Relatively common

Lichen Sclerosus

Introduction

Lichen sclerosus (LS) is a chronic disorder of the genitalia and the general skin, resulting in marked hypopigmentation, tissue thinning, areas of thickening and hyperplasia and scarring.

Synonyms for lichen sclerosus are lichen sclerosus et atrophicus (LS & A), hyperplastic dystrophy, and kraurosis vulvae, older terms that are no longer in use.

Epidemiology

Lichen sclerosus has been identified in patients of all ages including those in the first years of life.1 LS has two peak ages of presentation. The first occurs in prepubertal girls, and the other peak of incidence is in postmenopausal women. 2 Lichen sclerosus may improve with puberty but this is not always the case, as shown in at least one study.3 Long-term follow up is important regardless of age.

The prevalence is difficult to determine since patients with this disease may present to pediatricians, dermatologists, gynecologists and urologists, and many cases go unreported. Estimates range from 1 in 30 elderly women, to 1 in 59 women in a general gynecology practice, to 1 in 300 to 1000 patients referred to dermatologists. 4 5 6 7 8

Etiology

The etiology is unknown but several theories have been proposed.

LS has been weakly linked with immune dysregulation and autoimmune disease.9 10 11 Autoimmune diseases occur in 20% of patients and 22% of their families. 12

The genetic contribution to LS is complex. Familial cases have been reported in identical and non-identical twins and siblings, but the inheritance pattern is not clearly established. 13 Gene regulators of human leukocyte antigens (HLA) have been studied in search of associations between HLA and LS, but none has been found with HLA type 1 antigens. An association has been demonstrated with LS and HLA type 2 antigens that are expressed on immunocompetent cells that normally recognize foreign particles. 14

T-lymphocytes dominate the inflammatory infiltrate of LS. T-cell receptor gene studies of affected vulvar skin show a monoclonal population of the rearranged gamma chain gene for the T-cell receptor. Experts postulate that this gene rearrangement could explain the increased risk of malignant transformation in individuals with LS. 15

Since the basement membrane is the initial target of the inflammation of LS, the target antigen may lie in that region. Indeed, antibodies against the basement membrane zone have been found in 30% of patients with LS;16 in 67% there are circulating autoantibodies to the endothelial cell adhesion molecule.17 Current theory suggests that LS and possible associated malignancy may arise from oxidative stress as reactive oxygen species generated from chronic inflammation damage DNA.18

Infectious organisms have been postulated but never confirmed. 19

Hormonal influences are questioned since LS is observed in low estrogen physiological states such as prepuberty and postmenopause. There is, however, no association of LS with pregnancy, hysterectomy, or hormone replacement.20 In normal female genitals, the transition from vagina to vulva is marked by an increase in androgen receptors and a decrease in estrogen and progesterone receptors. Vulvar androgen receptor expression may be decreased in a subgroup of individuals with LS. 21 22 Recent work suggests that disturbance of androgen-dependent growth of the vulvar skin by oral contraceptive pills (OCPs), and especially OCPs with anti-androgenic properties, might trigger the early onset of LS in a subgroup of susceptible young women. 23

Symptoms and clinical features

The onset may be asymptomatic until the patient has sufficient scarring to produce dyspareunia or even urinary retention.24 Intractable vulvar and/or perianal pruritus and soreness is the most common complaint, as well as dysuria, dyspareunia, and pain on defecation.25 The itching can be severe enough to wake the patient at night and to be socially incapacitating by day.26 Uncontrollable scratching may lead to open excoriations, pain, dysuria, and dyspareunia.

The classic lesions are circumscribed, ivory white papules and plaques, and atrophic or thickened skin with ecchymoses and hemorrhage from repeated scratching. Crinkled skin texture change is classic and generally pathognomonic,

Lichen Sclerosus

although a shiny, smooth texture also occurs.27

Lichen Sclerosus

If there is repeated scratching, hyperkeratosis and superficial erosions develop. As the disease progresses the labia minora adhere to the interlabial sulci.

Agglutination of the Labia Minora to the Interlabial sulcus

Fissures may be seen at architectural interfaces or on any surface.

Fissures

The fissures are painful and can become infected secondarily with bacteria or yeast. 28 The inflammation causes pigmentary disturbance with hyperpigmentation in the region of the labia minora, a cause of concern and diagnostic uncertainty since melanoma is then in the differential. 29

Post-Inflammatory Hyperpigmentation

The disease may start in the periclitoral area, spreading to involve the entire labia minora and interlabial sulcus, and then extending down through the perineum and the perianal area, forming the typical figure-of-eight pattern.

Lichen Sclerosus

One study found LS to be located as follows: on the labia (100%), clitoris (70.4%), perineum (67.9%), buttocks (32.3%), perianal area (32.1%), crural area (8.6%), urethra (3.7%).30 With time, atrophy of all the subcutaneous tissue leads to gradual effacement and eventual complete disappearance of the clitoris and/or labia minora.

Lichen Sclerosus

In end-stage disease, the opening of the vagina may be stenosed or even closed.

Lichen Sclerosus

Patchy involvement of the vulva can occur. In mild cases, there may be only simple hypopigmentation. Sometimes only scattered white guttate papules are seen; in others, there are thick white plaques. 31

Lichen Sclerosus

Secondary changes are common. Scratching produces varying degrees of purpura, erosions, and excoriation. Scarred areas may be torn by attempts at sexual intercourse. Some patients show Koebnerization (the induction of new lesions by physical trauma). Repeated scratching causes lichenification that can be frankly warty. The mucous membrane of the vagina is not involved, but there may be some mucosal involvement at the edge of mucocutaneous junctions leading to introital narrowing. 32

LS rarely affects the oral mucosa, but may appear as white plaques on the lips or buccal mucosa.33 10% of patients may have involvement of other body areas, especially the trunk and arms. 34

Cancer risk

Vulvar cancer related to LS is a controversial subject. The risk of development of invasive squamous cell carcinoma in a woman with LS is about 5%,35 but various studies show a range between 0-20%.36 37 LS is also associated with vulvar intraepithelial neoplasia. 38

Assessment of malignant transformation risk in vulvar lichen sclerosus has long been a concern. A retrospective chart review of 129 adult patients with lichen sclerosus who had been under surveillance for a minimum of three years was performed. Squamous cell carcinoma was seen only in non-compliant patients,39 as suggested in two previous studies.4041A recent study of 976 women histologically or clinically designated as having LS who had a one month minimum follow-up were selected. The median age at diagnosis was 60 (8-91) years. The median follow-up was 21 1-339) months. 34 patients developed neoplasms (incident risk:3.5%). The probability of neoplasia occurrence at 24, 60, 120, 180, 240, and  300 months was 1.2%, 3.0%, 7.1%, 11.0%, 21.6% and 36.8% respectively. The authors concluded that the higher probability of malignant transformation in the long period suggests a careful and lifelong follow- up in all LS patients.42

Accumulating data give clues to the relationship of LS and cancer. As mentioned above, experts theorize that T-cell receptor gene rearrangement could explain the increased risk of malignant transformation in individuals with LS.43 The monoclonal origin of LS suggests that clonal expansion may occur prior to epithelial atypia.44 Genetic and tumor marker alterations precede morphological atypia: markers of neoplasia- increased growth fraction, increased apoptosis- and alterations in the expression of p53 and its regulator have been linked with histologic progression from LS to vulvar cancer. 45 A high degree of chromosome 17 aneuploidy affecting the p53 gene is found in LS adjacent to cancer.46 Allelic imbalances have been demonstrated in 43% of vulvar LS biopsies. 47 And changes in cell cycle proteins have been linked to the progression of lichen sclerosus to vulvar cancer. 48

Psychosexual effects

LS may have a profound effect on women who may feel mutilated and less feminine. Scarring may lead to dyspareunia as well as sexual dysfunction.49 Validation of their concerns with proper clinical treatment can make a huge difference in outlook; emotional support and sexual counseling from a professional may be necessary. Support from other women can be invaluable.

Pregnancy

LS may present for the first time during pregnancy.50 The incidence of LS in pregnancy is unknown, and the effect of pregnancy on existing LS is not well studied. Women have reported improvement as well as worsening. 51 Mode of delivery is also not well studied. We do not recommend routine Cesarean section delivery if LS is well controlled and the vulvar epithelium is supple, elastic, and not inflamed. We do suggest Cesarean delivery for significant adhesions and inflamed skin with the opinion that obstetrical laceration in severely affected epithelium will have prolonged, possibly on-going morbidity.

Diagnosis

Diagnosis is made based on the clinical pattern and histopathology.

Note: The clinical features are lost in the glare of over-bright lighting.

Pathology/Laboratory Findings

Contrary to many references in texts and atlases, in the early stages of LS both the clinical appearance and the histologic picture from biopsy may be difficult to interpret.52 Features may be similar to psoriasis or lichen planus: irregular acanthosis, mild hyperkeratosis, hypergranulosis, mild lichenoid lymphocytic infiltrate with lymphocyte tagging and dilated blood vessels immediately under the basement membrane, focal basement membrane thickening, luminal hyperkeratosis of adnexal structures, submucosal edema and homogenization, lymphocyte exocytosis. 53 Only later in the disease may the pathogonomic findings of thinned epidermis with hyperkeratosis, a wide band of homogenized collagen beneath the dermo-epidermal junction, and a lymphocytic infiltrate beneath the homogenized area. 54 .

But if LS has been present for a long period of time (especially since childhood), characteristic histological findings may be absent.55

Therefore considerable clinical judgment combined with biopsy findings must be united for diagnosis. Biopsy may not be helpful if a potent topical steroid has been used since hyalinization of lichen sclerosus is lost.56 A nonspecific biopsy does not rule out lichen sclerosus, although classic histologic findings confirm the diagnosis.57

Differential diagnosis

Differential diagnosis includes inflammatory disease (vitiligo, morphea), erosive disease (lichen planus, cicatricial pemphigoid, pemphigus vulgaris), infection (condyloma, herpes simplex virus), neoplasia (VIN, SCC. extra-mammary Paget disease) and primary dermatoses (eczematous, allergic or irritant contact dermatitis), lichen simplex chronicus, and papulosquamous disease (seborrheic dermatitis, inverse psoriasis). Also in the differential are post-menopausal atrophy, and sexual abuse (in children).

Treatment/management

General treatments

  • Education that this is a chronic disease that is managed, not cured. Safety of topical steroids must be discussed. (See below).
  • Gentle cleansing with a very mild cleanser (Cetaphil cleanser).
  • Avoidance of strong soaps and detergents.
  • Use of ventilated cotton clothing.
  • Avoidance of panty liners.
  • Use of a mild lubricant for sexual intercourse (e.g., a tiny dab of light olive oil).
  • If very itchy, use cool gel packs applied directly to the vulva for burning and itching (keep gel pack in refrigerator in a freezer bag with a zippered closure).
  • Cool or luke warm sitz baths are soothing. The skin should be patted dry gently just before application of medication.

Specific treatments

Topical steroids

Topical super-potent steroids are the most effective,58 59 and are the treatment of choice. 60 Randomized, controlled trials to support one ultrapotent steroid over another of for the length of treatment are lacking. But vulvar LS is a chronic skin disorder, and we routinely advise maintenance therapy with superpotent steroid ointment, as symptoms often recur in women who terminate therapy.61 Time to recurrence may vary from months to years. Over-use of superpotent and potent topical corticosteroids may induce atrophy, telangiectasia, and striae as early as two to three weeks following daily application; however, long-term follow-up of LS patients has not generally demonstrated these steroid-induced changes since the modified mucous membranes of the labia and clitoris are relatively resistant to the side effects of topical corticosteroids. 62 63

Treatment needs to be individualized. We prescribe halobetasol or clobetasol 0.05% ointment twice a day for 6 to 8 weeks in severe cases, once a day for 6 to 8 weeks in moderate cases and devise an individual maintenance program, varying from one to three times weekly. Note: Ultra-potent steroids in the anal area are to be used with caution. For severe involvement, they can be used with proper local care (see general care above) for two weeks only. After this, a lower potency steroid such as desonide is used.

Some patients prefer ointments and others prefer creams but, in general, corticosteroid creams should be avoided because they contain irritants not found in ointments. In children, use mid- to high-potency steroid ointment. Oral glucocorticoids are effective but usually not indicated given the risk of systemic side effects and the high efficacy of topical steroids. With proper treatment, the response of lichen sclerosus is usually dramatic. Maintenance topical therapy is long-term. Overuse and thinning of the skin must be avoided by showing the patient exactly where to put the ointment and how little is required (a dot 3 mm wide.)

The clinician expects that symptoms will come under control. Fissures and erosions will clear. Plaques will disappear. Purpura usually goes. Whitening may regress but it may remain and its resolution is not a treatment goal. Loss of architecture, that is, reabsorption of labia minora, fusion of prepuce over clitoris, or anterior and posterior synechiae, does not regress. Occasionally the hood of the clitoris becomes “unstuck” if it is mildly adherent.

If the risk of secondary candidiasis exists, topical Nystatin ointment or ketoconazole cream may be used over the steroid or weekly fluconazole 150 mg orally may be given.

If the patient is unwilling to use maintenance therapy, then we examine her every three to six months because asymptomatic recurrence resulting in scarring and loss of architecture can occur over a relatively short period of time. Some patients will achieve long-term remission without maintenance therapy, but it is impossible to predict who these patients are.

Other topical treatments

Topical tacrolimus and pimecrolimus — topical calcineurin inhibitors –appear to have some efficacy for vulvar LS, and may be useful as alternative treatment options. In a 12-week randomized trial of 38 patients with vulvar LS that compared pimecrolimus 1% cream to clobetasol 0.05% cream, both agents significantly reduced patient symptoms and improved histopathologic inflammation. 64 The degree of improvement in histopathologic inflammation with clobetasol was superior, supporting the status of superpotent topical corticosteroids as the preferred choice for initial therapy.

Additional support for the utility of topical calcineurin inhibitors comes from uncontrolled studies and case reports. Patients with vulvar LS, including some with topical corticosteroid-refractory disease, have exhibited improvement with pimecrolimus cream65 or tacrolimus ointment. 66

Tacrolimus burns on application, and is often discontinued by patients for this reason. Although the US Food and Drug Administration has issued a “black box” warning for topical calcineurin inhibitors due to concern regarding an elevated risk for internal malignancy, a definitive relationship between these agents and internal malignancy has not been established. The impact of topical calcineurin inhibitor therapy on risk for vulvar SCC in patients with vulvar LS is unknown.

Topical oxatomide may help relieve pruritus through its antihistamine effects, but the course of disease is not affected. 67

Intralesional steroids

For major itching and lichenification unresponsive to topical steroids, use intralesional triamcinolone (Kenalog-10) diluted, 1 ml of triamcinolone with 2 ml saline. Use EMLA anesthetic cream under plastic wrap for 20 minutes minimum to reduce the discomfort from the injections. Repeat the injections monthly for a total of four months, depending on the response. Patients need education that they are temporarily immunosuppressed, may experience slight increase or decrease in mood temporarily, may have elevated blood sugar for a few days, or may experience transient vaginal bleeding. This is an area of caution: Intralesional Kenalog is used in whitened plaques of lichen sclerosus that have not responded to steroids, but only after biopsy (even if repeat biopsy) to rule out squamous cell carcinoma.

Other drugs:

There are no well-studied therapies in women who fail to respond to corticosteroids. Given the high therapeutic efficacy of these agents, we investigate causes of steroid failure in women who have persistent symptoms before resorting to a trial of an alternative drug. (Persistent symptoms below).

Estrogen

Topical estrogen is valuable in the maintenance of vulvo-vaginal epithelial integrity yielding elastic and supple tissue, but has no role in the treatment of the intense inflammation of lichen sclerosus.

Progesterone and testosterone:

Small randomized trials have generally shown that progesterone and testosterone creams are less effective than clobetasol. 68 Testosterone was associated with more side effects and less histological improvement than clobetasol 69 and testosterone maintenance therapy worsened symptoms after initial clobetasol therapy. 70 Placebo controlled trials of testosterone cream have reported conflicting results regarding efficacy. 71 72 We do not prescribe these hormones for LS treatment.

Retinoids:

Retinoids may reduce connective tissue degeneration in LS.73 In a single randomized trial, treatment with oral acitretin (20 to 30 mg per day for 16 weeks) was effective. 74 Doses of 8 to 30 mg daily for four months have been used. In an observational series, topical use of tretinoin improved the symptoms, gross appearance, and histopathologic features of LS with minimal side effects.75 However, side effects with the use of these agents include cheilitis, xerosis, teratogenicity, elevated liver enzymes, hypertriglyceridemia, abdominal pain, and alopecia. If a trial of retinoids is being considered, Consultation with a dermatologist is recommended before initiating therapy.

Cyclosporine

Cyclosporine has been used in only 10 patients with vulvar lichen sclerosus. 76 77 Of these, three had significant improvement, five had some response, and two had no response.

Other therapy:

A trial of photodynamic therapy (PDT) with 20% 5-aminolevulinic acid caused significant burning.78 Although itching improved in 8 of 12 women, the course of the disease was not changed. In a more recent study, PDT was reportedly very effective in 100 patients who had partial or full remission of clinical objective signs and subjective symptoms. 79

The use of adipose derived stem cells has been described,80 with promising results. More research is needed at this time.

Biologics have been use with one positive report of success with intralesional injection.81 On the other hand, lichen sclerosus has developed in a patient receiving imatinab for leukemia.82

Surgery

There is a 50% recurrence rate in patients who have been treated with surgery, even with full thickness skin grafts, 83 since lichen sclerosus can also develop in grafted tissue.84 Laser surgery is not a common treatment for LS also because of recurrences.85 For the same reason, cryosurgery has not gained wide acceptance. 86

Surgical intervention in lichen sclerosus is indicated only for the post-inflammatory sequelae of the disease, 87 including introital stenosis, fourchette adhesions, adhesions of the labia minora, and clitoral adhesions.

For introital narrowing, a vulvoperineoplasty (modified Fenton’s procedure) is indicated to remove the adhesions and construct a new introitus. The scarred area is excised; then a wide dissection and mobilization of the posterior wall of the vagina, reduction of the height of the perineal body, and advancement and eversion of the posterior vaginal wall are performed. 88 Adhesions recur if only lysis or scar excision is done, without the vaginal advancement.

Synechiae at the fourchette often tear during sexual intercourse or with vaginal examination.

They are a source of dyspareunia (as well as frustration) as they heal only to tear again. Median perineotomy (Fenton’s procedure) includes incising the adhesion, perineal skin, vestibular mucous membrane and the summit of the perineal body. The mucosal edges are undermined and sutured transversely with interrupted sutures. 89

Labial adhesions may compromise the introitus or urethra.

Fusion of the labia minora

They may be divided with cold knife or carbon dioxide laser. Refusion is a constant challenge. Essential management includes on-going control of LS with steroids. In addition, we have had success with motivated patients by instructing them to apply a barrier of petrolatum three times daily with an upward fingertip sweep to manually separate the labia on a frequent basis.

Clitoral adhesions from fusion of the prepuce may be symptomless. Orgasm may still be full and satisfying. In some women, aesthetic considerations and/or the complaint of diminished intensity of orgasm may lead to efforts to free the scarred prepuce from the glans. Accumulation of smegma under the fused hood may result in a clitoral pseudocyst. The adhesions are carefully incised with cold knife or carbon dioxide laser. Prevention of recurrence of adhesion may be achieved by resection of a tricorn shaped piece of the clitoral hood, everting the free edge, or by excision of the clitoral hood (circumcision). 90 In our experience women seldom consent to these procedures; we have had success with the combination of steroid management of LS and thrice daily application of petrolatum with gentle manual retraction of the hood.

Follow-up

Schedule follow-up appointments according to need, frequently at first, then every six to twelve months. Follow-up is more than ensuring symptoms control: it is also a cancer prevention exercise,91 and an effort to prevent further scarring in women.In a recent study of 46 women with pre-pubertal onset of lichen sclerosus, all patients achieved initial objective disease suppression with induction treatment using potent topical corticosteroids. Of patients compliant with treatment 93.9% had sustained complete disease remission with no scarring. Of the non-compliant patients, those applying intermittent or no long-term topical corticosteroids, 8% achieved complete control on maintenance treatment, 23% experienced disease progression during treatment, with three patients developing scarring during follow up. 92

Persistent symptoms

Given the high efficacy of steroids, when the treatment “is not working,” it is important to make sure the patient is complying with the prescribed corticosteroid therapy. Before considering alternatives or more aggressive treatment it is essential to consider a number of reasons for suboptimal treatment response.

Correct application of ointment: Make sure the patient is applying the steroid to the right place and in the right amount (a thin layer to the affected area) and frequency. Women often are unclear as to where to put the ointment unless they are shown repeatedly with a mirror. The elderly or infirm may not be able to apply the topical properly. If they use too much steroid, their symptoms may not abate. They are often afraid of applying ultrapotent topical steroids to the anogenital region, 93 because of inaccurate information and because of frightening package instructions on the insert with the topical steroid.

Secondary complicating conditions: Consider secondary complicating conditions including on-going burning, irritation, and pain from infection with bacterial cellulitis, vulvar candidiasis, or vaginal candidiasis.94 Obtain cultures to exclude superinfection by staphylococcus, streptococcus, or candida. We treat infected patients with appropriate antibiotics or antimycotic drugs.

Menopausal women may have symptoms related to atrophy, which will respond to topical estrogen cream.

Superimposed pain: A diagnosis of superimposed vulvar pain from a known disorder should be considered if pain persists despite resolution of pruritus and dermal changes.95 It is likely that this pain represents neuropathic pain, which is pain arising from abnormal neural activity secondary to disease, irritation, or injury of the nervous system that persists in the absence of ongoing disease or acute injury. (Vulvodynia section of Annotation K: Vulvar pain and provoked and unprovoked vulvodynia).

Irritant reaction: Contact irritation or allergy to the topical medication may be present. A topical steroid with a different base or consultation with an allergy specialist should be considered.

Very thickened areas may not respond to topical steroids, but may respond to intralesional injection; however, malignancy should be excluded by biopsy. We consider repeating the biopsy to confirm the diagnosis or exclude an alternative diagnosis, especially to exclude malignancy. We send the biopsy specimen to a dermatopathologist for review.

We try tacrolimus cream if the patient has fissuring that fails to respond to the measures described above. We prescribe a tiny amount of 0.03% cream twice daily for a month and then reevaluate. Application of a base of petrolatum ointment or clobetasol first may help to prevent burning. Burning often resolves after a week or two.

In cases of true treatment failure, we suggest consultation with a dermatologist who has expertise in management of vulvar disease.

PEARLS

  • LS has multiple appearances, not just whitened skin. Early LS may be erythematous.
  • LS does not always produce itching.
  • LS is a chronic disease and requires chronic management. Use of topical steroids has been shown safe on the vulva since 1988.
  • Clinical judgment is essential in diagnosis. Negative biopsy does not rule the disease out. Classical findings do confirm it. Often it is suspected and the patient must be followed.
  • Biopsy will be non-specific if disease has been present for a long time or if a steroid has been used within the past two weeks.
  • When symptoms do not respond, always consider malignancy.

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