Extragenital bullous lichen sclerosus Maxwell B. Sauder, MD,a Jaclyn Linzon-Smith, MD,b and Jennifer Beecker, MD, CCFP(EM), FRCPCa Ottawa, Ontario, Canada Lichen sclerosus is an inflammatory skin condition characterized by inflammation of the papillary dermis that leads to white scarlike plaques. It occurs classically in the genitals but also has extragenital manifestations with a variety of clinical presentations including a bullous variant. The purpose of this review is to characterize extragenital bullous lichen sclerosus, suggest that it may be more common than dermatologists realize, and discuss treatment of both routine and recalcitrant cases. ( J Am Acad Dermatol 2014;71:981-4.) Key words: bullous; cyclosporine; extragenital; lichen sclerosus; methotrexate; treatment.
ichen sclerosus (LS) is an inflammatory skin condition characterized by white scarlike plaques. LS occurs classically in the genitals but also has extragenital manifestations. Scattered throughout the literature are ‘‘atypical’’ cases of bullous genital and extragenital LS. Extragenital bullous LS is traditionally thought of as a rare variant of LS; however, no good epidemiologic studies have been done to support this idea. Given the number of case reports of extragenital bullous LS, the assumption that it is a rare variant may not be accurate. The purpose of this review is to characterize extragenital bullous LS and discuss a therapeutic ladder for this often difficult-to-treat disease.
EPIDEMIOLOGY Classic genital LS is an uncommon disease with a prevalence difficult to estimate because of: (1) underreporting; (2) multiple names, including blurring of LS with morphea before 1940; (3) management by both dermatology and gynecology; and (4) asymptomatic presentations. A prevalence of 0.1% to 0.3% of patients was calculated by Wallace1 in 1971. Studies have reported contradicting female:male ratios ranging from 10:1 to 1:1. In women, there is a bimodal distribution occurring prepubescently and postmenopausally. In men, the disease typically manifests in the fourth decade.2 Extragenital involvement of LS has been estimated between 15% to 20% of all patients with From the Division of Dermatology, Department of Medicinea and Faculty of Medicine,b University of Ottawa. Funding sources: None. Conflicts of interest: None declared. Accepted for publication June 23, 2014. Reprint requests: Maxwell B. Sauder, MD, Division of Dermatology, University of Ottawa, 737 Parkdale Ave, Room 10, Ground Floor
Abbreviations used: BMZ: basement membrane zone LS: lichen sclerosus UV: ultraviolet
LS.3 However, to our knowledge, there have been no reports on the epidemiology of extragenital bullous LS. A literature search was performed using PubMed, yielding 26 reports with a total of 31 patients dating from 1936 to present.4-29 A 32nd patient is reported in this review (see ‘‘Treatment’’ section). The female:male ratio was 7:2 with an average age of 62 years, similar to classic genital LS. More than half (18) of the reported cases were within the last 22 years from 1992 to present; the remaining 13 cases were reported in the preceding 56-year period (1936-1992). The low number of cases found in the literature, especially prior to 1992, is likely a result of the aforementioned difficulties in identifying the prevalence of LS. Although this literature review does not show any trend, the number of cases reported (31), especially during the last 22 years, might suggest that extragenital bullous LS is more common than dermatologists may realize.
PATHOGENESIS The origin of genital LS is unknown. Theories include: genetic predisposition, autoimmunity, trauma, East, Ottawa Hospital, Civic Campus, Ottawa, Ontario K1Y 4E9, Canada. E-mail: [email protected]
Published online July 31, 2014. 0190-9622/$36.00 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.06.037
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infection, and hormonal abnormalities. Currently, the BMZ.32 Secondly, edema of the papillary dermis autoimmunity in predisposed individuals is favored. disrupts the collagen fibers supporting the Several circulating antibodies have been found superficial capillaries and flattens the rete ridges. in a greater proportion of patients with LS than in This weakened state coupled with epidermal atrocontrol subjects. IgG antibodies against extracellular phy may allow for blister formation with minimal matrix 1 protein were shown in 74% of LS group trauma or sheering forces from regular movement.4 30 serum versus 7% in control group serum. Extracellular matrix 1 protein TREATMENT helps to regulate the baseThe treatment of extraCAPSULE SUMMARY ment membrane zone genital bullous LS is similar (BMZ). In addition, several to that of genital LS (Table II). Extragenital bullous lichen sclerosus (LS) studies have demonstrated presents as flaccid bullae favoring the bullous pemphigoid antigen First-line therapies trunk and proximal limbs. 180 and 230 (BP180 and Recommended first-line Extragenital bullous LS can be treated BP230, respectively) antitherapies include supersimilarly to classic LS. Methotrexate can bodies against the BMZ in potent topical corticosteroids be used in resistant or extensive cases. patients with LS; yet, the with or without maintenance most recent study showed topical calcineurin inhibitors, Extragenital bullous LS may be more no statistical difference intralesional corticosteroids, common than dermatologists realize and versus control subjects.31 Of or oral corticosteroids. Based can present a therapeutic challenge. relevance to bullous LS, all of on the reported cases of the aforementioned antiextragenital bullous LS, the bodies target proteins within or regulating the most common treatment is the application of topical BMZ. Similar to bullous pemphigoid, theoretically corticosteroids,4-6,8,11-13,16,17,20 a relatively safe and an autoimmune attack of these proteins could result inexpensive modality. in bullae formation. The majority of cases used topical clobetasol propionate 0.05%, a class-1 super-potent steroid, once or twice daily with or without occlusion. Symptomatic CLINICAL FEATURES response can be achieved within days to weeks; Classic LS is characterized by ivory-white sclerotic however, extragenital LS often does not respond as atrophic plaques, most commonly in the anogenital well as classic LS.33 In 1 case, topical clobetasol was region. Extragenital LS can occur anywhere on the body but favors the trunk (abdomen, chest, used initially for 2 weeks to achieve control followed and back) and proximal extremities. Presenting by long-term daily use of pimecrolimus cream to symptoms are dryness and pruritus, but often ensure remission.4 In limited disease, intralesional extragenital LS can go unnoticed. Bullous LS may corticosteroids at anti-inflammatory doses (triamcinobe both genital and extragenital, with flaccid lone acetonide \10 mg/mL) may be used.25 bullae that may be hemorrhagic. The flaccid bullae Systemic steroids have been used with similar lead to ulcerations and erosions that initially heal with effects to topicals.7,10 Because of the side effects of significant postinflammatory erythema, and eventusystemic corticosteroids, their use should be limited ally obtain the characteristic ivory-white sclerotic to widespread disease where topical application plaques. A multitude of morphologic variants of LS would be challenging, or cases refractory to topical have been reported including bullous LS (Table I). treatment. Three reported cases used systemic antibiotics because of presumed secondary infections or the PATHOLOGY belief that extragenital bullous LS is a reaction to Early in the disease course, LS shows a lymphoBorrelia burgdorferi.8,10,16 As extragenital bullous LS cytic vacuolar interface dermatitis with epidermal likely does not have an infectious cause, the use of atrophy and orthohyperkeratosis. The most characantibiotics is recommended only if a secondary teristic changes are edematous homogenization of infection is present but not for primary disease the collagen and a loss of elastic fibers in the management. papillary dermis eventually leading to hyalinization and sclerosus of the papillary dermis. Histologically, bullae formation (Fig 1) has Second-line therapies been explained through 2 mechanisms. Firstly, the For patients who do not achieve adequate vacuolar dermatitis can lead to liquefaction degenclinical control with corticosteroids, methotrexate eration of the basal layer disrupting the stability of or phototherapy may be used. d
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Table I. Lichen sclerosus: Morphologic variants Morphologic variants of LS Bullous Ulcerative Annular Desquamative Telangiectatic or angiokeratomatous Verrucous or keratotic Oral Vitiligoid LS, Lichen sclerosus.
Fig 1. Extragenital bullous lichen sclerosus (LS); 800-m magnification of a subepidermal bullae within a plaque of LS.
To illustrate the effectiveness of methotrexate, the authors’ present a case of a 69-year-old woman with widespread biopsy-confirmed extragenital bullous LS. The patient failed to respond to super-potent topical steroids and had complications secondary to prednisone and acitretin including elevated transaminases, gamma-glutamyltransferase, and alkaline phosphatase. She was transitioned to methotrexate starting at 5 mg weekly titrating up to 20 mg while tapering the prednisone. Clinical response was seen within weeks and her liver enzymes normalized within months. The patient remains on methotrexate and in remission. Although methotrexate is commonly used in morphea, a literature review found only 2 studies with a total of 8 patients with LS treated with methotrexate.7,34 All 8 of the cases had extragenital involvement, but only 1 with bullae. All cases responded with a clinically significant reduction in severity or clearing and were bridged with either systemic or topical steroids. In follow-up at least 3 months posttreatment, the average response was a 75% reduction of area involved. The case described by the authors is the second reported case of extragenital bullous LS treated with methotrexate and demonstrated complete disease control. For difficult cases of extragenital bullous LS or
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Table II. Extragenital bullous lichen sclerosus: Recommended treatments First-line therapies Superpotent topical corticosteroids 6 maintenance topical calcineurin inhibitors Intralesional corticosteroids Oral corticosteroids Second-line therapies Methotrexate 6 corticosteroids Phototherapy Third-line therapies Retinoids Cyclosporine
extragenital LS, methotrexate may be considered when first-line therapies have failed or produced adverse drug events, or there is extensive debilitating involvement. There are case reports and series of the use of ultraviolet (UV)A, psoralen plus UVA, and narrowband UVB in the treatment of extragenital LS. UVA1 is most frequently associated with significant clinical improvement. One study concluded that the extragenital lesions cleared more effectively than the genital lesions.35 Psoralen plus UVA has been reported to reduce pruritus and lesions, leaving only minimal scarring in extragenital LS.36 One case of narrowband UVB reported resolution of clinical lesions within 3 months.37 There are no reported cases of extragenital bullous LS treated with phototherapy. Further studies are required to determine if phototherapy may be a useful modality. Third-line therapies Acitretin has been reported as treatment in cases of genital LS that included ulcerations and erosions. In a double-blind placebo-controlled study measuring clinical response, 14 of the 22 patients receiving acitretin (20-30 mg/d) for 16 weeks responded versus 6 of the 24 patients in the placebo-controlled group.38 The lymphocytic inflammatory infiltrate of LS theoretically suggests that an immunomodulator might be effective. Cyclosporine can be used to achieve acute disease control while transitioning to a maintenance treatment. One study of 5 patients with recalcitrant genital LS were treated for 3 months with cyclosporine at an initial dose of 3 to 4 mg/kg/d and decreased to 1 mg/kg/d.39 All patients demonstrated subjective improvement beginning in the first month with only mild adverse drug events. Conclusion and recommendations In conclusion, extragenital bullous LS may be more common than dermatologists realize. The
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treatment of this disease entity is similar to genital LS with potent topical corticosteroids being first-line therapy. For those patients not responsive to topical steroids, the authors report a case of remission using methotrexate bridged with oral steroids, but phototherapy, acitretin, and cyclosporine may be other useful therapies. The authors thank Dr Y. Ayroud for providing the histopathology images. REFERENCES 1. Wallace HJ. Lichen sclerosus et atrophicus. Trans St Johns Hosp Dermatol Soc 1971;57:9-30. 2. Fistarol SK, Itin PH. Diagnosis and treatment of lichen sclerosus: an update. Am J Clin Dermatol 2013;14:27-47. 3. Powell JJ, Wojnarowska F. Lichen sclerosus. Lancet 1999;353: 1777-83. 4. Shiver M, Papasakelariou C, Ahmad Brown J, Wirges M, Kincannon J. Extragenital bullous lichen sclerosus in a pediatric patient: a case report and literature review. Pediatr Dermatol 2014;31:383-5. 5. Kimura A, Kambe N, Satoh T, Togawa Y, Suehiro K, Matsue H. Follicular keratosis and bullous formation are typical signs of extragenital lichen sclerosus. J Dermatol 2011;38:834-6. 6. Ballester I, Ba~ nuls J, Perez-Crespo M, Lucas A. Extragenital bullous lichen sclerosus atrophicus. Dermatol Online J 2009;15:6. 7. Kreuter A, Tigges C, Gaifullina R, Kirschke J, Altmeyer P, Gambichler T. Pulsed high-dose corticosteroids combined with low-dose methotrexate treatment in patients with refractory generalized extragenital lichen sclerosus. Arch Dermatol 2009;145:1303-8. 8. Madan V, Cox NH. Extensive bullous lichen sclerosus with scarring alopecia. Clin Exp Dermatol 2009;34:360-2. 9. Kowalewski C, Kozlowska A, Zawadzka M, Wozniak K, Blaszczyk M, Jablo nska S. Alterations of basement membrane zone in bullous and non-bullous variants of extragenital lichen sclerosus. Am J Dermatopathol 2004;26:96-101. 10. Breier F, Khanakah G, Stanek G, Kunz G, Aberer E, Schmidt B, et al. Isolation and polymerase chain reaction typing of Borrelia afzelii from a skin lesion in a seronegative patient with generalized ulcerating bullous lichen sclerosus et atrophicus. Br J Dermatol 2001;144:387-92. 11. Gomez-Calcerrada MR, del Cerro Heredero M, Sanchez MH, Fernandez RS, de Eusebio Murillo E, Yus ES. Bullous and hemorrhagic lesions. Arch Dermatol 1999;135:81-6. 12. Hallel-Halevy D, Grunwald MH, Yerushalmi J, Halevy S. Bullous lichen sclerosus et atrophicus. J Am Acad Dermatol 1998;39: 500-1. 13. Boulinguez S, Bernard P, Lacour JP, Nicot T, Bedane C, Ortonne JP, et al. Bullous lichen sclerosus with chronic hepatitis C virus infection. Br J Dermatol 1997;137:474-5. 14. Garcıa-Doval I, Peteiro C, Sanchez-Aguilar D, Toribio J. Extensive bullous lichen sclerosus et atrophicus unresponsive to hydroxychloroquine. Clin Exp Dermatol 1996;21:247. 15. Wakelin SH, James MP. Extensive lichen sclerosus et atrophicus with bullae and ulcerationeimprovement with hydroxychloroquine. Clin Exp Dermatol 1994;19:332-4. 16. Marren P, De Berker D, Millard P, Wojnarowska F. Bullous and hemorrhagic lichen sclerosus with scalp involvement. Clin Exp Dermatol 1992;17:354-6.
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