REVIEW Pediatric Dermatology 1–7, 2015

Pediatric Lichen Sclerosus: A Review of the Epidemiology and Treatment Options Lana X. Tong, B.A.,*,† Grace S. Sun, M.D.,‡ and Joyce M.C. Teng, M.D., Ph.D‡ *David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, †Department of Health Policy and Management, Harvard School of Public Health, Boston, Massachusetts, ‡Department of Dermatology, Stanford University, Palo Alto, California

Abstract: Lichen sclerosus (LS) is a rare, chronic, inflammatory disease of the skin that primarily affects postmenopausal women but may occur in men and children as well. Approximately 7% to 15% of cases are believed to occur in children. The epidemiologic data for LS have been limited and treatment options are not well studied, particularly in children. We reviewed new developments available in the current literature on the epidemiology and management of LS for children.

Lichen sclerosus (LS), also known as lichen sclerosus et atrophicus, is a rare, chronic, inflammatory disease that primarily affects the anogenital region. It is a complex skin condition, with many genetic, physiologic, and environmental factors contributing to its pathogenesis. First described by Hallopeau in 1887 (1), LS is considered to be an autoimmune disease, although its etiology is controversial and remains unclear (2). LS is known to be associated with other autoimmune conditions, such as alopecia areata, autoimmune thyroiditis, vitiligo, and pernicious anemia (3). LS is more common in women than men, usually presenting in the fifth or sixth decade of life. Approximately 7% to 15% of cases occur in children (4,5). It usually presents with atrophic or ivory-white patches, ecchymoses, and sclerosis. Chronic pruritus and subsequent excoriation lead to superficial erosions and hyperkeratosis. As the disease progresses, fissures, superinfection, and symmetric hypermelanosis may also occur (2). Because of scarring in severe disease, labial resorption, burying of the clitoris, and

introitus narrowing can be observed in girls and women and urethral strictures in boys and men. Scarring of the vaginal introitus results in adhesions, and the vagina becomes susceptible to tearing because of a lack of elasticity (6). Sexual activity may become difficult or cause significant distress. LS has also been associated with the development of squamous cell carcinoma (SCC). Extragenital symptoms have been observed in 11% of patients (7). Therefore accurate diagnosis and appropriate treatment are crucial. Epidemiologic data are difficult to gather because patients tend to present to many different specialists, such as dermatologists, pediatricians, gynecologists, and urologists. There are also a wide variety of treatment options available, which can lead to improper treatment regimens, particularly in children. METHODS We searched PubMed for published studies from 1970 to August 2014 on the epidemiology and treatment

Address correspondence to Joyce M.C. Teng, M.D., Ph.D., 700 Welch Road, 301 G, Palo Alto, CA 94304, or e-mail: [email protected] DOI: 10.1111/pde.12615

© 2015 Wiley Periodicals, Inc.

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options available for LS using the search strings “lichen sclerosus,” “lichen sclerosus et atrophicus,” “children,” “pediatric,” “treatment,” “epidemiology,” “management,” and “therapy.” These categories included the subterms “lichen,” “sclerosus,” “atrophicus,” “therapeutic,” “therapeutics,” “child,” and “pediatrics.” Only articles written in English were included. Bibliographies were examined for additional articles meeting inclusion criteria. Sixty-six articles were reviewed for this article. Grades of evidence used to evaluate the existing data for each treatment option for LS (Table 1) were based on the criteria determined by the Institute for Clinical Systems Improvement (8). Level Ia refers to evidence from meta-analyses of randomized controlled trials (RCTs); Ib refers to evidence from at least one RCT; IIa refers to evidence from at least one non-RCT; IIb refers to at least one experimental study; III refers to evidence from case, correlation, or comparative studies; and IV refers to evidence from expert opinions.

Epidemiology and Etiology LS has an estimated prevalence of 1:60 to 1:1,000 in adults and children in the United States (2,9). Its true prevalence is difficult to estimate because many patients are asymptomatic and may also be hesitant to report their condition, in addition to a frequent incidence of misdiagnosis (10). The etiology of LS is complex and probably multifactorial. Because of its association with other autoimmune diseases, such as alopecia areata and thyroid disease, and a family history of autoimmune conditions, it is thought that the pathogenesis of LS is possibly autoimmune with underlying genetic predisposition, which recent studies have supported (11,12). Thyroid disease has been shown to have a prevalence in LS patients 5 to 30 times greater than in the general population. LS has been shown to run in families, and human leukocyte antigen DR and DQ haplotypes are thought to play a role in pathogenesis (13).

TABLE 1. Summary of Treatment Options for Pediatric Lichen Sclerosus (LS) Treatment option

Therapeutic effect

Side effects

Literature support

Topical corticosteroids

 Anti-inflammatory  Vasoconstrictive  Occlusive

    

Topical immune modulators

 Antiinflammatory

 Burning sensation  Black box warning of skin

Chi et al (37) Focseneanu et al (38) Kiss et al (43) Fischer and Rogers (39) Garzon and Paller (40) Vincent and Mackinnon (41) Jørgensen and Svensson (42) Smith and Quint (44) Chi et al (37) Goldstein et al (46) Hengge et al (47) Matsumoto et al (49)

Oral retinoids

 Antiinflammatory  Antiproliferative  Normalization

cancer and lymphomas

of epithelial keratinocyte differentiation

Topical androgens, estrogen, progesterone

Skin atrophy Hypopigmentation Burning sensation Irritation Adrenal suppression

 Tissue strengthening  Increased capillary

perfusion

 Stimulation of

 Dry skin  Arthralgias, back pain  Hyperglycemia,      

dyslipidemia Tinnitus Visual disturbance Increased intracranial pressure Inflammatory bowel disease Teratogenicity Depression, suicidal ideation

   

Acne Clitoromegaly Hirsutism Irregular menstruation

Level of evidence in children and adults* Ib; Ia (supportive)

IIa; Ia (supportive)

Bousema et al (50) Ioannides et al (51) Niinimaki et al (52) Virgili et al (53)

III; Ib (supportive) (adults)

Val and Almeida (34) Chi et al (37) Friedrich (54)

III; Ia (nonsupportive) (adults)

fibroblast proliferation *Grades of evidence used to evaluate the existing data for each treatment option for LS were based on the criteria determined by the Institute for Clinical Systems Improvement (6). Level Ia refers to evidence from meta-analysis of randomized controlled trials (RCTs); Ib refers to evidence from at least one RCT; IIa refers to evidence from at least one non-RCT; IIb refers to at least one experimental study; III refers to evidence from case, correlation, or comparative studies; and IV refers to evidence from expert opinions.

Tong et al: Treatment and Epidemiology of Pediatric Lichen Sclerosus

Furthermore, LS has been associated with high levels of basement membrane zone immunoglobulin G antibodies in children and adults (14). Lesions have also been shown to overexpress tumor suppressor proteins such as p53 and proliferation markers (Ki67, minichromosome maintenance protein 3), which may reflect a greater risk of malignant transformation (15). As with other autoimmune conditions, LS presents more commonly in women. Approximately 7% to 15% of LS cases are thought to occur in children (5), presenting as early as the first few years of life. The bimodal distribution of incidence in postmenopausal women and young children are thought to be correlated with low estrogen states in individuals of these ages (2). A higher incidence of Turner’s syndrome and kidney disease have also been noted, suggesting that low estrogen states might be a contributing factor in the etiology of LS (16), although more in-depth studies are needed. Some vulvar LS lesions have also been found to have low levels of androgen receptors (17), with another study suggesting low 5-a reductase levels (18). It is unclear whether there is an association between LS and infectious etiologies such as hepatitis C virus and Borrelia burgdorferi (19). Other possible triggers include trauma, enhanced oxidative stress, and immunocytologic changes such as extracellular matrix protein 1 autoantibodies (20). Clinical Characteristics The presentation of LS may vary between children and adults. In children, LS tends to present with vulvar purpura or ecchymosis with petechia and erosions, which can be mistaken for sexual abuse. Patients typically complain of irritation and soreness. Urinary symptoms, constipation, and behavioral problems are especially common in children (10). There are also differences between the sexes in terms of clinical features. In girls, the anogenital region is frequently affected. In boys, the glans, foreskin, and urethra are usually involved, but the perianal area is often spared (21,22). LS may also be associated with phimosis in boys, with one prospective study by Kiss et al (23) demonstrating LS in 40% of phimosis cases, most frequently in boys ages 9 to 11 years old. Risk of SCC Girls with LS are also at risk of vulvar SCC if LS persists past puberty. LS does not carry a risk of SCC during childhood. The incidence of vulvar SCC for women in Western countries is 1.5 per 100,000 (24). In

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girls and women with LS, the risk is thought to be approximately 4% to 5%, with some studies reporting an incidence of up to 7% (4,25). Approximately 60% of vulvar SCC appears to be associated with LS, particularly in individuals without human papillomavirus (HPV) infections. Penile and pseudohyperplastic SCC is also associated with LS in boys, mostly in uncircumcised patients (26,27). There is wide variation in the incidence of penile SCC in boys with LS, ranging from 2% to 50%; the exact incidence is unclear because fewer cases are reported (21). Association with Morphea LS sometimes coexists with linear scleroderma or morphea, another autoimmune connective tissue disease, which is also more common in women and girls (28). Both diseases have been strongly associated with other autoimmune conditions and have similar histopathologic findings (29). It is thought that LS occurs more frequently in people with morphea than the general population (30). One study demonstrated an incidence of 5.7% of LS in adults and children with morphea (odds ratio 18.1; 95% confidence interval 2.6, 134.2; p < 0.001) (31). Extragenital LS occurs more frequently with morphea and is often detected after initial diagnosis with morphea. Furthermore, 25.9% of patients developed extragenital LS at the same site of a previous morphea lesion, suggesting that Koebner’s phenomenon may play a role as a trigger of LS . The two conditions can also be difficult to distinguish diagnostically (32). Furthermore, the familial coexistence of LS and morphea has been shown, supporting the hypothesis of a possible shared genetic predisposition to these conditions (33), although the association between the entities remains unclear. Nonetheless, a complete skin examination is warranted when one of the two disorders is diagnosed. Treatment The management of LS is primarily medical and focuses on symptomatic relief and reduction in atrophy, scarring, strictures, and prevention of malignant transformation. It remains controversial whether treating asymptomatic patients will prevent the development of SCC (34). First-line therapies consist of topical corticosteroids and immune modulators (35), but few large-scale studies or RCTs of LS treatment have been performed in children. The primary therapies of LS are summarized in Table 1. Treatment failure occurs frequently in children and is usually secondary to behavioral problems or parental anxiety

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(2). Extensive counseling and reassurance for patients and parents are critical when treating children. Other symptoms associated with LS include pruritus, pain, and discomfort. Antihistamines, such as diphenhydramine and hydroxyzine, should be used for any pruritus (35). Persistent pain can be managed using tricyclic antidepressants (amitriptyline, desipramine), gabapentin, or serotonin reuptake inhibitors (fluoxetine) (35). It is also important to implement strict moisturizing practices to reduce irritation. If symptoms do not improve, biopsy may be considered to confirm the diagnosis. Generally, precautions such as using hypoallergenic soap, avoiding scratching, and wearing loose cotton underclothing are recommended. Topical Corticosteroids High-potency topical corticosteroids are typically used in the treatment of LS because of their antiinflammatory effects. The most commonly used agents include clobetasol propionate and betamethasone valerate (35). LS is generally responsive to ultrapotent topical steroids, and steroids have been shown to reverse some histologic changes seen in LS (2,4,36). Ointments are the preferred vehicle because they have a low rate of contact dermatitis and good penetrance (35). Dosing ranges from weekly application to twice daily, and various regimens are recommended (34). A 2011 Cochrane Review by Chi et al (37) examined seven RCTs investigating the efficacy of common treatments for LS in adults but was unable to draw conclusions in children. They found that clobetasol propionate cream 0.05% was significantly more effective than placebo in reducing symptoms and inducing remission. In children, clobetasol ointment 0.05% was efficacious in the treatment of pediatric LS in a study of 36 girls, with 75% achieving complete response and 25% achieving partial response (38). Clobetasol cream and ointment have been shown to be effective in several other case series as well (39–42). An RCT examining the efficacy of mometasone furoate ointment 0.05% in 40 boys with LS found clinical improvement in 40% (43). Because of the recalcitrant nature of the condition, topical treatments are often administered using a tapering regimen. In a case series by Smith and Quint (44), clobetasol ointment was initiated twice daily for 2 weeks, then once daily for 2 weeks, followed by midpotency triamcinolone ointment 0.1% twice daily for 2 weeks, then daily for 2 weeks, and subsequent hydrocortisone ointment use as needed. The schedule

was found to be effective in 93% of the children treated. Other regimens from a separate study recommended clobetasol propionate or mometasone furoate ointment once daily for 1 month, then the treatment was reduced to three times weekly the second month and twice weekly the third month. Maintenance treatment is often needed weekly for years to prevent flares (34). Side effects of corticosteroids include skin atrophy, risk of superinfection, xerosis, hypopigmentation, burning, irritation, and rarely, suppression of the hypothalamic–pituitary axis (44). Although there have been theoretical concerns of greater risk of side effects in children because of the potential risk of greater absorption through their thinner skin, the use of topical steroids has been shown to be safe in children. LS typically does not occur on the hairbearing skin of the vulva; mucosal skin is particularly resistant to atrophy and can tolerate the application of ultrapotent topical steroids. Symptoms may recur upon cessation of corticosteroid application, so maintenance therapy is frequently recommended, which may vary by patient. Topical Immune Modulators Topical calcineurin inhibitors (TCIs) such as tacrolimus and pimecrolimus can also be used in the management of LS. They are antiinflammatory and immunomodulating, selectively inhibiting cytokine secretion such as interferon-c and interleukins 2, 4, and 10. Their advantage is thought to lie in less immunosuppression and risk of dermal atrophy than with corticosteroids. Although several case reports have demonstrated their efficacy (41,45), larger-scale clinical trials and data are limited. The primary side effect of TCIs is a burning sensation during application when first initiating treatment that tends to resolve with continued use (34). The ideal dosage and duration of treatment is unknown. In the 2011 Cochrane Review, although pimecrolimus was shown to be as effective as clobetasol propionate in reducing pruritus, it was significantly less effective at improving overall symptoms (37,46). A phase II trial using topical tacrolimus in 85 patients ranging in age from 5 to 85 years found complete remission in 43% and partial remission in 34% (47). TCIs are not approved for patients younger than 2 years of age. Furthermore, the black box warning of a possible causal association with lymphoma and skin cancer can be a deterrent to parents (48). The use of TCIs in the treatment of LS is offlabel and is significantly more expensive than topical

Tong et al: Treatment and Epidemiology of Pediatric Lichen Sclerosus

corticosteroids. This may present a problem in terms of insurance coverage if the results are not superior to that of topical steroids, but a case report by Matsumoto et al (49) describes a 5-year-old girl who responded to tacrolimus ointment 0.03% after failing treatment with topical steroids. Other Treatments Oral retinoids (etretinate, isotretinoin, acitretin) have been demonstrated to have efficacy in treating recalcitrant cases of LS in adults (50–53). By activating nuclear retinoic acid receptors, retinoids are thought to work through subsequent inhibition of interleukin 6, interferon-c, and migration inhibitory factor–related protein 8, which reduces inflammation and cell proliferation. Because of an extensive side effect profile, including teratogenicity, the use of systemic retinoids should be limited to recalcitrant cases in adults. Topical androgens, estrogen, and progesterone have also been used for their ability to strengthen tissue, increase capillary perfusion, and stimulate fibroblast proliferation (34,54), but the 2011 Cochrane Review found that they were not effective in treating LS and the authors did not recommend their use in children (37). Associated side effects include acne, clitoromegaly, irregular menstruation, hirsutism, and other signs of virilization. Other treatments that have been mentioned in the literature but do not have significant supporting data include antimalarials (hydroxychloroquine, chloroquine) (55,56), stanazolol (57), calcitriol (58), potassium para-aminobenzoate (59), narrowband ultraviolet B therapy (60), cryotherapy, cyclosporine, oxatomide, psoralen plus ultraviolet A therapy, antibiotics, and other types of phototherapy, such as photodynamic therapy in conjunction with topical 5aminolevulinic acid solution 20% (61). Surgical Treatment Surgical intervention may be necessary in cases with significant disease progression, particularly if anatomic distortion is observed (62). Vulvectomy in adults is not indicated unless malignancy is observed. Surgery typically plays a more significant role in penile LS, in which circumcision may be helpful in managing early LS in boys (63). Surveillance After resolution of acute symptoms, long-term followup is recommended because the clinical course in

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children is often unpredictable (16,64–66). LS does not usually resolve after puberty but oftentimes will improve (10). If the disease persists past puberty, patients should be closely monitored because they are at greater risk of SCC. Follow-up with a dermatologist is suggested annually until the patient is 18 years old, after which he or she may follow up yearly in primary or secondary care, such as gynecology, if the condition is no longer active (2). If the patient begins to reexperience symptoms, he or she should be referred back to dermatology. Patients should also be counseled regarding self-examination and educated regarding their risk of malignancy. Although LS often remits after treatment, any scarring acquired during periods of activity is permanent. CONCLUSION LS is a chronic, debilitating disease that may have tremendous ramifications for health and quality of life. Prompt diagnosis and aggressive therapy is warranted to reduce the morbidity and mortality associated with the disease. Further investigation regarding the prevalence of the condition in children and large-scale clinical studies examining the risks and benefits of different treatments in children are greatly needed. The possibility of recurrence should be kept in mind even after remission, and regular follow-up is strongly encouraged. REFERENCES 1. Klaber R. Lichen Sclerosus et Atrophicans (Hallopeau). Proc R Soc Med 1937;30:977–979. 2. Murphy R. Lichen sclerosus. Dermatol Clin 2010;28:707–715. 3. Harrington CI, Dunsmore IR. An investigation into the incidence of auto-immune disorders in patients with lichen sclerosus and atrophicus. Br J Dermatol 1981;104:563–566. 4. Powell JJ, Wojnarowska F. Lichen sclerosus. Lancet 1999;22:1777–1783. 5. Sahn EE, Bluestein EL, Oliva S. Familial lichen sclerosus et atrophicus in childhood. Pediatr Dermatol 1994;11:160–163. 6. Neill SM, Tatnall FM, Cox NH. Guidelines for the management of lichen sclerosus. Br J Dermatol 2002;147:640–649. 7. Thomas RH, Ridley CM, McGibbon DH et al. Anogenital lichen sclerosus in women. J R Soc Med 1996;89:694–698. 8. Greer N, Mosser G, Logan G et al. A practical approach to evidence grading. Jt Comm J Qual Improv 2000;26:700–712. 9. Nelson DM, Peterson AC. Lichen sclerosus: epidemiological distribution in an equal access health care system. J Urol 2011;185:522–525.

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Pediatric Lichen Sclerosus: A Review of the Epidemiology and Treatment Options.

Lichen sclerosus (LS) is a rare, chronic, inflammatory disease of the skin that primarily affects postmenopausal women but may occur in men and childr...
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