Chapter 65. Lichen Sclerosus

Lichen sclerosus (LS) is a chronic inflammatory dermatosis of the anogenital area that affects quality of life due to the severe itching. LS may also present with extragenital manifestations that are generally nonpruritic. Of note, vulvar disease seems to have an increased risk of squamous cell carcinoma, but the role of additional cofactors (e.g., human papillomavirus infection or prior radiotherapy) has not been defined.

The incidence of LS has not been precisely determined. It has been estimated to be in the order of 14 per 100,000 persons per year.1 LS is more prevalent in females, accounting for a 5:1 gender ratio. It preferentially affects women in the fifth or sixth decade of life and children younger than the age of 10 years.1,2 Up to 15% of LS cases occur in children, particularly in girls, and one study reported a prevalence of 1 in 900 premenarchal girls.3 A 0.07% incidence in males has recently been determined in a study of 153,432 male soldiers.4 Among blacks and Hispanics, the incidence in this group was 1.06%, whereas the incidence was only 0.051% in white soldiers.4 LS seems to be a prominent cause of phimosis; in one study, 14% of adolescent boys had LS, whereas 40% of phimosis cases in adult men were associated with LS.5 Similarly, a recent study of foreskins examined after therapeutic circumcision for phimosis confirmed many cases of unrecognized LS.6 As genital LS in males is almost exclusively seen in uncircumcised men, the rate of circumcision in a given population has a strong impact on the occurrence of the disease.

The cause of LS is unknown. While a genetic predisposition has generally not been found,7 a recent observational cohort study reported a high rate of familial LS cases.8 Of 1,052 females with LS, 126 (12%) had a positive family history of LS. Vulvar cancer was significantly increased in those patients with a family history of LS compared with those without (4.1% vs. 1.2%).8 This report proposes a likely genetic component in the etiology of LS. Evidence for the presumed infectious cause, such as acid-fast rods, spirochetes, or Borrelia, has not been found.7 Serologic and clinical evidence of thyroid disease, alopecia areata, pernicious anemia, and vitiligo suggested an association with LS. Extragenital LS is commonly seen in association with plaque-type morphea, and some authors have suggested a common pathomechanism. Recently, low-titer autoantibodies against the extracellular matrix protein-1 (ECM-1) and collagen XVII have been identified in 67% of LS.9,10 ECM-1 (see Chapter 137) may be involved in basement membrane and interstitial collagenous fiber assembly and growth-factor binding,11 and may also regulate blood vessel function.12 In addition, antibodies to the basement membrane protein bp180 have been detected in childhood vulval LS lesions in four of nine children analyzed.13 All antibodies were IgG-type. There was no clinical and family history of autoimmune diseases or autoantibodies in the children studied. Local irritation also seems to play a role in some cases. The disturbed function of fibroblasts with increased production of collagen has been demonstrated in LS.14,15

Cutaneous Lesions

Polygonal papules and porcelain-white plaques with atrophic fragile skin, fissures, telangiectasias, purpura, erythema, erosions, and different degrees of sclerosis are present in the anogenital area (Figs. 65-1A–65-1F); often the classical figure-8 pattern of the vulva and anus may be observed (see Fig. 65-1E). Blisters (occasionally hemorrhagic) may develop when the lichenoid infiltrate separates epidermis from the sclerotic dermis. The size of LS lesions may vary from a few millimeters to large portions of the trunk. Anogenital LS frequently causes intractable itching and soreness, dyspareunia, dysuria, discomfort with defecation, or genital bleeding and, with time, may lead to destructive scarring (see Fig. 65-1F). Gradual obliteration or synechiae of the labia minora and clitoris, as well as stenosis of the introitus, may also result (see Chapter 78). Male genital LS is usually confined to the glans penis, prepuce, or foreskin remnants (see Fig. 65-1A–65-1C). Penile shaft involvement is less common, whereas scrotal involvement is rare. Many male genital LS cases are simply diagnosed as phimosis. In severe cases, erections may become painful (see Chapter 77). Extragenital manifestations typically affect the thigh, the neck, trunk and lips; lesions are usually asymptomatic (Fig. 65-2). A recent clinical histopathological study has revealed 27 adult cases with lip involvement.16 Clinical presentation consisted of asymptomatic vitiligo-like lesions in 70% with a variable degree of dermal sclerosis confined to the papillary layer. This was in contrast to genital LS lesions that showed both papillary and reticular dermal sclerosis in the majority of cases. Therefore, the vitiligo-like LS needs to be added to this spectrum of oral lichenoid lesions.

Related Physical Findings

Except for the association with autoimmune thyroid disease, alopecia areata, pernicious anemia, morphea, and vitiligo, which should be ruled out, no additional related findings have been reported. In particular, genital infections by herpes simplex virus or Candida do not seem to be increased in LS patients.

Histopathology

Classical LS shows an atrophic epidermis and a lichenoid infiltrate at the dermal–epidermal junction.17 Papillary edema is usually seen in early LS, but is gradually replaced by fibrosis with homogenization of acid mucopolysaccharides as the lesion matures (Fig. 65-3). The lymphocytic infiltrate in LS contains abundant T cells, B cells, and antigen-presenting dendritic cells that are major histocompatibility complex class II+, CD8+, and CD57+.18,19 A monoclonal T-cell receptor γ-chain rearrangement has alluded to the existence of an LS antigen, potentially the ECM-1 protein, which is also recognized by the recently described autoantibodies.8,20 Epidermal hyperplasia and/or dysplasia associated with LS on vulvar specimens are associated with an increased risk of malignant transformation, especially in conjunction with infection by high-risk papillomaviruses.

Special Tests

Imaging studies are only needed in special situations (e.g., urinary obstruction secondary to stenosing genital LS). High-resolution ultrasound is occasionally used to document the depth of sclerosis.

A skin punch biopsy of a mature lesion will confirm the diagnosis if the diagnosis is not obvious by clinical examination. ECM-1 autoantibodies may be detected by specialized laboratories; a commercial enzyme-linked immunosorbent assay (ELISA) has recently become available.21 Despite the described association with autoimmune diseases, an autoimmune workup (e.g., antinuclear antibody, parietal cell antibody, vitamin B12 levels, thyroid function tests) is not generally recommended due to their relatively low occurrence.22 For the same reason, Borrelia antibody titers should not be analyzed, as they are not associated with LS.23 To exclude squamous cell carcinoma, repetitive biopsies may be indicated.

The differential diagnosis of LS and localized scleroderma (morphea) may be difficult (Box 65-1; see Fig. 65-2). Clinically, morphea may be confused with extragenital LS. Morphea represents a circumscribed connective tissue disease with a number of different presentations. Typical early plaque-type lesions show a lilac ring with progressive central induration and whitening and peripheral hyperpigmentation (see Chapter 64). Histologically, early morphea presents as a dense lymphocytic, superficial, and deep perivascular infiltrate with degeneration of collagen fibers. In later stages, inflammation is replaced by dermal fibrosis much like the changes seen in LS. Patients have been described with lesions typical of both plaque-type morphea and the chalky white, atrophic plaques of LS, suggesting that morphea and LS may share a common pathomechanism.24 Antinuclear antibodies may be positive in either morphea or LS.

Constipation is a common complication in children with anogenital LS.25 The associated purpura and discoloration often raise concern about child abuse, especially if LS is not recognized (see Chapter 106). LS in children has occasionally been associated with a perineal pyramidal protrusion, a common lesion that can be confused with condyloma and is also associated with constipation. This association further (erroneously) increases the suspicion of sexual abuse.26,27 It should be noted, however, that LS and child abuse may coexist28 and that some cases of LS have been linked with trauma of the anogenital region (see Chapter 106). See Box 65-2 for pitfalls in the diagnosis of LS.

Besides dyspareunia, urinary obstruction, constipation, secondary infection related to ulceration, and steroid use, squamous cell carcinoma represents the main complication in females (Fig. 65-4). The lifetime risk of developing squamous cell cancer as a complication of long-standing LS has been estimated in the order of 4%–6%.1,29 Age, long duration of LS, human papillomavirus infection, and evidence of hyperplastic changes represent significant risk factors.30,31 In males, painful erections and urinary obstruction represent the most frequent complications.

The prognosis of LS is good for most anogenital cases, especially for those in prepubertal children that may resolve spontaneously or may be healed after treatment with ultrapotent topical steroids.32 However, a recent study reported that childhood onset vulvar LS does not resolve at puberty.33 The authors prospectively studied 12 cases, of which nine patients, who still had active LS at puberty, continued to require maintenance therapy after menarche. Six of the 12 experienced significant disturbance of the vulvar architecture. Therefore, prepubertal LS does not necessarily resolve at puberty. A further case series reported the efficacy of topical clobetasol propionate 0.05% in childhood LS.34 Nine of 15 young girls suffered from a relapse about 1 year following the first clearing of the lesions. The authors also concluded that early aggressive treatment with ultrapotent corticosteroids enables the best clinical course of childhood LS.34 The disease is usually self-limiting, but requires treatment due to the severity of patient discomfort. Recalcitrant chronic LS causing erosions and progressive scarring may result in severe sexual dysfunction. Cosmetic improvement for extragenital cases and for chronic atrophic genital disease is rather poor.

Various attempts to treat LS have been undertaken. The single most effective treatment of LS is ultrapotent topical corticosteroids such as clobetasol.20,32–43 However, there is no systematic trial to support this common practice. Due to corticosteroid adverse effects, the treatment period with ultrapotent steroids should be limited, generally to 4–6 weeks. Treatment should be continued, when necessary, with less potent corticosteroids or calcineurin inhibitors (see below).

Case series using topical tacrolimus and pimecrolimus have shown clinical effectiveness.44–48 Although many of the effects of topical tacrolimus parallel those of corticosteroids,49 adverse effects such as atrophy, telangiectasias, and pigment changes do not occur. A recent multicenter, phase II trial has assessed the safety and efficacy of twice-daily application of tacrolimus ointment 0.1% in 84 patients (49 women, 32 men, and 3 girls) with longstanding LS (mean duration, 5.8 years), with a follow-up period of 18 months.50 Clearance of active LS was reached by 42.9% of patients, with at least 50% improvement in an additional 34.3% of patients. However, the duration of treatment to achieve an optimal response was up to 24 weeks.

Systemic therapy with retinoids, including isotretinoin, etretinate, and acitretin and oral tacrolimus, have been useful in small trials. Systemic antibiotics against borreliosis and penicillamine have not proved effective.

Destructive surgical therapies, such as cryotherapy,51 the tissue-vaporizing carbon dioxide lasers, and nonablative lasers such as the pulsed dye and Erb:YAG lasers, have been reported to work in LS but should only be used with caution. More recently, PUVA and UVA1 treatment have shown some promising success in LS. Vulvectomy should be limited to cases in which squamous cell carcinoma has been detected.52–54

Female LS patients should be particularly monitored for any sign of secondary genital malignancy. Prepubertal LS in girls may resolve spontaneously; however, some of these patients may eventually suffer from vulvodynia in adulthood. In case of LS-associated dyspareunia that interferes with sexual activity, the use of topical anesthetics should be considered.

Circumcision will generally resolve male genital LS and the associated phimosis, although potent topical steroids may obviate the need for surgery. Asymptomatic extragenital LS usually requires no treatment other than cover makeup in selected cases.

No truly preventive measures of LS have been reported. An interdisciplinary management is essential for the long-term control of LS. Specialists from gynecology, urology, pediatrics, and psychosomatic medicine should be involved in patient care and collaborate to prevent significant complications, including the monitoring for squamous cell cancer and corticosteroid adverse events. It has also been helpful to circulate information via patient organizations for LS.