Original Research Articles: Vagina and Vulva
Lichen sclerosus (LS) and lichen planus (LP) are T-cell–mediated inflammatory dermatoses directed against unknown epitopes on basal cells of squamous epithelium.1 Typically, LS affects anogenital skin of women and girls but may also occur on extragenital sites and in males.2 Vulvar LS usually presents with pruritus, pallor, and architectural change and may be lichenified because of provocation of an itch-scratch cycle. Lichen planus may affect any type of squamous epithelium from any site, although the vulva is a site of predilection. Three types of vulvar LP are recognized. Erosive LP is the most common and presents with pain and erythematous erosions on inner labia minora and vestibule; apposition of eroded surfaces may result in adhesions. The other 2 forms are hypertrophic, which appears as well-demarcated violaceous plaques, and typical, which resembles LP as found on extragenital skin.3,4
Vulvar LS is described with extragenital LP; the latter is typically oral disease and/or plaques on the extremities and torso.5–8 Several studies on genital dermatoses have mentioned LS and LP as comorbid on the vulva.4,9–12 The presence of LS is listed among exclusion criteria in a planned randomized trial on systemic therapy for erosive LP.13 None of these publications describe in detail the clinical and histopathologic features of comorbid vulvar LP and LS.
This study aims to assess the histopathologic characteristics of vulvar biopsies consistent with LP in women with a previous or concurrent histopathologic diagnosis of vulvar LS and to describe the clinical features of these cases.
MATERIALS AND METHODS
The Pathology North, Hunter New England database was searched between January 2010 and January 2016 for vulvar biopsies diagnosed with LP from women who had a previous or concurrent vulvar biopsy showing LS. Cases were included if the diagnosis of LP was confirmed after review of the hematoxylin and eosin (H&E) slides and the histopathologic description of LS noted a band of abnormal collagen. In cases of a nonconcurrent histopathologic diagnosis of LS, those slides were not retrieved and reviewed. A diagnosis of superimposed lichen simplex chronicus was recorded if hyperkeratosis and acanthosis were described in addition to LS. The Hunter New England Research Ethics and Governance Unit approved this retrospective histopathologic case series (HREC 15/11/18/5.02); signed written consent was obtained for use of clinical photographs.
Biopsy site was recorded as hair-bearing skin, hairless skin, mucocutaneous junction (MCJ), or squamous mucosa. Histopathologic features of MCJ included continuity with hairless skin or squamous mucosa, parakeratosis, absent granular cell layer, and reduced glycogen compared with squamous mucosa in estrogenized epithelium.14 This transition from hairless skin to squamous mucosa is also called Hart line, which circumferentially traverses the fossa navicularis, base of inner labia minora, and the inferior aspect of the clitoral frenulum.15 Site was described as unsure if erosion-limited assessment and site-specific skin appendages were absent. Erosion was defined as loss of the stratum corneum in skin or loss of the surface layers of squamous cells with intraepidermal neutrophils in nonkeratinized epithelium. In skin biopsies with assessable stratum corneum, its morphology was assessed as basket weave, intermediate, or compact.14 Drawings or clinical photographs were used when possible to identify biopsy location; this was assigned as vestibule if the clinician wrote “introitus,” “hymen,” or “fossa” and as labia minora if “fourchette” or “labia” were recorded. The dermal lymphocytic infiltrate was assessed as sparse, moderate, or dense. Epithelial thickness was measured at the thinnest site.
Cases of vulvar LP were grouped into 3 categories. Erosive LP could have a degenerative or regenerative pattern. Degenerative erosive LP was defined as erosion, a closely applied band-like lymphocytic infiltrate, absence of dermal homogenization, and evidence of basal layer damage such as squamatization or vacuolar change.16 The regenerative pattern was characterized by reduced maturation, increased nucleus to cytoplasm ratio, and the presence of mitoses, in addition to erosion, the band-like lymphocytic infiltrate, and absence of dermal homogenization. Basal layer vacuolar change and scattered keratin deposits (civatte bodies) were absent.9 Hypertrophic LP was defined as hyperkeratosis, hypergranulosis, acanthosis with elongated rete ridges, basal vacuolar change predominantly at the tips of rete ridges, papillary dermal fibrosis, and a lymphocytic infiltrate.4 Typical LP was defined similarly to that seen on the following extra-anogenital sites: hyperkeratosis, wedge-shaped hypergranulosis, jagged “saw-tooth” acanthosis, basal layer damage in the form of vacuolization and civatte bodies, and a closely applied dermal lymphocytic infiltrate.16
Clinical data collected included age, autoimmune disease, diabetes mellitus, examination findings, medication at biopsy, microbiological results, treatment and response, clinician-reported adherence to treatment recommendations, vulvar neoplasia, and duration of follow-up. χ2 and Student t test were used to compare proportions and means, respectively (Stata v11.2; College Station, Tex).
Thirty-one cases of comorbid LP and LS met inclusion criteria with a mean age of 69.5 years (range = 43–90 years). Lichen sclerosus showed superimposed lichen simplex chronicus in 3 cases (10%). There were 30 cases of LP in biopsies of inner labium minus or vestibule; the histopathologic characteristics of these are summarized in Table 1. The 1 excepted case had typical LP at hair-bearing skin of the inferior labium majus and noncontiguous LS at hairless skin of labium minus. Biopsies labeled by clinicians as labium minus could be hairless skin, MCJ, or squamous mucosa; specimens labeled as vestibule were either MCJ or mucosa. The junction between LP and LS was displayed in 1 labial biopsy (see Figure 1). There were no significant differences between biopsy site in epithelial thickness, erosion, lymphocytic infiltrate, or basal layer pattern. One third (10/30) of the cases showed a regenerative pattern of LP.
In 26 cases with detailed clinical notes, erythema was noted at all biopsy sites. In 23 of the 26 cases, clinicians reported peripheral pallor in addition to central erythema. The pattern of erythema was described as circumferential in 20 (77%), localized in 4 (15%), and multifocal in 2 (8%). Clinical photographs were available in 9 cases; these suggested erythematous erosions of variable location and size that extended to or beyond the expected position of the MCJ. In some women, architectural distortion limited the assessment of the likely location of Hart line. In cases without a photograph, clinical descriptions were inadequate to draw conclusions about the boundaries of each disease.
The clinical appearance of LP did not differ between those with a degenerative versus regenerative pattern; this is illustrated by three cases. A 63-year-old woman with diabetes mellitus and a clinical diagnosis of vulvar LS presented with increased pain; examination suggested focal LP on a background of LS (see Figure 2A). The left inner labial biopsy demonstrated regenerative erosive LP at the MCJ and the perineal specimen showed LS (see Figures 2B, C). A 62-year-old woman presented with pruritus and pain, and examination was consistent with comorbid disease (see Figure 3A). The clinical photograph demonstrated multifocal erythematous erosions, including one that extended beyond the expected location of Hart line to the edge of the remnant right labium minus. The result of the biopsies taken from a vestibular erosion on the right and the left labium minus showed regenerative erosive LP and LS, respectively (see Figures 3B, C). A 79-year-old woman with longstanding extragenital LS presented with vulvar pain and pruritus and examination showed marked central erythema abutting pallor, in keeping with comorbid LP and LS (see Figure 4A). The photograph showed erythematous erosions extending over the entire residual inner labia minora. Histopathology confirmed LS at outer labium majus and a degenerative pattern of erosive LP at inner labium minus (see Figures 4B, C).
All but 1 woman (30/31, 97%) were postmenopausal and 19% (5/26) had diabetes mellitus (see Table 2). The following 3 women had notation of extragenital dermatoses: oral LP in 1, LS in 1, and psoriasis in 1. Of the 26 women with clinical notes, all were treated with topical steroid ointment, usually betamethasone dipropionate 0.05%. In Australia, clobetasol proprionate is only available through compounding pharmacies; this was requested in 3 cases. In addition to fluconazole and topical estrogen, other supplemental therapies included antihistamines (3 cases), clindamycin vaginal cream (1 case), systemic antibiotics for streptococcal superinfection (1 case), and physiotherapy (1 case). Clinicians obtained a vulvovaginal microbiological swab in 12 cases, of which 3 showed Candida albicans. The 3 surgeries performed for dermatosis were excision of a lichenified plaque to exclude neoplasia, division of anterior adhesions, and Fenton procedure (longitudinal division of posterior adhesions sutured transversely). There was no differentiated vulvar intraepithelial neoplasia or squamous cell carcinoma recorded in these cases for a mean follow-up of 41.5 months (range = 3–180 months), but 1 woman had excisions for both low- and high-grade squamous intraepithelial lesions of the vulva.
Using strict criteria at a single pathology service in 6 years, 31 cases of comorbid LP and LS were encountered, suggesting that this phenomenon is not rare. In view of the scant literature about this topic to date, it is likely that comorbid disease is underrecognized by clinicians. In a third of these cases, the epithelium shows basal layer regeneration, a pattern that may be confused with differentiated vulvar intraepithelial neoplasia or other neoplasia by pathologists unfamiliar with this entity.9
Lichen planus and sclerosus occurring on the same person have been called “overlap syndrome.”5 However, previous reports describe each diagnosis in a separate physical location; the 2 dermatoses do not overlap. This study documents that when both diagnoses occur on the vulva, almost invariably, the erosive LP occurs on inner labia minora and vestibule with LS peripherally contiguous to the LP. A fortuitous specimen showed the junction of LS and LP seen as an abrupt end to the dermal homogenization of LS where the epithelium becomes eroded. The data and clinical photographs presented in this study suggest that the transition point sometimes occurs on hairless skin, lateral to Hart line. The premise that vulvar erosive LP involves hairless skin deserves further investigation.
There are several potential explanations for inattention to comorbid LP and LS. If clinicians identify and treat 1 dermatosis, there is less impetus to look for another diagnosis. Clinicians may be unfamiliar with subtle differences in color and texture that help distinguish LS and LP on vulvar skin.3,17 The pale skin peripheral to LP may be labeled as Wickham striae, a clinical term without well-documented histopathological correlation on vulvar skin. Conversely, in women with a diagnosis of LS, clinicians may interpret the erythema of LP as candidal superinfection or “atrophy with labial fusion.”8,18 The histopathologic diagnosis of comorbid LP and LS usually requires 2 genital biopsies, and both women and clinicians may be reticent to do this.
The lack of consensus-based histopathologic diagnostic criteria for genital LP is another challenge to recognition of comorbid LP and LS. The rate of nonconfirmatory biopsy in clinically diagnosed LP is at least 30%, and the regenerative pattern of erosive LP has only recently been described.9,19–21 In this series, erosion could not be definitively diagnosed in 3 cases, but the other histopathologic criteria for vulvar LP were met. The interpretation of genital skin biopsies showing that a lichenoid tissue reaction without subepidermal abnormal collagen remains the subject of investigation and controversy.22–24 Pathologists should inspect for subtle features such as focal hyalinization and favor LS if present.
It may be suggested that this study has little clinicopathological significance because LP and LS are both lichenoid dermatoses managed similarly with topical steroid ointment. However, nonrecognition of comorbid pathology has implications in the realms of clinical management, health care policy, and research. Failure to identify both diagnoses may be associated with inadequate or misplaced topical therapies, resulting in iatrogenic treatment failure. Anterior fusion or introital scarring ascribed to LS may instead relate to LP, and the potential for vaginal agglutination in LP may be overlooked. The extragenital sites associated with each diagnosis may not be examined if the vulvar disease goes unrecognized. The UK national guideline on vulvar conditions advises long-term specialist management for LP, while women with treatment-responsive LS are directed to ongoing care with a general practitioner.25 Previous studies of vulvar LS and LP that have not considered the possibility of comorbid disease should be critically appraised. Interventional studies of steroid alternatives should take into account that these agents may have different efficacy and risks in each diagnosis.21 In studies of the association between chronic dermatoses and vulvar cancer, failure to recognize both dermatoses may lead to misattribution of neoplastic risk.9,17,26
There are manifold implications for future research. It is unknown what proportion of vulvar LP cases is accompanied by LS and vice versa; this study did not aim to address that question. Because vulvar LP is less common than LS, it is possible that a significant fraction of LP cases have comorbid LS, whereas proportionally fewer LS cases are complicated by LP. In designing severity scores for assessment of LS and LP, comorbid disease might be considered within those tools rather than automatically excluded. This study augments the argument that clinical trials enrolling women with LS and LP should incorporate histopathology and use this information to stratify response to interventions.21 It is unknown whether different treatment approaches may be useful for regenerative versus degenerative patterns of LP or whether all cases cycle between these 2 phases.
Access to biopsies from clinics specialized in vulvovaginal disorders permits the study of comorbid LP and LS but introduces a selection bias of more difficult cases with recalcitrant symptoms or dramatic clinical findings. The limitations of this study are those inherent to the retrospective design including incomplete clinical data and differences in practice between clinicians. A comprehensive examination of the mouth and extragenital skin was not always documented. Less than half of cases had microbiological assessment; of those who did, one quarter had a candidal superinfection. Universal clinical photography would have permitted a more nuanced description of the anatomic location and architectural change associated with the dual diagnoses. The nonconcurrent LS biopsies were not retrievable in many cases, either because they went to other pathology services or occurred many years previously. The LS diagnosis was considered to be reliable in the context of a pathology report describing hyalinized collagen, another biopsy of a lichenoid tissue reaction, and a clinical diagnosis of LS usually made by a specialist.
In summary, comorbid vulvar LP and LS are not rare; clinicians suspecting one should evaluate for signs of the other and consider separate biopsies of morphologically distinct areas. Clinicopathological correlation is an invaluable tool in assessing biopsies when comorbid LP and LS are suspected, because the regenerative pattern of LP may otherwise be overlooked or misdiagnosed.
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Keywords:Copyright © 2017 by the American Society for Colposcopy and Cervical Pathology
vulva; comorbid; lichen planus; lichen sclerosus; overlap