To define comprehensive criteria for the classification and differential diagnosis of tumid lupus erythematosus (LE).
To define comprehensive criteria for the classification and differential diagnosis of tumid lupus erythematosus (LE).
A prospective study of patients fulfilling the classical description of tumid LE was performed. Clinical evaluation, histopathologic and direct immunofluorescence analyses of skin specimens, and serologic evaluation were conducted. The inflammatory cell infiltrate was quantitatively investigated by immunohistochemical analysis of fresh frozen skin specimens using multiple lymphocytic markers.
Fifteen patients were followed for a mean of 7 years. Smooth, indurated, nonscarring, pink to violaceous papules, plaques, or nodules, devoid of surface changes were distributed on sun exposed sites. The mean lesion duration was 2 years, female:male ratio was 8:7, and racial distribution was 11 white, 2 Hispanic, and 2 African American patients. Histopathologic findings included a superficial and deep, perivascular, and frequently periadnexal infiltrate of lymphocytes, mucin deposition throughout the dermis, and absent to focal dermal-epidermal junctional involvement. Direct immunofluorescence immunoreactants and low titer antinuclear antibodies were variably present. Immunohistochemical findings included a predominance of pan-T cell marker CD3-expressing (78.0% ± 6.3%) T lymphocytes. Most were CD4 expressing (82.7% ± 8.0%) helper T cells; a minority were CD8 expressing (31.3% ± 14.0%) cytotoxic T cells. The CD4:CD8 ratio was 3.1 (±1.3):1. One patient developed systemic LE and one a discoid LE lesion.
Comprehensive clinical, histopathologic, and immunohistochemical criteria for the classification of tumid LE are proposed that differentiate tumid LE from other cutaneous disorders that may be clinically and histologically indistinguishable. The chronic, benign course indicates that tumid LE be classified as a form of chronic cutaneous LE, although it may be a cutaneous feature of systemic LE.
Lupus erythematosus (LE) is an autoimmune disease with heterogeneous presentations often involving the skin. Criteria for the classification of the most severe form, systemic LE, have been established by the American College of Rheumatology (ACR, formerly American Rheumatism Association) (1, 2). The cutaneous forms of LE may be divided into acute, subacute, and chronic skin lesions (3, 4). The acute cutaneous LE lesions, which are most frequently associated with systemic LE, include diffuse alopecia, oral ulcers, erythematous/edematous plaques, and bullae. The subacute cutaneous LE lesions, which are less frequently associated with systemic LE, include psoriasiform and annular polycyclic lesions. The chronic cutaneous LE lesions, which are infrequently associated with systemic LE, include discoid LE, hypertrophic LE, lupus profundus, palmoplantar (acral) LE, and scarring alopecia. In this article, we present criteria for classifying patients with another subset of the chronic form, tumid LE, and for differentiating it from other skin diseases.
First reported in 1909 by Erich Hoffman at a meeting of the Berlin Dermatological Society, lupus erythematodes tumidus was the term used to describe the condition of 2 patients with erythematous, indurated, facial lesions, with minimal to absent surface change (5). Similar lesions in LE patients have been reported outside the United States (6–21). Despite these reports, comprehensive criteria for definition and differential diagnosis of tumid LE remain elusive. It has often been difficult to distinguish tumid LE from other cutaneous disorders that present in a similar manner clinically and histologically, which has led to much confusion in the literature (12–19).
Because the identification of tumid LE has not been made with the same set of criteria among physicians, we set out to propose a uniform classification to assemble and compare data from different sources. In this article, we present the largest and longest followed series of cases of tumid LE in the US and the results of our clinical, serologic, histopathologic, immunopathologic, and immunohistochemical investigations. Comprehensive criteria are selected for the classification of tumid LE and for differential diagnosis of diseases presenting with similar clinical features.
Fifteen patients were evaluated prospectively in the Charles C. Harris Skin and Cancer Pavilion at New York University Medical Center and in 2 private practices (AGF and NAS) from 1986 to 2001. The inclusion criteria utilized for this study were based on the methods used in developing the ACR criteria for systemic LE, which state that patients were “diagnosed by whatever clinical and laboratory methods the physician deemed appropriate” (1). Patients included in the current study were initially diagnosed using the clinical and histopathologic features described in the original description of tumid LE (5).
The data collected for each patient included the clinical, histopathologic, immunopathologic, and laboratory manifestations listed in Table 1, whether or not the investigators believed them to be significant for classification criteria, as was done in assembling systemic LE criteria (1). Patient age, sex, and race were recorded. Lesion duration, morphology, color, texture, size in centimeters, anatomic location, and distribution were also recorded.
|Case||Age, years||Sex||Race||Sites involved||Photosensitivity||Lesions||Duration, years||Followup, years||H & E||Colloidal iron||PAS||DIF||ANA||CD3, %||CD4, %||CD8, %||CD4:CD8|
|1||70||F||W||Lft cheek, Lft chest†||Pos||E, Pa, & N||0.67||4||S & D, PA, FI (DFJ), PN||P, R, PA||Pos||Neg||Neg||80.0||68.5||24.0||2.9|
|2||64||F||W||Lft leg†||Neg||E, N||0.04||14||S & D, PA||P, R, PA||ND||ND||ND||ND||ND||ND||ND|
|3||51||M||W||Lft cheek†||Pos||E, N||0.50||4||S & D, PA, FI (DFJ)||P, R, PA||ND||ND||1:40 sp||87.9||83.8||42.5||2.0|
|4||37||M||AA||Temples, Lft shoulder†||Pos||E, 1 Pa, & Pl||0.92||12||S & D||P, R||ND||Neg||1:80 sp; 1:160 ncl||ND||ND||ND||ND|
|5||43||M||W||Cheeks, Lft preauricular†||Pos||E, Pa, & Pl||5.00||12||S & D||P, R||ND||I, IgG, G, IgM||1:40 sp||ND||ND||ND||ND|
|6||62||F||W||Lft cheek†||Pos||E, Pl||1.60||4||S & D, PA||P, PA||Neg||L IgG, G IgM||Neg||80.0||90.0||18.8||4.8|
|7||26||M||W||Nose, cheeks, arms†||Pos||E, I Pl, & N||0.60||15||S & D||P, R||ND||ND||Neg||ND||ND||ND||ND|
|8||37||M||W||Forehead, cheeks†||Pos||N||3.00||3||S & D, PA, FI (DEJ)||P, R||Pos||L IgG, G IgM||Neg||72.5||80.0||17.5||4.6|
|9||47||M||W||Back†||Neg||E, N||2.50||9||S & D||ND||ND||Neg||Neg||77.5||90.0||52.5||1.7|
|10||34||F||H||Cheeks, Rt mandible†||Pos||E, N||0.83||14||S & D||P, R||ND||ND||ND||ND||ND||ND||ND|
|11||50||F||H||Forehead,† arms, flank||Pos||E, N||0.40||4||S & D||ND||ND||ND||ND||ND||ND||ND||ND|
|12||51||M||AA||Chest†||Pos||E, Pl||3.00||3||S & D||ND||ND||Neg||1:160 sp||70.0||83.8||32.5||2.6|
|13||53||F||W||Cheeks, chest, upper back†||Pos||E, Pa, & Pl||9.00||2||S & D, PA, FI (DEJ)||P, R||Neg||L IgM, F||ND||ND||ND||ND||ND|
|14||37||F||W||Rt arm†||Pos||E, I Pl||1.00||2||S & D, PA, FI (DEJ)||P, R, PA||Neg||L IgG, G IgM/A, C3, F||1:160 sp||ND||ND||ND||ND|
|15||40||F||W||Face, chest,† arms||Pos||E, M, T||1.50||2||S & D||P, R||Neg||Neg||Neg||ND||ND||ND||ND|
The number of skin biopsies performed per patient ranged from 1 to 3. Four-millimeter punch skin biopsy specimens were fixed in 10% formalin, processed in a routine fashion, embedded in paraffin, sectioned on a microtome, and stained with hematoxylin and eosin. Mucin deposition was analyzed by colloidal iron stain. The dermal-epidermal junction was examined by periodic acid-Schiff stain.
Direct immunofluorescence analysis was performed on cryostat sections of fresh frozen tissue. Tissue was placed in optimal cutting medium and maintained at −20°C. The following fluorescence-labeled antibodies and dilutions were used: goat anti-human IgG fluorescein isothiocyanate (FITC; Tago [Burlingame, CA] cat 2190; 1:80), goat anti-human C3 FITC (Whittaker [Walkersville, MD] C-232; 1:40), goat anti-human IgM FITC (Tago cat 2192; 1:20), goat anti-human IgA FITC (Tago cat 2191; 1:20), and goat anti-human fibrinogen (Cappel [West Chester, PA] 55169; 1:40).
Sera were prepared at dilutions of 1:40, 1:80, 1:160, 1:320, and 1:640 in phosphate-buffered saline and 4% bovine serum albumin. Sera were tested for the presence of antinuclear, anticentromere, and anti-double stranded DNA antibodies by the antinuclear antibody Hep-2 cell culture indirect immunofluorescence test system (Zeus 2500, Radisson, PA) and the anti-DNA test system (Zeus 1000), respectively. The presence of the anti-Sm, anti-Ro/SSA, anti-La/SSB, and anti-RNP antibodies were tested by enzyme-linked immunosorbent assay (Immunoconcepts [Sacramento, CA], cat SA7010). The secondary antibodies used in all cases were goat anti-human Ig FITC with Evans Blue counterstain (Tago cat 2190; 1:80). Slides were mounted in glycerol.
Immunohistochemistry was performed on cryostat sections of fresh frozen tissue. Primary antibodies were obtained from the following sources and applied at the following dilutions: anti-CD3 (Dako [Carpinteria, CA] A0452; 1:300), anti-CD4 (NovoCastra [Newcastle-upon-Tyne, UK] NCL-CD4-1F6; 1:50), and anti-CD8 (Dako M7103; 1:50). Secondary antibodies were obtained from the following sources and used at the following dilutions: biotinylated anti-mouse IgG (Vector [Burlingame, CA] BA-2000; 1:400) for anti-CD4 and anti-CD8, and biotinylated anti-rabbit IgG (Vector BA-1000; 1:800) for anti-CD3.
The percentages of cells reacting with each antibody (i.e., anti-CD3, -CD4, and -CD8) were calculated from microscopic evaluation of slides by 2 blinded investigators (MRA-A and MB). The positive cells were calculated from each antibody-labeled slide of cryostat sections by visual examination of the entire inflammatory cell infiltrate that was comprised in 4–6 high power (40× magnification) fields. The mean percent positive cells and SDs were calculated for each antibody and for each case. The ratio of CD4:CD8 positive cells was calculated from the mean percent positive cells for each case. The mean (± SD) of percent CD3 positive, percent CD4 positive, percent CD8 positive, and ratio of CD4:CD8 positive cells was then calculated.
The patients ranged in age from 26 to 70 years; the mean age was 47 (±12) years and the median was 47 years (Table 1). The female:male ratio was 8:7. There were 11 white, 2 Hispanic, and 2 African American patients. The reported duration of the lesions on presentation ranged from 2 weeks to 9 years; the mean was 2.04 years (±2.34) and the median was 2.19 years. The followup duration ranged from 2 to 15 years; the mean was 7 years (±5) and the median was 4 years.
The lesions were asymptomatic papules, plaques, and/or nodules (Figure 1 and Table 1). They were pink to violaceous in color, smooth, and indurated. Pertinent negative findings included the absence of surface changes, such as follicular plugs, atrophy, or scale, and the absence of scars. The lesions ranged in size from 0.5 to 5.0 cm in diameter. The number of lesions ranged from 1 to 4. The sites of involvement included face (11 of 15), arms (5 of 15), chest (4 of 15), upper back (2 of 15), flank (1 of 15), and legs (1 of 15) (Table 1). Photosensitivity, as defined by the ACR (2) as a “skin rash as a result of an unusual reaction to sunlight by patient report or by physician observation,” was a feature in 13 of 15 (87%) cases. The initial clinical differential diagnoses included polymorphous light eruption, pseudolymphoma, lymphocytic infiltrate of the skin, discoid LE, erythematous/edematous plaques of acute LE, urticaria of acute LE, granuloma annulare, and cutaneous mucinosis associated with systemic LE.
The histopathologic features in all (100%) cases included a moderate to dense, superficial and deep perivascular infiltrate, which was predominantly composed of lymphocytes (Figure 1 and Table 1). In 7 (47%) of the 15 cases, the lymphocytic infiltrate was present in periadnexal areas.
Mucin deposition in moderate to abundant amounts was present throughout the papillary and reticular dermis in all (100%) cases. Mucin deposition was detected in the hematoxylin and eosin-stained sections and best appreci-ated with the colloidal iron stain (Figure 1 and Table 1). In 4 (27%) of the 15 cases, mucin deposition was abundant in periadnexal areas.
In 12 (80%) of 15 cases, an absence of changes was observed at the dermal-epidermal junction (Figure 1 and Table 1). In 3 (20%) of 15 cases, focal interface changes with vacuolar alterations and necrotic keratinocytes were noted at the dermal-epidermal junction. In 2 (13%) of 15 cases, focal interface changes were noted in hair follicle infundibula. In 2 (33%) of 6 cases that were examined with a periodic acid-Schiff stain, a thick basement membrane was noted (Table 1).
Five (50%) of 10 cases evaluated by direct immunofluorescence analysis were negative. Among the 5 (50%) cases with deposited immunoreactants, 4 displayed linear deposits of IgG and granular deposits of IgM at the basement membrane zone (Table 1). In 1 case, linear deposits of IgA, C3, and fibrin were also present, and 1 case demonstrated granular deposits of IgM and fibrin alone. Among those cases with deposited immunoreactants at the basement membrane zone, 3 (60%) of 5 displayed focal interface changes on histopathologic analysis.
In 5 (46%) of 11 cases evaluated serologically, ANAs were detected in titers ranging from 1:40 to 1:160 in a speckled pattern (Table 1). In 1 case, nucleolar staining was also observed. Anti-double stranded DNA, anticentromere, anti-Sm, anti-Ro/SSA, anti-La/SSB, and anti-RNP antibodies were negative in all cases.
We next evaluated the composition of the inflammatory cell infiltrate in the tumid LE lesions. Immunohistochemical analysis was performed on fresh frozen skin specimens from 6 cases using antibodies to the lymphocyte markers CD3, CD4, and CD8, and the mean percent marker positive cells was calculated (Figure 2 and Table 1). The majority of the cells in the inflammatory infiltrate reacted positively with antibody to the pan-T cell marker CD3, with a mean of 78.0% (±6.3) CD3 positive cells, indicating a predominance of T lymphocytes. The majority of the inflammatory cells, a mean of 82.7% (±8.0), also reacted positively with antibody to CD4, which labels helper T cells. A minority of a mean of 31.3% (±14.0) were CD8 positive cytotoxic T cells. The mean ratio of CD4:CD8 positive cells was 3.1 (±1.3):1.
The duration of followup evaluation ranged from 2 to 15 years; the mean was 7 years (±5) and the median was 4 years (Table 1). Systemic LE was present at the time of diagnosis in 1 of 15 patients. One lesion of discoid LE developed on the right cheek of 1 of 15 patients. The remaining 14 of 15 patients developed no evidence of systemic LE over the duration of followup.
Tumid LE is a form of cutaneous LE that has been reported intermittently over the past century, yet its definition has remained elusive (5–12). Tumid LE possesses features that are uncharacteristic of cutaneous LE, and that are difficult to distinguish from other disorders, resulting in much confusion in the literature (12–19). We present the largest, longest followed, and most systematically evaluated case series of tumid LE in the United States and propose the most comprehensive criteria to date for its classification and differential diagnosis (Table 2).
|Sensitivity, % (n/total)|
|Papules, plaques, and/or nodules||100 (15/15)|
|Pink to violaceous||93.3 (14/15)|
|Absence of surface changes||100 (15/15)|
|Chronic (>5 months)||93.3 (14/15)|
|Moderate to dense, superficial and deep, perivascular, lymphocytic infiltrate||100 (15/15)|
|Absent to focal dermoepidermal junctional involvement||100 (15/15)|
|Mucin deposition papillary and reticular dermis||100 (15/15)|
|Predominantly T cells (CD3+)||100 (6/6)|
|CD4 predominant (>68% of infiltrate)||100 (6/6)|
|CD8 minority (<50% of infiltrate)||83.3 (5/6)|
|CD4:CD8 ratio >2:1||83.3 (5/6)|
Criteria were selected by removing items from Table 1 with sensitivity less than 80%. Interpretation of the percentages in Table 2 must take into account the effects of sampling variation and of “not done” items. Clinical criteria include papules, plaques, or nodules that are pink to violaceous in color, devoid of surface changes, nonscarring, distributed in photosensitive sites, and chronic (>5 months). Histopathologic criteria include a moderate to dense, superficial and deep, perivascular, predominantly lymphocytic infiltrate, which is frequently periadnexal; absent to focal dermal-epidermal junction involvement; and moderate to abundant amounts of mucin throughout the dermis. Immunohistochemical criteria include a predominance of T cells and a predominance of CD4 over CD8 lymphocytes with a mean ratio of roughly 3:1 (Table 2).
Based on the data presented here, tumid LE is best classified as a form of chronic cutaneous LE. First, the cutaneous lesions were fixed and of long duration, persisting for months to years. Second, the serologic profile was similar to other forms of chronic cutaneous LE; half of the patients had low titer (≤1:160) ANAs, and the remaining autoantibody panel was negative. Third, the association with systemic disease was low; during the followup period, 1 patient developed systemic LE. In addition, 1 patient developed a discoid LE lesion elsewhere. The sex ratio in tumid LE of 8 F:7 M is similar to that seen in the chronic cutaneous forms of LE, and is in contrast to the female predominance observed in systemic LE of 8–10 F:1 M. The immunohistochemical characteristics of tumid LE lesions described here, indicating a predominance of CD4 over CD8 lymphocytes, are consistent with those found in other forms of chronic cutaneous LE (20, 21). Thus, its clinical and immunohistochemical features, and chronic, benign course indicate that tumid LE be classified as a subtype of chronic cutaneous LE.
It is important to emphasize the potential pitfalls in the diagnosis of this form of cutaneous LE. The classic findings of most forms of cutaneous LE that clinicians and pathologists use for diagnosis are distinctly lacking in tumid LE. Pertinent clinical signs that one would observe in discoid LE, such as the surface changes of follicular plugs, atrophy, scale, and scars (3, 4), are negative in tumid LE. The histologic hallmark of most forms of acute, subacute, and chronic cutaneous LE, the involvement of the dermal-epidermal junction by the inflammatory cell infiltrate, is typically absent in tumid LE. In 80% of tumid LE cases, dermal-epidermal junctional involvement was absent; in 20%, involvement was focal. The laboratory studies that clinicians use to evaluate patients with LE are also frequently negative in tumid LE patients. The ANA and direct immunofluorescence findings are negative in half of the patients. Thus, the combined clinical, histopathologic, and immunohistochemical criteria proposed here are necessary for avoiding these potential pitfalls in the diagnosis of tumid LE.
The immunohistochemical criteria proposed here allow one to differentiate tumid LE from other cutaneous disorders that, prior to this report, have been indistinguishable clinically and histologically (Table 3). Tumid LE can be differentiated by the predominance of T lymphocytes and the predominance of CD4 over CD8 lymphocytes in the inflammatory infiltrate. In pseudolymphoma, there are variable numbers of B and T lymphocytes (17). In polymorphous light eruption (PMLE) (22, 23) and a recently described lymphocytic infiltration of the skin (23–25), the reverse CD marker ratio is seen with a predominance of CD8 over CD4 lymphocytes. In contrast, the original description of lymphocytic infiltration of the skin by Jessner and Kanof (13) and subsequent cases demonstrating a predominance of CD4 over CD8 lymphocytes (23, 26) are likely tumid LE (17 and Kanof N: personal communication).
|Tumid LE||Pink to violaceous Indurated Photodistributed||S & D lymphocytic||+||±||Predominantly T cells CD4>CD8||Low-titer ANA Low incidence SLE|
|Polymorphous light eruption||Bright erythematosus Edematous Photodistributed||S & D lymphocytic||−||−||Predominantly T cells CD8>CD4 (22, 23)||Negative|
|Lymphocytic infiltration of the skin||Erythematous||S & D lymphocytic||−||−||Predominantly T cells CD8>CD4 (23–25)||Negative|
|Pseudolymphoma||Erythematous Infiltrated||S & D pattern lymphocytic||−||−||Variable B and T cells (17)||Negative|
|Erythematous/edematous plaques of acute LE||Erythematous Edematous||S lymphocytic interface edema or lcv (29)||±||+||Predominantly T cells CD4/CD8 variable||ANA High incidence SLE|
|Cutaneous mucinosis of SLE (30–34)||Flesh colored||S lymphocytic ± interface||+||+||Scant infiltrate||ANA, α-ds DNA Ab High incidence SLE|
|Granuloma annulare, interstitial||Flesh colored to erythematosus||S & D lymphocytic I histiocytic||+||−||Histiocytes||Negative|
A high rate of photoinduced lesions of short duration, lasting days to weeks, among LE patients recently described in Germany (12) may be due to either a higher incidence of tumid LE in that population or the inadvertent inclusion of other cutaneous disorders, such as PMLE, among those cases. The latter possibility is supported by their findings of urticaria-like lesions on clinical examination, spontaneous resolution of lesions within a few days to weeks, edema in the papillary dermis in all cases, and slight amounts of mucin deposition on histopathologic examination. In contrast, the lesions among our cases were indurated rather than urticarial; in no case did spontaneous resolution in days to weeks occur; nor was edema, a characteristic of PMLE, present on histopathologic examination. The hallmark finding present among all of our cases was moderate to abundant amounts of mucin deposition; slight amounts of mucin, as reported in the German study, are a normal finding. The role of photoinduction of lesions, which has been extensively utilized by the German group, remains to be determined. Phototesting is not utilized as a diagnostic criterion of LE in the US, does not necessarily correlate with photosensitivity as defined by the ACR, and does not differentiate between PMLE and tumid LE (2, 27, 28). Based on the findings presented here, PMLE and tumid LE can be definitively distinguished by immunohistochemical analysis: PMLE is characterized by a predominance of CD8 over CD4 lymphocytes (22, 23), whereas tumid LE demonstrates a CD4 predominance. Application of the comprehensive criteria proposed here should eliminate the confusion between these disorders in the future (Table 3).
Although therapeutic response is beyond the scope of this study, a brief mention is warranted. Patients were treated with the antimalarial hydroxychloroquine (200 mg, orally, twice daily). Slow improvement of lesions was observed over the course of months. This is in contrast to the German study, which demonstrated spontaneous or rapid resolution over the course of days to weeks, either due to differences in our study populations or possible inclusion of PMLE cases (12). The fixed chronicity and slow resolution after initiation of therapy of tumid LE lesions in our population is consistent with other forms of chronic cutaneous LE.
These proposed criteria for classifying patients with tumid LE should enable clinicians to diagnose and differentiate this atypical variant of chronic cutaneous LE from other common cutaneous disorders. Since tumid LE may be a feature of SLE, it is important that definitive criteria be established.