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Lichen Sclerosus and in Women and Girls

Article in Clinical Obstetrics and Gynecology · March 2015 DOI: 10.1097/GRF.0000000000000090 · Source: PubMed

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Bethanee J Schlosser Ginat W Mirowski Northwestern University Indiana University-Purdue University Indianapolis

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Lichen Sclerosus and Lichen Planus in Women and Girls

BETHANEE J. SCHLOSSER, MD, PhD,* and GINAT W. MIROWSKI, DMD, MDw z *Departments of Dermatology and Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; w Department of Oral Pathology, Medicine, Radiology, Indiana University School of Dentistry; and z Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana

Abstract: Lichen planus and lichen sclerosus are com- providers with chronic vulvovaginal mon, chronic inflammatory vulvar dermatoses with sig- symptoms and may be refractory to initial nificant morbidity. The course may wax and wane but disease often persists for decades. These autoimmune and/or empiric treatments. It is impera- diseases have varied clinical presentations that extend tive that providers take adequate time to beyond the genitalia. Management is best undertaken thoroughly evaluate women with these using a multidisciplinary approach and active patient challenging conditions. involvement. The first-line treatment of both conditions A focused history including medica- is superpotent topical corticosteroids. Supportive meas- ures and adjunct therapies can optimize patient out- tions and complementary substances as comes. Patients who fail to improve despite correct well as personal hygiene regimens, a re- medication use should be re-evaluated, and clinicians view of systems, and a directed physical should be vigilant in detecting concomitant contact examination are necessary to determine dermatitis, secondary , and malignancy. the extent of disease involvement and ex- Key words: lichen sclerosus, lichen sclerosus et atro- phicus, lichen planus, , vagina, dermatology acerbating factors. Patients themselves may not be aware that the root cause of their vulvovaginal complaints may affect other anatomic sites, and it is the respon- Introduction sibility of the clinician to query about and Women with vulvovaginal lichen planus search for all potentially involved loca- (VVLP) and/or vulvar lichen sclerosus tions. Both lichen planus (LP) and lichen (VLS) often present to their gynecologic sclerosus (LS) exhibit the Koebner phe- nomenon, an isomorphic response in Correspondence: Bethanee J. Schlosser, MD, PhD, Department of Dermatology, 676 N St. Clair, Suite which lesions occur in areas of trauma. A 1600, Chicago, IL 60611. E-mail: [email protected] thorough review of systems and directed The authors declare that they have nothing to disclose. laboratory testing should be obtained to

CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 58 / NUMBER 1 / MARCH 2015

www.clinicalobgyn.com | 125 126 Schlosser and Mirowski evaluate for potential associated systemic altered self-antigens or exogenous anti- illnesses (ie, disease). Treatment gens.1 Activated T cells in early lesions should target both symptoms and clinical seem to target antigenically altered basal disease; asymptomatic patients require keratinocytes, whereas in older lesions, ongoing care to limit progressive disfig- suppressor T cells predominate. Associated urement and to survey for premalignant autoimmune conditions such as thyroid and malignant disease. A multidiscipli- disease, , , and celiac nary approach helps to establish the diag- disease seem to be less prevalent for VVLP nosis, direct therapy, and maximize than for VLS.2 treatment success. EPIDEMIOLOGY There are no comprehensive population LP studies to establish the incidence or prev- alence of LP. The incidence of oral LP is INTRODUCTION estimated to be 1/1000 patients, whereas LP is an autoimmune inflammatory dis- the incidence of is believed order that affects both the skin and mu- to be less. Estimates of prevalence for cous membranes. On the skin, LP is VVLP vary but are generally <1%. Dis- characterized by pruritic, violaceous, pol- proportionate prevalence rates are re- ygonal papules, and plaques associated ported from specialty clinics. For with fine white striae. The presence of example, in a large study of 3350 women papules with scale results in the classifica- attending a specialized vulvar clinic, 3.7% tion of cutaneous LP as a papulosqua- were documented to have LP based on mous eruption. vulvar histology. Of these women, 17.6% The onset of cutaneous lesions may had erosive disease.3 In a study of 37 occur abruptly, and pruritus is typically women presenting with cutaneous LP to severe. Despite the intense pruritus, ex- a dermatology department, 51% were coriations are rarely found; when excor- found to have vulvar involvement.4 iations are present, other causes of pruritus such as or CLINICAL PRESENTATION should be considered. VVLP may present insidiously with painful In contrast to cutaneous LP, VVLP is erosions and desquamation of the vulva often characterized by painful erythema, and vagina typically in the fifth or sixth erosions, and vaginitis. Similarly, oral LP decade though young adults and the elderly also exhibits painful erythema and ero- may be affected. Symptoms may last for sions of the mucous membranes and des- decades and be misdiagnosed as ‘‘recurrent quamation of the gingivae. Thus, LP with yeast’’ or ‘‘herpes’’ . mucosal involvement is characterized most often as an erosive rather than a SYMPTOMS papulosquamous dermatosis. Other mu- VVLP is a common, mucocutaneous con- cosal sites of involvement, including the dition that is often misdiagnosed. Nonspe- conjunctiva, ear, esophagus, and larynx cific symptoms include pain, discomfort, may precede, follow, or occur concur- pruritus, burning, and rawness of the gen- rently with vulvovaginal disease. italia associated with dysuria, , and postcoital bleeding. PATHOGENESIS In a prospective study of 114 women The etiology of LP is unknown. Evidence with erosive VVLP seen in academic vulv- suggests that LP is a T-cell–mediated dis- al clinics, the most frequent symptoms at ease that is an autoimmune response to presentation were vulvar pain/soreness www.clinicalobgyn.com Lichen Sclerosus and Lichen Planus 127

(80%), pruritus (65%), dyspareunia Type I, classic LP, is identical to the (61%), irritation (48%), dryness (27%), typical papulosquamous LP of glabrous vaginal discharge (24%), dysuria (23%), skin. This presentation is rarely seen on perianal symptoms (21%), difficulty the vulva, but white reticulation may be obtaining a cervical smear (18%), and seen on the labia minora and clitoral poor urinary stream (11%).5 Up to hood. Papular LP lesions may occur on 21% of patients with VVLP may be the perineum and perianal skin. asymptomatic.4 Type II, hypertrophic LP, is the least common morphology of VVLP. Patients present with white thickened and hyper- FINDINGS keratotic violaceous plaques of the mu- cous membranes. The morphology of primary lesions on Type III, erosive LP, is the most com- vulvar skin results in the recognition of 3 monly recognized presentation of VVLP. clinical types of vulvar LP. It is essential Clinical findings range from mild macular that clinicians are familiar with all of these mucosal erythema to extensive erosions varied presentations to optimally diag- and scarring.6 nose and treat affected patients. Patients Cooper and Wojnarowska5 prospec- may exhibit more than 1 morphology tively found that the most common vulvar concurrently or sequentially (Fig. 1). findings in patients with erosive VVLP were erosions (97%), white reticulations (at the periphery of erosions; 82%), clito- ral burying (59%), introital narrowing (59%), and erythema (45%). The differ- ential diagnosis of VVLP is presented in Table 1. Erythematous/violaceous papules and/ or diffuse erythema without scale may be found in the inguinal and anogenital folds as well as in the axillae and inframam- mary creases. The inherent moisture and apposition of skin surfaces in these areas minimizes the finding of scale. This pat- tern is termed inverse LP. Vaginal involvement has been reported in up to 70% of patients and may present as diffuse erythema, erosions, and/or ul- ceration.7 Purulent vaginal discharge may be seen with involvement of the vagina, but its absence does not exclude vaginal disease.8–10 LP of the uterine cervix has also been reported.11 As in all inflammatory dermatoses of the FIGURE 1. Vulvovaginal lichen planus with vulva, agglutination (partial or complete extensive erosion and agglutination of the left resorption) and loss of normal architecture labium minus, near complete agglutination of may result in scarring of the clitoral hood the right labium minus and clitoral hood, with burying of the clitoris (68%) and nar- introital narrowing, and flat-topped perianal rowing of the introitus (59%) (Fig. 1). With papules. vaginal inflammation, , synechiae, and

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TABLE 1. Clinical Differential Diagnosis of Vulvovaginal Lichen Planus and Vulvar Lichen Sclerosus Papules and plaques with or Inflammatory: without scale Acrodermatitis enteropathica Chronic cutaneous erythematosus Chronic graft vs. host disease (chronic, allergic or irritant) Eczematous dermatitis Lichen planus Lichen sclerosus (hypertrophic) Lichenoid drug reaction rosea Prurigo nodularis vulgaris Seborrheic dermatitis Infectious: (intertrigo, pseudomembranous) Condylomata acuminata Condyloma lata/secondary Sarcoptes scabiei infestation Neoplastic (benign or malignant): Extramammary Paget’s disease Fox-Fordyce disease Squamous cell carcinoma Syringomas Vulvar intraepithelial neoplasia (Bowen’s disease, bowenoid papulosis, squamous cell carcinoma in situ) Erythematous patches Inflammatory: Acute graft vs. host disease Chemotherapy-induced mucositis (mild) Contact dermatitis (acute, allergic or irritant) Intertrigo Inverse psoriasis Inverse seborrheic dermatitis Lichen planus Lichenoid drug reaction Plasma cell mucositis (Zoon’s vulvitis) Infectious: Candidiasis (erythematous) Group A streptococcal infection Group B streptotoccal infection Tinea incognito Neoplastic (benign or malignant): Extramammary Paget’s disease Vulvar intraepithelial neoplasia (Bowen’s disease, bowenoid papulosis, squamous cell carcinoma in situ) Erosions and ulcers Inflammatory: Aphthae Chemotherapy-induced mucositis (severe) Contact dermatitis (acute, allergic or irritant) Hailey-Hailey disease (benign familial ) Lichen planus Lichen sclerosus Mucous membrane pemphigoid Pemphigus vulgaris Infectious: Candidiasis (erosive, ulcerative) infection Varicella zoster virus infection Neoplastic (benign or malignant): Basal cell carcinoma www.clinicalobgyn.com Lichen Sclerosus and Lichen Planus 129

TABLE 1. (Continued) Extramammary Paget’s disease Squamous cell carcinoma Hypopigmented patches Inflammatory: Atrophic vulva, estrogen deficiency Chemical leukoderma Chronic graft vs. host disease Lichen sclerosus Vitiligo Purpura Inflammatory: Atrophic vulva, estrogen deficiency from topical corticosteroid use Lichen sclerosus Mucous membrane pemphigoid Venous varicosity Trauma Neoplastic (benign or malignant): Angiokeratoma Fabry’s disease (angiokeratoma corporis diffusum) Kaposi sarcoma Fissures Inflammatory: Contact dermatitis (allergic, irritant) Crohn’s disease Inverse psoriasis Inverse seborrheic dermatitis Lichen planus Lichen sclerosus Lichen simplex chronicus Trauma Infectious: Candidiasis Group A streptococcal infection Group B streptococcal infection Staphylococcus aureus infection Hyperpigmentation Physiological: Physiological pigmentation Postinflammatory hyperpigmentation Infectious: Condylomata acuminata Tinea versicolor Neoplastic (benign or malignant): Melanocytic , benign or dysplastic Genital melanosis/lentiginosis Laugier-Hunziker syndrome Peutz-Jeghers syndrome Pigmented basal cell carcinoma Seborrheic Vulvar intraepithelial neoplasia (Bowen’s disease, bowenoid papulosis, squamous cell carcinoma in situ)

adhesions develop, and sexual function and MULTIFOCAL LP urination become progressively more pain- Pelisse and colleagues have documented ful and difficult.5,9,10 Urethral stenosis may that LP can and often does affect multiple also develop. mucosal sites within the same patient.12–14

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Initially, this concept was best recognized as vaginal discharge, ranging from normal including oral and genital mucosa; current to copious. The presence of an elevated understanding of LP recognizes additional pH, immature parabasal epithelial cells, mucosal sites of disease. Patients may ex- white blood cells, and/or red blood cells hibit any combination of vulvar, vaginal, should raise the possibility of vaginal in- and oral involvement either sequentially or volvement (Table 3). concomitantly. Disease morphology and severity may vary independently. When HISTOPATHOLOGY genital and oral involvement occurs, the Histopathologic findings vary with the clin- term vulvo-vaginal-gingival LP has been ical presentation and site of involvement. In invoked. However, oral disease may include both the skin and mucous membranes, the sites other than the gingivae such as the presence of cytoid bodies (Civatte bodies, buccal mucosa and tongue. Genital and oral colloid bodies, eosinophilic hyaline spheres, involvement in men has been termed the dyskeratotic keratinocytes), wedge-shaped peno-gingival syndrome with similar se- hypergranulosis, basal layer squamatization quential or concurrent involvement.13 with liquefaction degeneration, loss of the Although scarring rarely occurs in the oral , and pointed rete cavity, scarring figures prominently at other ridges in the setting of a band-like lympho- mucosal sites such as the esophagus, larynx, histiocytic inflammatory infiltrate is highly middle ear, and conjunctivae. Nongenital suggestive of LP. involvement of LP is presented in Table 2. The histologic findings of erosive lesions often are not specific. A mixed lymphohis- DIAGNOSTIC EVALUATION tiocytic infiltrate can be seen in LS, allergic There are no serologic tests to support a reactions, graft versus host disease, mucous diagnosis of LP. Patients with vaginal membrane pemphigoid, lupus erythemato- LP may exhibit variable degrees of sus, pemphigus vulgaris or LP.

TABLE 2. Nongenital Findings in Lichen Planus

Anatomic Site Findings and/or Symptoms Oral cavity: buccal mucosa, Reticulated: net-like, lacy or web-like appearance (Wickham’s gingivae, lips, tongue striae), typically asymptomatic Erosive/ulcerative: painful erythema, erosions, or ulcerations Papular: white papules Plaque-like: hyperkeratotic papules or plaques Atrophic: erythematous patches or desquamative gingivitis Bullous: fluid-filled vesicles Esophagus: proximal and/or distal Erosions, white pseudomembranes, strictures or webs Dysphagia, difficulty swallowing, globus sensation May require or have undergone repeated surgical dilatation Conjunctivae Conjunctival injection, erosion, pterygium formation, shortening of sulcus Ear Erythema, scaling, and cerumen accumulation Pruritus, decreased hearing acuity Skin, scalp, nails Pruritic purple polygonal papules on flexural areas Hypertrophic white plaques with severe itching Pink patches of scarring alopecia Pterygium formation at base of nails www.clinicalobgyn.com Lichen Sclerosus and Lichen Planus 131

TABLE 3. Microscopic Evaluation of Vulvovaginal Dermatoses and Infections

Vulvovaginal Bacterial Atrophic Lichen Lichen Feature candidiasis vaginosis vaginitis sclerosus planus DIV Discharge amount, color, mmm or NL, mm, gray scant NL mm or mm, character white, curd- NL yellow- like green pH NL mm mm NL mm mm Immature parabasal cells — — mm — mm mm WBCs mm or NL — mm or — mm, mm NL + RBCs Lactobacilli NL kk kk NL kk kk Clue cells — + + — — — — Pseudohyphae, ++————— buds, or spores

Modified from Sobel.15 mm indicates increased; DIV, desquamative inflammatory vaginitis; NL, normal; RBC, red blood cell; WBC, white blood cell.

In both mucosal and cutaneous LP, di- In 2012, an electronic Delphi consensus rect immunofluorescence studies often re- exercise was completed to develop diag- veal a shaggy band of IgG, IgM, IgA, C3, nostic criteria for VVLP. A series of sur- and fibrin at the basement membrane. Civ- veys were administered to 73 experts in atte bodies may stain positively with IgG, vulvar disease.17 Nine clinical and/or his- IgM, IgA, or C3. Immunofluorescence find- tologic criteria were identified as being ings may help to exclude other autoimmune important for the diagnosis of VVLP by erosive disorders (ie, mucous membrane at least 75% of the participants (Table 4). pemphigoid, pemphigus vulgaris).16 MALIGNANCY TABLE 4. Consensus Clinical and In patients with VVLP, the development Pathologic Diagnostic Criteria of premalignant intraepithelial neoplasia for Erosive Vulvar Lichen Planus and squamous cell carcinoma (SCC) of the vulva and at other mucosal sites has Clinical Features Histologic Features been documented. This risk seems to be Well-demarcated erosions Well-defined low. It is hypothesized that dysplasia and or glazed erythema at inflammatory band malignant transformation result from a the introitus below the Hyperkeratotic white dermoepidermal dysregulation in cellular replication, border to erythematous junction DNA damage, and altered epithelial in- areas or erosions with/ Lymphocytic tegrity due to the oxidative stress, cyto- without Wickham inflammation kines, and transcription factor signals striae in surrounding Lymphocytic seen in chronic inflammation in mucosal skin inflammation Pain and burning Basal layer LP. Despite a growing appreciation for Scarring or loss of normal degeneration the occurrence of vulvar SCC in women architecture with VVLP, the incidence of this rare con- Vaginal inflammation dition is not known. In 1 survey, 10 of 145 Involvement of other patients with LP had a history of or current mucosal sites genital malignant neoplasm.10 This included Simpson RC, et al 2013.17 7 new cases of vulvar intraepithelial

www.clinicalobgyn.com 132 Schlosser and Mirowski neoplasia (VIN), 2 cases of genital/SCC, patients.22 In addition, circulating auto- and 1 oral SCC. In a study of 95 patients, to extracellular matrix protein 2 new cases of vulvar SCC were found.18 In 1 have been demonstrated in 74% of the retrospective evaluation of 131 patients patients with VLS (vs. 7% of controls) with VVLP, 2 patients had VIN at presen- and were associated with more extensive tation. These 2 patients did not develop a disease and disease duration of more than recurrence, and no other malignancies de- 1 year.23 veloped in any other patients.8 Multiple studies have demonstrated a strong association between LS and other autoimmune disorders (28.4% of 190 LS adult women with VLS vs. 8.7% of con- trols),2 specifically autoimmune thyroid INTRODUCTION disease, vitiligo, alopecia areata, and per- LS is the most common vulvar inflamma- nicious anemia.2,24,25 tory dermatosis with the potential excep- A role for hormones in the pathogene- tion of contact dermatitis. LS was first sis of LS has been postulated. Reduced described in 1887 and over time has also numbers of androgen receptors in VLS been termed , vulvar dys- have been shown in a small number of trophy, guttate , lichen albus, studies.26,27 Other studies have shown and LS et atrophicus. LS is a chronic that estrogen receptor beta is highly ex- inflammatory, -mediated der- pressed in VLS but is absent in normal matosis that predominantly affects the tissues. Estrogen receptor alpha was not genital skin and mucosa. LS occurs 6 to expressed in the fibrovascular layer of 10 times more frequently in females than diseased vulvar tissue.28 males and typically exhibits a chronic, Similar to LP, LS exhibits koebneriza- relapsing course. tion with an inherent tendency to occur in areas of trauma or chronic irritation as PATHOGENESIS well as after radiation therapy. There are LS is believed to be autoimmune in na- no data to support a role for any infec- ture. However, the exact pathogenesis tious agent in the pathogenesis of VLS and target antigen are not known. Fami- including Borrelia burgdorferi. lial predisposition has been reported in LS; 1 study demonstrated that 12% of EPIDEMIOLOGY 1000 VLS patients in the UK had a pos- Peak incidence of VLS has a bimodal itive family history of LS.19 The inheri- distribution, most commonly occurring tance pattern has not been established. during the prepubertal and midlife (peri- A study of human leukocyte antigen menopausal and newly postmenopausal) associations demonstrated that LS pa- years.29 Of notable importance, however, tients had a statistically significant differ- a substantial number of women (17% to ence in expression of DQ7, DQ8, or DQ9 40%) will experience onset of symptoms antigens compared with controls.20 An- and cutaneous changes of VLS during the other study demonstrated that haplotype reproductive years.25,30 DRB1*12/DQB1*0301/04/09/010 con- One study from a pediatric vulvar clinic fers susceptibility to LS, whereas haplo- found the prevalence of premenarchal type DRB1*0301/04/DQB1*0201/02/03 LS to be 1 in 900.31 The mean age of seems to offer protection.21 presentation of VLS was 5 years (range, Circulating IgG antibodies to the base- 1 to 12 y), whereas the mean age at ment membrane zone proteins BP180 and diagnosis was 6.7 years (range, 3 to BP230 have been detected in 30% of VLS 14 y).31 A majority of girls with www.clinicalobgyn.com Lichen Sclerosus and Lichen Planus 133 prepubertal onset of LS have persistent activity after puberty and are at risk for progressive agglutination.32,33 In a 3-year study of a general gynecol- ogy clinic, the prevalence of VLS was 1.7%.34 The prevalence of VLS among a population referred to a dermatology clinic was between 1/300 and 1/1000 wom- en.29 In women, the mean age of symptom onset is 45 to 55 years.25,30 However, the mean age at diagnosis is 60 years suggest- ing a significant delay in diagnosis.30 Ex- tragenital (cutaneous) LS occurs in 9% of girls31 and 6% to 15% of women with FIGURE 2. Severe vulvar lichen sclerosus 25,30,35 demonstrating hypopigmented plaques with VLS. cigarette paper atrophy, complete agglutina- tion of the clitoral hood and labia minora, CLINICAL PRESENTATION burial of the clitoris and purpura at the right inferior medial labium majus. Symptoms The most common presenting symptom in patients with LS is pruritus, often worse ‘‘cigarette paper’’ appearance (Fig. 2). Ad- at night. Such nocturnal pruritus should ditional clinical findings include fissures, raise a suspicion for infestation including erosions, superficial ulcers, purpura, and Sarcoptes scabiei (scabies) and Enterobius ; bullae are less common. vermicularis (pinworms). Pain, dysuria, Clitoral hood edema and follicular accentu- urinary retention, and dyspareunia due ation of depigmentation and waxiness com- to fissures and/or erosions are also com- prise more subtle findings. Lichenification, mon. Painful defecation due to perianal the result of scratching and rubbing, may fissures can result in constipation, often confound the clinical picture. In a prospec- the presenting symptom in young girls, tive cohort study of 225 VLS patients, clin- and stool retention. It is important to note ical disease severity was not associated with that symptom severity does not necessa- patient age or disease duration.36 rily correlate with clinical disease severity. VLS most commonly affects the modified Some patients (7% of children, up to 39% mucous membranes, ie, the medial labia of adults) may be asymptomatic, even in majora, interlabial creases, labia minora, the setting of advanced disease.31,34 clitoral hood, clitoris, and posterior four- Progressive vulvar agglutination may chette. Skin changes may also involve the result in dyspareunia and apareunia. Pa- genitocrural creases, perineum, and perianal tients may also experience abnormal mic- skin. Perianal LS occurs in 30% to 60% of turition, decreased strength of urinary women. In girls and women, a figure-of- stream, dysuria, and hematuria; increased eight or hourglass configuration with vulvar urinary frequency is not typical of VLS and perianal involvement is common. and its associated scarring. Current dogma holds that LS does not affect the vaginal mucosa. However, 2 case Findings reports (n = 3 women) have demonstrated LS characteristically exhibits ivory white that LS may affect the vaginal mucosa; (hypo/depigmented) patches and plaques vaginal prolapse was documented in 2 pa- with a waxy texture and/or epidermal wrin- tientsandwasnotcommentedoninthe kling prototypically described as having a third.37,38

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LS exhibits variable degrees of agglutina- necessary. For pediatric patients, a clin- tion/scarring with loss of tissue mass, tissue ical diagnosis of LS with a trial of topical resorption, and destruction of normal vulvar corticosteroids (TCS) is a reasonable architecture; scarring most frequently affects initial approach. Biopsy should be per- the clitoral hood, labia minora, posterior formed if: (1) the disease fails to respond fourchette, and vaginal introitus (Fig. 2). to appropriate treatment, (2) there is suspi- Agglutination of the clitoral hood may result cion for malignancy (including VIN, SCC, in complete burial of the clitoris such that it melanoma), or (3) there is concern for is no longer visible though still palpable and possible overlap with morphea (for extra- neurologically intact. Clitoral hood aggluti- genital lesions). Clinically suspicious find- nation may also result in the formation of a ings include nonhealing erosions and clitoral pseudocyst characterized by accu- ulcers, hyperkeratotic papules, friable nod- mulation of keratin debris with variable ules and areas of irregular pigmentation. pain. Similarly, the labia minora may be reduced in size or completely absent. - Histopathology ring of the introitus may result in decreased Classic histopathologic findings of LS introital aperture (both superiorly above the include an atrophic with loss level of the urethra and at the posterior of rete ridges, hyperkeratosis, and a band- fourchette) with potential sexual dysfunc- like lymphocytic inflammatory infiltrate tion. In severe cases, the introitus may be in the upper to mid . Interface almost completely sealed, thereby compro- dermatitis and dermal melanophages are mising the patient’s ability to urinate. also seen. The papillary and upper retic- Active or resolving LS can present with ular dermis initially shows edema but patchy hyperpigmentation. This pigmenta- eventually the collagen becomes more tion can exhibit variable shades of brown, dense, homogeneous, and deeply pink. black, or gray pigmentation and can be This hyalinized collagen typically sits strikingly irregular and varied. Biopsy may above the lymphocytic infiltrate. Histo- be required to differentiate postinflamma- logic features that help to differentiate LS tory hyperpigmentation from genital lentigi- from LP include a psoriasiform lichenoid nosis (melanosis) and atypical melanocytic infiltrate, basilar epidermotropism, loss proliferations including melanoma. of papillary dermal elastic fibers, base- Cutaneous LS manifests as hypopig- ment membrane thickening and epider- mented/white, waxy, wrinkled papules mal atrophy.16 Use of TCS results in and plaques, often with follicular plug- resolution of the lymphocytic inflamma- ging. Preferential locations include the tion and normalization of dermal colla- neck, upper back, breasts, axillae, abdo- gen hyalinization.39–41 men, and thighs. Rare sites of involve- Evidence of squamous cell hyperplasia ment include the scalp, face, mouth with acanthosis of the epidermis repre- (manifesting as white firm plaques on sents an increased risk for developing the lips, buccal mucosa, dorsal tongue, SCC and warrants further investigation.42 attached gingivae), and nails. Extrageni- tal lesions are typically asymptomatic. Malignancy The clinical differential diagnosis of The risk of developing vulvar SCC is VLS is presented in Table 1. generally quoted as 2% to 5%, but esti- mates vary significantly depending on Diagnostic Evaluation study design.25,30 The risk of developing There are no serologic tests to support a vulvar SCC is 246 to 300-times greater in diagnosis of LS. Diagnostic biopsy is ideal women with VLS compared with women but may not always be practical or who do not have VLS.43,44 Retrospective www.clinicalobgyn.com Lichen Sclerosus and Lichen Planus 135 evaluation of excised vulvar SCC speci- TABLE 5. Vulvar Allergens and Irritants mens has revealed the concomitant pres- Chronic moist environment: sweat, vaginal 45,46 ence of LS in 34% to 61%. Risk secretions (normal and pathologic), semen, factors for developing vulvar SCC include urinary or fecal incontinence elderly age (possibly a surrogate marker Soaps, washes, cleansers for longer duration of disease), hyperker- Feminine hygiene products: tampons, sanitary pads, vaginal douches, hygiene sprays, atotic clinical lesions, and the presence of suppositories, lubricants squamous dysplasia on histopathology. Topical medications: anesthetics (ie, benzocaine), Malignant transformation has been re- antifungals, antihistamines ported in patients with poorly controlled (ie, diphenhydramine), corticosteroids, estrogen or untreated VLS. It has not been deter- Contraception: condoms, vaginal sponge, spermicides mined whether effective treatment of VLS Toilet paper reduces the risk of malignant transforma- Synthetic fabrics (ie, polyester) tion. The mean time interval between Underwear elastic/latex onset of VLS and diagnosis of vulvar SCC has been estimated to be 4 to 10 years but varies considerably.43,47 Verru- are preferred as they provide increased cous carcinoma, basal cell carcinoma, potency, increased absorption and act as melanoma, and Merkel cell carcinoma water-insoluble emollients. In contrast to have been reported in patients with VLS; creams, ointments are less likely to contain there seems to be no increased frequency preservatives, alcohol, or propylene glycol of these malignancies relative to the thus reducing the risk of intolerance due to general population. Vulvar malignancy burning and secondary allergic or irritant in pediatric-onset VLS has not been reactions. We instruct our patients to apply reported. a pea-sized amount of TCS to the affected areas of the vulva; if perianal disease is also General Approach to the Treatment of present, use of an additional pea-sized Inflammatory Vulvar Dermatoses amount on the perianal skin may be war- Goals of treatment are to relieve local and ranted. Patients with vaginal disease re- extragenital symptoms and to minimize quire additional therapy and instruction further scarring and morbidity. Once the (see below). Areas for topical therapy are diagnosis of VVLP or VLS is made and demonstrated to the patient during the before treatment is initiated, all potential examination utilizing a hand mirror, and etiologic and exacerbating factors should patients may also be provided with clinical be determined and addressed (Table 5). A photographs or an anatomic diagram dem- multidisciplinary approach is imperative onstrating areas of disease involvement. and should include gynecologists, derma- The patient’s vision, mobility, and habitus tologists, dentists, physical therapists with should be considered when formulating a proficiency in women’s health/pelvic floor, treatment plan; patients must be able to see ophthalmologists, otolaryngologists, gas- and reach the targeted treatment areas. troenterologists, urologists, neurologists, Patient educational handouts are available and pain specialists to maximize treatment through the International Society for the success and reduce morbidity for these Study of Vulvovaginal Disease (http:// complex patients. Supportive care by a www.issvd.org). psychologist, sexual therapist, and rela- In general, superpotent TCS, the gold tionship counselor is often helpful for some standard of care for both VVLP and VLS, patients. are initiated twice daily and subsequently For topical therapy of vulvar inflamma- tapered, both in frequency of use and po- tory dermatoses, ointment formulations tency of TCS, as the patient’s symptoms and

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TABLE 6. Clinical Pearls for the Treatment of Vulvovaginal Lichen Planus and Vulvar Lichen Sclerosus

Medications Dose Clinical Pearls Clobetasol propionate Apply BID initially; as symptoms Reevaluate every 2-4 wk ointment (0.05%) improve, taper to QHS, then QOHS, If symptoms worsen, consider HSV or then alternate QOHS with Candida infection midpotency topical corticosteroid Desonide ointment Apply QOHS or 2-3 /wk Given low potency, use for maintenance (0.05%) treatment but not for initial therapy Reevaluate every 3 mo Hydrocortisone acetate Insert per vagina BID initially; as Rectal formulations are commercially suppositories (25 mg) symptoms and signs improve, taper to available QHS, then QOHS Vaginal suppositories may be Taper to 2 /wk over several months compounded at various doses Hallmarks of control include decreased number of immature parabasal epithelial cells, reduction in vaginal pH, and reduced WBCs and/or RBCs on normal saline wet mount examination Intralesional (intradermal, submucosal) Indicated for recalcitrant or acetonide (3-10 mg/ injection of <10 mg total every 4 wk, hyperkeratotic lesions after mL) not to exceed 4 times per year malignancy has been excluded by histopathology Oral prednisone or Taper over 2-4 wk Use for acute flares to transition to prednisolone (0.5- topical corticosteroids or systemic 1.0 mg/kg/d) steroid-sparing agents Tacrolimus 0.03% and Use BID for 4 wk until symptoms Burning may limit use 0.1% ointment improve then taper to QHS, 3 /wk topically and per or weekly vagina

BID indicates twice daily; HSV, herpes simplex virus; QHS, once daily at bedtime; QOHS, every other day at bedtime; RBC, red blood cell; WBC, white blood cell. examination findings improve (Table 6). Topical calcineurin inhibitors (tacrolimus, Thirty grams of corticosteroid ointment ) applied twice daily may be should be an adequate amount for once- used as second-line therapy for those patients daily treatment of genital skin for 3 months. who do not respond to or experience adverse Maintenance therapy with 30 g used over 6 effects from TCS. An increased risk of cuta- to 12 months is considered to be safe. neous malignancy with the use of topical Side effects of TCS such as atrophy and calcineurin inhibitors has been suggested.48 striae formation may be magnified due to In postmenopausal patients, hormone physiological occlusion (eg, at inguinal replacement therapy with topical or sys- crura, proximal medial thighs, gluteal temic estrogen ameliorates underlying cleft). This is true for all TCS potencies atrophy due to estrogen deficiency. Many including over the counter therapy. Close patients find estradiol vaginal tablets observation is warranted with all TCS to (10 mcg/tablet, Vagifems) easy to use, limit atrophy, striae, and telangiectasia and this formulation decreases the risk formation. Secondary infection with Can- of secondary irritation due to creams. dida species or (tinea incog- Despite its historical use, topical testos- nito) and reactivation of herpes simplex terone is ineffective for and has no role in virus may occur with the use of TCS. the management of VLS. In addition, www.clinicalobgyn.com Lichen Sclerosus and Lichen Planus 137 adverse effects including clitoromegaly further minimize koebnerization, irritants, may result from its use. potential allergens, and physical manipula- Preferential use of systemic/oral treat- tion should be avoided. Burning and pain ments when available (ie, oral antihist- may be minimized with Sitz baths, ice amines, oral antifungals, etc.) can also packs, cool compresses, and application limit irritant or allergic reactions. Non- of oatmeal solutions. Systemic antihist- sedating (loratadine 10 mg, fexofenadine amines will control itching and limit 180 mg, cetirizine 10 mg daily in morning) rubbing. Topical emollients such as petro- and sedating antihistamines (diphenhydr- latum, A and D ointment or Aquaphors amine 25 to 50 mg, hydroxyzine 10 to decrease friction, increase hydration, and 50 mg, doxepin 10 to 30 mg daily at bed- may be soothing to the patient. time) can be used for associated pruritus Patients may develop persistent vulvar while topical medications are initiated. pain (secondary ) despite ad- In severe or acute exacerbations of symp- equate resolution of skin changes; treat- toms, secondary infection (ie, Candida spe- ment with topical anesthetics (lidocaine cies, herpes simplex virus) or concomitant ointment 5%) or systemic neuropathic contact dermatitis/mucositis (ie, irritant, al- pain modulators (amitriptyline, gabapen- lergic) must be considered (Table 5). Infec- tin, pregabalin, etc.) may be considered tious agents should be treated systemically after other causes of vulvar pain have when possible and may require ongoing been excluded. suppressive therapy. If contact dermatitis is suspected, all topical products should be TREATMENT OF VVLP discontinued, and the patient should be advised to use only water for hygiene. Medical Therapy Causative irritants may be identified by Although no single therapeutic regimen sequential reintroduction of individual has been shown to be universally effective products. Cutaneous patch testing may be in the treatment of mucosal LP, the first- indicated to further evaluate for allergic line treatment of VVLP is the application contact dermatitis. of superpotent TCS.8–10 Most patients Patients should be evaluated for con- can be successfully managed with TCS comitant infection (, candidiasis, alone. In a retrospective review of 131 herpes simplex virus infection, etc.) and patients from a private dermato-gynecol- other dermatologic (allergic or irritant con- ogy practice, TCS were effective in induc- tact dermatitis, LP, etc.) or gynecologic ing good control of symptoms in (atrophic vaginitis, bacterial vaginosis, conjunction with good clinical improve- etc.) conditions upon initial evaluation ment in 55% of patients. In the same and during all subsequent encounters. series, to achieve a similar degree of im- Any identified pathology should be provement, 23.7% of patients required treated, preferentially with oral medication both TCS and oral prednisolone, whereas to avoid potential for developing allergic or 16.8% responded to oral prednisolone irritant contact dermatitis. alone.8 In a separate study of erosive VVLP in an academic center, 75% of SUPPORTIVE MEASURES patients had good or partial improvement Supportive measures are an important ad- in symptoms with TCS monotherapy.5 junct in the care of these complex patients. Women with vaginal involvement require Patients should be instructed to avoid con- intravaginal therapy in addition to topical tact with extraneous substances on the vulvar treatment. In 1 study, 60 women were vulva. After bathing with water, the area treated with intravaginal hydrocortisone should be patted dry, not rubbed. To 25 mg (1/2–1) suppositories twice daily.49

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The frequency was tapered to twice weekly general anesthesia and involves blunt after several months of improvement. Over- and sharp dissection carefully undertaken all, 81% of these women reported signifi- to limit the risk of rectal perforation and cant improvement of burning, pruritus, to assist in successfully lysing adhesions. dyspareunia, and vaginal discharge, and Intraoperative and postoperative vaginal 76.8% improved objectively on examina- dilators and TCS with or without local tion (ie, erythema, erosion). Vaginal stenosis estrogen therapy must be used routinely did not significantly improve.49 and diligently to prevent new adhesions Various systemic treatments including and scars from forming. griseofulvin, dapsone, minocycline com- In a small case series from Finland, 5 bined with nicotinamide, oral retinoids, patients with stenosing VVLP who had hydroxychloroquine, azathioprine, cyclo- been treated with methotrexate and both phosphamide, cyclosporine, mycopheno- superpotent corticosteroid cream and ta- late mofetil, methotrexate, etanercept, crolimus ointment were then treated with adalimumab, and thalidomide have been surgical dilatation. All patients reported tried with varied and often disappointing symptomatic relief and only minimal to results. Cytotoxic and systemic immuno- moderate restenosis of the vagina after 2 suppressive agents may be beneficial, but to 41 months.51 In a retrospective self- adverse effects limit their use to cases of administered survey, 11 women who had severe and refractory disease. undergone surgery for VVLP-associated Vaginal dilators are used to both treat adhesions, 55% of patients were able to and prevent adhesions and synechiae due engage in sexual intercourse and were to apposition of inflamed and/or eroded sexually active, whereas 75% had de- vaginal mucosa. The dilator is coated with creased urinary symptoms or infections. corticosteroid ointment or estrogen vagi- Most (91%) stated that they were happy nal cream and used on a tapering sched- with the results and would recommend ule. In a small case series of patients the procedure to others despite persistent (n = 3) treated with tacrolimus 0.1% sexual difficulties.52 ointment on the vulva, 2 patients also utilized a graduated vaginal dilator TREATMENT OF VLS coated with estrogen cream twice daily There are few randomized, controlled tri- for 1 week, followed by 3 times weekly.50 als to support the therapeutic approach to All patients reported significant improve- LS.53 VLS typically is very responsive to ment in vulvovaginal symptoms, and TCS. Extragenital LS is generally resist- those who utilized dilator therapy experi- ant to treatment. enced increased diameter and depth of dilator insertion and were able to resume Medical Therapy sexual intercourse.50 Complete or partial relief of symptoms has been reported in 95% of 255 girls and Surgical Therapy of the Vagina women with VLS after 3 months of daily Surgical intervention for vaginal syne- use of superpotent TCS. Complete clin- chiae is contraindicated in patients with ical response was demonstrated in 23% of active, ongoing inflammatory VVLP. Pre- patients, and partial clinical response oc- mature surgical intervention will worsen curred in 68% reinforcing that treatment activity of VVLP resulting in more chal- of VLS must be determined based on a lenging disease control and greater mor- combination of both patient-reported bidity. Surgical lysis of synechiae is symptoms and clinical examination find- recommended only once VVLP is under ings.30 Long-term use of TCS as regular excellent control. This surgery requires maintenance therapy is required for www.clinicalobgyn.com Lichen Sclerosus and Lichen Planus 139 sustained disease control in the great ma- treatment, symptoms and clinical findings jority of patients. Prolonged use of TCS were improved. Adverse effects included including clobetasol propionate 0.05% nausea, mild hypertrichosis, and mucosi- ointment has been shown to be safe and tis but did not result in interruption of effective.54 treatment.59 A double-blind, randomized, prospec- For VLS, increasing age (above 70 y) is tive study of 55 girls and women (mean associated with poor response to treat- age, 46.6 y; age range, 4 to 73 y) with VLS ment and failure to remit.43 demonstrated that clobetasol propionate 0.05% ointment was significantly more SURGICAL INTERVENTION effective than tacrolimus 0.1% ointment. Surgical treatment is only indicated for After 3 months of treatment, both treat- functionally significant vulvar and introi- ment groups experienced improvement in tal scarring once active inflammation has symptoms and signs of LS, but signifi- resolved. Patients should be monitored cantly greater numbers of patients treated for at least 6 months for recurrence of with clobetasol propionate 0.05% oint- active disease before undergoing surgery. ment experienced complete resolution of Regular use of superpotent/potent TCS LS-associated symptoms and signs.55 after vulvar surgery is essential to prevent Topical cyclosporine (200 mg/d of cy- flares of LS (given the Koebnerization closporine oral solution, 50 mg 4 times phenomenon) and to minimize the risk daily for 8 wk) had minimal impact on of reagglutination and stenosis. VLS in a single small pilot study.56 Cost may be prohibitive.56 PHYSICAL TREATMENT MODALITIES Positive impact of calcipotriol 0.005% The use of phototherapy (narrowband ointment applied twice daily under occlu- UVB, psoralen-UVA, and UVA1) for ex- sion to extragenital LS lesions for 12 tragenital LS has been reported in case weeks has been documented in a single reports and small case series. A random- case report. Irritation may limit use of ized trial comparing 3 months of medium- calcipotriol ointment on genital skin.57 dose UVA1 phototherapy (4 times/wk) to Systemic retinoids may have a role in once daily clobetasol propionate 0.05% hyperkeratotic or hypertrophic disease ointment in 30 women with VLS revealed that is refractory to superpotent TCS after that the 2 treatments had similar impact malignancy has been excluded. In a dou- on clinician grading of VLS but that ble-blind, placebo-controlled study of re- UVA1 had less impact on pruritus and fractory VLS, 63% of patients responded quality of life.60 to acitretin (20 to 30 mg/d for 16 wk) compared with 25% of those receiving placebo.58 Acitretin is a teratogen and Summary should not be used in women of child- Management of patients with VVLP and bearing potential. Acitretin is considered VLS can be challenging. The importance standard of care for reducing the risk of of the doctor-patient relationship cannot SCC in select populations (ie, post-solid be overemphasized. These patients can organ transplantation); its impact on ma- and do improve and often return to nor- lignant transformation in VLS is not mal function. known but may be protective. Patients with VVLP often have or may Oral cyclosporine (3 to 4 mg/kg/d ta- develop widespread, frequently debilitat- pered over 3 mo) was used in an open ing disease at additional mucosal sites, label, uncontrolled trial of 5 patients with and patients with VLS may develop ex- refractory VLS. At the end of 3 months of tensive cutaneous involvement. Thus,

www.clinicalobgyn.com 140 Schlosser and Mirowski it is imperative that patients undergo a review. Eur J Obstet Gynecol Reprod Biol. complete mucocutaneous evaluation to 2013;171:214–219. identify other sites of involvement and 7. Ridley CM. Chronic erosive vulval disease. Clin Exp Dermatol. 1990;15:245–252. potential malignant lesions. 8. Bradford J, Fischer G. Management of vulvova- With appropriate medication use and ginal lichen planus: a new approach. J Low Genit monitoring, disease control can be Tract Dis. 2013;17:28–32. achieved in 3 to 4 months in most patients, 9. Edwards L. Vulvar lichen planus. Arch Dermatol. but treatment regimens should be tailored 1989;125:1677–1680. for individual patients. Even when vulvar 10. Cooper SM, Haefner HK, Abrahams-Gessel S, et al. Vulvovaginal lichen planus treatment: a disease is well-controlled on maintenance survey of current practices. Arch Dermatol. regimens, patients should be seen in fol- 2008;144:1520–1521. low-up every 6 to 12 months to monitor 11. Gupta R, Bansal B, Singh S, et al. Lichen planus disease activity and potential complica- of uterine cervix—the first report of a novel site of tions (atrophy, scarring, dysplasia). Pa- occurrence: a case report. Cases journal. 2009;2: 9306. tients who fail to improve despite correct 12. Pelisse M. The vulvo-vaginal-gingival syndrome. medication use should be re-evaluated to A new form of erosive lichen planus. Int J Derma- ensure that the initial diagnosis was in- tol. 1989;28:381–384. deed correct and that there is no addi- 13. Rogers RS III, Eisen D. Erosive oral lichen planus tional superimposed pathologic process with genital lesions: the vulvovaginal-gingival syndrome and the peno-gingival syndrome. Der- (allergic/irritant contact dermatitis, infec- matol Clin. 2003;21:91–98. tion, malignant transformation). Areas of 14. Eisen D. The evaluation of cutaneous, genital, persistent erythema, erosion, or hyperker- scalp, nail, esophageal, and ocular involvement in atosis may represent malignant change; patients with oral lichen planus. Oral Surg Oral there should be a low threshold for biop- Med Oral Pathol Oral Radiol Endod. 1999;88: sying these lesions especially if the patient 431–436. 15. Sobel JD. Vaginitis. N Engl J Med. 1997;337: is not responding appropriately to treat- 1896–1903. ment. A multidisciplinary approach is 16. Fung MA, LeBoit PE. Light microscopic criteria imperative to reduce morbidity and opti- for the diagnosis of early vulvar lichen sclerosus: a mize patient outcomes. comparison with lichen planus. Am J Surg Pathol. 1998;22:473–478. 17. Simpson RC, Thomas KS, Leighton P, et al. Diagnostic criteria for erosive lichen planus affecting the vulva: an international electronic- References Delphi consensus exercise. Br J Dermatol. 2013; 1. Thornhill MH. Immune mechanisms in oral li- 169:337–343. chen planus. Acta Odontol Scand. 2001;59: 18. Santegoets LA, Helmerhorst TJ, van der Meijden 174–177. WI. A retrospective study of 95 women with a 2. Cooper SM, Ali I, Baldo M, et al. The association clinical diagnosis of genital lichen planus. J Low of lichen sclerosus and erosive lichen planus of the Genit Tract Dis. 2010;14:323–328. vulva with : a case- 19. Sherman V, McPherson T, Baldo M, et al. The control study. Arch Dermatol. 2008;144:1432–1435. high rate of familial lichen sclerosus suggests 3. Micheletti L, Preti M, Bogliatto F, et al. Vulval a genetic contribution: an observational lichen planus in the practice of a vulval clinic. Br J cohortstudy. J Eur Acad Dermatol Venereol. 2010; Dermatol. 2000;143:1349–1350. 24:1031–1034. 4. Lewis FM, Shah M, Harrington CI. Vulval in- 20. Marren P, Yell J, Charnock FM, et al. The volvement in lichen planus: a study of 37 women. association between lichen sclerosus and antigens Br J Dermatol. 1996;135:89–91. of the HLA system. Br J Dermatol. 1995;132: 5. Cooper SM, Wojnarowska F. Influence of 197–203. treatment of erosive lichen planus of the vulva 21. Gao XH, Barnardo MC, Winsey S, et al. The on its prognosis. Arch Dermatol. 2006;142: association between HLA DR, DQ antigens, and 289–294. vulval lichen sclerosus in the UK: HLA DRB112 6. Lewis FM, Bogliatto F. Erosive vulval lichen and its associated DRB112/DQB10301/04/09/010 planus—a diagnosis not to be missed: a clinical haplotype confers susceptibility to vulval lichen www.clinicalobgyn.com Lichen Sclerosus and Lichen Planus 141

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