Clinicopathologic Diagnostic Criteria for Vulvar Lichen Planus

” ” 317 vulval, 92%) and – ”“ 11 8,9 lichen planus, Other symptoms The aims of this Symptoms most “ Vulvovaginal LP 8 5 vulvar, 23 “ 23 – – and ” 4 6,21 Dyspareunia is reported in 14,15,18,21 te clinicopathologic correlation. AGINA V METHODS The mean age of women with nonerosive The diagnosis is occasionally made in 13,14,16,18,21,22 20 ing the search terms – 17 – Women with syndrome vulvovaginal-gingival Multiple factors contribute to underestimation of 18 The most common is likely to be the erosive vulvovaginal-gingival, 8 – 8,13 17 6 65%). – 12 ”“ – – 13 Darion Rowan, FACD, 10 3 ULVA AND 91%, but a case note audit found less than half of women The clinical presentation of vulvar LP is described primarily The International Society of the Study of Dis- Vulvovaginal Vulvar LP usually affects postmenopausal women. The mean Three types of LP occur on the vulva: erosive, classic, and Lichen planus at any site is estimated to affect 2% of women, – :V vulvovaginal, consensus statement are topathologic describe findings the clinical that features yieldvide a and recommendations diagnosis histo- that of facilita vulvar LP and to pro- form, followed by hypertrophic, anddifficult to then ascertain classic. given However, previous thistopathologic studies' is lack discernment of clinical between and the his- 3 types. commonly attributed to erosive LP are pain (50% pruritus (42% occurs in 25%chronic to vaginal complaints in 57% postmenopausal women, and of istologically his- women with confirmed in oral 3.7%ary LP, of vulvar causes women clinic. 6% attending a of multidisciplin- prevalence: some cases are asymptomatic, womenand defer care medical seeking, practitioners fail to make the diagnosis. of LP seem to havefest an in earlier adolescence. age of onset, and disease may mani- Epidemiology and symptoms 52% LP is 63 years, with a wide range of 21 to 88 years. reproductive-age women, with lower ageslished of ranges. 26 to 34 years in pub- in single-center retrospective cohorts basedsis. on a Some clinical studies diagno- combinenot erosive and uniformly nonerosive report LP; these location do and type. eases (ISSVD) tasked the Difficult Pathologic Diagnoses committee with development of aof consensus document vulvar for LP, lichen the sclerosus diagnosis (LS),traepithelial and neoplasia differentiated vulvar (dVIN). The in- literature LP subgroup review performed us a age in retrospective cohort studies57 restricted to erosive to disease is 67 years. hypertrophic. with the oral cavity most commonly involved. had documentation of sexual impacts. “ restricted to articles published during286 or publications, of after which 1990. 68 (24%) There were were casethe reports editor, or 85 letters (30%) to were focused on(16%) a were different condition, reviews and or 46 guidelines. Thirty-onesearch (11%) articles original addressed the re- clinicalsis and/or pathologic of diagno- LP;comorbidities, the management, and remainder outcomes. The focused committeepraised on ap- the pertinent publications, etiology, synthesized them epidemiology, intoreview, a critical then generatedAfter diagnostic the LP criteria group reached and agreement,within recommendations. the the article was committee disseminated andconsensus. The underwent document then further was revisions approvedmembership. by Signed to vote of written achieve the consents ISSVD wereclinical obtained photographs. for use of the RTICLE a — A )acloselyap- Edward Wilkinson, MD, d Pathology NSW 5 for the ISSVD Difficult Pathologic Diagnoses Committee* ) evidence of basal 1,2 c 1,5 ESEARCH The histopathologic R 3,4 ) absent subepithelial sclero- Volume 24, Number 3, July 2020 e • s: erosive, classic, and hypertrophic. 329) mediated chronic inflammatory – – The reason for epitopic alteration is RIGINAL The International Society of the Study of 2 Department of Pathology, Immunology, and 3 O ) disease affects hairless skin, mucocutaneous b Tania Day, MD, PhD, 2020;24: 317 The pathophysiology involves epitopic alteration 1 lncptooia correlationClinicopathological yields the most reliable di- and James Scurry, FRCPA, vulva, vagina, erosive lichen planus, classic lichen planus, The aim of the study was to describe the clinical and histopath-

Maternity and Gynaecology, John Hunter Hospital, Newcastle, The clinicopathologic diagnosis of erosive LP incorporates 5 2 ) a glazed well-demarcated, red macule or patch at labia minora, a

Hunter Hospital, 2 Lookout Rd, NewAustralia. Lambton E-mail: Heights, [email protected] NSW 2305, Darion Rowan, Maria Angelica Selim, JamesEdward Scurry, Wilkinson, Kathryn and Welch, Mario Preti. behalf of theterms ASCCP. of This the Creative is Commons Attribution-Non anLicense Commercial-No Derivatives 4.0 open-access (CCBY-NC-ND), where article itthe distributed is work under permissible provided the to itway download or is and used properly share commercially cited. without permission The from work the cannot journal. be changed in any ichen planus (LP) is askin disorder. T-cell Faculty of Health and Medicine, University of Newcastle, New South Wales, Omnicare Women's Health, Auckland, New Zealand; and J Low Genit Tract Dis The authors have declared that there* are Jill no Albritton, conflicts Tania Day, of Debra interest. S. Heller, Claudia Perrera, Gianluigi Radici, Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on DOI: 10.1097/LGT.0000000000000532 Hunter New England, Newcastle, New SouthReprint Wales, Australia requests to: Tania Day, MD, PhD, Maternity and Gynaecology John Lab Medicine, University of Florida College of Medicine, Gainesville, FL; manifestation of thisband process of is lymphocytes adjacent to a damaged epithelium. lichenoid tissue reaction New South Wales, Australia; unknown, but a similar phenomenonease (GVHD) occurs and lichenoid in drug reactions. graft-versus-host dis- agnosis of vulvar LP.Disease appearance overlaps with otherdermatologic, infectious, and physiologic, neoplastic entities; a low threshold for biopsy at all distinct morphologically areas is recommended. Use ofologic the criteria histopath- described in this document may reduce the nondiagnostic biopsy rate for clinically diagnosed LP. Key Words: hypertrophic lichen planus, regenerative, degenerative ( Australia; Journal of Lower Genital Tract Disease 1 4 Conclusions: Results: Materials and Methods: Objective: Clinicopathologic Diagnostic Criteria for Vulvar Lichen Planus ologic features required forplanus a (LP), which clinicopathologic is divided diagnosis into of 3 type vulvar lichen of epithelial basal cells, leading tocellular lymphocytic attack damage and a and cycle of repair. uvvgnlDiseasesVulvovaginal tasked the Difficult Pathologic Diagnoses committee with development of adiagnosis consensus of document vulvar for LP,lichen sclerosus, the and differentiated clinicopathologic vulvar intraepithelial neoplasia. The LP subgroup reviewed thediagnostic literature criteria, and then formulated approved by the International Society ofof the Diseases Vulvovaginal Study membership. junction, and/or nonkeratinized squamous epithelium, ( criteria: ( vestibule, and/or vagina, ( layer damage, categorized as degenerative or regenerative, (

plied band-like lymphocytic infiltrate, and ( sis. The clinicopathologic diagnoses of classicrequire and a characteristic clinical hypertrophic appearance accompanied LP by hyperkeratosis, each hypergranulosis, acanthosis, basal layer degeneration,lymphocytic infiltrate, a and closely absent dermal applied sclerosis, withshowing marked hypertrophic epithelial LP abnormality compared with classic LP. L

Downloaded from http://journals.lww.com/jlgtd by BhDMf5ePHKbH4TTImqenVBMw8cOsTrAm31mBmE+A1czBq2ga3kGGqBufqZk6iwZpO93TnKa60V8= on 08/17/2020 Downloaded from http://journals.lww.com/jlgtd by BhDMf5ePHKbH4TTImqenVBMw8cOsTrAm31mBmE+A1czBq2ga3kGGqBufqZk6iwZpO93TnKa60V8= on 08/17/2020 Day et al. Journal of Lower Genital Tract Disease • Volume 24, Number 3, July 2020

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. include vaginal discharge (8%–24%) and dysuria (8%–23%).14,21,22 plaques, a white papules or plaques surrounded by the red patch, In 2 cohorts that combine erosive and nonerosive disease, 10% to and white delineation at the junction between normal and abnor- 34% of women were asymptomatic.6,8 A study restricted to nonerosive mal epithelium (see Figures 1–3). LP found pruritus as the main symptom in 81% of women, with Vaginal disease is reported in 20% to 85% of women with the remainder reporting pain (13%) or no symptoms (6%).11 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,” Evaluation “painful friable hemorrhagic mucosa,” and “a variable discharge, Vulvovaginal Examination—Erosive LP. Awell- which is often serosanguinous.”10,20 Most studies do not identify demarcated, glazed red macule or patch at the labia minora, rates of vaginal synechia and obliteration; those that do report vestibule, and/or vagina is present in 81% to 97% of women adhesions in 10% to 50%.18,20,22 In absence of scarring, vaginal with a clinical diagnosis of erosive LP14,16,22 (see Figure 1). erythema and friability may be difficult to distinguish from The color is red-to-purple, rather than the orange-red associated desquamative inflammatory vaginitis (DIV) and severe vulvovaginal with plasma cell vulvitis.10,24 Clinicians often describe the candidiasis (VVC).6 Several groups undertook vaginal biopsies, but red areas as “erosions” because of their shiny appearance, the absent or brief descriptions of histopathologic diagnostic criteria but loss of the upper epithelium is not universally confirmed preclude confidence in the results.18–20 It is not possible to further on histopathology.8,20,25 The shape of these areas is not well comment on the clinicopathologic diagnosis of vaginal erosive described, but published photographs often display a bilateral or LP, given its relative rarity, a likely preference to biopsy from vulva horseshoe morphology affecting inner labia minora and clitoral rather than vagina, and other limitations of the literature.17–20,27 frenulum and/or posterior fourchette.6,12,13,16,22,25 Disease may The descriptions of vulvar architectural change also vary also extend onto the adjacent clitoral hood and/or interlabial sulci among authors, with several different phrases used for abnormal- (see Figure 2). Disease features vary over time relating to the ities thought to be consistent with LP and reported rates of 42% to cycle of epithelial injury and repair, as also suggested in LS.28–35 95%14,16–18,20,21 (see Figure 2). Cohorts describe buried clitoris in Many terms are used for white areas that often accompany 29% to 68% and introital narrowing in 25% to 59%.14,16 One the red patches/macules, including “Wickham striae,”“white re- study notes labial resorption in 78%, whereas another subdivides ticulation,”“lacy border,” and “scalloped hyperkeratotic margin,” labial adhesions into anterior (8.4%), posterior (26%), or both with widely varying rates reported (7%–82%).14,20–22,26 Some au- (7.6%).16,17,21 Surgical division of adhesions was performed in thors additionally report white plaques or “hyperkeratosis” in 15% 11% to 18%.14,21,22 A study of 40 women with vulvovaginal- to 22%.14,22 The variation in nomenclature likely reflects an array gingival syndrome notes architectural change in 70%, described of findings representative of erosive LP. These include a as “variable loss of the labia minora, fusion of the labia minora an- superimposed fine white lacy pattern, lateral white papules and teriorly, loss of the interlabial sulci, and burying of the clitoris.”20

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.

Similar descriptions are used for anatomic changes associated with excoriation12,31 (see Figure 6). There is a high rate of erro- with LS, and it is unclear whether the patterns are reliably distin- neous provisional diagnosis, with clinicians suspecting LS (28%), guishable. Agglutination of apposed surfaces is more characteris- lichen simplex chronicus (LSC, 14%), neoplasia (14%), or psori- tic of LP, whereas fibrotic retraction is more consistent with LS. asis (10%).11 It is unknown whether hypertrophic LP is associated Assessment of architectural change is complicated by the possibil- with architectural change; evaluation of this is complicated by co- ity of comorbid LS with both mechanisms occurring in parallel.25 morbidity with LS or erosive LP.

Comorbid Dermatologic Disease. The presence of any form Vulvovaginal Examination—Classic and Hypertrophic of lichenoid dermatosis increases the likelihood of another on LP. Classic LP appears as a moderately to well-demarcated the vulva and elsewhere.6,32,33 Vulvar erosive LP cohorts describe homogenous plaque(s) or papule(s) on hairless or hair-bearing involvement of the oral cavity in 32% to 68%, esophagus in 1% to skin of the vulva and/or perianus.11,28,29 The color may be 3%, anal canal in 2% to 13%, and lacrimal duct in 1%.13–16,21,22 gray-white, pink-red, or purple-brown (see Figure 4). Plaques Meanwhile, comorbid nonerosive LP is identified on the vulva in or papules may be solitary, multifocal, or bilateral.11 The surface 3%, and on nongenital skin or scalp in 11% to 40%.13–16,20,22,33 contour is smooth but grouped papules may look pebbly. There Evaluation of extragenital sites varies among clinicians; a British may be overlying lacy reticulation, often called Wickham striae, audit identified its occurrence in 60% of cases.15 but the same term is applied to white areas associated with The best estimate for the prevalence of comorbid vulvar LP erosive LP. Involvement of hair follicles may lead to scarring and LS comes from the hELP trial, in which 180 women with ero- alopecia.29 Clinicians sometimes describe findings as “subtle” sive LP were screened for participation and 13% were excluded or “unusual.”11 There are no reports of architectural change because of coexisting LS.34 In a study of 31 biopsy-proven cases attributable to classic LP. of comorbid LP and LS, erosive LP abutted LS at the labia minora Hypertrophic LP has a dramatic clinical appearance that dif- in all but 1 case.25 There are multiple case reports of genital LS fers depending on vulvar or perianal location. On the vulva, this concurrent with extragenital LP, but the opposite situation is not usually involves a moderately demarcated circumferential pink- well documented.6,35–37 red plaque that extends onto labia majora. The anterior commis- Psoriasis is a common proliferative skin disease related to ab- sure, labia minora, and interlabial sulci often are edematous with normal activation of CD4 and CD8 cells and associated with other a macerated or mottled surface. On hair-bearing skin of labia immunologically mediated diseases.38 Psoriasis was reported in majora, the color and texture may transition to gray-pink with in- 4.5% of women with clinical erosive LP,and 14% of women with creased skin markings11,30 (see Figure 5). Perianal hypertrophic biopsy-proven classic LP.11,13 Clinical and histopathologic simi- LP presents as a circumferential red to violaceous plaque, often larity between psoriasis and LSC may impact detection.39

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.

Previous Studies on Clinical Diagnostic Criteria and practice bulletin recommends a universal approach to biopsy for Indications for Biopsy suspected inflammatory dermatoses to exclude disorders with a similar presentation, such as immunobullous disease.42 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” Classic and Hypertrophic LP. There is no previous (40%), architectural change (20%), Wickham striae (12%), pain publication addressing consensus diagnostic criteria for vulvar 15 nonerosive LP. Classic LP is uncommon on the vulva, and its on palpation (12%), and concomitant oral disease (8%). A 11,28 subsequent international electronic-Delphi (e-Delphi) exercise diversity of appearances is unfamiliar to most nondermatologists. on diagnostic criteria involved 73 members of the ISSVD.40 It The pink-red plaques of hypertrophic LP lead to confusion generated 6 clinical criteria: (a) well-demarcated glazed erythema with psoriasis, extramammary Paget disease (EMPD), high- at the introitus, (b) a hyperkeratotic white border, (c)painor grade squamous intraepithelial lesion (HSIL, also called usual burning, (d)scarringorlossofarchitecture,(e) vaginal VIN, and previously termed VIN 2/3 or carcinoma in situ), and inflammation, and (f) involvement of other mucosal sites. There severe or superinfected LS. However, once clinicians learn the were also 3 histopathologic criteria. The authors proposed any 3 typical appearance, the rate of erroneous provisional diagnosis should decrease. Biopsy is ideally accompanied by a clinical of the 9 features sufficed for diagnosis. This system was applied 8,11 retrospectively to 72 women with a firm clinical diagnosis, of photograph to facilitate clinicopathologic correlation. whom 62.5% had accessible biopsy reports with the majority being diagnostic.16 More than 90% of women had pain and glazed Summary of Clinical Diagnostic Criteria. The manifestations erythema, respectively, and 88% had architectural change; thus, of erosive LP differ across individuals, but the most universal 97% achieved a diagnosis of LP via history and examination. feature is a well-demarcated, glazed red macule or patch located The authors highlighted that features of LP are nonspecific and on the vestibule, labia minora, and/or vagina. This appearance is often shared with LS, so increasing the number of required required for clinical diagnosis but is also shared by HSIL, dVIN, criteria might decrease false-positives. and immunobullous disorders. The literature contains varied This e-Delphi exercise asked participants about the require- descriptions and rates of supportive features, such as shape, border, ment for biopsy and encountered discrepant opinions, with 52% architectural change, vaginal and extragenital involvement, and stating that histopathologic criteria do not need to be satisfied to comorbid diseases, but in combination these strengthen the make a diagnosis.40 British and European guidelines take a restric- clinical diagnosis (see Table 1). When there is a constellation of tive approach to biopsy with advised indications of uncertain diag- indistinct erythema with various supportive features, biopsy is nosis or suspicion of neoplasia, and report that only 25% of biopsies advised to solidify the diagnosis. demonstrate “classic” features.10,41 This is likely an underestimate; Nonerosive LP occurs on hairless and hair-bearing vulvar in a recent study, the rate of diagnostic biopsy was 60%.16 The US and perianal skin, with classic and hypertrophic types each having

FIG 4. Classic LP: pink-white plaque with an irregular border on the left inferior labium majus. a characteristic appearance (see Table 2). There is morphologic be altered by excoriation. The lichenoid tissue reaction requires variation between cases relating to color, severity, comorbid derma- evidence of epithelial basal layer damage accompanied by a toses, and superinfection. Postinflammatory hyperpigmentation closely applied band-like lymphocytic infiltrate. The subepithelial may occur with either form.29 Biopsy is often required because of collagen must be assessed for sclerosis or fibrosis. Sclerosis is de- uncertain diagnosis and exclusion of neoplasia. fined as partial or complete obliteration of the boundaries between collagen bundles, resulting in a glassy pink appearance; synonyms “ ” “ ”46 Histopathology include hyalinized and homogenized. Sclerosisischaracter- istic of LS and its presence excludes LP. Fibrosis is defined as an General Principles. Histopathologic diagnosis of vulvar LP increased quantity of thickened and separated bundles of collagen. begins with identification of the type of epithelium as hair- It results from tissue damage of any kind, including trauma, irrita- bearing skin, hairless skin, mucocutaneous junction (MCJ), tion, and chronic inflammation. Thus, a mild fibrosis is sometimes or nonkeratinized squamous epithelium. Histologic features of seen within the infiltrate of LP.3 However, substantial fibrosis is MCJ include parakeratosis, reduced glycogen compared with more consistent with LS.47–49 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. Erosive LP There is no evidence to date for the occurrence of erosive LP The basal layer damage of erosive LP is subdivided into 2 on hair-bearing skin. Classic and hypertrophic LP occur on hair- categories: degenerative and regenerative (see Table 3). These pat- less and hair-bearing skin, but not on nonkeratinized squamous terns likely correspond to points in a cycle of T-cell–mediated epithelium.11 Sites consistent with erosive LP have fine collagen injury and epithelial repair. fibers and may contain minor vestibular glands or superficial se- baceous glands. Hair-bearing skin shows hair follicles, thicker col- 1. Degenerative. lagen bundles, and apocrine glands. Clinicians play an important role in site assessment by labeling specimens with laterality and Squamous epithelium shows a thinly keratinized surface, ab- an anatomic location, rather than a “clock-face” position. This al- sent or minimal acanthosis, and a flat junction between epithelium lows the pathologist to identify whether keratinization, rete ridge and lamina propria/dermis (see Figure 7). The basal layer has ev- morphology, and lymphocytic infiltrate are normal or abnormal idence of damage seen as apoptotic bodies, squamatization, and/ for that location.43–45 or vacuolar degeneration.4 Squamatization is defined as a change The next steps are layer-by-layer identification of abnormal- in morphology of normal basilar keratinocytes to more horizon- ities and aggregation into reaction patterns.46 In pruritic disorders, tally disposed cells with a mature squamous appearance.3,45 Lym- abnormalities in the stratum corneum and granular cell layers may phocytosis is common and may be dense at the basal layer. The

FIG 5. Hypertrophic LP: circumferential edematous pink plaque extending onto labia majora, with maceration anteriorly. lamina propria/dermis contains a closely applied band-like lympho- (see Table 4). Some cases will lack diagnostic features of either cytic infiltrate; this may have scattered plasma cells and eosinophils.3 and are labeled “lichenoid dermatitis.”2,11 A subset of specimens with a degenerative basal layer will display epithelial morphology indistinguishable from classic 1. Classic LP 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 The stratum corneum shows hyperkeratosis and the granular adjacent to or within the red patch. cell layer displays homogenous or wedge-shaped hypergranulosis (see Figure 9). In pruritic lesions, this is occasionally replaced by 2. Regenerative. parakeratosis and agranulosis. The prickle cell layer is acanthotic, often with spiky rete ridges. The basal layer has vacuolar change, Squamous epithelium lacks a surface keratin layer and is apoptotic bodies, and/or squamatization, as well as lymphocyto- thinned (see Figure 7).25,50 There is loss of maturation with en- sis.3 The dermis contains a closely applied band-like lymphocytic larged and hyperchromatic nuclei, sometimes accompanied by infiltrate that also may have histiocytes, plasma cells, and occa- mitotic activity.25,50,51 The junction with the lamina propria/ sional neutrophils and eosinophils; rarely, the infiltrate appears dermis is flat. The infiltrate is like that seen in the degenerative granulomatous. Pigment incontinence is common, and skin ap- pattern with possible addition of scattered neutrophils. pendage involvement occurs in 25%.11 Ten to 20% of cases display the required changes in the dermis, prickle, and basal layers Both the degenerative and regenerative patterns may be seen but have a compact stratum corneum or a normal granular cell in the same woman or the same specimen.25 When seen together, layer; it is reasonable to apply a diagnosis of classic LP in the degenerative changes are often lateral to the regenerative pat- this situation.11,43 tern. Erosion occurs in both, though more commonly in the regenerative subtype. Erosion may be focal or confluent and is seen as 2. Hypertrophic LP. loss of the upper layers of epithelium with neutrophils in residual cell layers. The hyperkeratotic subset of the degenerative pattern is The upper epidermis is markedly abnormal with hyper- not diagnostic of erosive LP; clinicopathologic correlation is re- keratosis and hypergranulosis (see Figure 10). Scale crust, a quired specifying the biopsy site as a white papule or plaque asso- 3,6,11,14 manifestation of excoriation, replaces the hyperkeratosis and ciated with a glazed red patch. hypergranulosis in up to one-third of cases.11 The histopathologic findings of scale crust are parakeratosis, agranulosis, cellular de- Nonerosive LP. Classic and hypertrophic LP is differentiated bris, neutrophils, bacteria, and inspissated serum. Deep acanthosis based on morphology at the keratin, granular, and prickle layers with irregular rete morphology is universal. The rete ridges may

FIG 6. Perianal hypertrophic LP comorbid with LS: excoriated circumferential perianal red plaque, edema over the perineum, and vulvar pallor with architectural change. be psoriasiform, saw-toothed, or branched. Basal layer degenera- TABLE 1. Examination Findings to Support a Diagnosis of tion is focal in up to 50% of cases; this may be subtle and limited Vulvar Erosive LP to the tips of rete ridges, the basal layer at the tops of papillary pro- 4,11 cesses, or both. Marked lymphocytosis occurs in a third of Descriptor Examination finding cases and complicates determination of vacuolar change.11 The dermal infiltrate is similar to classic LP. Vertically orientated fi- Required features brosis in the papillary dermis is a manifestation of chronic rubbing Site Labia minora or scratching.4 Vestibule Pseudoepitheliomatous hyperplasia (PEH) is sometimes Vagina seen in nonerosive LP, particularly the hypertrophic type.11,31,52 Color Glazed red PEH manifests as tentacles, separated nests, and single Contour Macule or patch keratinocytes extending from hair follicles, eccrine ducts, Demarcation Well-demarcated and/or epidermis into dermis. Squamous cells have plump vesic- Supportive features ular nuclei, prominent nucleoli, and are mitotically active. There Shape Bilateral and/or U-shaped is an accompanying inflammatory infiltrate. It is often difficult Border White, may be lacy or raised for pathologists to distinguish between PEH and squamous cell 53,54 Architectural change Midline fusion of labia minora carcinoma (SCC). Features that support SCC include adjacent Adhesions between affected HSIL or dVIN, a deep lesion, atypical nuclei, and abnormal mi- apposed structures toses. Clinicopathological correlation with expert multidisciplin- Reduced introital dimensions ary review is advised before extirpative procedures. In some Vaginal adhesions or obliteration cases, the best option is close observation for response to potent Common comorbidities LS topical corticosteroids, which would confirm a nonneoplastic Other types and locations of LP disorder.11,31,54 Systemic autoimmune diseases The criteria for clinical diagnosis requires site, color, contour, and The 3 demarcation findings, and at least one additional feature from another Summary of Histopathologic Diagnostic Criteria. category. features common to diagnosis of all types of vulvar LP are (a) evidence of basal layer damage, (b) a closely applied band-like Histopathology should be obtained if clinical features are subtle or do not meet diagnostic criteria. Rarely, cases will display all clinical features lymphocytic infiltrate, and (c) absent sclerosis. Sites consistent and still contain VIN. with erosive LP include hairless skin, MCJ, and nonkeratinized

TABLE 2. Examination Findings to Support the Diagnoses of Vulvar Classic and Hypertrophic LP

Descriptor Classic LP Hypertrophic LP Required features Site Anywhere on vulvar skin Vulvar and/or perianal skin Color Pink-red Pink-red Purple-brown Violaceous Gray-white Contour Flat-topped plaque or papules Plaque Demarcation Moderately demarcated Moderately demarcated Supportive features Shape Variable Circumferential and ovoid Border Irregular Rounded Architectural change Nil Not well established Common comorbidities Other types and locations of LP Other types and locations of LP LS LS Systemic autoimmune diseases Systemic autoimmune diseases squamous epithelium; however, site assessment is complicated by both abnormal keratinization and erosion. The 2 morphologic normal skin a few millimeters from the lesion edge. Fixed drug eruption sometimes presents as a chronic recurring erosive categories of erosive LP are degenerative and regenerative, and 61 these may coexist. Nonerosive LP occurs on hairless and hair- vulvitis that flares with repeated exposures. Autoimmune — — progesterone dermatitis mimics FDE and may be noncyclic with bearing skin and is divided into 2 types classic and hypertrophic 62 each distinguished by characteristic epidermal features. Some a continuous exogenous trigger. Compromised barrier function and local immunosuppression cases display a nonsclerotic lichenoid tissue reaction without 63 features to specify type; these are called “lichenoid dermatitis” inherent to LP may promote vulvar HSIL. When HSIL man- and require clinicopathological correlation for diagnosis. PEH is ifests as a treatment-resistant red patch, it may be mistaken for seen in a minority of specimens and the principle criterion for erosive LP. The typical appearance of dVIN is a treatment- distinguishing it from SCC is lack of nuclear atypia. 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 thresh- Differential diagnosis old for biopsy in the setting of complex polymorphic lesions Clinical—Erosive LP. The differential diagnosis for erosive LP and poor treatment response. includes plasma cell vulvitis (PCV), DIV, mucous membrane Alone or in combination, VVC, estrogen deficiency, and pemphigoid, fixed drug eruption (FDE), autoimmune progesterone vulvodynia mimic mild erosive LP.16,24,44 Distinguishing between dermatitis, HSIL, dVIN, VVC, estrogen deficiency, vulvodynia, these is sometimes difficult, but only LP produces intravaginal ad- and normal.10,16,24,42,44 Plasma cell vulvitis and DIV are poorly hesions or midline labial fusion. Labial diminution and introital understood but likely to be immunologically mediated reactive narrowing because of menopause may be erroneously interpreted phenomena. Plasma cell vulvitis presents with pain and punctate as LP-associated architectural change.65,66 Erythema is a nonspe- or confluent orange-red vestibular discoloration.55,56 Desquamative cific finding present in mycotic or bacterial infection, psoriasis, inflammatory vaginitis is characterized by purulent vaginal contact dermatitis, vulvodynia, and the normal vulva.44,66–70 discharge, sometimes with mucosal petechiae.57,58 Both occur White blood cells and parabasal cells are seen on vaginal cytology across a wider age range than erosive LP and do not cause in a variety of conditions. In women with pain, erythema, and architectural change, but otherwise, symptoms and signs overlap. positive microscopy or culture for Candida albicans, the likely Arguing against a previous hypothesis that DIV is a variant of diagnosis is VVC or mycotic superinfection of underlying vaginal LP, studies report historical triggers in more than half of dermatologic disease.24,29,44,67,71,72 A study of nondiagnostic cases.57–59 Mucous membrane pemphigoid is a rare autoimmune biopsies from women with suspected dermatologic disease blistering disorder that affects multiple sites and results in suggested features likely to represent vulvodynia: poorly de- scarring.60 In addition to standard stains, diagnosis requires a marcated diffuse erythema, “erosion” at posterior fourchette, fresh specimen for direct immunofluorescence collected from and multifocal point erythema at the base of the hymen.44

TABLE 3. Histopathologic Categories of Vulvar Erosive LP

Anatomical layer Regenerative Degenerative Epithelial surface Nonkeratinized, superficial neutrophils Keratinized or nonkeratinized Rete ridge morphology Absent/reduced Absent/reduced or Irregular or saw-tooth acanthosis in the hyperkeratotic subtype Basal layer Nuclear enlargement, nuclear hyperchromasia, Apoptotic bodies, squamatization, and/or vacuolar change loss of maturation, and increased mitotic activity Lymphocytosis Lymphocytosis Dermis/lamina propria Band-like closely applied lymphocytic infiltrate Band-like closely applied lymphocytic infiltrate

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 Â4. B, Parakeratosis, absent rete ridges, basal layer vacuolar change, and apoptotic body (arrow), consistent with the degenerative pattern, H&E Â200. C, Erosion, enlarged hyperchromatic nuclei, and occasional mitotic figure (arrow), consistent with regenerative pattern, H&E Â200. 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.

Although a nondiagnostic report lessens the likelihood of erosive 2,75 LP,it cannot be excluded because of the possibility of suboptimal resolution are variable and sometimes prolonged. The site or timing of biopsy.44 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 11,76 Clinical—Classic and Hypertrophic LP. The differential persistent well-demarcated plaque. Likewise, the appearance diagnoses for classic and hypertrophic LP include LS, LSC, of EMPD ranges from subtle to obvious red patches or plaques psoriasis, FDE, HSIL, dVIN, and EMPD.2,11,12,29,73 Hypertrophic that may be exudative, scaly, shiny, or contain thick white areas “ ” LP may be indistinguishable from LS complicated by acute described as cake-icing. Again, biopsy is recommended at mor- contact dermatitis or mycosis.11 However, LS is usually more phologically distinct sites for unusual features and suboptimal porcelain-white with different textural changes, often with a treatment response. characteristic array of architectural alterations.11,25 Severe LSC shares characteristics with hypertrophic LP on hair bearing Histopathologic—Erosive LP, Degenerative Type. The skin—both demonstrate gray-pink discoloration, increased skin differential diagnosis of degenerative erosive LP includes LS, markings, and excoriation. However, LSC tends to be poorly GVHD, lichenoid drug reactions, and regressing melanoma. demarcated and less edematous.74 Psoriasis serves as a mimic Graft-versus-host disease is a histopathologic mimic for LP; for both classic and hypertrophic LP as it can manifest as thus, it is a clinical diagnosis based on previous bone marrow discrete red plaques or as diffuse labial erythema and edema. transplant.77 Clues to drug eruptions include mismatch between Features to support psoriasis include a waxing and waning the clinical and histopathologic features, excessive eosinophils, history, dry flaky skin on the scalp or ears, nail abnormalities, and biopsies with more than one inflammatory pattern present.2,75 and affected family members.73 Drug reactions are also difficult Like LP, actively regressing melanoma may show lymphocytosis, to distinguish from LP as many common medications are basilar apoptotic bodies, and a dense lymphocytic infiltrate. It implicated, and intervals between exposure, rash, cessation, and is distinguished by atypical melanocytes and a dense band of

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 Â4. B, Hyperkeratosis, basal layer vacuolar change, lymphocytosis, and apoptotic bodies (arrows), H&E Â200. C, nonkeratinized epithelium with lymphocytosis and basilar apoptotic bodies, H&E Â200.

TABLE 4. Clinical and Histopathological Features of Classic and Hypertrophic LP

Classic LP Hypertrophic LP Clinical features Red, gray-white, or purple-brown plaque or Circumferential red plaque over hairless and hair papules on hairless and/or hair bearing skin bearing skin of vulva or perianus Histopathology Stratum corneum Hyperkeratosis* Marked hyperkeratosis* Granular cell layer Hypergranulosis* Diffuse and marked hypergranulosis* Rete ridge morphology Mild to moderate acanthosis with irregular Marked acanthosis with deep and irregular rete ridges rete ridges, often spiky or saw-toothed Basal layer Apoptotic bodies, squamatization, and/or Apoptotic bodies, squamatization, and/or vacuolar change, vacuolar change may be confined to rete tips and/or basal layer above Lymphocytosis papillary processes Lymphocytosis Dermis Band-like closely applied lymphocytic infiltrate Band-like closely applied lymphocytic infiltrate Absent sclerosis Absent sclerosis Papillary dermal fibrosis *Stratum corneum and granular layer abnormalities may be altered by excoriation, particularly in hypertrophic LP.

as nuclear enlargement, pleomorphism, and increased mitoses, dermal melanophages; immunostaining for melanocyte markers 81 78 often accompanied by hyperchromasia or prominent nucleoli. facilitates diagnosis. Some of these features are present in regenerative erosive LP.43 The reason that sclerosis occurs in LS but not LP is un- Atypical mitotic figures favor neoplasia over reactive phenomena. known, but this is the feature that distinguishes between 11,47,48 Mild acanthosis and parakeratosis are subtle features supporting them. In LS, hyalinized collagen usually occurs in an ob- basaloid dVIN over erosive LP.50,81 Immunohistochemistry is an vious band, creating a trilaminar appearance of epithelium, 45 important tool in differentiating between the 3 entities. Block- pink sclerosis, and purple lymphocytes. Assessment of the positive p16 identifies the diagnosis of HSIL, although false- nonsclerotic lichenoid tissue reaction has been controversial. 82,83 “ ” negatives rarely occur. p53 is usually overexpressed in basilar Some authors describe this as early LS, but there is scant ev- nuclei of erosive LP and dVIN, so it is often unhelpful in idence for correlation between disease chronicity and abnormal 30,47,48,79,80 distinguishing between them. However, p53 is aberrant negative collagen. Subtle pericapillary sclerosis and a thick- in 30% of dVIN cases. This “knock-out” p53 pattern permits ex- ened basement membrane favor LS.2,47,48 A complete absence “ clusion of LP and facilitates mapping of dVIN margins in surgical of sclerosis does not exclude LS; the label of lichenoid derma- specimens.50,84,85 Prior human papillomavirus–independent SCC titis” is applied when there is a lichenoid tissue reaction with- 76 2,31 raises the pretest probability of dVIN. Clinicopathologic corre- out features specific to LS or any type of LP. lation with expert multidisciplinary review is essential before surgical treatment.50 Histopathologic—Erosive LP, Regenerative Type. The differential diagnosis for regenerative erosive LP includes Histopathologic—Classic LP. The differential diagnoses normal mucosa-associated lymphoid tissue (MALT), GVHD, for classic LP include nonsclerotic LS, lichenoid drug dVIN, and HSIL. Normal histology of the vestibule is not well reactions, and degenerative erosive LP.2,11 In all 3, histopathology described, but features consistent with MALT include exocytosis, may be nearly identical and the final diagnosis relies on lymphocyte-predominant infiltrate in the lamina propria, and clinicopathologic correlation. 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 Histopathologic—Hypertrophic LP. The features of chronic this as MALT and not supportive or diagnostic of LP. rubbing and scratching include orthokeratosis, hypergranulosis, Basaloid dVIN and HSIL both demonstrate nuclear atypia acanthosis, and vertically oriented fibrosis in the papillary and a subepithelial lymphocytic infiltrate.50,81 Atypia is defined dermis.86 When these changes complicate LS or psoriasis, the

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 Â100. B, Lymphocytosis, apoptotic bodies at rete ridges (thin arrows), and squamatization (thick arrow) mainly at tops of papillary processes.

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 Â100, B, Basal layer manifestations include lymphocytosis, scattered apoptotic keratinocytes (thin arrows), and squamatization (thick arrow), seen primarily at the rete tips, H&E Â200. histopathology may be reported as “lichenified” or “with histopathologic definitions and a dearth of experienced vulvar superimposed LSC.” It should be noted that hypertrophic LP pathologists. In addition, few publications describe vulvar clas- — sic and hypertrophic LP, and clinicopathologic extrapolation and classic LP seem to be 2 distinct entities not the former 11 being a lichenified version of the latter—and this is reflected in from extragenital disease is likely an oversimplification. the nomenclature.11 Future research should use this document's clinicopathologic Basal layer damage is the principle feature that identifies hy- criteria to identify and categorize LP and report treatment and pertrophic LP or lichenified LS; thus, basal cells must be carefully outcomes in the context of microbiologic, virologic, and inspected for apoptotic bodies and vacuolar change, especially at histopathologic comorbidities. the tips of rete ridges and tops of papillary processes.11 Several features favor lichenified LS over hypertrophic LP: psoriasiform Summary and Recommendations for Practice. The most hyperplasia, absent apoptotic bodies, thickened collagen fibers reliable diagnosis of vulvar LP is achieved through clinicopathologic with lymphocytes aligned in horizontal rows, pericapillary scle- correlation. The diagnoses of classic and hypertrophic LP each rosis, focal sclerosis at the tips of dermal papillae, and a band of 2,25,47 require their own characteristic clinical appearance, accompanied dermal fibrosis. Findings that support lichenified psoriasis by specific features at the 5 epidermal layers (Table 4). The include a normal basal layer, suprabasilar apoptotic keratinocytes, criteria for clinicopathologic diagnosis of erosive LP include and a papillary dermal lymphocytic infiltrate extending into 86 clinical appearance, site, and 3 histopathologic features: lymphocytic the suprapapillary plates. Corneal neutrophils and regular infiltrate, basal layer damage categorized as regenerative and psoriasiform rete ridges also favor psoriasis, but these may be lost degenerative, and absent sclerosis (see Table 5). Recommendations with lichenification. Lichenified mycosis also presents a diagnos- to facilitate clinicopathologic correlation include: tic challenge, as yeast or fungi may be absent even on periodic- acid Schiff staining. When a vulvovaginal swab is positive, it is • Clinicians should aim for universal clinical photography at the difficult to know if the organism represents the primary etiology initial examination for women with suspected LP. of lichenification, or colonization versus superinfection of an un- • 72 Use of words with specific histopathologic definitions, like ero- derlying pruritic dermatosis. Even with clinicopathologic corre- sion and hyperkeratosis, should be avoided when describing the lation, these situations are not easily distinguishable. clinical appearance of vulvar skin abnormalities. • Biopsies should be obtained from morphologically distinct Limitations of the Existing Literature and Areas for areas, as lichenoid dermatoses are often comorbid with each Future Research other and associated with both HSIL and dVIN. The singular obstacle to high-quality research in vulvar LP • Biopsies should be labeled with their specific anatomic site has been the lack of consensus-based clinicopathologic criteria and laterality. that distinguish it from other disorders.8,51,76 One explanation • Pathologists should indicate in their report the category of ero- for the disparate reports of symptoms, signs, and treatment out- sive LP—regenerative, degenerative, or both. comes is that women in studies of LP do not all have the disease • Communication between the clinician and pathologist is es- of interest or have an additional comorbid disease. The use of sential when there is a concern for neoplasia from either party, biopsy to guide study inclusion has been limited by the high and expert multidisciplinary review is recommended before nondiagnostic rate, which in turn relates to inadequate embarking on cytotoxic, ablative, or extirpative procedures.

TABLE 5. Summary of Minimum Clinicopathologic Criteria to Diagnose Vulvar Erosive LP

All 5 criteria must be present Signs 1. Well-demarcated glazed red macule or patch located on vestibule, labia minora, and/or vagina Histopathology 2. Nonkeratinized squamous epithelium, MCJ, and/or adjacent hairless skin 3. Band-like lymphocytic infiltrate, closely applied to the epithelium 4. Basal layer damage demonstrated as a: Degenerative pattern—apoptotic bodies, vacuolar change, and/or squamatization and/or Regenerative pattern—increased nucleus to cytoplasm ratio, mitoses, and diminished epithelial maturation 5. Sclerosis is absent

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