Lichen planus (LP) is a T-cell–mediated chronic inflammatory skin disorder.1 The pathophysiology involves epitopic alteration of epithelial basal cells, leading to lymphocytic attack and a cycle of cellular damage and repair.2 The reason for epitopic alteration is unknown, but a similar phenomenon occurs in graft-versus-host disease (GVHD) and lichenoid drug reactions.3,4 The histopathologic manifestation of this process is a lichenoid tissue reaction—a band of lymphocytes adjacent to damaged epithelium.
Lichen planus at any site is estimated to affect 2% of women, with the oral cavity most commonly involved.5 Vulvovaginal LP occurs in 25% to 57% of women with oral LP, causes 6% of chronic vaginal complaints in postmenopausal women, and is histologically confirmed in 3.7% of women attending a multidisciplinary vulvar clinic.6–8 Multiple factors contribute to underestimation of prevalence: some cases are asymptomatic, women defer care seeking, and medical practitioners fail to make the diagnosis.8,9
Three types of LP occur on the vulva: erosive, classic, and hypertrophic.10–12 The most common is likely to be the erosive form, followed by hypertrophic, and then classic. However, this is difficult to ascertain given previous studies' lack of clinical and histopathologic discernment between the 3 types.8 The aims of this consensus statement are to describe the clinical features and histopathologic findings that yield a diagnosis of vulvar LP and to provide recommendations that facilitate clinicopathologic correlation.
METHODS
The International Society of the Study of Vulvovaginal Diseases (ISSVD) tasked the Difficult Pathologic Diagnoses committee with development of a consensus document for the diagnosis of vulvar LP, lichen sclerosus (LS), and differentiated vulvar intraepithelial neoplasia (dVIN). The LP subgroup performed a literature review using the search terms “vulvar,” “vulval,” “vulvovaginal,” “vulvovaginal-gingival,” and “lichen planus,” restricted to articles published during or after 1990. There were 286 publications, of which 68 (24%) were case reports or letters to the editor, 85 (30%) were focused on a different condition, and 46 (16%) were reviews or guidelines. Thirty-one (11%) original research articles addressed the clinical and/or pathologic diagnosis of LP; the remainder focused on etiology, epidemiology, comorbidities, management, and outcomes. The committee appraised the pertinent publications, synthesized them into a critical review, then generated diagnostic criteria and recommendations. After the LP group reached agreement, the article was disseminated within the committee and underwent further revisions to achieve consensus. The document then was approved by vote of the ISSVD membership. Signed written consents were obtained for use of the clinical photographs.
Epidemiology and symptoms
Vulvar LP usually affects postmenopausal women. The mean age in retrospective cohort studies restricted to erosive disease is 57 to 67 years.8,13–17 The diagnosis is occasionally made in reproductive-age women, with lower ages of 26 to 34 years in published ranges.13–17 Women with vulvovaginal-gingival syndrome of LP seem to have an earlier age of onset, and disease may manifest in adolescence.18–20 The mean age of women with nonerosive LP is 63 years, with a wide range of 21 to 88 years.11
The clinical presentation of vulvar LP is described primarily in single-center retrospective cohorts based on a clinical diagnosis. Some studies combine erosive and nonerosive LP; these do not uniformly report location and type.6,21–23 Symptoms most commonly attributed to erosive LP are pain (50%–92%) and pruritus (42%–65%).13,14,16,18,21,22 Dyspareunia is reported in 52%–91%, but a case note audit found less than half of women had documentation of sexual impacts.14,15,18,21–23 Other symptoms include vaginal discharge (8%–24%) and dysuria (8%–23%).14,21,22 In 2 cohorts that combine erosive and nonerosive disease, 10% to 34% of women were asymptomatic.6,8 A study restricted to nonerosive LP found pruritus as the main symptom in 81% of women, with the remainder reporting pain (13%) or no symptoms (6%).11
Evaluation
Vulvovaginal Examination—Erosive LP
A well-demarcated, glazed red macule or patch at the labia minora, vestibule, and/or vagina is present in 81% to 97% of women with a clinical diagnosis of erosive LP14,16,22 (see Figure 1). The color is red-to-purple, rather than the orange-red associated with plasma cell vulvitis.10,24 Clinicians often describe the red areas as “erosions” because of their shiny appearance, but loss of the upper epithelium is not universally confirmed on histopathology.8,20,25 The shape of these areas is not well described, but published photographs often display a bilateral or horseshoe morphology affecting inner labia minora and clitoral frenulum and/or posterior fourchette.6,12,13,16,22,25 Disease may also extend onto the adjacent clitoral hood and/or interlabial sulci (see Figure 2). Disease features vary over time relating to the cycle of epithelial injury and repair, as also suggested in LS.28–35
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FIG 1: Erosive LP: bilateral well-demarcated glazed red patch over vestibule and inner labia minora with a variable white edge and a white plaque on the right lateral border.
FIG 2: Erosive LP: bilateral glazed red patches extending over the interlabial sulci with adhesions on inner and outer surfaces of labia minora and clitoral hood.
Many terms are used for white areas that often accompany the red patches/macules, including “Wickham striae,” “white reticulation,” “lacy border,” and “scalloped hyperkeratotic margin,” with widely varying rates reported (7%–82%).14,20–22,26 Some authors additionally report white plaques or “hyperkeratosis” in 15% to 22%.14,22 The variation in nomenclature likely reflects an array of findings representative of erosive LP. These include a superimposed fine white lacy pattern, lateral white papules and plaques, a white papules or plaques surrounded by the red patch, and white delineation at the junction between normal and abnormal epithelium (see Figures 1–3).
FIG 3: Erosive LP: bilateral well-demarcated glazed red patch over inner labia minora with multiple white papules/plaques distributed lateral to, medial to, and within the erythema; a comorbid lichenoid dermatitis is present on hairless skin.
Vaginal disease is reported in 20% to 85% of women with vulvar erosive LP, but there is limited information on its appearance.14–16,18,21–23 Studies report a spectrum of findings: “telangiectasias and patchy erythema,” “superficial erosions,” “painful friable hemorrhagic mucosa,” and “a variable discharge, which is often serosanguinous.”10,20 Most studies do not identify rates of vaginal synechia and obliteration; those that do report adhesions in 10% to 50%.18,20,22 In absence of scarring, vaginal erythema and friability may be difficult to distinguish from desquamative inflammatory vaginitis (DIV) and severe vulvovaginal candidiasis (VVC).6 Several groups undertook vaginal biopsies, but the absent or brief descriptions of histopathologic diagnostic criteria preclude confidence in the results.18–20 It is not possible to further comment on the clinicopathologic diagnosis of vaginal erosive LP, given its relative rarity, a likely preference to biopsy from vulva rather than vagina, and other limitations of the literature.17–20,27
The descriptions of vulvar architectural change also vary among authors, with several different phrases used for abnormalities thought to be consistent with LP and reported rates of 42% to 95%14,16–18,20,21 (see Figure 2). Cohorts describe buried clitoris in 29% to 68% and introital narrowing in 25% to 59%.14,16 One study notes labial resorption in 78%, whereas another subdivides labial adhesions into anterior (8.4%), posterior (26%), or both (7.6%).16,17,21 Surgical division of adhesions was performed in 11% to 18%.14,21,22 A study of 40 women with vulvovaginal-gingival syndrome notes architectural change in 70%, described as “variable loss of the labia minora, fusion of the labia minora anteriorly, loss of the interlabial sulci, and burying of the clitoris.”20 Similar descriptions are used for anatomic changes associated with LS, and it is unclear whether the patterns are reliably distinguishable. Agglutination of apposed surfaces is more characteristic of LP, whereas fibrotic retraction is more consistent with LS. Assessment of architectural change is complicated by the possibility of comorbid LS with both mechanisms occurring in parallel.25
Vulvovaginal Examination—Classic and Hypertrophic LP
Classic LP appears as a moderately to well-demarcated homogenous plaque(s) or papule(s) on hairless or hair-bearing skin of the vulva and/or perianus.11,28,29 The color may be gray-white, pink-red, or purple-brown (see Figure 4). Plaques or papules may be solitary, multifocal, or bilateral.11 The surface contour is smooth but grouped papules may look pebbly. There may be overlying lacy reticulation, often called Wickham striae, but the same term is applied to white areas associated with erosive LP. Involvement of hair follicles may lead to scarring alopecia.29 Clinicians sometimes describe findings as “subtle” or “unusual.”11 There are no reports of architectural change attributable to classic LP.
FIG 4: Classic LP: pink-white plaque with an irregular border on the left inferior labium majus.
Hypertrophic LP has a dramatic clinical appearance that differs depending on vulvar or perianal location. On the vulva, this usually involves a moderately demarcated circumferential pink-red plaque that extends onto labia majora. The anterior commissure, labia minora, and interlabial sulci often are edematous with a macerated or mottled surface. On hair-bearing skin of labia majora, the color and texture may transition to gray-pink with increased skin markings11,30 (see Figure 5). Perianal hypertrophic LP presents as a circumferential red to violaceous plaque, often with excoriation12,31 (see Figure 6). There is a high rate of erroneous provisional diagnosis, with clinicians suspecting LS (28%), lichen simplex chronicus (LSC, 14%), neoplasia (14%), or psoriasis (10%).11 It is unknown whether hypertrophic LP is associated with architectural change; evaluation of this is complicated by comorbidity with LS or erosive LP.
FIG 5: Hypertrophic LP: circumferential edematous pink plaque extending onto labia majora, with maceration anteriorly.
FIG 6: Perianal hypertrophic LP comorbid with LS: excoriated circumferential perianal red plaque, edema over the perineum, and vulvar pallor with architectural change.
Comorbid Dermatologic Disease
The presence of any form of lichenoid dermatosis increases the likelihood of another on the vulva and elsewhere.6,32,33 Vulvar erosive LP cohorts describe involvement of the oral cavity in 32% to 68%, esophagus in 1% to 3%, anal canal in 2% to 13%, and lacrimal duct in 1%.13–16,21,22 Meanwhile, comorbid nonerosive LP is identified on the vulva in 3%, and on nongenital skin or scalp in 11% to 40%.13–16,20,22,33 Evaluation of extragenital sites varies among clinicians; a British audit identified its occurrence in 60% of cases.15
The best estimate for the prevalence of comorbid vulvar LP and LS comes from the hELP trial, in which 180 women with erosive LP were screened for participation and 13% were excluded because of coexisting LS.34 In a study of 31 biopsy-proven cases of comorbid LP and LS, erosive LP abutted LS at the labia minora in all but 1 case.25 There are multiple case reports of genital LS concurrent with extragenital LP, but the opposite situation is not well documented.6,35–37
Psoriasis is a common proliferative skin disease related to abnormal activation of CD4 and CD8 cells and associated with other immunologically mediated diseases.38 Psoriasis was reported in 4.5% of women with clinical erosive LP, and 14% of women with biopsy-proven classic LP.11,13 Clinical and histopathologic similarity between psoriasis and LSC may impact detection.39
Previous Studies on Clinical Diagnostic Criteria and Indications for Biopsy
Erosive LP
On interview of 25 British specialists, there was no diagnostic feature considered pathognomonic for erosive LP. Findings most commonly sought were “introital erosions” (40%), architectural change (20%), Wickham striae (12%), pain on palpation (12%), and concomitant oral disease (8%).15 A subsequent international electronic-Delphi (e-Delphi) exercise on diagnostic criteria involved 73 members of the ISSVD.40 It generated 6 clinical criteria: (a) well-demarcated glazed erythema at the introitus, (b) a hyperkeratotic white border, (c) pain or burning, (d) scarring or loss of architecture, (e) vaginal inflammation, and (f) involvement of other mucosal sites. There were also 3 histopathologic criteria. The authors proposed any 3 of the 9 features sufficed for diagnosis. This system was applied retrospectively to 72 women with a firm clinical diagnosis, of whom 62.5% had accessible biopsy reports with the majority being diagnostic.16 More than 90% of women had pain and glazed erythema, respectively, and 88% had architectural change; thus, 97% achieved a diagnosis of LP via history and examination. The authors highlighted that features of LP are nonspecific and often shared with LS, so increasing the number of required criteria might decrease false-positives.
This e-Delphi exercise asked participants about the requirement for biopsy and encountered discrepant opinions, with 52% stating that histopathologic criteria do not need to be satisfied to make a diagnosis.40 British and European guidelines take a restrictive approach to biopsy with advised indications of uncertain diagnosis or suspicion of neoplasia, and report that only 25% of biopsies demonstrate “classic” features.10,41 This is likely an underestimate; in a recent study, the rate of diagnostic biopsy was 60%.16 The US practice bulletin recommends a universal approach to biopsy for suspected inflammatory dermatoses to exclude disorders with a similar presentation, such as immunobullous disease.42
Classic and Hypertrophic LP
There is no previous publication addressing consensus diagnostic criteria for vulvar nonerosive LP. Classic LP is uncommon on the vulva, and its diversity of appearances is unfamiliar to most nondermatologists.11,28 The pink-red plaques of hypertrophic LP lead to confusion with psoriasis, extramammary Paget disease (EMPD), high-grade squamous intraepithelial lesion (HSIL, also called usual VIN, and previously termed VIN 2/3 or carcinoma in situ), and severe or superinfected LS. However, once clinicians learn the typical appearance, the rate of erroneous provisional diagnosis should decrease. Biopsy is ideally accompanied by a clinical photograph to facilitate clinicopathologic correlation.8,11
Summary of Clinical Diagnostic Criteria
The manifestations of erosive LP differ across individuals, but the most universal feature is a well-demarcated, glazed red macule or patch located on the vestibule, labia minora, and/or vagina. This appearance is required for clinical diagnosis but is also shared by HSIL, dVIN, and immunobullous disorders. The literature contains varied descriptions and rates of supportive features, such as shape, border, architectural change, vaginal and extragenital involvement, and comorbid diseases, but in combination these strengthen the clinical diagnosis (see Table 1). When there is a constellation of indistinct erythema with various supportive features, biopsy is advised to solidify the diagnosis.
TABLE 1: Examination Findings to Support a Diagnosis of Vulvar Erosive LP
Nonerosive LP occurs on hairless and hair-bearing vulvar and perianal skin, with classic and hypertrophic types each having a characteristic appearance (see Table 2). There is morphologic variation between cases relating to color, severity, comorbid dermatoses, and superinfection. Postinflammatory hyperpigmentation may occur with either form.29 Biopsy is often required because of uncertain diagnosis and exclusion of neoplasia.
TABLE 2: Examination Findings to Support the Diagnoses of Vulvar Classic and Hypertrophic LP
Histopathology
General Principles
Histopathologic diagnosis of vulvar LP begins with identification of the type of epithelium as hair-bearing skin, hairless skin, mucocutaneous junction (MCJ), or nonkeratinized squamous epithelium. Histologic features of MCJ include parakeratosis, reduced glycogen compared with nonkeratinized epithelium, and a sparse to moderate dermal lymphocytic infiltrate.43 The MCJ varies in size between individuals, and its absence suggests previous vulvar surgery.
There is no evidence to date for the occurrence of erosive LP on hair-bearing skin. Classic and hypertrophic LP occur on hairless and hair-bearing skin, but not on nonkeratinized squamous epithelium.11 Sites consistent with erosive LP have fine collagen fibers and may contain minor vestibular glands or superficial sebaceous glands. Hair-bearing skin shows hair follicles, thicker collagen bundles, and apocrine glands. Clinicians play an important role in site assessment by labeling specimens with laterality and an anatomic location, rather than a “clock-face” position. This allows the pathologist to identify whether keratinization, rete ridge morphology, and lymphocytic infiltrate are normal or abnormal for that location.43–45
The next steps are layer-by-layer identification of abnormalities and aggregation into reaction patterns.46 In pruritic disorders, abnormalities in the stratum corneum and granular cell layers may be altered by excoriation. The lichenoid tissue reaction requires evidence of epithelial basal layer damage accompanied by a closely applied band-like lymphocytic infiltrate. The subepithelial collagen must be assessed for sclerosis or fibrosis. Sclerosis is defined as partial or complete obliteration of the boundaries between collagen bundles, resulting in a glassy pink appearance; synonyms include “hyalinized” and “homogenized.”46 Sclerosis is characteristic of LS and its presence excludes LP. Fibrosis is defined as an increased quantity of thickened and separated bundles of collagen. It results from tissue damage of any kind, including trauma, irritation, and chronic inflammation. Thus, a mild fibrosis is sometimes seen within the infiltrate of LP.3 However, substantial fibrosis is more consistent with LS.47–49
Erosive LP
The basal layer damage of erosive LP is subdivided into 2 categories: degenerative and regenerative (see Table 3). These patterns likely correspond to points in a cycle of T-cell–mediated injury and epithelial repair.
TABLE 3: Histopathologic Categories of Vulvar Erosive LP
Squamous epithelium shows a thinly keratinized surface, absent or minimal acanthosis, and a flat junction between epithelium and lamina propria/dermis (see Figure 7). The basal layer has evidence of damage seen as apoptotic bodies, squamatization, and/or vacuolar degeneration.4 Squamatization is defined as a change in morphology of normal basilar keratinocytes to more horizontally disposed cells with a mature squamous appearance.3,45 Lymphocytosis is common and may be dense at the basal layer. The lamina propria/dermis contains a closely applied band-like lymphocytic infiltrate; this may have scattered plasma cells and eosinophils.3
FIG 7: Erosive LP at inner labium minus. A, Degenerative (thick arrows) and regenerative (thin arrow) epithelial morphologies and a dense band-like lymphocytic infiltrate, hematoxylin and eosin H&E ×4. B, Parakeratosis, absent rete ridges, basal layer vacuolar change, and apoptotic body (arrow), consistent with the degenerative pattern, H&E ×200. C, Erosion, enlarged hyperchromatic nuclei, and occasional mitotic figure (arrow), consistent with regenerative pattern, H&E ×200. D, p16 is negative in the regenerative area and nonblock-positive in the degenerative area,. E, p53 shows overexpression of basal nuclei across degenerative and regenerative areas.
A subset of specimens with a degenerative basal layer will display epithelial morphology indistinguishable from classic LP (see Figure 8). In these cases, there is hyperkeratosis, hypergranulosis, and irregular or saw-toothed acanthosis of the prickle cell layer.3,6,11,14 This may correspond with a white area adjacent to or within the red patch.
FIG 8: Degenerative erosive LP with both nonkeratinized and hyperkeratotic epithelium at inner labium minus. A, Junction between nonkeratinized squamous epithelium and a hyperkeratotic area, accompanied by a closely applied moderate stromal lymphocytic infiltrate, H&E ×4. B, Hyperkeratosis, basal layer vacuolar change, lymphocytosis, and apoptotic bodies (arrows), H&E ×200. C, nonkeratinized epithelium with lymphocytosis and basilar apoptotic bodies, H&E ×200.
Squamous epithelium lacks a surface keratin layer and is thinned (see Figure 7).25,50 There is loss of maturation with enlarged and hyperchromatic nuclei, sometimes accompanied by mitotic activity.25,50,51 The junction with the lamina propria/dermis is flat. The infiltrate is like that seen in the degenerative pattern with possible addition of scattered neutrophils.
Both the degenerative and regenerative patterns may be seen in the same woman or the same specimen.25 When seen together, the degenerative changes are often lateral to the regenerative pattern. Erosion occurs in both, though more commonly in the regenerative subtype. Erosion may be focal or confluent and is seen as loss of the upper layers of epithelium with neutrophils in residual cell layers. The hyperkeratotic subset of the degenerative pattern is not diagnostic of erosive LP; clinicopathologic correlation is required specifying the biopsy site as a white papule or plaque associated with a glazed red patch.3,6,11,14
Nonerosive LP
Classic and hypertrophic LP is differentiated based on morphology at the keratin, granular, and prickle layers (see Table 4). Some cases will lack diagnostic features of either and are labeled “lichenoid dermatitis.”2,11
TABLE 4: Clinical and Histopathological Features of Classic and Hypertrophic LP
The stratum corneum shows hyperkeratosis and the granular cell layer displays homogenous or wedge-shaped hypergranulosis (see Figure 9). In pruritic lesions, this is occasionally replaced by parakeratosis and agranulosis. The prickle cell layer is acanthotic, often with spiky rete ridges. The basal layer has vacuolar change, apoptotic bodies, and/or squamatization, as well as lymphocytosis.3 The dermis contains a closely applied band-like lymphocytic infiltrate that also may have histiocytes, plasma cells, and occasional neutrophils and eosinophils; rarely, the infiltrate appears granulomatous. Pigment incontinence is common, and skin appendage involvement occurs in 25%.11 Ten to 20% of cases display the required changes in the dermis, prickle, and basal layers but have a compact stratum corneum or a normal granular cell layer; it is reasonable to apply a diagnosis of classic LP in this situation.11,43
FIG 9: Classic LP at interlabial sulcus. A, Hyperkeratosis, hypergranulosis, acanthosis with spiky rete ridges, basal layer damage, a dense closely applied lymphocytic infiltrate, and pigment incontinence, H&E ×100. B, Lymphocytosis, apoptotic bodies at rete ridges (thin arrows), and squamatization (thick arrow) mainly at tops of papillary processes.
The upper epidermis is markedly abnormal with hyperkeratosis and hypergranulosis (see Figure 10). Scale crust, a manifestation of excoriation, replaces the hyperkeratosis and hypergranulosis in up to one-third of cases.11 The histopathologic findings of scale crust are parakeratosis, agranulosis, cellular debris, neutrophils, bacteria, and inspissated serum. Deep acanthosis with irregular rete morphology is universal. The rete ridges may be psoriasiform, saw-toothed, or branched. Basal layer degeneration is focal in up to 50% of cases; this may be subtle and limited to the tips of rete ridges, the basal layer at the tops of papillary processes, or both.4,11 Marked lymphocytosis occurs in a third of cases and complicates determination of vacuolar change.11 The dermal infiltrate is similar to classic LP. Vertically orientated fibrosis in the papillary dermis is a manifestation of chronic rubbing or scratching.4
FIG 10: Hypertrophic LP at labium majus. A, marked hyperkeratosis and wedge-shaped hypergranulosis, acanthosis with irregular rete ridges, dense closely applied lymphocytic infiltrate, and vertically oriented fibrosis in the dermal papillae, H&E ×100, B, Basal layer manifestations include lymphocytosis, scattered apoptotic keratinocytes (thin arrows), and squamatization (thick arrow), seen primarily at the rete tips, H&E ×200.
Pseudoepitheliomatous hyperplasia (PEH) is sometimes seen in nonerosive LP, particularly the hypertrophic type.11,31,52 PEH manifests as tentacles, separated nests, and single keratinocytes extending from hair follicles, eccrine ducts, and/or epidermis into dermis. Squamous cells have plump vesicular nuclei, prominent nucleoli, and are mitotically active. There is an accompanying inflammatory infiltrate. It is often difficult for pathologists to distinguish between PEH and squamous cell carcinoma (SCC).53,54 Features that support SCC include adjacent HSIL or dVIN, a deep lesion, atypical nuclei, and abnormal mitoses. Clinicopathological correlation with expert multidisciplinary review is advised before extirpative procedures. In some cases, the best option is close observation for response to potent topical corticosteroids, which would confirm a nonneoplastic disorder.11,31,54
Summary of Histopathologic Diagnostic Criteria
The 3 features common to diagnosis of all types of vulvar LP are (a) evidence of basal layer damage, (b) a closely applied band-like lymphocytic infiltrate, and (c) absent sclerosis. Sites consistent with erosive LP include hairless skin, MCJ, and nonkeratinized squamous epithelium; however, site assessment is complicated by both abnormal keratinization and erosion. The 2 morphologic categories of erosive LP are degenerative and regenerative, and these may coexist. Nonerosive LP occurs on hairless and hair-bearing skin and is divided into 2 types—classic and hypertrophic—each distinguished by characteristic epidermal features. Some cases display a nonsclerotic lichenoid tissue reaction without features to specify type; these are called “lichenoid dermatitis” and require clinicopathological correlation for diagnosis. PEH is seen in a minority of specimens and the principle criterion for distinguishing it from SCC is lack of nuclear atypia.
Differential diagnosis
Clinical—Erosive LP
The differential diagnosis for erosive LP includes plasma cell vulvitis (PCV), DIV, mucous membrane pemphigoid, fixed drug eruption (FDE), autoimmune progesterone dermatitis, HSIL, dVIN, VVC, estrogen deficiency, vulvodynia, and normal.10,16,24,42,44 Plasma cell vulvitis and DIV are poorly understood but likely to be immunologically mediated reactive phenomena. Plasma cell vulvitis presents with pain and punctate or confluent orange-red vestibular discoloration.55,56 Desquamative inflammatory vaginitis is characterized by purulent vaginal discharge, sometimes with mucosal petechiae.57,58 Both occur across a wider age range than erosive LP and do not cause architectural change, but otherwise, symptoms and signs overlap. Arguing against a previous hypothesis that DIV is a variant of vaginal LP, studies report historical triggers in more than half of cases.57–59 Mucous membrane pemphigoid is a rare autoimmune blistering disorder that affects multiple sites and results in scarring.60 In addition to standard stains, diagnosis requires a fresh specimen for direct immunofluorescence collected from normal skin a few millimeters from the lesion edge. Fixed drug eruption sometimes presents as a chronic recurring erosive vulvitis that flares with repeated exposures.61 Autoimmune progesterone dermatitis mimics FDE and may be noncyclic with a continuous exogenous trigger.62
Compromised barrier function and local immunosuppression inherent to LP may promote vulvar HSIL.63 When HSIL manifests as a treatment-resistant red patch, it may be mistaken for erosive LP. The typical appearance of dVIN is a treatment-resistant white or red lesion on a background of LS, an appearance potentially misidentified as erosive LP.50 Rarely, HSIL and dVIN coexist.64 The clinician must maintain a low threshold for biopsy in the setting of complex polymorphic lesions and poor treatment response.
Alone or in combination, VVC, estrogen deficiency, and vulvodynia mimic mild erosive LP.16,24,44 Distinguishing between these is sometimes difficult, but only LP produces intravaginal adhesions or midline labial fusion. Labial diminution and introital narrowing because of menopause may be erroneously interpreted as LP-associated architectural change.65,66 Erythema is a nonspecific finding present in mycotic or bacterial infection, psoriasis, contact dermatitis, vulvodynia, and the normal vulva.44,66–70 White blood cells and parabasal cells are seen on vaginal cytology in a variety of conditions. In women with pain, erythema, and positive microscopy or culture for Candida albicans, the likely diagnosis is VVC or mycotic superinfection of underlying dermatologic disease.24,29,44,67,71,72 A study of nondiagnostic biopsies from women with suspected dermatologic disease suggested features likely to represent vulvodynia: poorly demarcated diffuse erythema, “erosion” at posterior fourchette, and multifocal point erythema at the base of the hymen.44 Although a nondiagnostic report lessens the likelihood of erosive LP, it cannot be excluded because of the possibility of suboptimal site or timing of biopsy.44
Clinical—Classic and Hypertrophic LP
The differential diagnoses for classic and hypertrophic LP include LS, LSC, psoriasis, FDE, HSIL, dVIN, and EMPD.2,11,12,29,73 Hypertrophic LP may be indistinguishable from LS complicated by acute contact dermatitis or mycosis.11 However, LS is usually more porcelain-white with different textural changes, often with a characteristic array of architectural alterations.11,25 Severe LSC shares characteristics with hypertrophic LP on hair bearing skin—both demonstrate gray-pink discoloration, increased skin markings, and excoriation. However, LSC tends to be poorly demarcated and less edematous.74 Psoriasis serves as a mimic for both classic and hypertrophic LP as it can manifest as discrete red plaques or as diffuse labial erythema and edema. Features to support psoriasis include a waxing and waning history, dry flaky skin on the scalp or ears, nail abnormalities, and affected family members.73 Drug reactions are also difficult to distinguish from LP as many common medications are implicated, and intervals between exposure, rash, cessation, and resolution are variable and sometimes prolonged.2,75 The distribution is usually generalized, but dramatic genital symptoms may result in referral to a vulvar specialist.
Differentiated VIN and HSIL must be considered for any persistent well-demarcated plaque.11,76 Likewise, the appearance of EMPD ranges from subtle to obvious red patches or plaques that may be exudative, scaly, shiny, or contain thick white areas described as “cake-icing.” Again, biopsy is recommended at morphologically distinct sites for unusual features and suboptimal treatment response.
Histopathologic—Erosive LP, Degenerative Type
The differential diagnosis of degenerative erosive LP includes LS, GVHD, lichenoid drug reactions, and regressing melanoma. Graft-versus-host disease is a histopathologic mimic for LP; thus, it is a clinical diagnosis based on previous bone marrow transplant.77 Clues to drug eruptions include mismatch between the clinical and histopathologic features, excessive eosinophils, and biopsies with more than one inflammatory pattern present.2,75 Like LP, actively regressing melanoma may show lymphocytosis, basilar apoptotic bodies, and a dense lymphocytic infiltrate. It is distinguished by atypical melanocytes and a dense band of dermal melanophages; immunostaining for melanocyte markers facilitates diagnosis.78
The reason that sclerosis occurs in LS but not LP is unknown, but this is the feature that distinguishes between them.11,47,48 In LS, hyalinized collagen usually occurs in an obvious band, creating a trilaminar appearance of epithelium, pink sclerosis, and purple lymphocytes.45 Assessment of the nonsclerotic lichenoid tissue reaction has been controversial. Some authors describe this as “early LS,” but there is scant evidence for correlation between disease chronicity and abnormal collagen.30,47,48,79,80 Subtle pericapillary sclerosis and a thickened basement membrane favor LS.2,47,48 A complete absence of sclerosis does not exclude LS; the label of “lichenoid dermatitis” is applied when there is a lichenoid tissue reaction without features specific to LS or any type of LP.2,31
Histopathologic—Erosive LP, Regenerative Type
The differential diagnosis for regenerative erosive LP includes normal mucosa-associated lymphoid tissue (MALT), GVHD, dVIN, and HSIL. Normal histology of the vestibule is not well described, but features consistent with MALT include exocytosis, lymphocyte-predominant infiltrate in the lamina propria, and absent basal layer damage.43,44,68,69 When pathologists identify morphologically normal squamous epithelium accompanied by a lymphocytosis and a moderate infiltrate, they should recognize this as MALT and not supportive or diagnostic of LP.
Basaloid dVIN and HSIL both demonstrate nuclear atypia and a subepithelial lymphocytic infiltrate.50,81 Atypia is defined as nuclear enlargement, pleomorphism, and increased mitoses, often accompanied by hyperchromasia or prominent nucleoli.81 Some of these features are present in regenerative erosive LP.43 Atypical mitotic figures favor neoplasia over reactive phenomena. Mild acanthosis and parakeratosis are subtle features supporting basaloid dVIN over erosive LP.50,81 Immunohistochemistry is an important tool in differentiating between the 3 entities. Block-positive p16 identifies the diagnosis of HSIL, although false-negatives rarely occur.82,83 p53 is usually overexpressed in basilar nuclei of erosive LP and dVIN, so it is often unhelpful in distinguishing between them. However, p53 is aberrant negative in 30% of dVIN cases. This “knock-out” p53 pattern permits exclusion of LP and facilitates mapping of dVIN margins in surgical specimens.50,84,85 Prior human papillomavirus–independent SCC raises the pretest probability of dVIN.76 Clinicopathologic correlation with expert multidisciplinary review is essential before surgical treatment.50
Histopathologic—Classic LP
The differential diagnoses for classic LP include nonsclerotic LS, lichenoid drug reactions, and degenerative erosive LP.2,11 In all 3, histopathology may be nearly identical and the final diagnosis relies on clinicopathologic correlation.
Histopathologic—Hypertrophic LP
The features of chronic rubbing and scratching include orthokeratosis, hypergranulosis, acanthosis, and vertically oriented fibrosis in the papillary dermis.86 When these changes complicate LS or psoriasis, the histopathology may be reported as “lichenified” or “with superimposed LSC.” It should be noted that hypertrophic LP and classic LP seem to be 2 distinct entities—not the former being a lichenified version of the latter—and this is reflected in the nomenclature.11
Basal layer damage is the principle feature that identifies hypertrophic LP or lichenified LS; thus, basal cells must be carefully inspected for apoptotic bodies and vacuolar change, especially at the tips of rete ridges and tops of papillary processes.11 Several features favor lichenified LS over hypertrophic LP: psoriasiform hyperplasia, absent apoptotic bodies, thickened collagen fibers with lymphocytes aligned in horizontal rows, pericapillary sclerosis, focal sclerosis at the tips of dermal papillae, and a band of dermal fibrosis.2,25,47 Findings that support lichenified psoriasis include a normal basal layer, suprabasilar apoptotic keratinocytes, and a papillary dermal lymphocytic infiltrate extending into the suprapapillary plates.86 Corneal neutrophils and regular psoriasiform rete ridges also favor psoriasis, but these may be lost with lichenification. Lichenified mycosis also presents a diagnostic challenge, as yeast or fungi may be absent even on periodic-acid Schiff staining. When a vulvovaginal swab is positive, it is difficult to know if the organism represents the primary etiology of lichenification, or colonization versus superinfection of an underlying pruritic dermatosis.72 Even with clinicopathologic correlation, these situations are not easily distinguishable.
Limitations of the Existing Literature and Areas for Future Research
The singular obstacle to high-quality research in vulvar LP has been the lack of consensus-based clinicopathologic criteria that distinguish it from other disorders.8,51,76 One explanation for the disparate reports of symptoms, signs, and treatment outcomes is that women in studies of LP do not all have the disease of interest or have an additional comorbid disease. The use of biopsy to guide study inclusion has been limited by the high nondiagnostic rate, which in turn relates to inadequate histopathologic definitions and a dearth of experienced vulvar pathologists. In addition, few publications describe vulvar classic and hypertrophic LP, and clinicopathologic extrapolation from extragenital disease is likely an oversimplification.11 Future research should use this document's clinicopathologic criteria to identify and categorize LP and report treatment and outcomes in the context of microbiologic, virologic, and histopathologic comorbidities.
Summary and Recommendations for Practice
The most reliable diagnosis of vulvar LP is achieved through clinicopathologic correlation. The diagnoses of classic and hypertrophic LP each require their own characteristic clinical appearance, accompanied by specific features at the 5 epidermal layers (Table 4). The criteria for clinicopathologic diagnosis of erosive LP include clinical appearance, site, and 3 histopathologic features: lymphocytic infiltrate, basal layer damage categorized as regenerative and degenerative, and absent sclerosis (see Table 5). Recommendations to facilitate clinicopathologic correlation include:
TABLE 5: Summary of Minimum Clinicopathologic Criteria to Diagnose Vulvar Erosive LP
- Clinicians should aim for universal clinical photography at the initial examination for women with suspected LP.
- Use of words with specific histopathologic definitions, like erosion and hyperkeratosis, should be avoided when describing the clinical appearance of vulvar skin abnormalities.
- Biopsies should be obtained from morphologically distinct areas, as lichenoid dermatoses are often comorbid with each other and associated with both HSIL and dVIN.
- Biopsies should be labeled with their specific anatomic site and laterality.
- Pathologists should indicate in their report the category of erosive LP—regenerative, degenerative, or both.
- Communication between the clinician and pathologist is essential when there is a concern for neoplasia from either party, and expert multidisciplinary review is recommended before embarking on cytotoxic, ablative, or extirpative procedures.
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