Lichen Sclerosus

Lichen sclerosus, usually appearing in the dermatologic literature under the names of lichen sclerosus et atrophicus, balanitis xerotica obliterans, and kraurosis vulvae, is an inflammatory disease with a multifactorial origin. A past association of lichen sclerosus and genital squamous cell carcinoma is not as close as once thought. Once considered primarily a surgical problem, especially when the genitals are involved, lichen sclerosus will respond to a variety of systemic and topical therapies.

Lichen sclerosus (LS), usually reported in the dermatologic literature as lichen sclerosus et atrophicus, is an inflammatory disease of unknown cause and incompletely characterized pathogenesis. Beginning with the initial case reports at the turn of the century, there has been much confusion in the literature because of the plethora of terms used to describe LS. Different names have been applied depending on the lesional location and the specialty of the author. More than 15 years ago, gynecologists standardized the terminology used in reporting vulvar dystrophies, including LS. Because the majority of reported cases of LS involve the female genitalia and because of the multiplicity of synonyms for LS one of the factors that makes the body of LS-related literature less accessible, we recommend that the gynecologists' term lichen sclerosus be used in future reports of LS, lichen sclerosus et atrophicus, and balanitis xerotica obliterans (BXO). Interest in LS remains high because of the pervasive, erroneous concept that LS itself is a premalignant condition.

HISTORY

Hallopeau is usually credited with the first clinical description of what was to be later called lichen sclerosus et atrophicus. In 1887 he described a patient with coalescent papules on the trunk and forearms who also had pruritis and lichenification of the vulva.¹ However, in 1875 Weir described a patient with vulvar and oral ichthyosis and provided an excellent clinical description of LS, possibly the first published case of this disease.² During the next 11 years Hallopeau described three more cases of what he believed to be a unique form of atrophic lichen planus.^3-5 Darier⁶ commented on Hallopeau's original case, but it was not until 1892 that Darier⁷ formally described the typical histological features of LS. In the decades after Hallopeau's description many noteworthy independent observers discovered LS and applied their own names to what, in retrospect, was clinically and histologically the same disease. Some of the more frequent and widely published early synonyms for LS include lichen plan atrophique (Hallopeau,¹ 1887), lichen plan scléreux (Darier,⁷ 1892), Kartenblattförmige Sklerodermie (playing card or cardboard-like scleroderma; Unna,⁸ 1894), Weissflecken Dermatose (white spot disease; Westberg,⁹ 1901), lichen albus (von Zumbusch,¹⁰ , 1901), lichen planus sclerosus et atrophicus (Montgomery and Ormsby,¹¹ 1907), dermatitis lichenoides chronica atrophicans (Csillag,¹² 1909), kraurosis vulvae (Breisky,¹³ 1885), and balanitis xerotica obliterans (Stühmer,¹⁴ 1928).

Much of the world literature on LS is confounded with other entities under such terms as circumscribed scleroderma, leukoplakic vulvitis, primary atrophic vulvitis, atrophic and bullous lichen planus, acrodermatitis chronica atrophicans, and bullous scleroderma. Although most of the dermatologic literature reports lichen sclerosus et atrophicus, the shortened lichen sclerosus has appeared sporadically since the 1920s. However, Friedrich¹⁵ in 1976 argued that LS was more dystrophic than atrophic. Lichen sclerosus was formally adopted by the International Society for the Study of Vulvar Disease¹⁶ and was abandoned in the gynecologic literature. In accordance with this standardization in nomenclature, the term lichen sclerosus will be used unless it is unclear that all data and opinions in some older reports refer exclusively to LS and not a blend of LS and other disease entities (often the case in discussions of leukoplakia and kraurosis).

The controversy about the relation of LS to lichen planus (LP) and scleroderma began early and continues to this day. Hallopeau believed that LS is a form of LP because of occasional oral findings.¹⁷ Others counter with the histologic features of oral lesions so typical of LS that the existence of oral LS is recognized^18-25 even as the sole manifestation.²⁶ Until recently, some authors still argued for a close relation of LS with LP, proposing that if enough sections were cut in a biopsy specimen, typical LP would be found.²⁷ Others, while accepting LS as a distinct entity, suggest that Hallopeau's original cases were really atrophic LP.¹⁷ Although most recent reports do not link LS and LP except as coincidental findings, the association of LS and morphea (localized scleroderma) remains a topic of research and debate and will be discussed in detail later.

Divisive to the establishment of consistent principles of diagnosis and treatment was the parallel work on the nature and therapy of different medical disciplines. The gynecologic literature predates Hallopeau with Breisky's description of kraurosis vulvae in 1885.¹³ The urologic literature dates back to Stühmer's description¹⁴ of balanitis xerotica obliterans in 1928. Ormsby and Mitchell²⁸ first connected LS with kraurosis vulvae in 1920, and Freeman and Laymon,^29,30 made the same association with balanitis xerotica obliterans in 1941. Table I chronicles key events leading to our current understanding of LS.

Table 1: Significant events in the history of LS

CLINICAL PRESENTATION

LS can affect all age groups with reported onset from 6 months of age to late adulthood.^21,31,32 Most patients described in the literature are Caucasian, but the fact that most studies come out of Great Britain and the United States may create a reporting bias. LS has been reported in native Africans,^33,34 Oriental patients,³⁵ and other dark-skinned patients.^36-41 The majority are women, but that reflects the intensive study of vulvar leukoplakia over the years. The reported female-to-male ranges from nearly 10:1,^42,43 to nearer 5:1,^21,44-47 to about 1:1.^48,49 More cases of purely genital involvement are reported than purely non-genital. However, firm epidemiological data are lacking for many reasons. Gynecologists and urologists do not generally perform a complete cutaneous examination, and dermatologists often exclude a genital examination. Furthermore, an anatomic definition of what constitutes vulvar versus perineal versus genital versus groin is lacking.⁵⁰ Table II summarizes cases known or suspected to be LS.

Table 2: A review of LS cases^1-377 (N = 5207)

Data expressed as total number of LS cases within each category. SCC, Squamous cell carcinoma.

In women, prepubertal, perimenopausal, and postmenopausal vulvar and perineal involvement are most common. Symptoms include pruritis, burning pain, dyspareunia, dysuria, vaginal discharge, anal or genital bleeding,^41,51,52 labial stenosis or fusion,^53,54 and, especially in children, constipation.^55,56 Most cases reported in men occur on the glans penis and/or prepuce in prepubertal boys and middle-aged men. Male symptoms include sudden phimosis in a previously retractable foreskin,⁵⁷ adhesions to the glans,²⁹ decreased sensation on the glans, painful erections, meatal stenosis, dysuria, urethral discharge, and urinary obstruction.^58-61 Ulceration of the glans can occur, even after circumcision.^21,52

Extragenital LS is most common on the neck and shoulders and is generally asymptomatic in both sexes. Pruritis occasionally occurs. Less common presentations include infraorbital LS,⁶² scarring alopecia,⁶³ involvement of the palms and/or soles,^64-68 appearance in acrochordons,⁶⁹ or on the scrotum.⁷⁰ The latter is surprisingly rare considering the frequency of genital labial involvement.^71,72 Borda et al.⁷³ proposes a vitiligoid variant in which pigmentary changes exist without papules and plaques. Oral LS is usually asymptomatic,¹⁸ although not invariably.²²

Typically, the eruption of LS begins as white, polygonal papules that coalesce into plaques. The appearance of being splashed with whitewash (Fig. 1) led to the early appellation of white spot scleroderma.⁷⁴ Characteristic are comedo-like plugs or evenly spaced dells (Fig. 2) in the surface of the plaque that correspond to appendageal ostia. The grouping of dells in coalescent papules has been described as cribriform or corymbiform.⁷⁵ The plugs and dells may disappear with time as the lesion ages, leaving a smooth, often porcelain-white plaque. Milia may occasionally be apparent.⁷⁶ Early LS may have a vesicular component,⁷⁷ and early genital LS may be characterized by edema of the clitoral foreskin⁷⁸ as well as labial telangiectases and purpura.²¹ Fissuring may occur in the perineal midline and other intertriginous areas.⁷⁹ Bullous LS, often accompanied by intralesional hemorrhage,^73,80-82 may be localized or generalized.^83-86 The frenulum may be obliterated,^87,88 and the glans may have a mottled appearance (Fig. 3). A sclerotic white ring at the preputial opening is diagnostic.^57,88-90 Late LS has been described as verrucous on the elbows⁹¹ and other sites^24,73 and hyperkeratotic on the knees.⁴⁰ However, such findings in a genital location would suggest other dystrophic or infectious diseases. Late LS in women is characterized by obliteration of the labia minora and periclitoral structures.^21,92 Many terms are used to describe the involvement of labial, perineal, and anal areas, including figure-8,⁵⁵ keyhole,⁵⁵ hourglass,^93,94 and the more poetic butterfly and lotus flower⁹² (Fig. 4).

LS in children is histologically identical to that in adults.⁵⁵ However, it represents a special subset of LS for several reasons. Ten percent to 15% of LS cases occur in children, the majority of which involve the female genitalia.⁵² Again, the incidence is uncertain because of delay or failure to diagnose LS, masking of LS by secondary changes,⁹⁵ a tendency for spontaneous involution, and a reluctance to seek medical care for what may be perceived as child sexual abuse.⁹⁶ Because of the traumatic appearance of hemorrhagic and bullous LS, it is discussed in the pediatric literature as an entity often confused with sexual abuse.^21,97-103 However, it cannot be assumed that the diagnosis of LS excludes sexual abuse. In a 7-year-old girl initial improvement with treatment was followed by dramatic worsening and subsequent confirmation of sexual abuse.¹⁰⁴

At least half of the cases of genital LS in girls will involute by menarche,^21,105,106 and the earlier the onset of LS, the more likely the resolution.⁴³ However, not all will resolve,^101,107 and despite resolution, scarring and pigmentary changes may persist.^{21,52,56,105,108} Many women with LS will recall childhood symptoms of pruritis. However, it is unclear whether LS in these women represents persistence, recurrence, or is unrelated to this history.^21,103 Extragenital involvement may⁴³ or may not⁹⁶ be predictive of resolution. Spontaneous resolution, when it occurs, is attributed to a changing hormonal milieu and increasing endogenous androgen levels. However, because most patients also receive at least symptomatic therapy, few resolutions are truly spontaneous.

LS AND THE ISOMORPHIC PHENOMENON

LS exhibits the isomorphic or Koebner phenomenon. Stühmer¹⁴ and Madden¹⁰⁹ considered circumcision the cause of LS of the glans penis. However, most believe that trauma or chronic infection in the uncircumcised state leads to LS.^58,110,111 LS has appeared on the penis after surgery for squamous cell carcinoma¹¹² and after correction of genital abnormalities in a case of gonadal dysgenesis.¹¹³ Bale et al.¹¹⁴ described seven boys in whom LS developed after surgery to correct hypospadias.

The isomorphic phenomenon may also contribute to vulvar LS.¹¹⁵ Inciting factors include warmth and moisture,¹¹⁶ low-grade infections including pinworms,^{95,106,117,118} tight or nylon underwear,¹¹⁹ trauma from bicycle riding,⁵⁵ superficial radiation therapy for pruritis,¹²⁰ or repeated masturbation.¹²¹ Postoperative Koebnerization is often cited as a reason for the high recurrence rate after vulvectomy to treat LS.^51,122,123

LS may also appear in extragenital surgical sites,^53,80,124 such as cholecystectomy^69,125 and other surgical scars.^126-128 In two patients LS of the trunk occurred after radiation therapy for breast cancer as much as 8 years later.¹²⁹ Solar radiation and sunburn were reported to induce LS in at least 3 patients.^34,43,130 LS appeared at the site of old scald burns decades later in another patient.¹³¹ One case involved elbow plaques of LS believed to be caused by trauma and rubbing.¹³²

The concept that friction from clothing may cause LS has been advanced several times, for example, brassiere straps suspected of causing subclinical shoulder trauma eventuating in LS.^133,134 In fact, most LS cases reported in the early dermatologic literature, including Hallopeau's, occurred on the back and shoulders.^135,136 The contribution of solar radiation in these cases in unknown. Friction as the stimulus of the isomorphic phenomenon is not confined to irritation by external agents. Many consider the trauma of skin rubbing against skin the ultimate trigger of genital and extragenital LS.^69,125,137

HISTOLOGIC CHARACTERISTICS

The characteristic histologic features of LS is critical in identifying cases reported under other names. Although variations exist because of lesion duration, the overall appearance is surprisingly consistent despite differences in patient age and lesion location.^138-141 A compact orthohyperkeratosis usually underlies a markedly thinned epidermis. The hyperkeratosis usually overlies a markedly thinned epidermis. The hyperkeratosis may be such that the stratum corneum is thicker than the remainder of the epidermis (Fig. 5). Vacuolar degeneration of the basal layer is usual, especially in earlier lesions. When extensive, it may cause bulla formation (Fig. 6). Acanthosis, unless it is a part of a superimposed lichen simplex chronicus,^139,140 is not a feature of LS, nor is cellular atypia.^142,143 These findings in genital lesions suggest a hyperplastic or mixed dystrophy that may have malignant potential. Follicular occlusion by a cornified plug earlier in the course may eventuate in atrophy and disappearance of appendageal surfaces, including apocrine glands¹⁴⁴ (Fig. 7). Most striking are the morphologic changes in the papillary dermis that becomes homogenized and edematous early and hyalinized and sclerotic later (Fig. 8). The superficial vascular plexus is pushed deeper so that it appears to be in the mid dermis.¹⁴⁰

Investigation into the nature of the papillary dermal changes may provide clues to the cause of LS. Wallace²¹ did not believe special stains were particularly helpful. However, others have used special stains and techniques to define the pathologic changes more accurately. Increased ground substance^145,146 composed of neutral¹⁴⁷ and acid¹³⁹ mucopolysaccharides is evident in the edematous papillary dermis. Most agree the elastic tissue of the papillary dermis degenerates to the point of complete absence in some cases.^{22,53,105,148-152} However, Mann and Cowan¹⁵³ found normal to increased amounts of elastin in an ultrastructural examination of extragenital LS. They conjectured that elastin was modified so as to stain poorly with orcein. Other ultrastructural studies have shown both degeneration of subepidermal elastin and changes in collagen.^{95,138,146,148,154,155} Type IV collagen and basement membrane itself become fragmented;^{95,114,145,146,154} focal thickening of reduplicated basement membrane can also be seen.^147,153 In the papillary dermis collagen types I and III show variation in fiber diameter and gross alterations in alignment progressing to disintegration and eventual loss.^139,149 Evidence of collagen regeneration is seen in treated LS.¹⁴⁹ Microscopic evidence is of an active collagen degeneration and regeneration cycle in static and untreated LS belies the old appellation atrophicus.^{95,138,146,153-155} This cycle of destruction and regeneration causes sclerosis in late lesions. Sánchez at al.¹⁵¹ described the histologic curiosity of vulvar LS with loss of papillary dermis elastin coexisting with an underlying nevus elasticus, an elastic tissue hamartoma characterized by dense, mid-dermal elastic fibers.

A lichenoid mononuclear infiltrate may be dense and extensive or relatively sparse and patchy, especially in older lesions. Plasma cells have been reported;^88,114 others believe this is more likely in similar diseases such as acrodermatitis chronica atrophicans.¹⁵⁷ Eosinophils are an unusual finding,^35,158 but, Janovski and Ames¹⁵⁹ found significant tissue eosinophilia in 10% of their specimens. Mast cells may be increased,^74,95,160 or unchanged.¹⁵⁴ Additional findings in LS include a characteristic nerve degeneration and regeneration in the papillary dermis^141,161 and milia, thought to be of eccrine origin,^114,162 in 15% of routine histopathologic specimens. Hewitt¹³⁸ describes a detailed histologic grading system for vulvar LS that could be applied in other studies of LS.

GENITAL LS AND THE RISK OF MALIGNANCY

The treatment of genital LS has been primarily surgical until recently. Issues concerning male genital LS (BXO) are relatively straightforward. Some initially suggested restricting the diagnosis BXO to those cases in which there was meatal stenosis (seen in up to 25% of patients).^87,163 Meatal stenosis can occur without involvement of the remainder of the glans penis.^88,164 The term kraurosis penis appears sporadically but never achieved widespread use.¹⁰⁹ Reports of LS in circumcised men^52,57,165 are conspicuous in a literature dominated by the concept that LS arises only in the incompletely or uncircumcised man^95,110 caused by irritation, chronic balanitis, or subclinical trauma.

An understanding of the relation between LS and the foreskin is confounded by the frequent failure to report indications and age at circumcision of patients with LS. When LS appears in circumcised men, a history of previous phimosis or adhesions is common. This many imply a preexisting LS condition because new onset or worsening phimosis and adhesion of the prepuce to the glans corona are key signs of male LS. LS, once considered rare in males,¹⁶⁶ may be much more frequent than thought.^61,114,167 Even in prepubertal boys, examination of foreskins submitted to histopathologic examination for various conditions (usually phimosis) reveals a significant percentage of LS (3.5% to 19%),^{57,60,61,114,168} often unsuspected. Skewing the statistics further, many normal, nonretractile prepubertal foreskins are submitted under the diagnosis of phimosis, a condition that is diagnosed far more often that it truly occurs.^169,170 If only truly sclerosed and stenotic foreskins were considered under this diagnosis, the incidence of LS can be as high as 95%.^171-173

Despite an oft-quoted association of penile LS and cancer,⁵⁹ we found only nine clearly defined cases.^112,174-176 At least two associated malignancies, Bowen's disease^48,177 and verrucous carcinoma,¹⁷⁸ may have contributing factors such as human papillomavirus (HPV) infection. Penile malignancies are associated with phimosis-related hygiene problems, and it may be the phimosis itself rather than the LS that caused it that is the true risk factor. Nevertheless, for penile LS circumcision is considered the treatment of choice for both therapeutic and prophylactic purposes. Medical therapies are generally reserved for those who have already been circumcised or those with persistent symptoms after surgery. After circumcision, it is not uncommon, especially in young adults, to have persistent plaques, discoloration, and occasional ulceration.^21,89

As in male genital LS, the prevalence of female genital LS is likely to be much higher than Wallace's oft-quoted 1 in 300 to 1 in 1000.²¹ Up to 12% of patients with idiopathic vulvadynia [sic] may have LS.¹⁷⁹ Thorough autopsy studies and more liberal use of biopsy in patients with genital complaints could better define the prevalence of LS.¹⁸⁰

Adding to the confusion, the gynecologic literature on LS is replete with biases and taxonomic disorder. Reports contain various definitions of lichen sclerosus, kraurosis vulvae, gross atrophy, simple atrophy, senile atrophy, and vaginal dystrophy. The term leukoplakia is particularly obscure. Leukoplakia has been referred to as a clinical observation that became a microscopic diagnosis and, ultimately, a prognostic imperative.¹⁰² Most cases of kraurosis vulvae, and simple, gross, and senile atrophy, as well as many conditions termed leukoplakia represent LS.

In 1976, the International Society for the Study of Vulvar Disease (SSDIV) [sic] classified LS as a vulvar dystrophy and devised a new classification system to address the ambiguities of nomenclature. When hyperplastic dystrophy, a term developed for this system, caused confusion on its own, a 1987 consensus modified the nomenclature once again (Table III). LS under both these systems is clinically and histologically identical to an identity long known to dermatologists as lichen sclerosus et atrophicus. The renaming and reclassification of LS was adopted by the gynecologic community, although it has been slow to find its way into the dermatologic and urologic literature.^16,181,182 On the adoption of the ISSVD's recommendations, several terms were deleted from use. These included lichen sclerosus et atrophicus, leukoplakia, neurodermatitis, leukokeratosis, leukoplakic vulvitis, hyperplastic vulvitis, and kraurosis vulvae. The terms Bowen's disease, erythroplasia of Queyrat, and carcinoma simplex were deleted in favor of the inclusive term squamous cell carcinoma in situ. Paget's disease of the vulva remains in a separate disease.

Table 3: Nomenclature of vulvar disease

VIN, Vulvar intraepithelial neoplasia.
* According to the Vulvar dystrophy classification of the 1976 ISSVD committee.^16,182
† According to the Nonneoplastic epithelial disorders of skin and mucosa and Vulvar intraepithelial neoplasia classification of the 1987 ISSVD committee.¹⁸¹

The impetus behind standardization of terminology was an effort to determine the true malignant potential of vulvar LS. Wallace's malignancy rate was 4%, which he believed was artificially reduced by the number of his patients who had already undergone vulvectomy.²¹ The dominant figure in linking LS with cancer was Taussig. He wrote a series of articles between 1920 and 1940 in which vulvas, removed for malignancy, were examined and found also to have evidence of leukoplakia in 73% of specimens.^93,183-185 Others proposed that LS represented an advanced premalignant¹⁸⁶ condition with a transformation rate of 1% to 50% over the lifetime of the lesion.^{87,147,180,187-193} On the basis of these data, the treatment of choice for LS and other white lesions of the vulva was vulvectomy. After the observation that LS had a recurrence rate of up to 78% after surgery,^51,159 the recommendation was to try again,¹⁹⁴ take wider surgical margins,¹⁹⁵ or use frozen sections to ensure that all affected tissue was removed.¹⁸⁷ In the literature of genital LS from 1920 through the mid 1970s, up to 30% of the patients enrolled in a study may have undergone vulvectomy for LS, leukoplakia, or even intractable pruritis. As late as 1987, descriptions of a technique for prophylactic total vulvectomy was described in the dermatologic literature.¹⁹⁶ Vulvectomy is far from a benign procedure. Taussig¹⁸⁵ reported an operative mortality rate of almost 10% that he attributed to the older age of his patients.

Investigators subsequently noticed that cancers were most likely to arise in areas of hyperplastic or mixed dystrophy rather than contiguously with areas of clear-cut LS.^51,177 In addition, an unknown number of patients with squamous cell carcinoma and LS in early reports received ionizing radiation as therapy. The contribution of radiation to future malignancy in the setting of LS is unknown.¹⁹⁷ The prevailing thought is that although LS may be associated with other dystrophic changes with malignant potential, LS is not, itself, a premalignant condition and the association is more casual than causal.^{41,47,140,198-199} Furthermore, it was noted that conservative therapy could reverse the histologic changes of LS^200-201 and hyperplastic dystrophy. It was suggested that a therapeutic trial of conservative therapy with biopsies of persistent erosions, erythoplakia, or unusual-looking areas was more reasonable than immediate prophylactic vulvectomy.^120,202 Jeffcoate,¹¹⁹ in 1966, is usually credited with establishing the nonsurgical approach as appropriate for simple LS. However, sporadic reports of the widely appreciated malignant potential of LS appear to this day.

Recent studies support the concept that LS is not quiescently atrophic but is active metabolically. Studies measuring uptake of tritiated thymidine,²⁰³P-radiolabeled phosphate,²⁰⁴ and acridine orange²⁰⁵ suggest LS is significantly more active than unaffected skin. Flow cytometry reveals some LS lesions to have aneuploidy commensurate with actinic keratoses and keratoacanthomas.²⁰⁶ However, there are problems with studies supporting a neoplastic potential of LS. These include failure to appreciate the normally increased metabolic activity in genital versus nongenital skin and the possibility that mononuclear cell infiltrates may lead to false-positive results based on techniques that assess nuclear activity.²⁰⁷

A plausible explanation for the association of LS with cancer involves infection with HPV.^208,209 It has been proposed that LS provides the fertile field on which an oncogenic virus may cause dysplastic changes.²¹⁰ HPV is associated with hyperplastic dystrophy¹⁴² but is not consistently found in vulvar squamous cell carcinoma associated with LS.¹⁰²

Many techniques have been suggested to detect more significant dystrophy and dysplasia in the examination of a patient with LS. Cytologic study by Papanicolau smears from the external genitalia was suggested²⁰⁰ but has been criticized as too insensitive.^208,211 Acetowhitening in conjunction with colposcopy^142,212 can be useful in finding areas of more hypertrophic dystrophy. Use of toluidine blue may increase the sensitivity.^{92,180,200,208} However, false-positive findings may occur when toluidine blue stains lymphocyte nuclei in the lichenoid infiltrate under a thinned epidermis and mimics a more dysplastic process.²¹³ With or without adjunctive techniques any ulcerated, friable, thickened, red, and nodular areas should be subjected to biopsy. However, the potential sampling error inherent with punch biopsies should be kept in mind.^200,212

Although squamous cell carcinoma is the primary malignancy associated with LS, other tumors have been rarely reported. These include basal cell epithelioma^116,214 and melanoma.²¹⁵ Despite a single report of several basal cell epitheliomas arising in extensive LS of the shoulders,²¹⁶ it is generally accepted that cancer does not occur in extragenital or pediatric LS.²¹⁷

LS AND SCLERODERMA

In 1910 Ormsby cautioned not to confuse LS with scleroderma²¹⁸ and set the stage for what would be decades of debate regarding their association. Many authors have described coexistent LS and morphea, at all ages and in both sexes.^134,219-225 Morphea and LS coexisting in the same biospy specimen has likewise been described.^139,226,227 Although most reports describe extragenital LS associated with morphea, there is mention of genital LS and extragenital morphea.^105,228 Wallace²¹ reported 13 patients with morphea in his series of 380 patients. The frequency of the reported association leads many to assume a relation between the two.^72,229,230 With sequential biopsies, several investigators have reported transition from LS to morphea²²⁷ or vice versa.²⁴ Borda et al.⁷³ view LS as a scleroderma of the papillary dermis and classify LS as a subset of the greater body of scleroderma and pseudo-scleroderma diseases. They further resurrect the long-abandoned term white spot scleroderma as a transitional condition. Others view LS and morphea as manifestations of the same disease with morphea having a greater association with systemic disease.^231,232 The proposal that LS, morphea, and systemic scleroderma are borrelial disease has received much recent attention.²³³ Acrodermatitis chronica atrophicans (ACA), well established as a spirochetal disease, is often considered the bridge between LS and morphea because of the degree of clinical and histologic overlap it shows.^234-237

However, many investigators believe there are enough clinical and histologic differences between LS and morphea to argue they are distinct if not unrelated diseases, and that coexistent lesions are coincidental.^{45,148,150,238,239} Morphea does not have the immunoreactant deposition at the dermoepidermal junction and papillary dermis that LS often does.²⁴⁰ Different lectin staining patterns have also been reported; only LS stains with Eulex eropaeus.²⁴¹ The loss of elastic fibers characteristic of LS is not found in morphea¹⁵¹ ; beyond the differences in gross histologic features, changes in the dermal ground substance and dermoepidermal junction are distinct.¹⁴⁵ Collagen biosynthesis is generally increased in scleroderma and decreased in LS.^242,243 Transforming growth factor-b is increased in scleroderma and not in active LS.²⁴⁴ Morphea and ACA have similar nerve degeneration patterns that are distinct from LS.¹⁶¹ Patterson and Ackerman²⁴⁵ raised the issue that many cases diagnosed clinically and histologically as LS are actually morphea when sclerosus in the reticular dermis and subcutis are appreciated. They classify any case with involvement beyond the papillary dermis as morphea, regardless of how consistent the more superficial histologic characteristics may be with LS. They further suggest that the lack of significant infiltrate and minimal vacuolar interface changes in many cases in their series support a diagnosis of morphea. Earlier, however, Ackerman^139,140 noted that late sclerotic lesions of LS may have only sparse infiltrate and interface changes.

LS, HLA, AND AUTOIMMUNE ASSOCIATIONS

Beginning in 1910, with the report of a patient with both LS and diabetes mellitus,²¹⁸ attempts have been made to link LS with known or suspected autoimmune disorders or with the presence of autoantibodies.^246,247 Vitiligo and alopecia areata have been reported in association with genital and extragenital LS in both sexes.^{19,21,43,248-253} Thyroid disease, especially Graves' disease,^63,254,255 and both type I and type II diabetes are likewise reported in LS.^{48,87,105,147,224,256} Other conditions thought to be immune-mediated and associated with LS include lichen planus,^19,222,257 eczema and atopic dermatitis,^106,253 polymyalgia rheumatica,²⁵² psoriasis,²⁵¹ primary biliary cirrhosis,^124,258,259 fasciitis,^220,257 myositis,^231,260 lupus panniculitis,²⁵⁷ systemic lupus erythematosus,¹³² and achlorhydria, with or without pernicious anemia.^251,261,262

Various autoantibodies have been reported to be more common in patients with LS, including thyroid antimicrosomal, antigastric parietal cell, and antinuclear antibodies.^250,255,263 Anti-adrenal cortex¹²⁹ and anti-mitochondrial^259,264 antibodies are less commonly detected. A large study of 350 female patients with LS revealed 21.5% with at least one autoimmune disease and 42% with at least one autoantibody.¹⁸⁹ A comparable study of 25 men with LS revealed 20% with vitiligo or alopecia areata and 36% with autoantibodies (mostly antismooth muscle and antigastric parietal cell).^250,265,266 Direct immunofluorescence has demonstrated nonspecific deposition of IgM, C3, and fibrin at the dermoepidermal junction and papillary dermis.^267,268 Perivascular IgG and IgA were found in 63% of foreskins removed for LS.¹¹⁴ Elastic fibers with irregular diameters are seen in LS and are also characteristic of connective tissue disease.¹⁵⁴ Carli et al.²⁶⁹ recently characterized the inflammatory infiltrate in LS and demonstrated consistently increased numbers of Langerhans cells, regardless of the age of the lesion and amount of infiltrate.

Even advocates of an association of autoantibodies and autoimmune diseases with LS note that disease severity may be unrelated to these factors²⁵⁰ and that autoimmune conditions often predate the appearance of LS. Therefore an exhaustive search for these diseases is not mandated in a patient with LS.^270,271 Perhaps the most provocative association between LS and an autoimmune phenomenon is a description of paraneoplastic LS in the comments to a case report in 1973.²⁷² Here Curth described patients with unspecified internal malignancies whose LS was alleviated with tumor resection and flared with tumor recurrence. This is analogous to paraneoplastic pemphigus and has not been reported since.

Finally, LS has been reported in identical^65,273 and nonidentical twins,²⁷⁴ a pair of young sisters,¹⁰⁰ three adult sisters,²⁴⁸ mothers and daughters,^11,217 and a brother and a sister.³⁸ However, no consistent autosomal or X-linked genetic pattern has been determined and haplotype studies provide conflicting results.^44,275 HLA haplotypes reported to be associated with LS include HLA B-40,^217,276 Aw-30, Aw-31,²⁷⁷ DR-5, DR-7, B-21,²⁷⁸ A29, B-44,²⁷⁹ and B-27.²⁸⁰

PATHOGENESIS OF LS

Most early reports of LS suggested the victims were primarily women who were hysterical, excitable, or highly nervous.^218,281,282 As late as 1952 nervousness was reported as a risk factor for LS.¹²⁰ In 1903 Johnston and Sherwell⁷⁴ proposed that local interference with blood supply led to LS and this idea was echoed in 1993.⁶⁹ In 1913 Irvine²³⁷ injected serum from a patient with dermatitis atrophicans maculosa (which by its description may have been either LS or ACA) into healthy skin and produced an isolated atrophic plaque. Recent investigators have shown a subpopulation of dermal fibroblasts that proliferate on incubation with serum from patients with scleroderma.^283,284 The factors causing inflammation and fibrosis in LS and scleroderma may be immunologically related in the same way idiopathic scleroderma and chronic graft-versus-host disease share common clinical and histologic features.²²⁶

The concept that some, if not all, cases of LS might be caused by an infectious disease is not new. Beyond the possibility that a chronic garden variety infection might generate the isomorphic phenomenon^102,122 attempts to isolate the responsible organism have yielded conflicting results. Cantwell^285,286 proposed that an L-form, or cell-wall-deficient, atypical mycobacterium such as Mycobacterium, fortuitum caused scleroderma and LS. Large bodies, invariably acid fast with the Fite strain, were identified around deep dermal blood vessels, eccrine glands, nerves, and in the fat. These bodies were sometimes difficult to distinguish from lipofuchsin, melanin, and hemosiderin deposits, and there are no recent follow-up reports. Török et al.,⁹⁵ in a electronmicroscopic study of LS in children published in 1975, noted tubular particles in endothelial cells and fibrocytes that resembled paramyxovirus-like inclusion bodies. Despite the conclusion that these were probably not of viral origin and instead represented aberrant cytoplasmic tubules, the idea of a slow virus generating an autoimmune reponse was advanced. Others have also proposed an unspecified viral cause for LS.¹⁷²

In a 1913 case report of LS, the comment was made that the concern in properly classifying this new entity was unfounded because it was just another manifestation of syphilis.²⁸¹ Although syphilis has been reported in patients with LS,^18,287 a new spirochete is the center of interest. In addition to the research on the relation of Borrelia burgdorferi to scleroderma are many reports linking LS to this spirochete. ACA, once thought a form of scleroderma, and at times coexistent with LS,^157,256 is now well established as a borrelial disease.^234,288 Researchers have found spirochetes in the papillary dermis of as many as 48% of patients with LS, especially in early cases.²⁸⁹ Six of 13 patients with predominantly genital LS has spirochetes revealed by immunoperoxidase methods, inclduing a possible organism in a focus of basilar degeneration.²⁹⁰ Two patients with neuroborreliosis had both localized and generalized LS.²³³ Another patient with ACA and genital LS had spirochetes recovered from his urine.²⁵⁶

Tuffanelli²⁹¹ noted that false-positive borrelial immunofluorescence tests may occur because of coexistent connective tissue diseases and other spirochetal infections. Recognizing the problems with identifying spirochetes on special stains, a recent study employed the lymphocyte proliferative assay, a method of detecting prior T-cell sensitization to a specific antigen, and found their two patients with LS had both elevated borrelial antibodies and high lymphoproliferative responses.²³² Acceptance of a borrelial cause for LS is far from universal and there are several negative studies.^150,242 It would be difficult to explain all LS, especially the number of genital cases and those in very young children, on the basis of arthropod vector. Better modles for a spirochetal cause of LS might be those of endemic syphilis (bejel) or pinta. These spirochetal diseases are spread nonvenereally and affect even young children. In the case of pinta, the disease is confined to the skin.²⁹²

Independent of autoantibodies, a possible mechanism of spirochete-induced fibrosis was revealed by the observation that killed spirochetes induced a macrophage culture to produce interleukin 1 (IL-1).²⁹³ Fibroblasts, under the influence of IL-1, proliferate and increase secretion of collagenase and prostaglandin E₂. The continued production of IL-1 and other cytokines by Borrelia-activated T cells could maintain fibroblast stimulation resulting in the fibrosis in scleroderma and late LS.²³² It is thought this effect of spirochetal antigens explains the occurrence of disease without identifiable spirochetes. Spirochetes are not the only source of fibrosis-stimulating antigens. A cellular immune reponse to collagen itself was suggested by one scleroderma study,²⁹⁴ and a collagen-induced migration inhibition factor has been studied in fibrotic lung disease.²⁹⁵ Pneumococcal polysaccharides in the presence of serum can also induce DNA synthesis in fibroblasts in the absence of macrophages.²⁹⁶ In scleroderma, fibroblasts were found to secrete procollagen types I and III in a normal ratio but at a rate twice that of control cells.²⁹⁷

Although collagen changes in LS are often analagous to the changes in scleroderma, they exhibit some important differences. Some report decresed collagen synthesis, both type I and type III, in LS.^138,242,289 Others report a slight increase in the synthesis of a younger, more soluble type I collagen²⁴⁴ or evidence of increased turnover and intracellular degradation without a significant net gain or loss.²⁹⁸ Still others have detected increased ground substance and evidence of collagen degeneration and regeneration with fewer normal fibers.¹⁴⁶ Increased activity of amidase, an elastase-type protease, which is able to degrade human skin elastin, may cause the elastic tissue destruction in LS.^146,299 Retinoids down-regulate fibroblast proliferation and synthesis, which explains the utility of reinoids in treating LS.³⁰⁰

Suggested by frequent local recurrence after vulvectomy, the contribution of local factors to the development and presistence of LS is well recognized. Some attribute this to continued factors of friction from opposed skin surfaces,^125,137 chronic infection,^117,119 irritation from glycosuria or other sources of chronic irritation.¹¹⁹ However, such factors do not apply to all cases of genital LS and few cases of extragenital LS. More provocative regarding the relevance of local factors are reports of recurrent LS of the scalp several years after excision and grafting,⁶³ vulvar LS reappearing in a myocutaneous graft from the thigh,¹¹⁶ and an oft-quoted observation by Whimster,¹¹⁵ who reported that normal skin grafted to an involved vulva developed LS, whereas a graft of LS-involved skin applied to the donor site became normal in texture and appearance.

The interaction of hormones, fibroblasts, local changes in collagen, cytokines, and other growth factors have been studied for several decades without universal agreement on the pathogenesis of LS. Hormonal studies in LS center on the actions of testosterone. Androgen-sensitive fibroblasts in genital skin facilitate collagen and glycosaminoglycan production.^301,302 The increased testosterone metabolism in genital skin, which occurs at menarche, is believed to cause the spontaneous improvement that often occurs in childhood vulvar LS.³⁰³ In fact, adults with LS were found to have decreased serum levels of free testosterone, androstenedione, and fihydrotestosterone compared with control subjects. A defect in the function of 5a-reductase, an enzyme usually showing increased activity in genital skin compared with nongenital skin,^302,304,305 is believed to be the underlying defect predisposing these patients to LS.³⁰³ A study of risk factors for LS revealed that nonsmokers were significantly more likely to have LS than smokers. The authors conjecture that this is caused by the androgen-elevating effect of cigarette smoking.³⁰⁶

TREATMENT

LS was initially treated with a variety of irritating and keratolytic agents knowns as revulsives. This resulted in inflammation and tissue damage with anticipated clinical improvement. Such agents include salicylic acid, trichloroacetic acid, resorcin,^{65,67,74,281,287,307} thymol,^50,84,308 boric acid ointment,³⁰⁹ carbolic acid,⁹³ and carbol fuchsin.⁹⁴ Physically destructive methods include suction cups,²⁸¹ cryotherapy,^{21,94,197,208} fulguration and desiccation,^94,208,310 and tangential excision⁸¹ or dermabrasion.¹⁸ Carbon dioxide laser is the modern revulsive. Used now primarily for treatment of hyperplastic vulvar dystrophies,^208,210,212 it has been applied to both vulvar^102,311 and penile LS^312,313 with some benefit.

In the first half of the century genital and extragenital LS was treated with various forms of radiation from ultrasound²⁶⁰ to infrared⁸⁴ to Grenz rays.⁵⁰ More aggressive radiotherapy with topically applied thorium X^94,122 or hard x-rays^{41,53,80,93,185,218,314,315} persisted into the 1940s, even in children. Eventually, various authors pointed out how temporary^117,184 the benefits were and how evil radiation therapy¹⁸⁸ added clinical and histologic confusion as well as cancer risk to an otherwise benign process. The contribution of radiation therapy to the incidence of squamous cell carcinoma reported with LS in the earlier literature is uncertain. It is notable that most studies of the era report large numbers of patients so treated before the diagnosis of squamous cell carcinoma.^183-185

Bismuth (topically,⁴⁷ orally,^47,84 and parenterally^308,316,317) was extensively used into the 1960s. Parenteral and oral mercury was likewise popular at one time.^{49,247,281,307} An unusual, relatively recent use of mercury involved tattooing the vulva with mercuric sulfide for intractable vulvar pruritis.³¹⁸ Intravenous procaine^94,319 and topical cocaine⁹³ have also been used for persistent pruritis. However, allergic sensitization to topical anesthetics has been reported.⁹⁴ Injection of alcohol into LS lesions^320-322 or systemically in a gridlike fashion⁹² is still mentioned for relief of pruritis in recent texts on vulvar diseases. Antimalarials, orally^{47,228,231,257,323,324} and intralesionally,³²⁵ have been reported beneficial in both penile and vulvar LS and have been employed in all age groups. Intralesional hyaluronidase was reported to be of no benefit.¹⁸ Potassium para-aminobenzoate (4 to 24 gm/day)³²⁶ is reported to be effective, possibly by decreasing mucopolysaccharide production.⁸² However, one study suggested it is not effective in men before circumcision.⁴⁸ Chelation therapy^231,266 and topical crotamiton (often in conjunction wiht a topical steroid)^179,180,327 have been used in hopes of remission or relief of associated pruritis. Topical⁸⁰ and systemic antihistamines,^190,231 cool milk compresses, and application of vegetable shortening are also recommended for the pruritis of LS.³²⁸ One of the more dramatic surgical options for persistent vulvar pruritis, short of vulvectomy, is the Mering procedure that entails cutting the entire labial and pubic region to denervate the vulva.^329,330

Surgery might still be the primary therapy for LS were it not for the introduction of hormonal therapy with corpus luteal extract injections in 1922.⁹³ Parenteral adrenocorticotropic hormone (ACTH)^81,83 is a relatively recent innovation, whereas topical,^217,248,309 intraurethral³³¹ or intralesional^{88,111,165,325,332} hydrocortisone or triamcinolone^{21,323,333-335} have been the mainstays of genital¹⁰² and extragenital LS therapy.^260,316 Oral corticosteroids are likewise effective but generally reserved for patients with other indications for their use.²²² Combining topical steroids with other modalities such as keratolytics,⁶⁷ pramoxine,^180,328 or occlusive therapy³²³ has additional benefits. Marked benefit has been reported from brief courses (usually 2 weeks or less) of topical fluorinated steroids^{102,254,327,335} or clobetasol.⁵⁴ Such regimens are used even in children,^{56,96,101,103} and histologic regression of LS⁵⁴ may occur as well as remarkable relief of symptoms. A new approach to the nonsurgical treatment of phimosis is Jørgenssen and Swenson's 1993 report¹⁷³ in which clobetasol and gentle retraction were employed daily for up to 3 months and obviated the need for surgery in 70% of their patients. In this noncontrolled study, all patients failing to respond to topical therapy who underwent histologic examination of the foreskin were found to have LS.

Topical estrogen has benefitted both vulvar^80,160,316 and penile⁷⁷ LS, although some believe the results leave much to be desired. Intralesional estrogen was used in a case of penile LS³³⁶ as were oral conjugated estrogens²⁶⁰ ; both provided some symptomatic relief. Topically applied testosterone, 2% to 2.5%^87,74,337 in petrolatum or paraffin,¹⁰² has not only demonstrated clinical efficacy but also histologic regression,^254,338-340 although Cinberg³⁴¹ in his description of the first documented use of topical testosterone found minimal histologic regression despite significant clinical improvement. Reversal of abnormal touidine blue uptake was noted in one study.¹⁶⁰ Reported side effects include enlargement of the clitoris (5% to 50%),³⁴² increased libido (up to 50%), acne, virilization, and menstrual irregularities.^92,254 Increased serum levels of testosterone were not detected.²⁵³ Alternating testosterone with a topical corticosteroid is another strategy to minimize the side effects of either agent.⁹² Local irritation is common and may be minimized by reduction of the concentration of testosterone to as low as 0.5%^143,343 or compounding with a cream base instead of an ointment.³²⁹ Another means of avoiding the androgenic effects of testosterone, especially desirable in children, is the use of topical progesterone (200 mg in 2 ounces of hydrophilic ointment).^254,344,345 However, progesterone is generally not as effective in hyperplastic dystrophy and slower to relieve symptomatic LS than testosterone.^117,121 Enhanced efficacy can be achieved by applying the progesterone in the morning and a topical corticosteroid, such as betamethasone ointment, at night.³⁴⁵

Nutritional therapy has been used in the treatment of LS. Oral administration of dilute hydrochloric acid was recommended because of the association with achlorhydria.¹⁹⁵ Protein supplements, chlorophyll,¹⁹⁰ and wheat germ oil^94,122,346 were staples in early nutritional therapies. Various B vitamins, orally and parenterally, have been recommended including B₁,^308,347 B₁₂,^94,122 and B complex.³⁴⁷ Vitamin E has been recommended as adjunctive therapy²¹⁷ (orally, topically, and intramuscularly), although it was not believed to be especially effective.^47,348 Vitamin D has likewise been endorsed.⁸⁰ Use of topical vitamin D analogues such as calcipotriene is not reported. One recommended concoctopn contained vitamin F.⁵⁸ Oral and parenteral vitamin A has been proposed; the ealier reports recommend nutritional supplements such as cod liver oil.^{47,83,195,308,316,349-351} This is based on likening the hyperkeratosis seen in LS to a vitamin A deficiency and noting that achlorhydria, reported ofetn in LS, impairs absorption of vitamin A.³⁵¹ Intralesional vitamin A was advocated by one group.³⁵³ Although no recent literature strongly advocates nutritional therapy for LS, the echoes of vitamin A therapy continue in current research on the efficacy of retinoids. Etretinate has been employed in dosages of 0.37 mg.kg per day³⁴³ to 1 mg/kg per day³⁵⁴ with measurable succcess even in patients who had recurrent disease after vulvectomy.³⁵⁵ Severely dysplastic and hyperkeratotic lesions are most likely to recur after therapy.³⁴³ Some report concomitant histologic improvement,^51,355 whereas others have noted only a decrease in hyperkeratosis.^356,357 More recently acitretin (30 mg daily) has been used, and although pruritis was relieved, a large placebo response in this study made its ultimate efficacy less defined.²⁵ Of note, the subjective and objective grading scale used in this report may have applications in future studies.

Careful attention to hygiene is recommended, and efforts to treat coexistent vaginal infections^102,321 or balanitis are essential. Because of the possible role of spirochetes in some cases of LS and morphea, many recommend empirical treatment with antispirochetal antibiotics such as penicillin or doxycycline.^{184,232,233,291} The utility of this therapy in LS remains to be defined.

CONCLUSIONS AND UNANSWERED QUESTIONS

The true incidence of LS is unknown. Significant underreporting is likely for many reasons. These include faliure to recognize the condition, misdiagnosis as a related or unrelated disease, frequently asymptomatic patients, and reluctance to seek care because of embarassment or fear of legal complications (pediatric cases). Accurate epidemiology of LS is further hampered by fragmentation of case in various specialties (dermatology, gynecology, urology, pediatrics, family practice), many using different terminology for the same entity.

LS is an inflammatory condition caused by an incompletely defined response to a variety of mechanical and antigenic stimulu. These stimuli include, among others, trauma, spirochetal infection, and autoimmune diseases.

Further definition of the role of spirochetal diseases in LS is pivotal in making treatment recommendations. If this is a major cause of LS, the mode of transmission should be elucidated. Is the transmission via an insect vector (Lyme disease), sexually (venereal syphilis), or through casual person-to-person contact (endemic syphilis and pinta)?

LS and scleroderma, although clinically and histologically distinct entities that may coexist, share many pathogenic mechanisms. Perhaps they represent expressions of the same antigenic insult with LS being expressed in the papillary dermis and scleroderma in the reticular dermis and deeper. Differences in vascular adhesion molecuels, elastic network, and relative amounts of type I and III collagen may explain the differences between the two conditions. An unidentified genetic or environmental factor may determine which disease the patient acquires.

True LS is not itself a premalignant condition, although other white lesions that stimulate it, such as hyperplastic dystrophy, may be. LS should not be treated with aggressive surgical modalities. Prior radiation therapy may have artificially increased historical rates of malignant transformation. The contribution of human papillomavirus to current sporadic cases of LS-associated genital squamous cell carcinoma is unknown.

Urologists, in contrast to gynecologists, continue to view LS as primarily a surgical problem. Circumcision is still the most widely used primary therapy for genital LS in uncircumcised men. Reports of medical therapy are anecdotal and generally limited to persistent or recurrent lesions in patients already circumcised.

Medical therapies include retinoids and topical corticosteroids (including superpotent agents), testosterone, and progesterone. Other systemic and topical treatments have been used with variable success. Genital LS in children presents some special treatment concerns.

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