiology
The etiology and pathogenesis of LS have not been defined but may include genetic, infectious, environmental, and hormonal factors.
Several older studies linked borrelial or other infections with LS, but most subsequent studies have disputed this finding, with polymerase chain reaction (PCR)-based studies showing no increased incidence of borrelial infection. [12]
Exploration of genetic and autoimmune factors has not identified consistent, reproducible patterns, though autoantibodies to ECM protein 1 have been reported. The level of circulating autoantibodies may be as high as 28%, comparable to the rate seen in bullous lichen planus. [13] Baldo et al reported that more than 40% of vulvar LS and lichen planus patients have reactive T cells to the NC16A domain of bullous pemphigoid antigen 180 [11] ; however, others have suggested that the level of autoantibodies is poorly correlated to disease activity and treatment response. Women with LS have a higher rate of associated autoimmune disease (odds ratio, 4.3), especially for autoimmune thyroid disease, than men do. [14]
A genetic predisposition, based on family clustering, has been described. [15] Of patients with vulvar LS, 8-39% report a family history of the condition, whereas only 1% of male genital LS patients have a family history. [3]
Local irritation or trauma seems to play a role in some cases of LS, especially in genetically predisposed individuals. [16] However, the sequence of events that leads to the altered fibroblast function, microvascular changes, and hyaluronic acid accumulation in the upper dermis remains a subject of research.
Oral contraceptives in premenopausal women have been shown to give rise to a relative risk of 2.5, which suggests an altered hormonal axis as a possible contributory factor. [17]
LS may occur in association with other inflammatory conditions, including psoriasis. [18] This association is surprising because the histopathologic findings of LS and psoriasis are dissimilar.
A systematic review and meta-analysis of 21 case-control studies by Baglama et al found that both male and female LS patients had a higher incidence of certain dermatologic conditions (lichen planus, vitiligo, alopecia areata, atopic dermatitis, and psoriasis), certain cardiovascular risk factors (essential hypertension, obesity, dyslipidemia, and diabetes mellitus), genital warts, and hypothyroidism in comparison with control subjects. [19] However, there were no significant differences between males and females with respect to these associations.
Epidemiology
United States and international statistics
LS is a relatively common dermatosis, though its true prevalence has not been established and is probably underestimated. This may be because patients are distributed among different specialties (eg, gynecology, dermatology, family practice, and urology), but it may also be because one third of cases can be asymptomatic.
The prevalence of genital LS in prepubertal girls has been reported to be 0.1% (1 in 900). [20] The prevalence of vulvar LS in elderly nursing home women in one study was found to be 3% (1 in 30). [21] Another study found the rate to be approximately 1.7% among women seen in a gynecology practice.
A Danish study covering the period from 1997 to 2022 found that the incidence of biopsy-confirmed vulvar LS rose from 5.0 per 100,000 person-years at the beginning of the period to 35.7 per 100,000 person-years at the end. [22] The risk of vulvar squamous precancer and SCC increased as well.
The prevalence of male LS is thought to be influenced by the circumcision rate. [23] Given that male genital LS is seen almost exclusively in uncircumcised or incompletely circumcised men and boys, it follows that the circumcision rate in a given population would have an impact on the rate of LS in this subset.
The prevalence of extragenital LS is unclear. A study of foreskins submitted after therapeutic circumcision for phimosis revealed many cases of unrecognized LS. Extragenital LS is much less common than genital LS and is rare in children.
Age-, sex-, and race-related demographics
Vulvar LS can occur at any age, and incidence increases with age. In females, the two peaks of onset are during the prepubertal period and during the perimenopausal/postmenopausal period. It is noteworthy that both periods are characterized by low-estrogen states. It is not clear whether a hormonal relationship is involved or whether the low-estrogen state promotes koebnerization due to reduced lubrication. In males, the incidence increases after puberty and then decreases again in older age (>60 y).
The female-to-male ratio has ranged from 3:1 to 10:1. [3]
Neither genital nor extragenital LS has been shown to have any racial predilection.
Prognosis
For patients with more acute cases of genital LS, the prognosis is good, especially for those in the pediatric age group, in whom the condition may resolve spontaneously. For patients with extragenital LS or chronic atrophic genital disease, however, the likelihood of improvement is low.
Many pediatric cases improve with puberty, though some authors have suggested that the rate of spontaneous resolution may actually be lower than 25%. [24]
LS has no associated increased mortality unless the patient develops a malignancy in the area. Cancer arising in extragenital presentations is described only rarely and may be coincident with other factors.
Extragenital cases and many genital cases are asymptomatic, except for cosmetic changes or pruritus. Recalcitrant cases, especially those associated with erosion or progressive scarring, may result in severe sexual dysfunction.
An increased risk of SCC may exist in genital disease, but the magnitude of the increase in risk and the cofactors (eg, human papillomavirus [HPV] infection or prior radiotherapy) that may be involved have not been fully defined. Some have cited figures as high as 5% for the lifetime risk of vulvar SCC in patients with LS. [25] Older age, longer duration of LS, and evidence of hyperplastic or early vulvar carcinoma in situ changes appear to be significant risk factors. A 2009 study linked coexisting chlamydial infection and LS with an increased risk of SCC, but other sexually transmitted illnesses (eg, HPV infection) were not completely addressed. [26]
In patients who have been treated for vulvar cancer, the presence or absence of LS does not appear to affect the timing of recurrence.
Patient Education
Education relating to sexual dysfunction and dyspareunia may be required. Patients with genital LS should be educated on what changes (eg, ulceration) might indicate malignant transformation and thus mandate an immediate reevaluation.
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Lichen sclerosus demonstrating classic hourglass or figure 8 vulvar and perianal distribution. Courtesy of Wilford Hall Medical Center slide files.
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Extragenital lichen sclerosus demonstrating coalescing pitted white papules. Courtesy of Wilford Hall Medical Center slide files.
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Typical lichen sclerosus histology demonstrating homogenized edematous papillary (upper) dermis and effaced epidermis.
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More advanced vulvar lichen sclerosus; eroded areas need to be carefully examined and a biopsy sample should be taken to exclude coexistent squamous cell carcinoma. Courtesy of Wilford Hall Medical Center Dermatology slide files.
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Male genital lichen sclerosus may present with a sclerotic ring at the edge of the prepuce or anywhere on the glans itself. Advanced disease at the urethral os may lead to urinary obstruction. Courtesy of Wilford Hall Medical Center Dermatology Slide files.
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Late lichen sclerosus may show less edema in the upper dermis and more sclerosis throughout the dermis. Involvement of the lower dermis or fat may occur in lichen sclerosus/scleroderma overlap presentations.
