J Cutan Pathol 2015: 42: 693–698 doi: 10.1111/cup.12556 John Wiley & Sons. Printed in Singapore
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Eosinophils in lichen sclerosus et atrophicus Background: The classic histopathologic features of lichen sclerosus et atrophicus (LS) include lymphoplasmacytic inflammation below a zone of dermal edema and sclerosis. The presence of eosinophils in LS has received little attention, but the finding of tissue eosinophils, particularly eosinophilic spongiosis in LS, has been suggested as a marker for the coexistence of autoimmune bullous disease or allergic contact dermatitis (or both). We sought to determine whether the histopathologic presence of dermal eosinophils or eosinophilic spongiosis (or both) in biopsies from patients with LS is associated with autoimmune bullous disease, autoimmune connective tissue disease or allergic contact dermatitis. Methods: A retrospective review of the histopathology and medical records of 235 patients with LS who were evaluated from June 1992 to June 2012 was performed. Results: Sixty-nine patients (29%) had eosinophils on histopathology. Among patients with associated diseases, a statistically significant association between the eosinophil cohort and the cohort without eosinophils was not detected. Conclusions: The importance of eosinophils is uncertain, but our data suggest that the finding of tissue eosinophils alone is not sufficient to prompt an extensive workup for additional diagnoses.
Phillip J. Keith1 , Michael M. Wolz1 and Margot S. Peters1,2
Keywords: autoimmune disease, eosinophil, eosinophilic spongiosis, immunobullous disease, lichen sclerosus
Dr Margot S. Peters, MD, Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA Tel: +507 538 0601 Fax: +507 284 2072 e-mail: [email protected]
Keith PJ, Wolz MM, Peters MS. Eosinophils in lichen sclerosus et atrophicus. J Cutan Pathol 2015; 42: 693–698. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Patients with genital lichen sclerosus et atrophicus (LS) commonly present with patches that are white or erythematous to violaceous (or both). Sometimes these patches are accompanied by atrophy, erosions or lichenification (singly or in combination), with evolution from inflammation to dermal sclerosis. The pathogenesis of LS is not well understood, but genetic susceptibility and autoimmune mechanisms have been suggested as etiologic factors.1,2 Immunologically mediated diseases, such as psoriasis, appear to be more common in patients with LS.3 – 5 A large
Department of Dermatology, Mayo Clinic, Rochester, MN, USA and 2 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA Presented at the American Society of Dermatopathology Annual Meeting, Chicago, IL, November 6, 2014.
Accepted for publication May 28, 2015
retrospective review of LS patients reported that women, compared with men, have an increased risk of autoimmune thyroid disease.6 Histopathologically, LS is characterized by a band of inflammation below a zone of homogeneous paucicellular superficial dermal edema and sclerosis, with variable vacuolar interface degeneration and epidermal atrophy or lichenification. Reported direct immunofluorescence findings include fibrin deposition in the superficial dermis and at the dermal epidermal junction.7 Biopsies of LS often exhibit
Keith et al. a prominent inflammatory infiltrate composed mainly of lymphocytes and plasma cells. The presence of eosinophils in LS has received limited attention. Eosinophil infiltration in LS was first described in 1972.7 In 1998, Carlson et al.8 suggested that dermal eosinophils and eosinophilic spongiosis, among other features observed in biopsies of genital LS, were associated with a poor response to therapy and possible allergic contact dermatitis. Leonard et al.9 postulated that the presence of tissue eosinophils in LS, particularly eosinophilic spongiosis, may be an indication of coexistent bullous pemphigoid. Clinical features of vulvar pemphigoid may resemble those of LS.10 – 13 Most recently, Lester and Swick14 found that eosinophils are particularly common in male genital lesions of LS and in LS associated with squamous cell carcinoma. We therefore sought to determine whether the finding of dermal eosinophils or eosinophilic spongiosis (or both) in biopsy specimens of LS may be a clue to coexistent immunobullous disease, autoimmune disease or allergic contact dermatitis. Materials and methods After our institutional review board approved this study, we searched our clinical and pathology databases for the 20-year period from June 1992 to June 2012. We queried our institutional pathology database with the search terms LS and balanitis xerotica obliterans. Our institutional clinical database was searched for the diagnosis of LS according to the International Classification of Diseases, Ninth Revision. We identified 706 patients: 158 were excluded because the final diagnosis was not LS (e.g. lichenoid mucositis instead), 140 patients were excluded because their biopsies were not evaluated at our institution and 2 patients were excluded because histopathologic material was unavailable for review. Hematoxylin-eosin-stained sections from punch and shave biopsies of 406 patients were reviewed; 171 patients were excluded because their biopsies lacked the classically diagnostic histopathological pattern of LS (as described in the preceding Introduction section). In addition, cases were excluded if they showed deep fibrosis or adnexal trapping suggestive of morphea or morphea-LS overlap. The final study population of 235 patients comprised 17 patients with 2 biopsies, and 1 patient with 3 biopsies diagnostic for LS. A patient with more than one biopsy was included in the eosinophil
cohort if any biopsy contained eosinophils. Biopsies were labeled as originating from genital or perianal sites (169 biopsies; 72%); from the groin, buttocks, hip, flank, lower abdomen or lower back (25; 11%); from the chest or breast (10; 4%) and from the extremities, neck, back or abdomen (31; 13%). In each case, before the clinical information was known, an entire histopathological section was scrutinized for the presence and number of dermal eosinophils and for eosinophilic spongiosis at ×10 or ×20 magnification. Eosinophils were manually counted, and the number of eosinophils per section was recorded. The medical records of all patients were then reviewed to determine demographic features and presence or absence of documented immunobullous disease, autoimmune connective tissue disease (CTD) or allergic contact dermatitis. Fisher exact tests were used for both cumulative and individual statistical analyses for comparison between the number of LS patients with tissue eosinophils and an associated disease and the number of LS patients without tissue eosinophils who had an associated disease. A p value less than 0.05 was considered statistically significant. Results The average age of patients was 65.9 years (range, 4–97 years; SD, 14.1 years); 32 patients (14%) were male. Of the 235 LS patients studied, 69 (29%) had a biopsy of LS with dermal eosinophils and 166 (71%) had a biopsy without eosinophils. Only one patient had an LS biopsy with eosinophilic spongiosis (in addition to dermal eosinophils). Of the 69 patients with dermal eosinophils, 22% had biopsy from an extragenital site, and none of these patients had an associated disease. Autoimmune CTD, allergic contact dermatitis or immunobullous disease was documented in 16 of the 235 LS patients (6.8%): all 16 had genital LS and half had LS with eosinophils. Thus, 12% of the patients with LS biopsy containing eosinophils (8 of 69) had an associated disease, and 5% of the patients who had LS without eosinophils (8 of 166) had an associated disease. This difference was not statistically significant (p = 0.09). No patient with multiple biopsies had an associated disease. Among the 8 of 166 patients who had LS without eosinophils, 4 (2.4%) had CTD: 1 had systemic lupus erythematosus, 1 had subacute cutaneous lupus erythematosus (SCLE),
Eosinophils in lichen sclerosus Table 1. Dermal eosinophils in biopsy sections from patients with LS and coexistent disease
Feature Autoimmune CTD, allergic contact dermatitis, or immunobullous disease Autoimmune CTD Systemic LE Subacute cutaneous LE and Sjögren syndrome Subacute cutaneous LE Discoid LE Sjögren syndrome CREST syndrome Allergic contact dermatitis Nickel conﬁrmed by patch testing Nickel by history Multiple allergens conﬁrmed by patch testing§ Vagisil by history Fragrance conﬁrmed by patch testing Immunobullous disease Localized pemphigoid Generalized pemphigoid Mucous membrane pemphigoid
Total (N = 235)*
Eosinophils present (n = 69; 29%)
No. of eosinophils in section†, ‡
Eosinophils absent (n = 166; 71%)*
16 (6.8%) (p = 0.09)
7 (3.0%) (p = 0.42)
3 (4.3%) 0 1 0 1 1 0 3 (4.3%) 1 1 1 0 0 2 (2.9%) 1 1§ 0
5 (1–11) 0 3 0 11 1 0 1.6 (1–3) 1 1 3 0 0 2.5 (2–3) 2 3 0
4 (2.4%) 1 0 1 0 1 1 2 (1.2%) 0 0 0 1 1 2 (1.2%) 0 0 2
5 (2.1%) (p = 0.15)
4 (1.7%) (p = 0.58)
CREST, calcinosis cutis, Raynaud phenomenon, esophageal dysfunctions, sclerodactyly and telangiectasia; CTD, connective tissue disease; LE, lupus erythematosus; LS, Lichen sclerosus. *Values are presented as number of patients (percentage) or as number of patients. †Values are presented as mean (range) or as mean. ‡Of the 69 patients, 65% had 1–5 eosinophils per section, 17% had 6–10, 8% had 11–20 and 10% had more than 20. The average number of eosinophils per section among all 69 patients was 8.2 (range, 1–62). The average number of eosinophils in biopsies from patients without associated disease was 8.8 (range, 1–62). §Eosinophilic spongiosis and dermal eosinophils.
1 had CREST (calcinosis cutis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly and telangiectasia) syndrome and 1 had Sjögren syndrome. In the LS with eosinophils cohort, 3 of 69 had CTD (4.3%), including 1 patient with diagnoses of SCLE and Sjögren syndrome, 1 patient with discoid lupus erythematosus and 1 with Sjögren syndrome alone. The difference between these two cohorts was not statistically significant (p = 0.42) (Table 1). Two of the 166 patients (1.2%) in the LS cohort without eosinophils had an associated allergic contact dermatitis. One had a clinical history of contact dermatitis to Vagisil, and the other had allergic contact dermatitis to fragrance (confirmed by patch testing). Three of the 69 patients (4.3%) in the LS cohort with eosinophils had an allergic contact dermatitis. The allergic contact dermatitis in all five patients was extragenital and thus did not involve the sites affected by LS. Contact dermatitis to nickel was identified in two patients (one by history alone; one confirmed by patch testing), and another patient had a history of allergic contact dermatitis to
neomycin, bacitracin, parabens, fragrance and colophony (confirmed by patch testing). The difference between these two cohorts was not statistically significant (p = 0.15) (Table 1). Two of 166 patients (1.2%) in the LS cohort without eosinophils had mucous membrane pemphigoid (oral involvement only); 2 of the 69 patients (2.9%) in the LS cohort with eosinophils had pemphigoid (1 with generalized disease; 1 with localized scalp involvement). This difference was not statistically significant (p = 0.58). The patient with an LS biopsy containing eosinophilic spongiosis also had dermal eosinophils and had generalized bullous pemphigoid (Table 1). Eosinophils were found in 24% of patients with genital LS and in 31% of patients with extragenital LS. The histopathologic features from a patient in the eosinophil cohort are shown in Figs. 1 and 2. Of the 69 patients with eosinophils, 65% had 1–5 eosinophils per section, 17% had 6–10, 8% had 11–20 and 10% had more than 20 eosinophils per section. The average number of eosinophils per section among all 69 patients
Keith et al.
Fig. 1. Lichen sclerosus et atrophicus histopathology. Section shows characteristic compact hyperkeratosis, upper dermal pallor and sclerosis and mixed dermal inflammation (hematoxylin-eosin, original magnification ×10).
Fig. 2. Lichen sclerosus et atrophicus with dermal eosinophils. Section from the same patient as in Fig. 1 reveals numerous dermal eosinophils (hematoxylin-eosin, original magnification ×20).
was 8.2 (range, 1–62). The average number of eosinophils in LS biopsies from patients without associated disease was 8.8 (range, 1–62). The average number of eosinophils in biopsies from LS patients with CTD, allergic contact dermatitis or immunobullous disease was 3.1 (range, 1–11). An average of 2.6 eosinophils per section were observed in biopsies from patients with another disease compared with 9 eosinophils per section in cases without associated disease (p = 0.003). Discussion Our patient population resembles previously reported epidemiologic data showing that genital LS commonly affects elderly women15,16 and
children.17 We found similar percentages of eosinophils in our study group (31% of genital and 24% of extragenital cases) compared with the cohort reported by Carlson et al.,8 in which 35% of genital and 17% of extragenital cases had eosinophils. Twenty-five percent of their cases also showed spongiotic dermatitis, and 5% of those specimens exhibited eosinophilic spongiosis; the authors noted a correlation between persistent and progressive pruritus and the presence of eosinophils. Lester and Swick14 reported an association between eosinophils in LS and squamous cell carcinoma. None of our patients with LS also had an associated squamous cell carcinoma. To the best of our knowledge, our study is the largest to systematically evaluate the presence of eosinophils in LS and to determine whether tissue eosinophils might correlate with the coexistence of immunobullous disease, CTD or allergic contact dermatitis. The overall incidence of associated diseases in our LS population was low (6.8%); 12% of patients with LS biopsy containing eosinophils had an associated disease compared with 5% of LS cases without eosinophils. Our data suggest an association between the presence of eosinophils in LS and associated disease, but this observation was not statistically significant (p = .09). There was no statistically significant association between a specific type of associated disease and the presence or absence of tissue eosinophils (Table 1). In addition to the retrospective design of our study, a potential limitation may be exclusion of cases that lacked the stand-alone diagnostic histopathological pattern of LS. Because the main goal of our study was to evaluate an association between LS and associated allergic or autoimmune disease, we chose to use the classic histopathology as the gold standard for diagnosis, because photographs to verify the clinical diagnosis were inconsistently available, particularly of genital disease. We thus probably excluded patients with biopsies that exhibited histopathological features compatible with but not specific for LS, including interface dermatitis and epidermal acanthosis or atrophy8,14,18 because such patterns also may be seen in the disease associations we sought to determine. The presence of eosinophils has been shown in early or transitional cases of LS;14 however, this observation was not statistically significant when compared with cases of well developed LS. We also excluded cases that showed deep dermal fibrosis suggestive of morphea or morphea-LS overlap. There were no excisional biopsies to evaluate for
Eosinophils in lichen sclerosus eosinophilic fasciitis. Thus, we suggest that the narrow set of inclusion criteria is the strength of our study because it yielded a relatively homogenous study group defined by classic histopathology and further verified by clinical diagnosis. A goal of our study was to assess eosinophils as one does in daily dermatopathology practice, by scanning an entire section to judge the infiltrate. We thus chose to evaluate the number of eosinophils per section rather than by hot spot or specified number of fields. Biopsies from most of our patients who had LS with eosinophils were obtained with 3 or 4-mm punches, and the differences in eosinophil counts varied among sections of same or similar size. Eosinophilic spongiosis may be a histopathologic feature of immunobullous disease but also is observed in other disorders, including allergic contact dermatitis, drug reactions, incontinentia pigmenti, hypereosinophilic syndrome and eosinophilic cellulitis.19,20 We found only 1 patient with LS with eosinophilic spongiosis among the study group of 235 patients, representing 1 of only 4 patients with immunobullous disease (equally divided among LS patients with and without tissue eosinophils). The clinical significance of the rare finding of eosinophilic spongiosis in LS is indeterminate but could introduce consideration of pemphigoid. Patients with LS may have abnormal expression of basement membrane hemidesmosomal proteins.21 Autoantibodies to extracellular matrix protein 1, a protein found at the dermal epidermal junction, have been detected in patients with LS, and higher antibody titers are associated with
chronic and refractory disease.2,22 The role of these antibodies in LS pathogenesis is unclear. Interestingly, elevated BP180 and BP230 autoantibody levels have been reported in patients with LS23 – 25 but do not appear to correlate with disease severity.23,25 Although traditionally associated with allergic reactions, eosinophils have a role in tissue remodeling26 and are found in biopsy specimens from several dermatologic and extracutaneous fibrosing or sclerosing disorders,27 including ocular pemphigoid,28 morphea profunda,29 eosinophilic fasciitis,30,31 granuloma faciale,32,33 immunoglobulin G4-related sclerosing diseases,34 endomyocardial fibrosis associated with hypereosinophilic syndrome,35 eosinophilic angiocentric fibrosis of the upper respiratory tract and orbit,36,37 idiopathic retroperitoneal fibrosis, sclerosing mediastinitis, sclerosing cholangitis and pulmonary fibrosis.27 Thus, the common presence of tissue eosinophils in LS may be less a diagnostic marker for coexistent allergic or autoimmune disease than a reflection of the sclerosis that is integral to LS. Our data also stress the importance of clinicopathological correlation. The presence of eosinophils in a biopsy of LS should not alone prompt the clinician to look for an underlying associated disease, unless the clinical history or physical examination findings suggest another condition. Prospective long-term studies are needed to determine whether the degree of tissue eosinophilia during the inflammatory phase of LS correlates with its scarring sequelae.
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