Lichen Sclerosus

Clinical Overview

Lichen sclerosus (LS) is a chronic, inflammatory dermatosis predominantly affecting the anogenital region, characterized by white, atrophic plaques with a distinctive porcelain-white appearance. The condition shows a striking female predominance with a bimodal age distribution affecting prepubertal girls and postmenopausal women. While historically termed "lichen sclerosus et atrophicus," the contemporary nomenclature omits "et atrophicus" as atrophy is not invariably present. The condition carries significant implications for quality of life, sexual function, and carries a small but important risk of malignant transformation to squamous cell carcinoma, particularly in vulval disease. [1,2]

The disease presents a diagnostic and therapeutic challenge requiring long-term management and surveillance. Despite being a benign condition, LS profoundly impacts patients through intractable pruritus, dyspareunia, and psychosexual morbidity. Recent advances in understanding the pathophysiology have highlighted autoimmune mechanisms and genetic susceptibility factors, while evidence-based guidelines now provide robust frameworks for diagnosis and management. [3,4]

Epidemiology

Prevalence and Incidence

Lichen sclerosus affects approximately 1 in 300 to 1 in 1000 individuals in the general population, though true prevalence is likely underestimated due to underdiagnosis and underreporting. The condition demonstrates a marked female predominance with a female-to-male ratio of approximately 10:1. Vulval lichen sclerosus represents the most common presentation, affecting an estimated 1.7% of women in gynecological clinics. [5,6]

The bimodal age distribution is well-established, with peaks in prepubertal girls (age 7-10 years) and postmenopausal women (age 50-60 years). However, the condition can occur at any age including infancy and young adulthood. In men, lichen sclerosus typically affects the glans penis and prepuce, often presenting in the third to fifth decades of life. [7]

Geographic and Ethnic Variation

While lichen sclerosus occurs worldwide across all ethnic groups, most epidemiological data derives from European and North American populations. Some studies suggest lower prevalence in darker-skinned populations, though this may reflect diagnostic difficulty rather than true ethnic variation. The condition appears equally distributed geographically without clear environmental risk factors identified. [8]

Risk Factors

Several risk factors and associations have been identified:

Autoimmune diseases: Strong association with thyroid disease (particularly Hashimoto's thyroiditis and Graves' disease), vitiligo, alopecia areata, and pernicious anemia. Approximately 20-30% of patients with lichen sclerosus have concurrent autoimmune conditions. [9]

Genetic factors: Familial clustering occurs in up to 12% of cases, suggesting genetic susceptibility. HLA associations have been identified, particularly HLA-DQ7, HLA-DQ8, and HLA-DQ9 alleles. [10]

Hormonal factors: The bimodal age distribution and female predominance suggest hormonal influences, though specific mechanisms remain incompletely understood. Some improvement may occur during pregnancy with relapse postpartum. [11]

Local trauma: The Koebner phenomenon is well-documented, with lesions developing at sites of trauma, surgery, or radiotherapy. However, trauma is not a prerequisite for disease development. [12]

Pathophysiology

Molecular and Cellular Mechanisms

The pathogenesis of lichen sclerosus involves complex interactions between genetic predisposition, autoimmune mechanisms, hormonal factors, and local tissue responses. Current evidence supports a primarily autoimmune etiology with inflammatory and fibrotic components. [13]

Autoimmune mechanisms: Autoantibodies against extracellular matrix protein 1 (ECM-1) are detected in 60-80% of patients with lichen sclerosus, compared to less than 5% of controls. ECM-1 is highly expressed in skin and plays crucial roles in basement membrane stability and angiogenesis. Autoantibodies against ECM-1 correlate with disease activity and severity. Other autoantibodies identified include anti-basement membrane zone antibodies and anti-nuclear antibodies. [14]

Inflammatory cascade: Histological examination reveals a band-like lymphocytic infiltrate in the superficial dermis, predominantly composed of CD4+ and CD8+ T-lymphocytes with increased expression of inflammatory cytokines including interferon-gamma, interleukin-1, and tumor necrosis factor-alpha. This inflammatory milieu drives tissue remodeling and fibrosis. [15]

Fibrotic pathway: Transforming growth factor-beta (TGF-β) and its downstream SMAD signaling pathway play central roles in the fibrotic changes characteristic of lichen sclerosus. Activation of TGF-β/SMAD3 signaling promotes excessive collagen deposition, extracellular matrix accumulation, and tissue sclerosis. Recent research has explored targeting this pathway as a potential therapeutic strategy. [16]

Oxidative stress: Increased oxidative stress markers and reduced antioxidant capacity have been demonstrated in affected tissues, potentially contributing to DNA damage and cellular dysfunction. [17]

Hormonal influences: Reduced local estrogen and androgen receptor expression in affected tissues may contribute to tissue atrophy and impaired healing responses. However, systemic hormone replacement therapy has shown inconsistent efficacy. [18]

Histopathology

Characteristic histopathological features include:

• Epidermal changes: Hyperkeratosis, epidermal atrophy with flattening of rete ridges, and vacuolar degeneration of basal keratinocytes
• Dermal changes: Homogenization and hyalinization of collagen in the upper dermis creating a characteristically pale, eosinophilic zone beneath the epidermis
• Inflammatory infiltrate: Band-like lymphocytic infiltrate in the mid-dermis, typically separated from the epidermis by the zone of homogenized collagen
• Vascular changes: Dilated blood vessels and lymphatic channels in the superficial dermis
• Basement membrane: Thickening and reduplication of the basement membrane zone visible on electron microscopy

The presence of these features in combination provides diagnostic confirmation, though biopsy may not always be necessary when clinical features are typical. [19]

Clinical Presentation

Symptomatology

Pruritus: The hallmark symptom, often severe and intractable, characteristically worse at night. Pruritus severity does not always correlate with visible disease extent. Many patients experience years of symptoms before diagnosis. [20]

Pain and dyspareunia: Fissuring, erosions, and architectural changes lead to dyspareunia (pain during intercourse), which can be severe enough to preclude sexual activity. Vestibular involvement may cause introital pain. [21]

Urinary symptoms: Involvement of periurethral tissue can cause dysuria, weak urinary stream, or urinary retention in severe cases. Meatal stenosis may develop. [22]

Bleeding: Fissuring and fragile tissue may cause bleeding, either spontaneous or following minor trauma including intercourse. [23]

Asymptomatic: Some patients are asymptomatic, with lesions discovered incidentally during examination. [24]

Physical Examination Findings

Vulval Lichen Sclerosus

Early disease: Porcelain-white patches or plaques with a shiny, wrinkled ("cigarette paper") appearance. Lesions typically involve the labia majora, labia minora, clitoris, and perianal skin, creating a characteristic "figure-of-eight" or "keyhole" distribution around the vulva and anus. [25]

Progressive disease:

• Resorption of labia minora with fusion to labia majora
• Clitoral hood fusion with phimosis or complete burial of clitoris
• Loss of normal vulval architecture
• Narrowing of vaginal introitus (introital stenosis)
• Hyperkeratotic plaques with fissuring
• Ecchymoses (purpura) from minor trauma
• Erosions or ulceration
• Scarring with loss of elasticity

Advanced/complicated disease:

• Marked architectural distortion
• Severe introital stenosis precluding examination
• Meatal stenosis
• Posterior fourchette fissures
• Agglutination and complete loss of vulval architecture

The vaginal mucosa is characteristically spared, helping distinguish LS from lichen planus which commonly involves vaginal epithelium. [26]

Penile Lichen Sclerosus (Balanitis Xerotica Obliterans)

In males, lichen sclerosus presents as:

• White, sclerotic plaques on glans penis and prepuce
• Phimosis (inability to retract foreskin)
• Meatal stenosis
• Frenular involvement with scarring
• Rarely, involvement of penile shaft or scrotum

Penile lichen sclerosus can lead to urethral stricture disease requiring surgical intervention. [27]

Extragenital Lichen Sclerosus

Extragenital involvement occurs in approximately 15-20% of cases, most commonly on:

• Upper trunk (shoulders, submammary areas)
• Flexor surfaces of wrists
• Neck
• Oral mucosa (rare)

Extragenital lesions appear as white, atrophic papules or plaques, sometimes with follicular plugging. The morphology may differ from genital lesions, making diagnosis more challenging. [28]

Disease Staging and Severity Assessment

Several classification systems exist. The clinical scoring system for vulval lichen sclerosus assesses:

Extent of involvement: Percentage of vulval surface area affected Hyperkeratosis: Severity of white plaque formation Fissures/erosions: Presence and extent Architectural changes: Degree of labial fusion, clitoral burial, introital stenosis Ecchymoses: Presence of purpura Erythema: Active inflammation

Standardized photographic documentation aids monitoring disease progression and treatment response. [29]

Differential Diagnosis

Primary Differentials

Lichen planus: Distinguished by purple color, Wickham's striae, involvement of vaginal mucosa, and oral lesions. Histopathology shows sawtooth rete ridges and Civatte bodies. May coexist with lichen sclerosus (overlap syndrome). [30]

Vitiligo: Pure depigmentation without textural changes, sclerosis, or symptoms. Affects multiple body sites symmetrically. Biopsy shows absence of melanocytes without inflammation or sclerosis. [31]

Vulvovaginal candidiasis: Acute onset pruritus with erythema and white curd-like discharge. Responds rapidly to antifungal therapy. May coexist with lichen sclerosus. [32]

Contact dermatitis: History of exposure to allergen/irritant. Acute onset with vesiculation and oozing in acute phase. Patch testing may identify causative agent. [33]

Lichen simplex chronicus: Lichenification from chronic scratching without underlying sclerosis or white color. Responds to treatment of pruritus. [34]

Important Exclusions

Vulval intraepithelial neoplasia (VIN): May develop within areas of lichen sclerosus. Presents as raised, hyperkeratotic or pigmented plaques. Requires biopsy for diagnosis. High-grade VIN requires treatment to prevent progression to invasive squamous cell carcinoma. [35]

Squamous cell carcinoma: Nodules, ulceration, or rapidly growing lesions within areas of lichen sclerosus warrant urgent biopsy. Approximately 3-5% of women with vulval lichen sclerosus develop squamous cell carcinoma over long-term follow-up. [36]

Morphea/scleroderma: Localized scleroderma affecting anogenital region may resemble lichen sclerosus. Systemic features and antibody profile aid differentiation. [37]

Vulval aphthosis: Painful recurrent ulceration often associated with Behçet's disease or inflammatory bowel disease. Distinct from lichen sclerosus. [38]

Investigations

Diagnostic Approach

Clinical diagnosis: Typical presentation in characteristic distribution may permit clinical diagnosis without biopsy. The EuroGuiderm guideline recommends that experienced clinicians may diagnose lichen sclerosus clinically when features are classical. [39]

Biopsy indications:

• Atypical presentation or distribution
• Diagnostic uncertainty
• Suspicion of malignancy (nodules, ulceration, pigmentation changes)
• Non-response to first-line treatment
• Patient preference for histological confirmation

Biopsy technique: Perform 4mm punch biopsy from affected area, avoiding fissures or ulcerated regions which may show non-specific changes. Submit in formalin for routine histopathology. If malignancy suspected, ensure adequate depth of biopsy to assess invasion. [40]

Histopathological Examination

Standard hematoxylin and eosin staining reveals characteristic features described in pathophysiology section. Additional stains rarely needed but may include:

• PAS (Periodic Acid-Schiff) to exclude fungal infection
• Immunofluorescence if bullous disease suspected

Autoimmune Screening

Given strong association with autoimmune diseases, baseline screening should include:

• Thyroid function: TSH, free T4, thyroid peroxidase antibodies
• Full blood count: Screen for pernicious anemia
• Blood glucose or HbA1c: Screen for diabetes (associated condition)
• Antinuclear antibodies (ANA): If clinical features suggest connective tissue disease

Additional investigations directed by clinical suspicion of specific autoimmune conditions. [41]

Exclusion of Malignancy

In any patient with:

• Nodular or indurated lesions
• Persistent ulceration
• Bleeding unexplained by fissuring
• Pigmented areas within lichen sclerosus
• Rapid clinical change
• Non-response to treatment

Perform biopsy to exclude VIN or invasive squamous cell carcinoma. Multiple biopsies may be required if large area affected or multifocal suspicious features. [42]

Monitoring Investigations

Photographic documentation: Standardized vulvoscopy with photography aids monitoring disease progression and treatment response. [43]

Quality of life assessment: Validated tools such as the Dermatology Life Quality Index (DLQI) or Female Sexual Function Index (FSFI) quantify impact and treatment efficacy. [44]

Management

Treatment Goals

The primary aims of treatment are to:

1. Alleviate symptoms (pruritus, pain, dyspareunia)
2. Prevent disease progression and architectural changes
3. Reduce malignancy risk through disease control
4. Maintain or restore sexual function
5. Improve quality of life

Complete cure is rarely achievable; lichen sclerosus is a chronic condition requiring long-term management. Treatment goals focus on disease control and symptom management. [45]

First-Line Therapy: Topical Corticosteroids

Ultra-potent topical corticosteroids represent the gold-standard first-line treatment with the strongest evidence base. [46,47]

Recommended Regimens

Clobetasol propionate 0.05% ointment (or equivalent ultra-potent corticosteroid):

Induction phase (first 3 months):

• Apply once daily to affected areas for 4 weeks
• Then reduce to alternate days for 4 weeks
• Then reduce to twice weekly for 4 weeks
• Total 12-week induction course

Maintenance phase:

• Once or twice weekly application long-term
• Adjust frequency based on symptoms and disease activity
• Many patients require lifelong maintenance therapy

Application technique:

• Apply thin layer to affected areas only
• Use fingertip unit measurement (approximately 0.5g covers vulval area)
• Avoid normal skin where possible
• Apply after bathing when skin slightly moist for better absorption
• Typical monthly dose: 30g tube should last approximately 3 months during maintenance phase

Evidence Base

Systematic reviews demonstrate that ultra-potent topical corticosteroids achieve:

• Symptom improvement in 75-90% of patients
• Partial or complete clinical remission in 60-75%
• Reversal of early architectural changes if treated before irreversible scarring
• Reduced progression to malignancy (though data limited)

Response rates are highest when treatment initiated early before severe architectural changes develop. [48]

Adverse Effects

Appropriate use of ultra-potent corticosteroids in lichen sclerosus has a favorable safety profile:

• Skin atrophy: Rare with appropriate use; the diseased sclerotic skin is already atrophic
• Striae: Uncommon when applied to vulval skin
• Systemic absorption: Minimal with recommended doses
• HPA axis suppression: Very rare with appropriate dosing

Concerns about corticosteroid side effects should not prevent appropriate treatment. The risks of untreated disease far outweigh the risks of appropriate corticosteroid therapy. [49]

Second-Line Therapies

Topical Calcineurin Inhibitors

Tacrolimus 0.1% ointment or pimecrolimus 1% cream:

Indications:

• Patients who cannot tolerate or have contraindications to topical corticosteroids
• Maintenance therapy as steroid-sparing agents
• Extragenital lesions

Evidence: Smaller evidence base compared to corticosteroids. Case series and small trials show benefit, though generally less effective than ultra-potent corticosteroids. [50]

Application: Twice daily initially, then maintenance dosing similar to corticosteroids

Adverse effects: Burning/stinging on application (usually transient), no risk of atrophy

Caution: FDA black box warning regarding theoretical malignancy risk (based on animal data and post-transplant patients). No evidence of increased malignancy risk in lichen sclerosus patients using topical calcineurin inhibitors.

Topical Testosterone

Historically used but no longer recommended as first-line therapy. Evidence demonstrates inferior efficacy compared to topical corticosteroids. May cause virilizing side effects. Reserved for selected cases. [51]

Systemic Therapies

Very limited role in routine practice:

Systemic corticosteroids: Occasionally used for severe, recalcitrant disease or widespread extragenital involvement. Not suitable for long-term use due to adverse effects.

Methotrexate, hydroxychloroquine, cyclosporine: Case reports exist but no robust evidence. Consider in exceptional cases with multidisciplinary input.

Retinoids: Limited evidence; not routinely recommended.

Emerging and Experimental Therapies

Photodynamic therapy: Small studies show potential benefit but insufficient evidence for routine recommendation. [52]

Platelet-rich plasma/fibrin: Emerging research suggests potential for reducing inflammation and fibrosis through modulation of TGF-β/SMAD3 pathway. Requires further validation. [53]

JAK inhibitors: Early-phase research exploring topical and systemic JAK inhibitors. Not yet established therapy.

Laser therapy: CO₂ laser and fractional laser therapies under investigation. Current evidence insufficient for routine recommendation.

Surgical Management

Indications:

• Severe architectural distortion causing functional impairment
• Meatal/urethral stenosis
• Removal of premalignant or malignant lesions
• Phimosis in men (circumcision)

Procedures:

• Labial adhesiolysis: Division of labial adhesions
• Perineoplasty: Reconstruction of introitus
• Meatoplasty/meatotomy: Correction of meatal stenosis
• Clitoral adhesiolysis: Release of clitoral hood adhesions
• Circumcision: Definitive treatment for male phimosis due to lichen sclerosus

Important caveats:

• Surgery does not cure underlying disease; topical therapy must continue postoperatively
• Koebner phenomenon may cause disease flares at surgical sites
• Recurrence of adhesions common without ongoing topical treatment
• Surgery is adjunctive to medical management, not alternative

Management of Special Situations

Pediatric Lichen Sclerosus

Treatment principles similar to adults:

• Ultra-potent topical corticosteroids remain first-line
• May use moderate-potency steroids initially in very young children
• Spontaneous resolution may occur at puberty in some cases
• Lifelong follow-up recommended even if resolution occurs, as relapse possible
• Multidisciplinary approach involving pediatric dermatology/gynecology

Pregnancy and Lactation

• Topical corticosteroids considered safe during pregnancy and lactation
• Some patients experience temporary improvement during pregnancy
• Postpartum flares common

Male Genital Lichen Sclerosus

• Topical corticosteroids first-line, as for females
• Circumcision curative for preputial disease
• Glans disease requires ongoing topical therapy
• Urethral stricture disease may require urological intervention

Supportive and Adjunctive Measures

Emollients and barrier protection:

• Regular emollients (several times daily) maintain skin hydration
• Barrier ointments protect against urine/fecal irritation

Hygiene measures:

• Gentle cleansing with warm water or soap substitutes
• Avoid irritants (perfumed products, bubble baths, antiseptics)
• Pat dry rather than rubbing
• Wear cotton underwear; avoid tight clothing

Management of pruritus:

• Optimize topical corticosteroid therapy
• Sedating antihistamines at night if sleep-disturbing pruritus
• Emollients in refrigerator provide cooling relief

Management of dyspareunia:

• Water-based lubricants during intercourse
• Vaginal dilators if introital stenosis developing
• Psychosexual counseling as needed
• Liaison with specialist vulval/sexual health services

Patient education:

• Explain chronic nature requiring long-term treatment
• Emphasize importance of maintenance therapy even when asymptomatic
• Provide written information and support group details
• Discuss malignancy risk and importance of surveillance

Follow-Up and Surveillance

Monitoring Schedule

First 3 months: Review every 4-6 weeks during induction treatment to assess response and reinforce adherence.

After initial response: Review every 3-6 months for first year, then annually if stable.

Lifelong follow-up recommended given malignancy risk and chronic relapsing nature.

Assessment at Follow-Up

• Symptom review: Pruritus, pain, dyspareunia, bleeding, urinary symptoms
• Examination: Document disease extent, hyperkeratosis, fissures, architectural changes, suspicious lesions
• Photography: Standardized photographic documentation
• Treatment adherence: Review technique and frequency of topical therapy
• Side effects: Screen for adverse effects of treatment
• Quality of life: Assess impact on sexual function and wellbeing
• Biopsy: Perform if any suspicious features develop

Detection of Malignant Transformation

Educate patients in self-examination and red flag symptoms:

• Development of lumps, nodules, or thickened areas
• Persistent ulceration
• Bleeding not explained by fissuring
• Change in color (especially pigmentation)
• Rapid change in symptoms or appearance

Biopsy threshold should be low; multiple biopsies preferable to missed malignancy.

Prognosis and Complications

Natural History

Lichen sclerosus is a chronic condition with:

• Relapsing-remitting course: Most patients experience fluctuating severity
• Progression without treatment: Untreated disease typically progresses with increasing architectural changes
• Response to treatment: Majority achieve symptom control with appropriate therapy
• Spontaneous resolution: Rare in adults; may occur in prepubertal girls at puberty (30-50% cases)
• Lifelong disease: Most adults require long-term management

Malignancy Risk

Squamous cell carcinoma represents the most significant complication:

• Cumulative lifetime risk: 3-5% in women with vulval lichen sclerosus
• Risk increases with disease duration
• Most malignancies develop after age 60 years
• May be preceded by vulval intraepithelial neoplasia (VIN)
• Risk highest in areas of hypertrophic or erosive disease
• Treatment with corticosteroids may reduce malignancy risk (data limited)

Risk factors for malignancy:

• Long disease duration
• Poor disease control
• Hypertrophic disease variant
• Cigarette smoking
• Immunosuppression

Regular surveillance and low threshold for biopsy essential for early detection. [54]

Quality of Life Impact

Lichen sclerosus significantly impairs quality of life through:

Sexual dysfunction: Dyspareunia affects 70-80% of sexually active women with vulval lichen sclerosus. Architectural changes, pain, and psychological factors contribute. May lead to relationship strain and avoidance of intimacy. [55]

Psychological morbidity: Depression, anxiety, and body image concerns common. Chronic pruritus disrupts sleep. Social isolation may occur. [56]

Functional impairment: Severe architectural changes may impair urination, defecation, and mobility. Meatal stenosis can cause urinary retention.

Treatment burden: Lifelong requirement for topical therapy and medical follow-up represents significant burden. [57]

Holistic management addressing psychological and sexual health needs alongside medical therapy optimizes outcomes.

Prognosis by Site

Vulval lichen sclerosus: Chronic disease requiring lifelong management. Good symptom control achievable in most patients with appropriate treatment. Malignancy risk requires ongoing surveillance.

Penile lichen sclerosus: Circumcision may be curative for preputial disease. Glans disease requires ongoing management. Urethral strictures may recur after treatment.

Extragenital lichen sclerosus: Generally good prognosis with treatment. Malignant transformation very rare at extragenital sites.

Key Learning Points

1. Lichen sclerosus is a chronic inflammatory dermatosis predominantly affecting the anogenital region with characteristic porcelain-white sclerotic plaques.

2. Strong autoimmune association exists, particularly with thyroid disease. Screen all patients for autoimmune conditions.

3. Ultra-potent topical corticosteroids (clobetasol propionate 0.05%) represent gold-standard first-line treatment with excellent efficacy and safety profile.

4. Long-term maintenance therapy is typically required; lichen sclerosus is chronic with relapsing-remitting course.

5. Malignancy risk (3-5% lifetime risk of squamous cell carcinoma in vulval disease) mandates lifelong surveillance with low threshold for biopsy of suspicious lesions.

6. Early treatment prevents architectural changes: Labial fusion, clitoral burial, and introital stenosis are preventable with appropriate early therapy but often irreversible once established.

7. Significant quality of life impact: Dyspareunia, pruritus, and psychological morbidity require holistic management including psychological and sexual health support.

8. Multidisciplinary approach optimizes outcomes, involving dermatology, gynecology/urology, and specialist vulval services.

References

1. Fistarol SK, Itin PH. Diagnosis and treatment of lichen sclerosus: an update. Am J Clin Dermatol. 2013;14(1):27-47. doi:10.1007/s40257-012-0006-4

2. Fergus KB, Lee AW, Baradaran N, et al. Pathophysiology, Clinical Manifestations, and Treatment of Lichen Sclerosus: A Systematic Review. Urology. 2020;135:11-19. doi:10.1016/j.urology.2019.09.034

3. Kirtschig G, Wakelin SH, Wojnarowska F. EuroGuiderm guideline on lichen sclerosus-introduction into lichen sclerosus. J Eur Acad Dermatol Venereol. 2024;38(10):1857-1865. doi:10.1111/jdv.20103

4. Xie X, Wu D, Liu H, Chen Y. Advances in the pathogenesis of vulvar lichen sclerosus. Mol Biol Rep. 2024;51(1):394. doi:10.1007/s11033-024-09345-1

5. Pérez-López FR, Vieira-Baptista P, Phillips N, et al. Lichen sclerosus in women: a review. Climacteric. 2017;20(4):339-347. doi:10.1080/13697137.2017.1343295

6. Yeon J, Berzins K, Fischer G, Bradford J. Vulval lichen sclerosus: An Australasian management consensus. Australas J Dermatol. 2021;62(3):e389-e396. doi:10.1111/ajd.13638

7. Shieh C, Davis-Dao C, Ohlemeyer S, Santucci RA. Conservative Management of Penile and Urethral Lichen Sclerosus: A Systematic Review. J Urol. 2024;211(3):381-391. doi:10.1097/JU.0000000000003814

8. Neill SM, Lewis FM, Tatnall FM, Cox NH. British Association of Dermatologists' guidelines for the management of lichen sclerosus 2010. Br J Dermatol. 2010;163(4):672-682. doi:10.1111/j.1365-2133.2010.09997.x

9. Cooper SM, Ali I, Baldo M, Wojnarowska F. The association of lichen sclerosus and erosive lichen planus of the vulva with autoimmune disease: a case-control study. Arch Dermatol. 2008;144(11):1432-1435. doi:10.1001/archderm.144.11.1432

10. Gao XH, Barnardo MC, Winsey S, et al. The association between HLA DR, DQ antigens, and vulval lichen sclerosus in the UK: a case-control study. J Med Genet. 2005;42(2):135-139. doi:10.1136/jmg.2004.023416

11. Powell J, Wojnarowska F. Childhood vulvar lichen sclerosus: an increasingly common problem. J Am Acad Dermatol. 2001;44(5):803-806. doi:10.1067/mjd.2001.113474

12. Marren P, Yell J, Charnock FM, Bunce M, Wojnarowska F. The association between lichen sclerosus and antigens of the HLA system. Br J Dermatol. 1995;132(2):197-203. doi:10.1111/j.1365-2133.1995.tb05013.x

13. Pugliese JM, Morey AF, Peterson AC. Lichen sclerosus: review of the literature and current recommendations for management. J Urol. 2007;178(6):2268-2276. doi:10.1016/j.juro.2007.08.024

14. Oyama N, Chan I, Neill SM, et al. Autoantibodies to extracellular matrix protein 1 in lichen sclerosus. Lancet. 2003;362(9378):118-123. doi:10.1016/S0140-6736(03)13863-9

15. Terlou A, Santegoets LA, van der Meijden WI, et al. An autoimmune phenotype in vulvar lichen sclerosus and lichen planus: a Th1 response and high levels of microRNA-155. J Invest Dermatol. 2012;132(3 Pt 1):658-666. doi:10.1038/jid.2011.369

16. Sun SH, Deng Q, Xiong YJ, et al. Platelet-rich fibrin attenuates inflammation and fibrosis in vulvar lichen sclerosus via the TGF-β/SMAD3 pathway. Arch Dermatol Res. 2025;317(2):100. doi:10.1007/s00403-025-03718-8

17. Gunthert AR, Faber M, Knappe G, Hellriegel S, Emons G. Early onset vulvar lichen sclerosus in premenopausal women and oral contraceptives. Eur J Obstet Gynecol Reprod Biol. 2008;137(1):56-60. doi:10.1016/j.ejogrb.2007.06.006

18. Cattaneo A, Carli P, De Marco A, et al. Testosterone maintenance therapy. Effects on vulvar lichen sclerosus treated with clobetasol propionate. J Reprod Med. 1996;41(2):99-102.

19. Hasegawa M, Ishikawa O, Asano Y, et al. Diagnostic criteria, severity classification and guidelines of lichen sclerosus et atrophicus. J Dermatol. 2018;45(8):891-897. doi:10.1111/1346-8138.14339

20. Borghi A, Corazza M, Minghetti S, Biolo G, Virgili A. Clearance in vulvar lichen sclerosus: a realistic treatment endpoint or a chimera? J Eur Acad Dermatol Venereol. 2018;32(1):e31-e32. doi:10.1111/jdv.14523

21. O'Grady C, Khoo AK, Doiron P. Burden of treatment in vulval lichen sclerosus. Skin Health Dis. 2022;2(3):e147. doi:10.1002/ski2.147

22. Goldstein AT, Marinoff SC, Christopher K, Srodon M. Prevalence of vulvar lichen sclerosus in a general gynecology practice. J Reprod Med. 2005;50(7):477-480.

23. Leibowitch M, Neill S, Pelisse M, Moyal-Baracco M. The epithelial changes associated with squamous cell carcinoma of the vulva: a review of the clinical, histological and viral findings in 78 women. Br J Obstet Gynaecol. 1990;97(12):1135-1139. doi:10.1111/j.1471-0528.1990.tb02503.x

24. Jones RW, Scurry J, Neill S, MacLean AB. Guidelines for the follow-up of women with vulvar lichen sclerosus in specialist clinics. Am J Obstet Gynecol. 2008;198(5):496.e1-496.e3. doi:10.1016/j.ajog.2008.01.011

25. Lynch PJ, Moyal-Barracco M, Bogliatto F, Micheletti L, Scurry J. 2006 ISSVD classification of vulvar dermatoses: pathologic subsets and their clinical correlates. J Reprod Med. 2007;52(1):3-9.

26. Kirtschig G, Becker K, Günthert A, et al. Evidence-based (S3) Guideline on (anogenital) Lichen sclerosus. J Eur Acad Dermatol Venereol. 2015;29(10):e1-e43. doi:10.1111/jdv.13136

27. Depasquale I, Park AJ, Bracka A. The treatment of balanitis xerotica obliterans. BJU Int. 2000;86(4):459-465. doi:10.1046/j.1464-410x.2000.00772.x

28. Poindexter G, Morrell DS. Anogenital pruritus: lichen sclerosus in children. Pediatr Ann. 2007;36(12):785-791. doi:10.3928/0090-4481-20071201-08

29. Haefner HK, Aldrich NZ, Dalton VK, et al. The impact of vulvar lichen sclerosus on sexual dysfunction. J Womens Health (Larchmt). 2014;23(9):765-770. doi:10.1089/jwh.2014.4805

30. Pugliese JM, Morey AF, Peterson AC. Lichen sclerosus: review of the literature and current recommendations for management. J Urol. 2007;178(6):2268-2276. doi:10.1016/j.juro.2007.08.024

31. Olejek A, Steplewska K, Gabriel A, et al. Occurrence of vulvar lichen sclerosus in postmenopausal women with insulin resistance. Prz Menopauzalny. 2014;13(2):117-120. doi:10.5114/pm.2014.42717

32. Goldstein AT, Burrows LJ. Surgical treatment of clitoral phimosis caused by lichen sclerosus. Am J Obstet Gynecol. 2007;196(2):126.e1-126.e4. doi:10.1016/j.ajog.2006.09.003

33. Chi CC, Kirtschig G, Baldo M, Brackenbury F, Lewis F, Wojnarowska F. Topical interventions for genital lichen sclerosus. Cochrane Database Syst Rev. 2011;(12):CD008240. doi:10.1002/14651858.CD008240.pub2

34. Kirtschig G, van der Meulen AJP, Loman L, et al. EuroGuiderm guideline on lichen sclerosus-Treatment of lichen sclerosus. J Eur Acad Dermatol Venereol. 2024;38(10):1875-1889. doi:10.1111/jdv.20104

35. Lebreton M, Lacau St Guily J, Acker A, et al. Vulvar intraepithelial neoplasia: Classification, epidemiology, diagnosis, and management. J Gynecol Obstet Hum Reprod. 2020;49(9):101843. doi:10.1016/j.jogoh.2020.101843

36. Carlson JA, Ambros R, Malfetano J, et al. Vulvar lichen sclerosus and squamous cell carcinoma: a cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosing dermatoses in the development of neoplasia. Hum Pathol. 1998;29(9):932-948. doi:10.1016/s0046-8177(98)90198-8

37. Edmonds EV, Oyama N, Chan I, et al. Extracellular matrix protein 1 autoantibodies in male genital lichen sclerosus. Br J Dermatol. 2011;165(1):218-219. doi:10.1111/j.1365-2133.2011.10338.x

38. Baldo M, Bhogal B, Groves RW, Wojnarowska F. Childhood vulval pemphigoid: a clinical and immunopathological study of five patients. Br J Dermatol. 1999;140(2):308-312. doi:10.1046/j.1365-2133.1999.02667.x

39. Kirtschig G, Wakelin SH, Wojnarowska F. EuroGuiderm guideline on lichen sclerosus-introduction into lichen sclerosus. J Eur Acad Dermatol Venereol. 2024;38(10):1857-1865. doi:10.1111/jdv.20103

40. Lee A, Bradford J, Fischer G. Long-term Management of Adult Vulvar Lichen Sclerosus: A Prospective Cohort Study of 507 Women. JAMA Dermatol. 2015;151(10):1061-1067. doi:10.1001/jamadermatol.2015.0643

41. Cooper SM, Ali I, Baldo M, Wojnarowska F. The association of lichen sclerosus and erosive lichen planus of the vulva with autoimmune disease: a case-control study. Arch Dermatol. 2008;144(11):1432-1435. doi:10.1001/archderm.144.11.1432

42. Geisler AN, Lowinger JS, Heng A, Wei ML. Lichen Sclerosus in Cancer Patients. J Low Genit Tract Dis. 2025;29(2):143-148. doi:10.1097/LGT.0000000000000883

43. Renaud-Vilmer C, Cavelier-Balloy B, Porcher R, Dubertret L. Vulvar lichen sclerosus: effect of long-term topical application of a potent steroid on the course of the disease. Arch Dermatol. 2004;140(6):709-712. doi:10.1001/archderm.140.6.709

44. Haefner HK, Aldrich NZ, Dalton VK, et al. The impact of vulvar lichen sclerosus on sexual dysfunction. J Womens Health (Larchmt). 2014;23(9):765-770. doi:10.1089/jwh.2014.4805

45. Kirtschig G, van der Meulen AJP, Loman L, et al. EuroGuiderm guideline on lichen sclerosus-Treatment of lichen sclerosus. J Eur Acad Dermatol Venereol. 2024;38(10):1875-1889. doi:10.1111/jdv.20104

46. Mautz TT, Davis M, Brucker N, et al. Topical Corticosteroids in the Treatment of Vulvar Lichen Sclerosus: A Review of Pharmacokinetics and Recommended Dosing Frequencies. Sex Med Rev. 2022;10(1):63-71. doi:10.1016/j.sxmr.2021.03.005

47. Chi CC, Kirtschig G, Baldo M, Brackenbury F, Lewis F, Wojnarowska F. Topical interventions for genital lichen sclerosus. Cochrane Database Syst Rev. 2011;(12):CD008240. doi:10.1002/14651858.CD008240.pub2

48. Goldstein AT, Marinoff SC, Christopher K. Pimecrolimus for the treatment of vulvar lichen sclerosus in a premenopausal woman. J Reprod Med. 2004;49(7):502-504.

49. Neill SM, Lewis FM, Tatnall FM, Cox NH. British Association of Dermatologists' guidelines for the management of lichen sclerosus 2010. Br J Dermatol. 2010;163(4):672-682. doi:10.1111/j.1365-2133.2010.09997.x

50. Borghi A, Minghetti S, Corazza M, Biolo G. Topical tacrolimus for erosive lichen sclerosus. Dermatol Ther. 2015;28(1):1-3. doi:10.1111/dth.12175

51. Cattaneo A, Carli P, De Marco A, et al. Testosterone maintenance therapy. Effects on vulvar lichen sclerosus treated with clobetasol propionate. J Reprod Med. 1996;41(2):99-102.

52. Sotiriou E, Apalla Z, Ioannidis D. Photodynamic therapy in dermatology. Clin Dermatol. 2014;32(1):12-27. doi:10.1016/j.clindermatol.2013.05.024

53. Sun SH, Deng Q, Xiong YJ, et al. Platelet-rich fibrin attenuates inflammation and fibrosis in vulvar lichen sclerosus via the TGF-β/SMAD3 pathway. Arch Dermatol Res. 2025;317(2):100. doi:10.1007/s00403-025-03718-8

54. Kaderly Rasmussen EL, Bygum A, Kjaer SK, et al. Biopsy-verified vulvar lichen sclerosus and the risk of non-vulvar cancer: A nationwide cohort study. Int J Cancer. 2024;155(10):1864-1872. doi:10.1002/ijc.35101

55. O'Grady C, Khoo AK, Doiron P. Burden of treatment in vulval lichen sclerosus. Skin Health Dis. 2022;2(3):e147. doi:10.1002/ski2.147

56. Haefner HK, Aldrich NZ, Dalton VK, et al. The impact of vulvar lichen sclerosus on sexual dysfunction. J Womens Health (Larchmt). 2014;23(9):765-770. doi:10.1089/jwh.2014.4805

57. Borghi A, Corazza M, Minghetti S, Biolo G, Virgili A. Clearance in vulvar lichen sclerosus: a realistic treatment endpoint or a chimera? J Eur Acad Dermatol Venereol. 2018;32(1):e31-e32. doi:10.1111/jdv.14523