THE CIRCUMCISION REFERENCE LIBRARY
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.
[CIRP Note: The figures supplied with the article are not included in this file.]
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.1However, 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.2During the next
11 years Hallopeau described three more cases of what he
believed to be a unique form of atrophic lichen
planus.3-5Darier6commented on
Hallopeau's original case, but it was not until 1892 that
Darier7formally
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,11887), lichen
plan scléreux (Darier,71892),
Kartenblattförmige Sklerodermie ("playing card" or
"cardboard-like" scleroderma; Unna,81894), Weissflecken Dermatose ("white spot
disease"; Westberg,91901), lichen
albus (von Zumbusch, 10, 1901), lichen
planus sclerosus et atrophicus (Montgomery and
Ormsby,111907),
dermatitis lichenoides chronica atrophicans
(Csillag,121909), kraurosis
vulvae (Breisky,131885), and
balanitis xerotica obliterans (Stühmer,141928).
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, Friedrich15in 1976 argued
that LS was more "dystrophic" than "atrophic." "Lichen
sclerosus" was formally adopted by the International Society
for the Study of Vulvar Disease16and "et atrophicus" 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.17Others counter
with the histologic features of oral lesions so typical of LS
that the existence of "oral LS" is recognized18-25even as the sole manifestation.26Until 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.27Others, while
accepting LS as a distinct entity, suggest that Hallopeau's
original cases were really atrophic LP.17Although 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 1885.13The urologic
literature dates back to Stühmer's
description14of balanitis
xerotica obliterans in 1928. Ormsby and
Mitchell28first connected
LS with kraurosis vulvae in 1920, and Freeman and
Laymon,29,30made the same
association with balanitis xerotica obliterans in
1941. Table I chronicles key events leading to our current
understanding of LS.
| Year | Event | Key reference no.(s) |
| 1875 | Weir's report of possible vulvar and/or oral LS as "ichthyosis" | 2 |
| 1885 | Breisky describes kraurosis vulvae | 13 |
| 1887 | Hallopeau describes series of extragenital LS (and one possible vulvar case) | 1, 3-5 |
| 1892 | Darier formally describes classic histopathology of LS | 6, 7 |
| 1900-present | Concept that scleroderma and LS are closely related | 72, 73, 222, 227, 231, 290, 358 |
| 1901 | Pediatric LS described | 9, 53, 95, 96, 101, 103 |
| 1913-present | Concept that scleroderma is not closely related to LS | 45, 145, 148, 158, 238, 240, 281 |
| 1920 | Taussig establishes vulvectomy as treatment of choice for kraurosis vulvae, a premalignant condition | 93, 183-185; also 79, 186, 191, 196 |
| 1927 | Kyrle defines LS ("white spot disease") as entity sui generis | 359 |
| 1928 | Stühmer describes balanitis xerotica obliterans as postcircumcision phenomenon | 14 |
| 1936 | Retinoids (vitamin A) used in LS | 47, 195, 341, 349, 352, 353 |
| 1945 | Testosterone used in genital LS | 87, 92, 160, 254, 337, 338, 342 |
| 1961 | Modern use of corticosteroids | 21, 102, 165, 254, 337, 338, 342 |
| 1966 | Jeffcoate presents argument against vulvectomy for simple LS | 119; also 51, 198, 209 |
| 1971 | Progesterone used in LS | 254, 338, 344, 345 |
| 1971 | Wallace defines clinical factors and epidemiology of LS for all later reports | 21 |
| 1976 | Friedrich defines LS as a dystrophic, not atrophic condition; "et atrophicus" dropped | 15 |
| 1976 | International Society for Study of Vulvar Disease classification system. "Kraurosis" and "leukoplakia" no longer to be used | 16, 181, 182 |
| 1980 | Fluourinated and superpotent steroids used in LS | 54, 56, 96, 101-103, 254 |
| 1981 | Studies into HLA serotypes and LS | 44, 217, 273, 275-77, 279 |
| 1984 | Etretinate and acetretin used in LS | 25, 149, 343, 354-357 |
| 1987 | LS linked with Borrelia infection | 232, 233, 256, 289, 290 |
CLINICAL
PRESENTATION
LS can affect all age
groups with reported onset from 6 months of age to late
adulthood.21,31,32Most
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,33,34Oriental
patients,35and other
dark-skinned patients.36-41The majority
are women, but that reflects the intensive study of vulvar
"leukoplakia" over the years. The reported female-to-male
ranges from nearly 10:1,42,43to nearer
5:1,21, 44-47to about
1:1.48,49More 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.50Table II
summarizes cases known or suspected to be LS.
| Sex | ||
| Female | 4280 | |
| Male | 691 | |
| Unspecified | 236 | Demographics in metabolic studies often not specified. |
| Location | ||
| Genital | 4308 | Includes labial, perineal, perianal, and any penile location. |
| Extragential | 805 | Neck, shoulders, upper trunk most common sites reported. |
| Both | 355 | Excludes cases in which site is uncertain. |
| Associated Factors | ||
| Cancer | 283 | Almost all are SCC of the vulva. Includes unknown number of other vulvar dystrophies. |
| Autoimmune disease | 291 | Not always reported or sought. Thyroid disease, vitiligo, diabetes, and pernicious anemia most common. |
| Autoantibodies | 316 | Not always reported or sought. Thyroid antimicrosomal, gastric parietal cell, and antinuclear autobodies most common. |
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
sites24, 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 flower"92 (Fig.
4).
| Figure 1: Extragenital lichen sclerosus, gross morphology. |
| (to be added when I can get the journal out of the library) |
| Figure 2: Extragenital lichen sclerosus. |
| (to be added when I can get the journal out of the library) |
| Figure 3: Male genital lichen sclerosus. Irregular mottling of glans. |
| (to be added when I can get the journal out of the library) |
| Figure 4: Female genital lichen sclerosus (early). "Figure-8" dystrophy with fusion of clitoral hood, and obliteration of labia minora. |
| (to be added when I can get the journal out of the library) |
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,"116low-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 cholecystectomy69,125 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
| Figure 7: |
| (to be added when I can get the journal out of the library) |
| Figure 8: |
| (to be added when I can get the journal out of the library) |
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 men52,57,165are conspicuous in a
literature dominated by the concept that LS arises only in
the incompletely or uncircumcised man59,110
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 disease48,177 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.
| 1976 terminology* | 1987 terminology† | Histologic description |
| LS | LS | Hyperkeratosis, effacement of epidermis, variable interface vacuolization, homogenization and edema of papillary dermis, and lichenoid infiltrate |
| Hyperplastic dystrophy without atypia | Squamous cell hyperplasia | Hyperkeratosis, acanthosis, epithelial hyperplasia without atypia and not attributable to a more specific dermatosis |
| Mixed dystrophy without atypia | (Report both conditions above) | Features of LS and hyperplastic dystrophy without atypia |
| (no equivalent) | Other dermatoses | Typical findings of a specific infectious or inflammatory disease (i.e., psoriasis, condyloma) |
| Hyperplastic dystrophy with atypia | VIN | Degree of atypia or grade of VIN graded according to degree of squamous proliferation, nuclear atypia and pleomorphism, individual cell keratinization, mitotic activity above the basal layer, and disordered maturation |
| Mixed dystrophy with atypia | (Report both LS and VIN) | Features of both LS and VIN |
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 premalignant"186 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 LS200,201 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,203
32P-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 colposcopy142,212
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
epithelioma116,214 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, Ackerman139,140 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-mitochondrial259,264
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
identical65,273 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 phenomenon102,122 attempts to isolate the
responsible organism have yielded conflicting results.
Cantwell285,286 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.138,242,298
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 vulvar102,311
and penile LS312,313 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
X94,122 or "hard" x-rays41,53,80,93,185,218,314,315 persisted into the
1940s, even in children. Eventually, various authors pointed
out how temporary117,184
the benefits were and how "evil radiation therapy"188 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 parenterally308, 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 procaine94, 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
lesions320-322 or systemically in a
gridlike fashion92 is still mentioned for relief
of pruritis in recent texts on vulvar diseases.
Antimalarials, orally47, 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
therapy231, 260 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 intralesional88, 111,165,325,332 hydrocortisone or
triamcinolone21,323,333-335 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
steroids102,254,327,335 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
vulvar80,160,316
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,254,338-340although 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 oil94, 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
infections102,321 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.
REFERENCES:
http://www.cirp.org/library/treatment/BXO/meffert1/