Histopathologic findings in lupus erythematosus tumidus: Review of 80 patients

DERMATOPATHOLOGY

Histopathologic findings in lupus erythematosus tumidus: Review of 80 patients Annegret Kuhn, MD,a Monika Sonntag, MD,a Thomas Ruzicka, MD,a Percy Lehmann, MD,b and Mosaad Megahed, MDa Du ¨ sseldorf and Wuppertal, Germany Background: In a recent study, we demonstrated that lupus erythematosus (LE) tumidus (LET) is a distinct subset of cutaneous LE (CLE), which is clinically characterized by erythematous, urticaria-like, nonscarring plaques in sun-exposed areas. Objective: Our purpose was to analyze skin biopsy specimens from 80 patients with this disease and to determine whether it could be differentiated from other variants of CLE on histopathologic grounds. Methods: Skin biopsy specimens from 53 primary and 38 UVA- and/or UVB-induced lesions of 80 patients with LET were examined and compared with skin biopsy specimens from patients with discoid LE (DLE) and subacute CLE (SCLE). Results: Specimens from LET lesions showed a characteristic and diagnostic pattern of perivascular and periadnexal cellular infiltrates in the papillary and reticular dermis composed almost entirely of lymphocytes. In some cases, few scattered neutrophils were present. Furthermore, interstitial mucin deposition was observed in all specimens, as confirmed by colloidal iron staining. In contrast to discoid LE and subacute CLE lesions, epidermal atrophy or alteration at the dermoepidermal junction was not detected. Conclusion: Skin lesions of patients with LET present with specific histopathologic features, and the differences compared with subacute CLE and discoid LE further support the concept to consider LET as a separate entity of CLE. (J Am Acad Dermatol 2003;48:901-8.)

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upus erythematosus (LE) includes a wide spectrum of manifestations in many organ systems, and, therefore, classification of this disease and understanding of its different subsets are important for the primary care physician. Because the skin is the only area of involvement for many patients with LE,1,2 much attention has been given to the issue of classifying LE from the dermatologic perspective, but there is still considerable debate in this field.3-6 According to Gilliam and Sontheimer,7 there are 3 broad categories of cutaneous LE (CLE): acute (ACLE), subacute (SCLE), and chronic (CCLE). ACLE has been reported under the designations

From the Departments of Dermatology at Heinrich-Heine-University of Du¨sseldorf a and University of Witten-Herdecke.b Supported in part by a research grant from the Heinrich-Heine-University of Du¨sseldorf and by a Lise-Meitner Scholarship (Dr Kuhn). Conflict of interest: None identified. Reprint requests: Annegret Kuhn, MD, Department of Dermatology, Henrich-Heine-University of Du¨sseldorf, Moorenstrasse 5, D-40225 Du¨sseldorf, Germany. E-mail: [email protected]. Copyright © 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 ⫹ 0 doi:10.1067/mjd.2003.435

Abbreviations used: ACLE: CCLE: CLE: DLE: LE: LET: PLE: REM: SCLE:

acute cutaneous lupus erythematosus chronic cutaneous lupus erythematosus cutaneous lupus erythematosus discoid lupus erythematosus lupus erythematosus lupus erythematosus tumidus polymorphous light eruption reticular erythematous mucinosis subacute cutaneous lupus erythematosus

of malar erythema or “butterfly” rash; however, because dermatologists are not usually the primary health care professional to confront such patients as a result of the strong association between ACLE and systemic LE activity, few data concerning this form are available in the dermatologic literature.8 In contrast, SCLE is a distinct subset with specific clinical and serologic features introduced by Sontheimer et al9 in 1979. This subset occurs in 10% of patients with cutaneous manifestations of LE and is distinguishable from typical CCLE on the basis of the absence of scarring, the frequent occurrence of photosensitivity, and the distribution of widespread 901

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Table I. Study patients and skin biopsy specimens

Diagnosis

LET DLE SCLE

Patients (No.)

Biopsy specimens (No.)

Primary lesions (No.)

UVA

UVB

UVA/UVB

80 10 10

91 11 12

53 — —

17 5 5

11 4 5

10 2 2

UV-induced lesions (No.)

DLE, Discoid lupus erythematosus; LET, lupus erythematosus tumidus; SCLE, subacute cutaneous lupus erythematosus.

papulosquamous or annular lesions. Patients with SCLE typically have mild systemic disease consisting of arthralgias and other musculoskeletal symptoms, but no renal or central nervous system involvement. Furthermore, most patients have anti-Ro/SS-A antibodies and the human histocompatibility antigen HLA-DR3.10 Discoid LE (DLE), the most common subtype of CCLE, can be separated into 2 groups: localized and generalized. This distinction seems to be clinically meaningful because the widespread disease is frequently associated with laboratory abnormalities and systemic involvement.11,12 LE tumidus (LET) is a further subtype of CCLE that has been documented in the literature in only a few cases since first being described by Gougerot and Burnier13 in 1930. However, in the past few years, some case reports of patients with LET have been published indicating that the incidence of LET seems to be higher than found in earlier studies.14-16 In a recent article, our group17 demonstrated characteristic features of 40 patients with this disease and concluded that LET should be differentiated from other variants of CCLE. The clinical picture of LET is characterized by erythematous, succulent, urticarialike, nonscarring plaques in a characteristic distribution. The onset of the disease clusters in summer because of increased sun exposure, and more than 70% of patients show remarkable photosensitivity confirmed by results of provocative phototesting.18 In a few cases, there is a tendency for the skin lesions to coalesce in the periphery and to produce a gyrate or annular configuration, imitating the annular type of SCLE. Most patients with LET show complete resolution of skin lesions after systemic therapy with antimalarial agents, and in some cases skin lesions resolve spontaneously without any treatment. In 10% of patients, antinuclear antibodies are detected, but there is no evidence of systemic involvement in any of the reported cases. The purpose of this investigation was to evaluate the incidence of specific histopathologic features in 80 patients with LET seen retrospectively during a 16-year period at the Department of Dermatology, Heinrich-Heine University, Du¨ sseldorf, Germany. Because LET has not always been considered a sep-

arate entity, we found it worthwhile to analyze the histopathologic features of this disease and to determine whether skin lesions of this nonscarring, photosensitive type of CCLE can be distinguished from those of DLE and SCLE reliably by histologic examination.

MATERIALS AND METHODS Patients We investigated skin lesions from 80 patients with LET collected between 1984 and 2000, with a mean length of follow-up of 5.2 ⫾ 3.5 years. The criteria used to establish the diagnosis of LET have been described previously by our group17 and include the characteristic clinical picture of erythematous, urticaria-like, succulent, nonscarring plaques in sunexposed areas and the extreme photosensitivity reproduced by provocative phototesting in correlation with the histopathologic findings. Furthermore, antinuclear antibodies were assayed using a standard indirect immunofluorescence technique with commercially available HEp-2 cells. With this assay technique, serum titers of greater than 1:160 are clearly abnormal compared with those of controls. The diagnosis and subclassification of DLE and SCLE was on the basis of clinical and histologic criteria, and on phototesting results and serologic abnormalities.8 We evaluated biopsy specimens from primary skin lesions of 53 patients and from UVA- and/or UVBinduced skin lesions of 27 patients with LET. For control purposes, skin biopsy specimens from UVinduced lesions of 10 patients with DLE and 10 patients with SCLE were investigated after provocative phototesting. Skin biopsy specimens The material used for this study consisted of 91 lesional skin biopsy specimens from 80 patients with LET consisting of 53 primary skin lesions, 17 UVAand 11 UVB-induced skin lesions, and 10 induced skin lesions after combined UVA and UVB irradiation (Table I). Furthermore, skin biopsy specimens from 11 UV-induced skin lesions from patients with DLE and 12 UV-induced skin lesions from patients with SCLE were investigated after provocative pho-

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Table II. Histopathologic changes in 91 primary and UV-induced lesions of lupus erythematosus tumidus Histopathologic changes

Epidermis Atrophy Acanthosis Hyperkeratosis Parakeratosis Follicular plugging Dermoepidermal junction Normal Liquefaction degeneration Basement membrane thickening Dermis Infiltration Superficial Deep Type of inflammatory cells Lymphocytes Histiocytes Neutrophils Erythrocyte extravasation Edema Mucin deposition (colloidal iron staining)

Primary lesions, No (%) (n ⴝ 53)

UV-induced lesions, No. (%) UVA (n ⴝ 17)

UVB (n ⴝ 11)

UVA/UVB (n ⴝ 10)

0 (0) 2 (4) 2 (4) 1 (2) 0 (0)

0 (0) 0 (0) 0 (0) 5 (29) 0 (0)

0 (0) 0 (0) 4 (36) 2 (18) 0 (0)

0 (0) 0 (0) 2 (20) 2 (20) 0 (0)

53 (100) 0 (0) 0 (0)

17 (100) 0 (0) 0 (0)

11 (100) 0 (0) 0 (0)

10 (100) 0 (0) 0 (0)

53 (100) 47 (89)

17 (100) 15 (88)

11 (100) 2 (18)

10 (100) 9 (90)

53 (100) 39 (74) 25 (47) 3 (6) 8 (15) 53 (100)

17 (100) 8 (47) 8 (47) 6 (35) 1 (6) 17 (100)

11 (100) 7 (64) 4 (36) 5 (45) 1 (9) 11 (100)

10 (100) 7 (70) 3 (30) 2 (20) 1 (10) 10 (100)

totesting. All skin biopsy specimens were fixed in a 10% solution of formaldehyde and embedded in paraffin. Four–micrometer thick sections were stained with hematoxylin-eosin or colloidal iron, and processed for histologic examination and evaluation. Direct immunofluorescent examination of cryostat-cut sections was performed in primary lesions of 25 patients and in UV-induced lesions of 10 patients with LET. Microscopic evaluation Each specimen was examined by light microscopy and scored for the presence or absence of histopathologic features, including epidermal atrophy, acanthosis, hyperkeratosis, parakeratosis, follicular plugging, type and pattern of inflammatory infiltrate, dermal edema, and interstitial mucin deposition (Tables II and III). After all skin biopsy specimens were reviewed, the clinical diagnosis, provocative phototest results, and histopathologic features were evaluated using discriminant analysis. There was no attempt to correlate microscopic findings in specimens with the age of the lesion, stage of disease, or anatomic location. Provocative phototesting For provocative phototesting, we used a highpressure metal halide lamp (340-440 nm) (UVA1Sellas 2000 unit, Sellas Medizinische Gera¨ te, Gevelsberg, Germany) for UVA phototesting and a UV-800 unit lamp with fluorescent bulbs (285-350

nm) (Philipps TL 20 W/12, Waldmann, Villingen/ Schwenningen, Germany) for UVB phototesting. Irradiation output was measured using a UV-radiometer (UVAmeter, Mutzhas, Mu¨ nchen, Germany) and a UV-spectrometer (Waldmann). Minimal erythema dose, threshold dose for immediate pigment darkening, and minimal tanning dose were determined as previously described.19-21 Test reactions were read immediately and 24 hours after irradiation. For provocative phototesting, areas (4 ⫻ 5 cm) of uninvolved skin on the back were irradiated with single doses of UVA (60-100 J/cm2) and/or UVB (1.5 minimal erythema dose) daily for 3 consecutive days. Test areas were evaluated until specific skin lesions appeared for up to 4 weeks after the last irradiation. Criteria for a positive provocative phototest result required that (1) induced lesions clinically resembled LE, (2) histopathologic findings were compatible with LE, and (3) skin lesions developed slowly and persisted for several days or weeks.22,23

RESULTS Histopathologic findings in primary skin lesions of LET A total of 91 lesional skin biopsy specimens from 80 patients were evaluated, and the histopathologic features, which were consistent with LET, are summarized in Table II. As shown in Fig 1, A to C, a moderate to dense, fairly well-circumscribed dermal

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Table III. Histopathologic changes in UV-induced lesions of discoid lupus erythematosus and subacute cutaneous lupus erythematosus UV-induced lesions, No. (%) Histopathologic changes

Epidermis Atrophy Acanthosis Hyperkeratosis Parakeratosis Follicular plugging Dermoepidermal junction Normal Liquefaction degeneration Basement membrane thickening Dermis Infiltration Superficial Deep Type of inflammatory cells Lymphocytes Histiocytes Neutrophils Erythrocyte extravasation Edema Mucin deposition (colloidal iron staining)

DLE (n ⴝ 11)

SCLE (n ⴝ 12)

2 (18) 1 (9) 2 (18) 4 (36) 3 (27)

1 (8) 0 (0) 3 (25) 2 (17) 0 (0)

4 (36) 8 (73) 3 (27)

2 (17) 12 (100) 4 (33)

11 (100) 6 (55)

12 (100) 4 (33)

11 (100) 4 (36) 4 (36) 1 (9) 0 (0) 2 (18)

12 (100) 4 (33) 2 (17) 3 (25) 1 (8) 4 (33)

DLE, Discoid lupus erythematosus; SCLE, subacute cutaneous lupus erythematosus.

infiltrate is present in a perivascular and periadnexal distribution. Occasionally, the infiltrate, which is composed of lymphocytes and, in a few cases, also of neutrophils, extends into the subcutis. Abundant interstitial mucin deposition between collagen bundles is detected in all specimens, as confirmed by colloidal iron staining. Extravasated erythrocytes in the papillary dermis are present in some cases, and a slight dermal edema is observed in the papillary dermis but only in about one third of the specimens. In contrast to SCLE and DLE, epidermal changes such as follicular plugging or atrophy are absent, and only in a few specimens mild to moderate acanthosis or slight parakeratosis are seen. Vacuolar degeneration of the dermoepidermal junction and basement membrane thickening, which are main features of SCLE and DLE, have never been detected in specimens from patients with LET. Histopathologic findings in UV-induced skin lesions of LET As shown in Fig 1, D to I, there are nearly no differences in histopathologic findings between pri-

mary and UV-induced lesions of LET (Table II). However, the lymphocytic infiltrate of UV-induced lesions appears to be more dense and the amount of interstitial mucin deposition more sparse than in primary skin lesions. Furthermore, slight acanthosis and sunburn cells are observed in skin lesions provoked by UVB irradiation. Immunopathologic findings in primary and UV-induced skin lesions of LET Results of direct immunofluorescence of lesional skin biopsy specimens from patients with LET have been negative in most cases. In primary skin lesions, IgG was detected in 5 specimens and IgM in one specimen in a bandlike pattern at the dermoepidermal junction. However, further immunoglobulin classes (IgA) and complement components (C3) were not identified and all specimens from UVinduced lesions showed negative results. In addition, laboratory tests revealed antinuclear antibodies with a titer of greater than 1:160 (range: 1:160-1:640) in 10% of patients with LET; however, there was no significant correlation between positive results by direct immunofluorescence and positive antinuclear antibodies.

DISCUSSION In a recent study17 of 40 patients with LET, we considered this entity to be a distinctive subset of CCLE that has been neglected in the literature since first being described in 1930.13 The importance of re-evaluating this form lies in the clinical picture and course of the disease, and in its remarkable photosensitivity.18 The prognosis in patients with LET is generally more favorable than in those with other forms of CLE because none of the patients showed 4 or more of the American Rheumatism Association criteria for the diagnosis of systemic LE.24 In this study, we classified 80 patients as having LET on the basis of the findings of clinical and photobiologic examination, and confirmed that histopathologic changes in LET are distinct and different from those in DLE or SCLE. The most frequent histopathologic features in biopsy specimens from LET lesions are a fairly well-circumscribed lymphocytic dermal infiltrate in a perivascular and periadnexal pattern, and abundant interstitial mucin deposition. Occasionally, some neutrophils were also present. In a few cases, the epidermis is acanthotic and the dermis shows edema in its papillary part; however, in contrast to other forms of CLE, epidermal changes, such as atrophy and follicular plugging, and vacuolar degeneration of the dermoepidermal junction or basement membrane thickening are absent. Skin biopsy specimens from UV-induced lesions of LET taken after provocative phototesting presented with a sim-

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Fig 1. Histologic examination of skin lesions in lupus erythematosus tumidus. A-C, Primary lesions; D-F, UVA-induced lesions; G-I, UVB-induced lesions. Lymphocytic infiltration is present in papillary and reticular dermis in perivascular and periadnexal distribution (A, D, and G, scale bar ⫽ 800 ␮m; B, E, and H, scale bar ⫽ 200 ␮m), and interstitial mucin deposition is confirmed by colloidal iron staining (C, F, and I, scale bar ⫽ 200 ␮m).

ilar pattern compared with primary lesions; however, a more dense infiltrate of lymphocytes was seen and interstitial mucin deposition was less prominent. Histopathologic findings in primary skin lesions of DLE and SCLE have been studied in detail by several groups8,25-29 and show that there are variable degrees of hyperkeratosis, basal cell degeneration,

and mononuclear cell infiltration around the dermoepidermal junction extending into the dermis. In SCLE, hyperkeratosis and the inflammatory infiltrate are less prominent than in DLE, and the most useful characteristic feature of DLE that distinguishes it from SCLE is it being a superficial and deep indurated disease.26,27 Furthermore, histopathologic features of SCLE and DLE include epidermal atrophy

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with loss of rete ridges, vacuolar alteration of the dermoepidermal junction, and thickening of the basement membrane zone.26-30 In contrast to LET, the inflammatory infiltrate composed primarily of lymphocytes is occasionally sparse, but increased amounts of dermal mucin deposition may also be present. Furthermore, LET differs from DLE in that scarring is not present in LET, and patients are more likely to be initiated or exacerbated by UV light.23 As previously described by our group,22,31 no distinct histologic differences could be detected in UV-induced lesions after provocative phototesting with respect to DLE and SCLE (Table III). In UVA-induced skin lesions, only a few epidermal changes, such as atrophy or hyperkeratosis, and slight vacuolar degeneration of the dermoepidermal junction and smudging of the basal membrane zone are seen. Skin lesions induced by UVB irradiation are characterized by parakeratosis, few necrotic keratinocytes, and thinning of the epidermis with loss of rete ridges. In contrast to UVA-induced lesions, vacuolar alteration of the dermoepidermal junction and thickening of the basement membrane zone are more prominent. In some cases, the diagnosis of LE can further be substantiated on direct immunofluorescent examination by demonstrating immunoglobulin or complement components at the dermoepidermal junction. Initial studies indicated that these deposits are present in 60% of SCLE skin lesions compared with somewhat higher percentages for ACLE and DLE9; however, the significance of immune deposits at the dermoepidermal junction is unclear because they can also be identified in clinically uninvolved skin of these patients, and similar patterns can be found in other dermatologic conditions.32 Furthermore, immune deposits are seen in normal and sun-damaged skin but are usually not present in early UV-induced lesions of patients with LE.31,33,34 Thus, the presence of immune deposits at the dermoepidermal junction can help confirm the diagnosis of LE, but their absence does not necessarily rule out the diagnosis.8 In our study, biopsy specimens from primary skin lesions of only 6 patients with LET demonstrated immunoglobulin (IgG or IgM) deposits along the dermoepidermal junction, but additional immunoglobulin classes (IgA) and complement components (C3) were not identified in any specimen from primary or UV-induced lesions. The histopathologic findings of LET bear striking similarities to those of other diseases, such as polymorphous light eruption (PLE), Jessner’s lymphocytic infiltration of the skin, and reticular erythematous mucinosis (REM). In PLE, which also exhibits superficial and deep perivascular infiltrates of lym-

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phocytes and is devoid of changes along the dermoepidermal junction, differentiation from LET is best accomplished by colloidal iron staining, in which there is no mucin deposition in the reticular dermis.35 Furthermore, epidermal changes, such as spongiosis of variable extent and scale crusts, may be present in PLE, and there is usually a marked edema of the papillary dermis. In addition, correlation of the histopathologic features with the clinical picture can help confirm the diagnosis.36 The skin lesions arise mainly in spring and summer, and the time course of PLE, with its onset hours after intense sun exposure and spontaneous fading of lesions within hours or days, is very characteristic.37 When skin lesions are induced by experimental UV irradiation, patients with LET present with a much more delayed reaction after UV exposure and, in addition, these skin lesions persist for weeks or months, even if a sunblock is applied.23,38,39 Jessner’s lymphocytic infiltration of the skin is a relatively uncommon disorder with asymptomatic, papulonodular, nonscarring lesions on the face. Histologically, the lesions show a patchy perivascular and sometimes periadnexal infiltrate consisting of lymphocytes, few histiocytes, and plasma cells. The infiltrate often shows a tendency to arrange itself around cutaneous appendages and blood vessels, and it may extend into subcutaneous fat. In contrast to LET, mucin deposition in patients with Jessner’s lymphocytic infiltration of the skin was not described in the original report by Jessner and Kanof40 in 1953. However, Jessner’s lymphocytic infiltration of the skin has not always been considered a specific disease entity, and until today, no unanimity exists concerning its nosology.35,41 Several studies41,42-44 demonstrated that clinical and histologic criteria are insufficient to distinguish Jessner’s lymphocytic infiltration of the skin from the spectrum of CLE, and in a recent report,45 the occurrence of these 2 conditions in one family further supports the theory that Jessner’s lymphocytic infiltration of the skin is in the same disease spectrum as CLE. In our opinion, some patients described in the literature as having Jessner’s lymphocytic infiltration of the skin might represent LET, and the response to antimalarial agents and the positive phototesting results support our hypothesis. REM is a further rare disease with skin lesions ranging from erythematous, indurated papules to reticulated, macular erythema on the central aspect of the chest or upper portion of the back. In contrast to LET, young to middle-aged women are mostly affected. Interestingly, some authors also consider REM to be a variant of CLE because antimalarial agents have been reported as the most effective

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therapy and patients with REM have shown aggravation of the rash on exposure to sunlight.46,47 However, only few attempts have been made to quantify the light intolerance or to provoke the skin by phototesting48 and, in addition, treatment of REM with a large dose of UVB radiation has even been suggested.49 Histopathologic analysis of REM shows a epidermis with no or minimal vacuolar degeneration at the dermoepidermal junction and a mild to dense perivascular and perifollicular, mainly lymphocytes, infiltrate in the dermis with abundant mucin deposition.50 Immunofluorescent staining for immunoglobulin and complement deposition in lesional skin has mostly been negative.51 In this study, we described in detail the histopathologic findings in 80 patients with LET and we conclude that histologic examination and staining with colloidal iron are sufficiently characteristic so that a specific diagnosis can be made. Correlation of the histopathologic findings with the clinical picture and photoprovocation tests will confirm the diagnosis of LET and exclude other skin diseases, such as PLE, REM, and Jessner’s lymphocytic infiltration of the skin. We thank Magret Winkler, Angelika Moritz, and Nadja Hartmann for technical assistance.

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