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DOI: 10.1111/jdv.12654
ORIGINAL ARTICLE
Reticular erythematous mucinosis: histopathological and immunohistochemical features of 25 patients compared with 25 cases of lupus erythematosus tumidus E. Cinotti,1,2,* V. Merlo,1 W. Kempf,3 C. Carli,4 J. Kanitakis,5 A. Parodi,1 F. Rongioletti1,4 1
Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa and IRCCS San Martino-IST University Hospital, Genoa, Italy 2 Section of Dermatology, University Hospital of Saint-Etienne, Saint-Etienne, France 3 Kempf and Pfaltz, Histological Diagnostics and Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland 4 Department of Surgical and Diagnostic Sciences (DISC), Pathology Unit University of Genoa and IRCCS San Martino-IST University Hospital, Genoa, Italy 5 Department of Dermatology, Ed. Herriot Hospital Group, Lyon, France *Correspondence: E. Cinotti. E-mail: [email protected]
Abstract Background and objectives Reticular erythematous mucinosis (REM) and lupus erythematosus tumidus (LET) share similarities. However, to our knowledge no study extensively compared the histological features of these two conditions. The aim of this study is to compare the histological and immunohistochemical features of REM and LET. Methods We evaluated epidermal thickness, hyperkeratosis, dermo-epidermal junction changes, interstitial mucin deposition, vessel dilatation and pattern, type and density of the inflammatory infiltrate in 25 cases of REM and LET. Anti-CD3, anti-CD20, anti-CD68, anti-CD4, anti-CD8, anti-CD123, anti-CD2AP, anti-IgG and anti-C3 antibodies were tested in a subset of patients. Results Both diseases are characterized by perivascular dermal infiltrates of lymphocytes mainly CD4+ positive and increased dermal mucin. However, REM tended to show more scattered and more superficial lymphocytes with more superficial mucin and to have less frequent immunoglobulin and complement depositions along the dermo-epidermal junction. Plasmacytoid dendritic cells (PDCs) were less represented in REM, and were mainly found as single cells differently from LET. Conclusions REM and LET present some differences in the infiltrate, including PDCs, the mucin deposition and the immunoreactant deposition at the dermo-epidermal junction that justify the distinction of the two diseases and suggest different pathogenetic mechanisms. Received: xxxx; Accepted: xxxx
Conflicts of interest None.
Funding sources None.
Introduction The relationship between reticular erythematous mucinosis (REM), a rare condition classified among the primary cutaneous mucinoses, and lupus erythematosus tumidus (LET) is unclear.1 A study of REM histological features might help to understand the nosology of this disease and its relationship with LET. Up to date, most data concerning REM histological features derived from single case reports and the largest series of REM patients with recorded histological features included only nine subjects and dates back to 1982.2 Moreover, no large study analyses the inflammatory infiltrate to identify the subtypes of lymphocytes and the possible presence of plasmacytoid dendritic cells (PDCs).
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Recently, we performed two separated studies on the clinical and histopathological features of REM and LET.3,4 The study on REM was performed on the largest series of patients ever reported and found that the main characteristics that makes REM a distinct disease3 are the reticular pattern, the involvement of the midline of the chest and back, the variable response to sun exposure, and the possible association with other conditions such as malignancies and thyroid dysfunctions. The study on LET pointed out that minimal epidermal changes can be found in this disease, differently from what previously reported5,6 and that direct immunofluorescence (DIF) is positive in almost all cases, linking this entity to other forms of cutaneous lupus erythematosus (LE). In this
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context, we decided to conduct an extensive histological study to investigate the relation of these two entities, including our previously reported cases.3,4
Materials and methods
upper limbs. The histopathological criteria were the same for the two diseases and included a perivascular and perifollicular predominantly lymphocytic infiltrate, interstitial mucin deposition in the dermis and absent or minimal epidermal changes. None of the patients fulfilled the American College of Rheumatology criteria for systemic LE.
Patients
A retrospective study was conducted on 25 REM an 25 LET patients, whose clinical data have been partially reported previously3,4 and are summarized in Table 1. REM and LET were diagnosed by clinical and histopathological criteria.7 The common clinical criteria were the presence of erythematous macules and/or papules and/or plaques with a smooth surface, resolving without scarring or hyper/hypopigmentation. In REM the lesions had a firm consistence, a reticular configuration and were located in the midline of the back or chest (Fig. 1), whereas in LET the lesions were oedematous and sometimes annular, (Fig. 2) and were located in sun-exposed areas, including at least the face, the neck, the upper trunk and/or the
Biopsy procedure
Histopathology and DIF were performed on 5 mm punch biopsy specimens from lesional skin of the trunk and neck (REM) or face and upper limbs (LET). Histopathological and immunohistochemical studies For each specimen, epidermal thickness, hyperkeratosis, dermo-epidermal junction (DEJ) changes, interstitial mucin deposition and pattern, type and density of the inflammatory infiltrate were evaluated independently by two of us who are also pathologists (FR, CC). In 11 REM and 5 LET anti-CD3 (clone F7.2.38, dilution 1: 200, Dako, Glostrup, Denmark), anti-CD20 (clone L26, dilution 1: 50,
Table 1 Clinical features of the 25 cases of reticular erythematous mucinosis and lupus erythematosus tumidus Reticular erythematous mucinosis
Lupus erythematosus tumidus
Number of patients
25
25
Mean age (range)
45 years (29–83 years)
43 years (19–78 years)
Women/Men
16/9
13/12
Mean delay to diagnosis (not available in 2)
14.7 months
23 months
Skin Lesions Erythematous macules with reticular pattern
7 (28%)
Erythematous macules/papules with reticular pattern
7 (28%)
0
11 (44%)
0
Erythematous macules/papules with reticular pattern and isolated plaques Non-scarring, erythematous plaques without reticular and annular configuration
0
0
16 (64%)
Erythematous papules with annular configuration
0
6 (24%)
Non-scarring, erythematous plaques combined with papules in annular and arciform configuration
0
3 (12%)
Involved sites Chest
15 (60%)
Back
12 (48%)
5 (20%) 7 (28%)
Neck
2 (8%)
7 (28%)
Face
2 (8%)
13 (52%)
Upper Limbs
1 (4%)
9 (36%)
Abdomen
3 (12%)
0
Signs and symptoms of connective tissue disease at diagnosis Arthritis
0
Photosensitivity
3 (12%)
2 (8%) 24 (96%)
Malar Rash
0
2 (8%)
Other
0
0
Anti-nuclear antibodies >1/80
0/9
0/25
0/13
0/23
Other signs and symptoms of connective tissue disease at follow-up ≥12 months
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Reticular erythematous mucinosis
Figure 1 Clinical aspect of reticular erythematous mucinosis. Erythematous, macules and papules with a reticular configuration in the midline of the chest.
(a)
3
CA, USA) and anti-CD8 (clone C8/144B, dilution 1: 50, Dako) were tested, and in 8 REM and 5 LET anti-CD123 (clone 7G3, Dako) and anti-CD2AP (clone B-4, Cliniscience, Santa Cruz Biotechnology, Dallas, Texas, USA) staining were performed. The amount of CD3, CD4, CD8, CD68, CD123 and CD2AP positive cells was recorded as a percentage of the total inflammatory infiltrate based on the review of two histological sections per case, with manual counting performed by three of us (FR, CC and EC). A given specimen was assigned to a specific percentage of reactivity when all the investigators agreed on the grading score. Pattern of distribution and localization of PDCs, characterized by antiCD123 and anti-CD2AP positivity, were also considered. Clusters were defined as nodular aggregates containing at least 10 PDCs. Scattered cells were defined as single PDCs distributed throughout the inflammatory infiltrate. It was taken into consideration that CD123 not only stains PDCs but also decorates the endothelium of adjacent post-capillary venules. Direct immunofluorescence
DIF was performed in 11 REM and 19 LET patients. The following fluorescence-labelled antibodies, diluted in phosphate-buffered saline, were used: goat anti-human IgG (1/50), goat anti-human IgA (1/40), goat anti-human IgM (1/40), and goat anti-human C3 (1/40) (Dako). Statistical analysis
Statistical comparison between the histological and DIF features of REM and LET was assessed using the correlation coefficient.
Results (b)
The main clinical, histological and DIF characteristics of REM and LET cases are summarized in Tables 1 and 2. Both REM and LET histological examinations were characterized by perivascular lymphocytic infiltrates in the superficial dermis and dermal mucin deposition (Figs. 3–5). Density and localization of the inflammatory infiltrate
Figure 2 Clinical aspect of lupus erythematosus tumidus. (a) Erythematous annular plaques with a succulent appearance on the face. (b) Similar lesions on the shoulder.
LET showed a denser and deeper infiltration of lymphocytes and deeper deposition of mucin than REM. In REM the infiltrate was limited to the superficial dermis in the majority (16/25, 64%) of cases, whereas in 80% (20/25) of LET the lymphocytic infiltrate extended to the mid and deep dermis. The infiltrate had a perivascular distribution in all cases, but an additional tropism for hair follicles was seen in 100% of LET (Fig. 3c,d) and in 60% (15/25) of REM. Localization of mucin deposition
Dako) and anti-CD68 (clone KP1, diluted 1:50, Dako) specific antibodies were tested. In 9 REM and 5 LET additional staining with anti-CD4 (clone 1F6, dilution 1: 10, Novocastra, Carpinteria,
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Mucin stained by Alcian blue and colloidal iron was seen in the superficial dermis in 60% (15/25) of REM (Fig. 4a) and was present throughout the superficial and deep reticular dermis in 80% (20/25) of LET (Fig. 4b).
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Table 2 Histological and direct immunofluorescence features of the 25 cases of reticular erythematous mucinosis and lupus erythematosus tumidus
Number of patients
Reticular erythematous mucinosis
Lupus erythematosus tumidus
25
25
Epidermis
0.55
Atrophy
0
8 (32%)
Only focal atrophy
7 (28%)
0
Acanthosis
2 (8%)
3 (12%)
16 (64%)
14 (56%)
Normal thickness Hyperorthokeratosis
6 (24%)
8 (32%)
Parakeratosis
0
2 (8%)
Follicular hyperorthokeratosis
1 (4%)
Papillomatosis
7 (28%)
0
Spongiosis
0
1 (4%)
NA
Dermo-epidermal junction Normal
1 22 (88%)
21 (84%)
Vacuolar degeneration
3 (12%)
4 (16%)
Thickened basal membrane
0
2 (8%)
Only perivascular lymphocytic infiltrate in superficial dermis
9 (36%)
0
Perivascular and perifollicular lymphocytic infiltrate in superficial dermis
7 (28%)
5 (20%)
Only perivascular lymphocytic infiltrate in superficial and mid dermis
2 (8%)
0
Perivascular and perifollicular lymphocytic infiltrate in superficial and mid dermis
3 (12%)
0
Only perivascular lymphocytic infiltrate in superficial, mid and deep dermis
2 (8%)
0
Perivascular and perifollicular lymphocytic infiltrate in superficial, mid and deep dermis
2 (8%)
20 (80%)
15 (60%)
5 (20%)
Inflammatory Infiltrate
0.24
Mucin deposition In superficial dermis
0.17
In superficial and mid dermis
2 (8%)
In superficial, mid and deep dermis
8 (32%)
20 (80%)
4/11
16/19
Direct immunofluorescence positivity Granular IgM at dermal-epidermal junction
Correlation coefficient for each group of features
0
3 (27%)
8 (42%)
Granular IgM on superficial vessels
0
5 (26%)
Granular C3 deposits on dermal-epidermal junction
1 (9%)
9 (47%) 5 (26%)
Granular C3 on superficial vessels
1 (9%)
Granular IgG deposits on dermal-epidermal junction
0
1 (5%)
IgA deposits on epidermal nuclei
0
2 (10%)
0.22
Additional histological features
Immunohistochemical studies
Additional features of REM were slight pigment incontinence with few melanophages in 20% (5/25) of patients, oedema in the superficial dermis in 32% (8/25), sparse eosinophils in 8% (2/25) and few mast cells in one case. Angiectasias of the superficial capillaries were present in all the 16 REM evaluated for this aspect.
In the 11 REM tested with anti-CD3, anti-CD20 and anti-CD68 antibodies, the infiltrate was composed predominantly of T lymphocytes, with a percentage of CD3+ cells variable from 75% to 95% (Fig. 5a), and a small proportion of CD68 positive macrophages (from 5% to 15%). CD20+ B lymphocytes were found
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Figure 3 Histological examination of reticular erythematous mucinosis (a,b) and lupus erythematosus tumidus (c,d). (a) and (c), Perivascular and perifollicular lymphocytic infiltrate and interstitial mucin deposition in the superficial dermis without interface changes (Haematoxylin and eosin stain, 4x). (b), Perivascular lymphocytic infiltrate with interstitial mucin (Haematoxylin and eosin stain, 10x). (d), The infiltrate tends to show a denser and deeper infiltration of lymphocytes than reticular erythematous mucinosis (Haematoxylin and eosin stain, 10x).
5
(a)
(b)
(c)
(d)
(a)
(b)
Figure 4 Mucin deposition in reticular erythematous mucinosis and lupus erythematosus tumidus. In reticular erythematous mucinosis (a) mucin is present in the superficial dermis, whereas in lupus erythematosus tumidus (b) mucin deposition is more abundant and diffuse (Alcian blue stain, 10x).
only in one case and in small number (5%). In nine patients the proportion between CD4+ T helper lymphocytes and CD8+ T cytotoxic lymphocytes was also evaluated. In 78% (7/9) of them the ratio was in favour of CD4 (2:1 or 3:1) (Fig. 5b,c), whereas in one patient the infiltrate was made almost exclusively by CD4+ cells, and in another patient 95% of the infiltrate was composed of CD8+ lymphocytes and of only 5% of CD4+ cells. PDCs were evident in the dermal infiltrate in 50% (4/8) of REM and were found as scattered cells throughout the superficial dermal infiltrate forming sometimes small clusters or as single cells beneath the epidermis (Fig. 6a). In LET the infiltrate was composed predominantly of CD3+ cells (Fig. 5d). Both CD4 and CD8 positive cells were present in all the five cases analysed with anti-CD4 and anti-CD8 immunostainings, with a ratio in favour of CD4 in all cases (2:1) (Fig. 5e,
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f). PDCs were evident in the dermal infiltrate in 80% (4/5) of LET cases and formed small perivascular and periadnexal clusters, sometimes with also a deeper involvement (Fig. 6b). Statistical analysis
A high correlation was found between REM and LET for the histological features of the epidermis (q=0.55) and the DEJ (q=1), whereas a poor correlation was found for the localization of the infiltrate (q= 0.24) and of mucin (q=0.17) and for the DIF findings (q=0.22) (Table 2).
Discussion The relation between REM and LET is matter of debate.3 REM is considered as an idiopathic, primary form of cutaneous mucinosis,7,8 but it shares several clinical and histological features with
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(a)
(d)
(b)
(e)
(c)
(f)
Figure 5 Immunohistochemical study of reticular erythematous mucinosis (a,b,c) and lupus erythematosus tumidus (d,e,f). (a,d), The infiltrate is composed predominantly of CD3 + lymphocytes (anti-CD3 stain, 10x). (b,e) Prevalence of CD4 + cells in the perivascular infiltrate (anti-CD4 stain, 10x). (c,f) CD8 + cells are less represented than CD4 + cells (anti-CD8 stain, 10x).
LET that prompted some authors to consider REM as a disorder closely related or associated to cutaneous LE, in particular LET. Conversely, there is also some debate as to whether LET itself is a separate subtype of chronic cutaneous LE or a nonspecific manifestation within the LE classification system.9 Clinically, both REM and LET show the erythematous plaquelike clinical aspect of lesions, the lack of significant immune
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serological abnormalities and the response to anti-malarial drugs. However, some distinct clinical features have been identified for REM.3 Histologically, both diseases are characterized by a perivascular and periadnexal lymphocytic infiltrate and dermal interstitial mucin deposition.3,4 However, our study found some histological differences.
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(a)
(b)
Figure 6 Plasmacytoid dendritic cells in reticular erythematous mucinosis and lupus erythematosus tumidus. (a), Plasmacytoid dendritic cells are evident in the dermal infiltrate as scattered cells forming sometimes small aggregates throughout the infiltrate in reticular erythematous mucinosis (anti-CD2AP, 20x) (a), and as small perivascular and periadnexal clusters in lupus erythematosus tumidus (b) (antiCD2AP, 10x).
All cases of LET tended to show a more prominent and deeper dermal infiltrate and deeper deposition of mucin than REM. Another peculiarity was that the infiltrate had more tropism for adnexa in LET than REM, being in all cases perifollicular besides perivascular. The epidermis was more involved in LET than REM. In particular, atrophy concerned about 30% of LET and REM, but in REM this was focal. Spongiosis was observed in one LET patient and none REM, although the literature reports the possible presence in REM.10 Focal vacuolar changes were a possible finding in both REM and LET (12–16%). The basal membrane was never thickened in REM, as already described by Bleehen et al.,10 contrary to LET where PAS staining showed a thickened basal membrane zone in 8% (2/25) of cases. Slight incontinentia pigmenti with few melanophages was a finding in REM (20%) as already reported by Astle et al.11 Additional histological characteristics that emerged from our series were oedema of the dermis and the presence of angiectasias in REM. The dermal oedema can explain the possible urticaria-like clinical aspect of REM and the angiectasias the intense erythematous colour of lesions. The literature also reports red blood extravasation12 and neoangiogenesis13 that were not found in our study. In our series, DIF was positive in only 27% of REM cases and in particular we found at the DEJ granular deposits of IgM in 27% and C3 in 10%. These data are in line with a study from the literature14 reporting IgM and C3 along the DEJ in 23% and 11% of REM respectively. However, DIF is rarely performed in REM and when performed it is often negative. Interestingly, our lesions with IgM deposits along the DEJ corresponded to the cases with focal vacuolar degeneration of the DEJ and focal epidermal atrophy, being therefore suggestive of an immune-mediated damage of the DEJ. The literature also
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reports one case of IgA deposition that has not been found in our series. Concerning LET, DIF was positive in 64% of patients and in all these cases IgM or IgG and/or C3 were present at the DEJ suggesting that immunoglobulins and complement have a more prominent role in mediating the tissue damage than in REM. In the literature, DIF positivity in LET varies according to the different studies: a German study6 indicates a positivity in about a quarter of patients, while a Japanese study found a positivity in up to 50%.17 In one LET patient we could find IgG deposits on the DEJ, a finding that has never been reported for REM. We should notice that granular IgM and C3 could be found in normal sun-exposed skin and especially on the face.15,16 This might also be a reason why DIF on skin biopsies from sun-exposed areas from LET patients is more often positive than those on skin biopsies from the back or chest of REM patients. Usually, the infiltrate of REM is predominantly lymphocytic (helper T cells) admixed with scattered mast cells,1 histiocytes,1 neutrophils,18 eosinophils19 and plasma cells.20,21 In our study, we investigated if there were differences in the lymphocytic subpopulations of REM and LET in an effort to determine whether the lymphocyte subtypes could be diagnostically useful to differentiate the two diseases and suggest different pathogenesis. In REM and LET the infiltrate was composed predominantly of lymphocytes, with 85–95% CD3 positive T lymphocytes and a small proportion of CD68+ macrophages (5–15%). These aspects are in line with the literature, if we exclude the study performed by Chavaz et al.,22 which denied that the REM lymphocytic infiltrate consists mainly of T cells. The ratio CD4/CD8 was in favour of CD4, except in one case of REM where 95% of T-lymphocytes were CD8+. The predominance of CD4+ cells in REM was already documented by Bulengo-Ransby et al.,23 who also found a slight CD8+ lymphocyte exocytosis not confirmed by our data.
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PDCs are bone marrow-derived CD123 and CD2AP-positive dendritic cells that are capable of producing large amounts of interferon-alpha (IFN).24 PDCs are an infrequent finding in normal skin, but they have recently been observed in skin lesions of LE, LET, REM, psoriasis, atopic dermatitis, dermatomyositis and Jessner’s lymphocytic infiltrate of skin.24,25 Tomasini et al.25 found CD123/CD2AP+ cells in 66.7% (2/3) of REM and 100% (32/32) of LET. With our study, we confirmed the presence of PDCs in both diseases, with a higher prevalence in LET (80%) compared to REM (50%). Moreover, PDCs were constantly detected as distinct perivascular and periadnexal clusters in LET, sometimes with a deeper involvement, while in REM they were found as scattered and more rarely as small clusters throughout the superficial infiltrate or beneath the epidermis. The pathogenesis of LET and REM is unknown, but in recent years it has been hypothesized that in LE comes into play the activation of PDCs in response to infective agents,1 anti-nucleic acid autoantibody24 and apoptosis of keratinocytes after UV radiation.9 Our data suggests that also in REM PDCs could play a role, but factors inducing their activation remain obscure. Moreover, there is increasing evidence that a network of IFNassociated cytokines, chemokines and adhesion molecules promotes tissue injury in cutaneous LE and that in LET there is a significantly increased expression of TNF-a, TGF-b, IL-10, IL12p40 and CXCL9 as compared to cutaneous discoid LE.26 For REM there are no studies about IFN expression, but a study reported that the fibroblasts of patients with REM exhibit an abnormal response to stimulation by exogenous interleukin (IL)-1b.27 In conclusion, our study confirms that REM shows some histological overlap with LET. Common features include perivascular and perifollicular T-lymphocytic infiltrates with an increased CD4/CD8 ratio, dermal mucin deposition and possible presence of PDCs. However, our data highlight also some differences that justify the distinction of the two diseases.3 REM showed a less dense and less deep cell infiltrate with more superficial mucin deposition and less frequent immunoglobulin and complement depositions along the DEJ. Although both LET and REM show the presence of PDCs in the infiltrate, the percentage of positive cases and the number of PDCs clusters are more represented in LET, sometimes also with periadnexal distribution and a deeper involvement. The significance of these differences is unclear but it could depend either on the topographic distribution of the presumptive aetiologic agent or on the type of receptor activation, such as Toll-Like Receptors (TLR)-7 or TLR9. However, the same response of the two diseases to hydroxychloroquine that is a well-known TLR9 antagonist may suggest a possible common pathogenetic pathway.25
References 1 Thareja S, Paghdal K, Lien MH, Fenske NA. Reticular erythematous mucinosis–a review. Int J Dermatol 2012; 51: 903–909.
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2 Quimby SR, Perry HO. Plaquelike cutaneous mucinosis: its relationship to reticular erythematous mucinosis. J Am Acad Dermatol 1982; 6: 856– 861. 3 Rongioletti F, Merlo V, Riva S et al. Reticular erythematous mucinosis: a review of patients characteristics, associated conditions, therapy and outcome in 25 cases. Br J Dermatol 2013; 169: 1207–1211. 4 Cozzani E, Christana K, Rongioletti F, Rebora A, Parodi A. Lupus erythematosus tumidus: clinical, histopathological and serological aspects and therapy response of 21 patients. Eur J Dermatol 2010; 20: 797–801. 5 Kuhn A, Richter-Hintz D, Oslislo C, Ruzicka T, Megahed M, Lehmann P. Lupus erythematosus tumidus–a neglected subset of cutaneous lupus erythematosus: report of 40 cases. Arch Dermatol 2000; 136: 1033– 1041. 6 Kuhn A, Sonntag M, Ruzicka T, Lehmann P, Megahed M. Histopathologic findings in lupus erythematosus tumidus: review of 80 patients. J Am Acad Dermatol 2003; 48: 901–908. 7 Rongioletti F, Rebora A. Mucinoses. In Bolognia J, Jorizzo JL, Schaffer JV, eds. Dermatology, 2nd edn. Elsevier Saunders, London, 2008. 8 Steigleder GK, Gartmann H, Linker U. REM syndrome: reticular erythematous mucinosis (round-cell erythematosis), a new entity? Br J Dermatol 1974; 91: 191–199. 9 Rodrıguez-Caruncho C, Bielsa I. Lupus erythematosus tumidus: a clinical entity still being defined. Actas Dermosifiliogr 2011; 102: 668– 674. 10 Bleehen SS, Slater DN, Mahood J, Church RE. Reticular erythematous mucinosis: light and electron microscopy, immunofluorescence and histochemical findings. Br J Dermatol 1982; 106: 9–18. 11 Astle NJ, Rasmussen JA. A reticulated eruption on the chest. reticular erythematous mucinosis. Arch Dermatol 1987; 123: 523–524. 12 Morison WL, Shea CR, Parrish JA. Reticular erythematous mucinosis syndrome. Report of two cases. Arch Dermatol 1979; 115: 1340–1342. 13 Keczkes K, Jadhav P. REM syndrome (reticular erythematous mucinosis): report of a further case or variant of it. Arch Dermatol 1977; 113: 335– 338. 14 Gasior-Chrzan B, Husebekk A. Reticular erythematous mucinosis syndrome: report of a case with positive immunofluorescence. J Eur Acad Dermatol Venereol 2004; 18: 375–378. 15 Fabre VC, Lear S, Reichlin M, Hodge SJ, Callen JP. Twenty percent of biopsy specimens from sun-exposed skin of normal young adults demonstrate positive immunofluorescence. Arch Dermatol 1991; 127: 1006– 1011. 16 Leibold AM, Bennion S, David-Bajar K, Schleve MJ. Occurrence of positive immunofluorescence in the dermo-epidermal junction of sun-exposed skin of normal adults. J Cutan Pathol 1994; 21: 200– 206. 17 Nishiyama M, Kanazawa N, Hiroi A, Furukawa F. Lupus erythematosus tumidus in Japan: a case report and a review of the literature. Mod Rheumatol 2009; 19: 567–572. 18 Mansouri P, Farshi S, Nahavandi A, Safaie-Naraghi Z. Pimecrolimus 1 percent cream and pulsed dye laser in treatment of a patient with reticular erythematous mucinosis syndrome. Dermatol Online J 2007; 13: 22. 19 Dauden E, Pe~ nas PF, Buezo GF, Fraga J, Garcıa-Diez A. Reticular erythematous mucinosis associated with human immunodeficiency virus infection. Dermatology 1995; 191: 157–160. 20 Dodd HJ, Sarkany I, Sadrudin A. Reticular erythematous mucinosis syndrome. Clin Exp Dermatol 1987; 12: 36–39. 21 Miyoshi K, Miyajima O, Yokogawa M, Sano S. Favorable response of reticular erythematous mucinosis to ultraviolet B irradiation using a 308nm excimer lamp. J Dermatol 2010; 37: 163–166. 22 Chavas P, Polla L, Saurat JH. Paramyxovirus-like inclusions and lymphocyte type in the REM syndrome. Br J Dermatol 1982; 106: 741–742. 23 Bulengo-Ransby SM, Ellis CN, Griffiths CE, Cantu-Gonzalez G, Dubin HV, Voorhees JJ. Failure of reticular erythematous mucinosis to respond to cyclosporine. J Am Acad Dermatol 1992; 27: 825–828.
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24 McNiff JM, Kaplan DH. Plasmacytoid dendritic cells are present in cutaneous dermatomyositis lesions in a pattern distinct from lupus erythematosus. J Cutan Pathol 2008; 35: 452–456. 25 Tomasini D, Mentzel T, Hantschke M et al. Plasmacytoid dendritic cells: an overview of their presence and distribution in different inflammatory skin diseases, with special emphasis on Jessner’s lymphocytic infiltrate of the skin and cutaneous lupus erythematosus. J Cutan Pathol 2010; 37: 1132–1139.
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26 Gambichler T, Genc Z, Skrygan M et al. Cytokine and chemokine ligand expression in cutaneous lupus erythematosus. Eur J Dermatol 2012; 22: 319–323. 27 Izumi T, Tajima S, Harada R, Nishikawa T. Reticular erythematous mucinosis syndrome: glycosaminoglycan synthesis by fibroblasts and abnormal response to interleukin-1 beta. Dermatology 1996; 192: 41–45.
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DOI: 10.1111/jdv.12654
ORIGINAL ARTICLE
Reticular erythematous mucinosis: histopathological and immunohistochemical features of 25 patients compared with 25 cases of lupus erythematosus tumidus E. Cinotti,1,2,* V. Merlo,1 W. Kempf,3 C. Carli,4 J. Kanitakis,5 A. Parodi,1 F. Rongioletti1,4 1
Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa and IRCCS San Martino-IST University Hospital, Genoa, Italy 2 Section of Dermatology, University Hospital of Saint-Etienne, Saint-Etienne, France 3 Kempf and Pfaltz, Histological Diagnostics and Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland 4 Department of Surgical and Diagnostic Sciences (DISC), Pathology Unit University of Genoa and IRCCS San Martino-IST University Hospital, Genoa, Italy 5 Department of Dermatology, Ed. Herriot Hospital Group, Lyon, France *Correspondence: E. Cinotti. E-mail: [email protected]
Abstract Background and objectives Reticular erythematous mucinosis (REM) and lupus erythematosus tumidus (LET) share similarities. However, to our knowledge no study extensively compared the histological features of these two conditions. The aim of this study is to compare the histological and immunohistochemical features of REM and LET. Methods We evaluated epidermal thickness, hyperkeratosis, dermo-epidermal junction changes, interstitial mucin deposition, vessel dilatation and pattern, type and density of the inflammatory infiltrate in 25 cases of REM and LET. Anti-CD3, anti-CD20, anti-CD68, anti-CD4, anti-CD8, anti-CD123, anti-CD2AP, anti-IgG and anti-C3 antibodies were tested in a subset of patients. Results Both diseases are characterized by perivascular dermal infiltrates of lymphocytes mainly CD4+ positive and increased dermal mucin. However, REM tended to show more scattered and more superficial lymphocytes with more superficial mucin and to have less frequent immunoglobulin and complement depositions along the dermo-epidermal junction. Plasmacytoid dendritic cells (PDCs) were less represented in REM, and were mainly found as single cells differently from LET. Conclusions REM and LET present some differences in the infiltrate, including PDCs, the mucin deposition and the immunoreactant deposition at the dermo-epidermal junction that justify the distinction of the two diseases and suggest different pathogenetic mechanisms. Received: xxxx; Accepted: xxxx
Conflicts of interest None.
Funding sources None.
Introduction The relationship between reticular erythematous mucinosis (REM), a rare condition classified among the primary cutaneous mucinoses, and lupus erythematosus tumidus (LET) is unclear.1 A study of REM histological features might help to understand the nosology of this disease and its relationship with LET. Up to date, most data concerning REM histological features derived from single case reports and the largest series of REM patients with recorded histological features included only nine subjects and dates back to 1982.2 Moreover, no large study analyses the inflammatory infiltrate to identify the subtypes of lymphocytes and the possible presence of plasmacytoid dendritic cells (PDCs).
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Recently, we performed two separated studies on the clinical and histopathological features of REM and LET.3,4 The study on REM was performed on the largest series of patients ever reported and found that the main characteristics that makes REM a distinct disease3 are the reticular pattern, the involvement of the midline of the chest and back, the variable response to sun exposure, and the possible association with other conditions such as malignancies and thyroid dysfunctions. The study on LET pointed out that minimal epidermal changes can be found in this disease, differently from what previously reported5,6 and that direct immunofluorescence (DIF) is positive in almost all cases, linking this entity to other forms of cutaneous lupus erythematosus (LE). In this
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context, we decided to conduct an extensive histological study to investigate the relation of these two entities, including our previously reported cases.3,4
Materials and methods
upper limbs. The histopathological criteria were the same for the two diseases and included a perivascular and perifollicular predominantly lymphocytic infiltrate, interstitial mucin deposition in the dermis and absent or minimal epidermal changes. None of the patients fulfilled the American College of Rheumatology criteria for systemic LE.
Patients
A retrospective study was conducted on 25 REM an 25 LET patients, whose clinical data have been partially reported previously3,4 and are summarized in Table 1. REM and LET were diagnosed by clinical and histopathological criteria.7 The common clinical criteria were the presence of erythematous macules and/or papules and/or plaques with a smooth surface, resolving without scarring or hyper/hypopigmentation. In REM the lesions had a firm consistence, a reticular configuration and were located in the midline of the back or chest (Fig. 1), whereas in LET the lesions were oedematous and sometimes annular, (Fig. 2) and were located in sun-exposed areas, including at least the face, the neck, the upper trunk and/or the
Biopsy procedure
Histopathology and DIF were performed on 5 mm punch biopsy specimens from lesional skin of the trunk and neck (REM) or face and upper limbs (LET). Histopathological and immunohistochemical studies For each specimen, epidermal thickness, hyperkeratosis, dermo-epidermal junction (DEJ) changes, interstitial mucin deposition and pattern, type and density of the inflammatory infiltrate were evaluated independently by two of us who are also pathologists (FR, CC). In 11 REM and 5 LET anti-CD3 (clone F7.2.38, dilution 1: 200, Dako, Glostrup, Denmark), anti-CD20 (clone L26, dilution 1: 50,
Table 1 Clinical features of the 25 cases of reticular erythematous mucinosis and lupus erythematosus tumidus Reticular erythematous mucinosis
Lupus erythematosus tumidus
Number of patients
25
25
Mean age (range)
45 years (29–83 years)
43 years (19–78 years)
Women/Men
16/9
13/12
Mean delay to diagnosis (not available in 2)
14.7 months
23 months
Skin Lesions Erythematous macules with reticular pattern
7 (28%)
Erythematous macules/papules with reticular pattern
7 (28%)
0
11 (44%)
0
Erythematous macules/papules with reticular pattern and isolated plaques Non-scarring, erythematous plaques without reticular and annular configuration
0
0
16 (64%)
Erythematous papules with annular configuration
0
6 (24%)
Non-scarring, erythematous plaques combined with papules in annular and arciform configuration
0
3 (12%)
Involved sites Chest
15 (60%)
Back
12 (48%)
5 (20%) 7 (28%)
Neck
2 (8%)
7 (28%)
Face
2 (8%)
13 (52%)
Upper Limbs
1 (4%)
9 (36%)
Abdomen
3 (12%)
0
Signs and symptoms of connective tissue disease at diagnosis Arthritis
0
Photosensitivity
3 (12%)
2 (8%) 24 (96%)
Malar Rash
0
2 (8%)
Other
0
0
Anti-nuclear antibodies >1/80
0/9
0/25
0/13
0/23
Other signs and symptoms of connective tissue disease at follow-up ≥12 months
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Figure 1 Clinical aspect of reticular erythematous mucinosis. Erythematous, macules and papules with a reticular configuration in the midline of the chest.
(a)
3
CA, USA) and anti-CD8 (clone C8/144B, dilution 1: 50, Dako) were tested, and in 8 REM and 5 LET anti-CD123 (clone 7G3, Dako) and anti-CD2AP (clone B-4, Cliniscience, Santa Cruz Biotechnology, Dallas, Texas, USA) staining were performed. The amount of CD3, CD4, CD8, CD68, CD123 and CD2AP positive cells was recorded as a percentage of the total inflammatory infiltrate based on the review of two histological sections per case, with manual counting performed by three of us (FR, CC and EC). A given specimen was assigned to a specific percentage of reactivity when all the investigators agreed on the grading score. Pattern of distribution and localization of PDCs, characterized by antiCD123 and anti-CD2AP positivity, were also considered. Clusters were defined as nodular aggregates containing at least 10 PDCs. Scattered cells were defined as single PDCs distributed throughout the inflammatory infiltrate. It was taken into consideration that CD123 not only stains PDCs but also decorates the endothelium of adjacent post-capillary venules. Direct immunofluorescence
DIF was performed in 11 REM and 19 LET patients. The following fluorescence-labelled antibodies, diluted in phosphate-buffered saline, were used: goat anti-human IgG (1/50), goat anti-human IgA (1/40), goat anti-human IgM (1/40), and goat anti-human C3 (1/40) (Dako). Statistical analysis
Statistical comparison between the histological and DIF features of REM and LET was assessed using the correlation coefficient.
Results (b)
The main clinical, histological and DIF characteristics of REM and LET cases are summarized in Tables 1 and 2. Both REM and LET histological examinations were characterized by perivascular lymphocytic infiltrates in the superficial dermis and dermal mucin deposition (Figs. 3–5). Density and localization of the inflammatory infiltrate
Figure 2 Clinical aspect of lupus erythematosus tumidus. (a) Erythematous annular plaques with a succulent appearance on the face. (b) Similar lesions on the shoulder.
LET showed a denser and deeper infiltration of lymphocytes and deeper deposition of mucin than REM. In REM the infiltrate was limited to the superficial dermis in the majority (16/25, 64%) of cases, whereas in 80% (20/25) of LET the lymphocytic infiltrate extended to the mid and deep dermis. The infiltrate had a perivascular distribution in all cases, but an additional tropism for hair follicles was seen in 100% of LET (Fig. 3c,d) and in 60% (15/25) of REM. Localization of mucin deposition
Dako) and anti-CD68 (clone KP1, diluted 1:50, Dako) specific antibodies were tested. In 9 REM and 5 LET additional staining with anti-CD4 (clone 1F6, dilution 1: 10, Novocastra, Carpinteria,
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Mucin stained by Alcian blue and colloidal iron was seen in the superficial dermis in 60% (15/25) of REM (Fig. 4a) and was present throughout the superficial and deep reticular dermis in 80% (20/25) of LET (Fig. 4b).
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Table 2 Histological and direct immunofluorescence features of the 25 cases of reticular erythematous mucinosis and lupus erythematosus tumidus
Number of patients
Reticular erythematous mucinosis
Lupus erythematosus tumidus
25
25
Epidermis
0.55
Atrophy
0
8 (32%)
Only focal atrophy
7 (28%)
0
Acanthosis
2 (8%)
3 (12%)
16 (64%)
14 (56%)
Normal thickness Hyperorthokeratosis
6 (24%)
8 (32%)
Parakeratosis
0
2 (8%)
Follicular hyperorthokeratosis
1 (4%)
Papillomatosis
7 (28%)
0
Spongiosis
0
1 (4%)
NA
Dermo-epidermal junction Normal
1 22 (88%)
21 (84%)
Vacuolar degeneration
3 (12%)
4 (16%)
Thickened basal membrane
0
2 (8%)
Only perivascular lymphocytic infiltrate in superficial dermis
9 (36%)
0
Perivascular and perifollicular lymphocytic infiltrate in superficial dermis
7 (28%)
5 (20%)
Only perivascular lymphocytic infiltrate in superficial and mid dermis
2 (8%)
0
Perivascular and perifollicular lymphocytic infiltrate in superficial and mid dermis
3 (12%)
0
Only perivascular lymphocytic infiltrate in superficial, mid and deep dermis
2 (8%)
0
Perivascular and perifollicular lymphocytic infiltrate in superficial, mid and deep dermis
2 (8%)
20 (80%)
15 (60%)
5 (20%)
Inflammatory Infiltrate
0.24
Mucin deposition In superficial dermis
0.17
In superficial and mid dermis
2 (8%)
In superficial, mid and deep dermis
8 (32%)
20 (80%)
4/11
16/19
Direct immunofluorescence positivity Granular IgM at dermal-epidermal junction
Correlation coefficient for each group of features
0
3 (27%)
8 (42%)
Granular IgM on superficial vessels
0
5 (26%)
Granular C3 deposits on dermal-epidermal junction
1 (9%)
9 (47%) 5 (26%)
Granular C3 on superficial vessels
1 (9%)
Granular IgG deposits on dermal-epidermal junction
0
1 (5%)
IgA deposits on epidermal nuclei
0
2 (10%)
0.22
Additional histological features
Immunohistochemical studies
Additional features of REM were slight pigment incontinence with few melanophages in 20% (5/25) of patients, oedema in the superficial dermis in 32% (8/25), sparse eosinophils in 8% (2/25) and few mast cells in one case. Angiectasias of the superficial capillaries were present in all the 16 REM evaluated for this aspect.
In the 11 REM tested with anti-CD3, anti-CD20 and anti-CD68 antibodies, the infiltrate was composed predominantly of T lymphocytes, with a percentage of CD3+ cells variable from 75% to 95% (Fig. 5a), and a small proportion of CD68 positive macrophages (from 5% to 15%). CD20+ B lymphocytes were found
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Figure 3 Histological examination of reticular erythematous mucinosis (a,b) and lupus erythematosus tumidus (c,d). (a) and (c), Perivascular and perifollicular lymphocytic infiltrate and interstitial mucin deposition in the superficial dermis without interface changes (Haematoxylin and eosin stain, 4x). (b), Perivascular lymphocytic infiltrate with interstitial mucin (Haematoxylin and eosin stain, 10x). (d), The infiltrate tends to show a denser and deeper infiltration of lymphocytes than reticular erythematous mucinosis (Haematoxylin and eosin stain, 10x).
5
(a)
(b)
(c)
(d)
(a)
(b)
Figure 4 Mucin deposition in reticular erythematous mucinosis and lupus erythematosus tumidus. In reticular erythematous mucinosis (a) mucin is present in the superficial dermis, whereas in lupus erythematosus tumidus (b) mucin deposition is more abundant and diffuse (Alcian blue stain, 10x).
only in one case and in small number (5%). In nine patients the proportion between CD4+ T helper lymphocytes and CD8+ T cytotoxic lymphocytes was also evaluated. In 78% (7/9) of them the ratio was in favour of CD4 (2:1 or 3:1) (Fig. 5b,c), whereas in one patient the infiltrate was made almost exclusively by CD4+ cells, and in another patient 95% of the infiltrate was composed of CD8+ lymphocytes and of only 5% of CD4+ cells. PDCs were evident in the dermal infiltrate in 50% (4/8) of REM and were found as scattered cells throughout the superficial dermal infiltrate forming sometimes small clusters or as single cells beneath the epidermis (Fig. 6a). In LET the infiltrate was composed predominantly of CD3+ cells (Fig. 5d). Both CD4 and CD8 positive cells were present in all the five cases analysed with anti-CD4 and anti-CD8 immunostainings, with a ratio in favour of CD4 in all cases (2:1) (Fig. 5e,
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f). PDCs were evident in the dermal infiltrate in 80% (4/5) of LET cases and formed small perivascular and periadnexal clusters, sometimes with also a deeper involvement (Fig. 6b). Statistical analysis
A high correlation was found between REM and LET for the histological features of the epidermis (q=0.55) and the DEJ (q=1), whereas a poor correlation was found for the localization of the infiltrate (q= 0.24) and of mucin (q=0.17) and for the DIF findings (q=0.22) (Table 2).
Discussion The relation between REM and LET is matter of debate.3 REM is considered as an idiopathic, primary form of cutaneous mucinosis,7,8 but it shares several clinical and histological features with
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(a)
(d)
(b)
(e)
(c)
(f)
Figure 5 Immunohistochemical study of reticular erythematous mucinosis (a,b,c) and lupus erythematosus tumidus (d,e,f). (a,d), The infiltrate is composed predominantly of CD3 + lymphocytes (anti-CD3 stain, 10x). (b,e) Prevalence of CD4 + cells in the perivascular infiltrate (anti-CD4 stain, 10x). (c,f) CD8 + cells are less represented than CD4 + cells (anti-CD8 stain, 10x).
LET that prompted some authors to consider REM as a disorder closely related or associated to cutaneous LE, in particular LET. Conversely, there is also some debate as to whether LET itself is a separate subtype of chronic cutaneous LE or a nonspecific manifestation within the LE classification system.9 Clinically, both REM and LET show the erythematous plaquelike clinical aspect of lesions, the lack of significant immune
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serological abnormalities and the response to anti-malarial drugs. However, some distinct clinical features have been identified for REM.3 Histologically, both diseases are characterized by a perivascular and periadnexal lymphocytic infiltrate and dermal interstitial mucin deposition.3,4 However, our study found some histological differences.
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(a)
(b)
Figure 6 Plasmacytoid dendritic cells in reticular erythematous mucinosis and lupus erythematosus tumidus. (a), Plasmacytoid dendritic cells are evident in the dermal infiltrate as scattered cells forming sometimes small aggregates throughout the infiltrate in reticular erythematous mucinosis (anti-CD2AP, 20x) (a), and as small perivascular and periadnexal clusters in lupus erythematosus tumidus (b) (antiCD2AP, 10x).
All cases of LET tended to show a more prominent and deeper dermal infiltrate and deeper deposition of mucin than REM. Another peculiarity was that the infiltrate had more tropism for adnexa in LET than REM, being in all cases perifollicular besides perivascular. The epidermis was more involved in LET than REM. In particular, atrophy concerned about 30% of LET and REM, but in REM this was focal. Spongiosis was observed in one LET patient and none REM, although the literature reports the possible presence in REM.10 Focal vacuolar changes were a possible finding in both REM and LET (12–16%). The basal membrane was never thickened in REM, as already described by Bleehen et al.,10 contrary to LET where PAS staining showed a thickened basal membrane zone in 8% (2/25) of cases. Slight incontinentia pigmenti with few melanophages was a finding in REM (20%) as already reported by Astle et al.11 Additional histological characteristics that emerged from our series were oedema of the dermis and the presence of angiectasias in REM. The dermal oedema can explain the possible urticaria-like clinical aspect of REM and the angiectasias the intense erythematous colour of lesions. The literature also reports red blood extravasation12 and neoangiogenesis13 that were not found in our study. In our series, DIF was positive in only 27% of REM cases and in particular we found at the DEJ granular deposits of IgM in 27% and C3 in 10%. These data are in line with a study from the literature14 reporting IgM and C3 along the DEJ in 23% and 11% of REM respectively. However, DIF is rarely performed in REM and when performed it is often negative. Interestingly, our lesions with IgM deposits along the DEJ corresponded to the cases with focal vacuolar degeneration of the DEJ and focal epidermal atrophy, being therefore suggestive of an immune-mediated damage of the DEJ. The literature also
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reports one case of IgA deposition that has not been found in our series. Concerning LET, DIF was positive in 64% of patients and in all these cases IgM or IgG and/or C3 were present at the DEJ suggesting that immunoglobulins and complement have a more prominent role in mediating the tissue damage than in REM. In the literature, DIF positivity in LET varies according to the different studies: a German study6 indicates a positivity in about a quarter of patients, while a Japanese study found a positivity in up to 50%.17 In one LET patient we could find IgG deposits on the DEJ, a finding that has never been reported for REM. We should notice that granular IgM and C3 could be found in normal sun-exposed skin and especially on the face.15,16 This might also be a reason why DIF on skin biopsies from sun-exposed areas from LET patients is more often positive than those on skin biopsies from the back or chest of REM patients. Usually, the infiltrate of REM is predominantly lymphocytic (helper T cells) admixed with scattered mast cells,1 histiocytes,1 neutrophils,18 eosinophils19 and plasma cells.20,21 In our study, we investigated if there were differences in the lymphocytic subpopulations of REM and LET in an effort to determine whether the lymphocyte subtypes could be diagnostically useful to differentiate the two diseases and suggest different pathogenesis. In REM and LET the infiltrate was composed predominantly of lymphocytes, with 85–95% CD3 positive T lymphocytes and a small proportion of CD68+ macrophages (5–15%). These aspects are in line with the literature, if we exclude the study performed by Chavaz et al.,22 which denied that the REM lymphocytic infiltrate consists mainly of T cells. The ratio CD4/CD8 was in favour of CD4, except in one case of REM where 95% of T-lymphocytes were CD8+. The predominance of CD4+ cells in REM was already documented by Bulengo-Ransby et al.,23 who also found a slight CD8+ lymphocyte exocytosis not confirmed by our data.
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PDCs are bone marrow-derived CD123 and CD2AP-positive dendritic cells that are capable of producing large amounts of interferon-alpha (IFN).24 PDCs are an infrequent finding in normal skin, but they have recently been observed in skin lesions of LE, LET, REM, psoriasis, atopic dermatitis, dermatomyositis and Jessner’s lymphocytic infiltrate of skin.24,25 Tomasini et al.25 found CD123/CD2AP+ cells in 66.7% (2/3) of REM and 100% (32/32) of LET. With our study, we confirmed the presence of PDCs in both diseases, with a higher prevalence in LET (80%) compared to REM (50%). Moreover, PDCs were constantly detected as distinct perivascular and periadnexal clusters in LET, sometimes with a deeper involvement, while in REM they were found as scattered and more rarely as small clusters throughout the superficial infiltrate or beneath the epidermis. The pathogenesis of LET and REM is unknown, but in recent years it has been hypothesized that in LE comes into play the activation of PDCs in response to infective agents,1 anti-nucleic acid autoantibody24 and apoptosis of keratinocytes after UV radiation.9 Our data suggests that also in REM PDCs could play a role, but factors inducing their activation remain obscure. Moreover, there is increasing evidence that a network of IFNassociated cytokines, chemokines and adhesion molecules promotes tissue injury in cutaneous LE and that in LET there is a significantly increased expression of TNF-a, TGF-b, IL-10, IL12p40 and CXCL9 as compared to cutaneous discoid LE.26 For REM there are no studies about IFN expression, but a study reported that the fibroblasts of patients with REM exhibit an abnormal response to stimulation by exogenous interleukin (IL)-1b.27 In conclusion, our study confirms that REM shows some histological overlap with LET. Common features include perivascular and perifollicular T-lymphocytic infiltrates with an increased CD4/CD8 ratio, dermal mucin deposition and possible presence of PDCs. However, our data highlight also some differences that justify the distinction of the two diseases.3 REM showed a less dense and less deep cell infiltrate with more superficial mucin deposition and less frequent immunoglobulin and complement depositions along the DEJ. Although both LET and REM show the presence of PDCs in the infiltrate, the percentage of positive cases and the number of PDCs clusters are more represented in LET, sometimes also with periadnexal distribution and a deeper involvement. The significance of these differences is unclear but it could depend either on the topographic distribution of the presumptive aetiologic agent or on the type of receptor activation, such as Toll-Like Receptors (TLR)-7 or TLR9. However, the same response of the two diseases to hydroxychloroquine that is a well-known TLR9 antagonist may suggest a possible common pathogenetic pathway.25
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2 Quimby SR, Perry HO. Plaquelike cutaneous mucinosis: its relationship to reticular erythematous mucinosis. J Am Acad Dermatol 1982; 6: 856– 861. 3 Rongioletti F, Merlo V, Riva S et al. Reticular erythematous mucinosis: a review of patients characteristics, associated conditions, therapy and outcome in 25 cases. Br J Dermatol 2013; 169: 1207–1211. 4 Cozzani E, Christana K, Rongioletti F, Rebora A, Parodi A. Lupus erythematosus tumidus: clinical, histopathological and serological aspects and therapy response of 21 patients. Eur J Dermatol 2010; 20: 797–801. 5 Kuhn A, Richter-Hintz D, Oslislo C, Ruzicka T, Megahed M, Lehmann P. Lupus erythematosus tumidus–a neglected subset of cutaneous lupus erythematosus: report of 40 cases. Arch Dermatol 2000; 136: 1033– 1041. 6 Kuhn A, Sonntag M, Ruzicka T, Lehmann P, Megahed M. Histopathologic findings in lupus erythematosus tumidus: review of 80 patients. J Am Acad Dermatol 2003; 48: 901–908. 7 Rongioletti F, Rebora A. Mucinoses. In Bolognia J, Jorizzo JL, Schaffer JV, eds. Dermatology, 2nd edn. Elsevier Saunders, London, 2008. 8 Steigleder GK, Gartmann H, Linker U. REM syndrome: reticular erythematous mucinosis (round-cell erythematosis), a new entity? Br J Dermatol 1974; 91: 191–199. 9 Rodrıguez-Caruncho C, Bielsa I. Lupus erythematosus tumidus: a clinical entity still being defined. Actas Dermosifiliogr 2011; 102: 668– 674. 10 Bleehen SS, Slater DN, Mahood J, Church RE. Reticular erythematous mucinosis: light and electron microscopy, immunofluorescence and histochemical findings. Br J Dermatol 1982; 106: 9–18. 11 Astle NJ, Rasmussen JA. A reticulated eruption on the chest. reticular erythematous mucinosis. Arch Dermatol 1987; 123: 523–524. 12 Morison WL, Shea CR, Parrish JA. Reticular erythematous mucinosis syndrome. Report of two cases. Arch Dermatol 1979; 115: 1340–1342. 13 Keczkes K, Jadhav P. REM syndrome (reticular erythematous mucinosis): report of a further case or variant of it. Arch Dermatol 1977; 113: 335– 338. 14 Gasior-Chrzan B, Husebekk A. Reticular erythematous mucinosis syndrome: report of a case with positive immunofluorescence. J Eur Acad Dermatol Venereol 2004; 18: 375–378. 15 Fabre VC, Lear S, Reichlin M, Hodge SJ, Callen JP. Twenty percent of biopsy specimens from sun-exposed skin of normal young adults demonstrate positive immunofluorescence. Arch Dermatol 1991; 127: 1006– 1011. 16 Leibold AM, Bennion S, David-Bajar K, Schleve MJ. Occurrence of positive immunofluorescence in the dermo-epidermal junction of sun-exposed skin of normal adults. J Cutan Pathol 1994; 21: 200– 206. 17 Nishiyama M, Kanazawa N, Hiroi A, Furukawa F. Lupus erythematosus tumidus in Japan: a case report and a review of the literature. Mod Rheumatol 2009; 19: 567–572. 18 Mansouri P, Farshi S, Nahavandi A, Safaie-Naraghi Z. Pimecrolimus 1 percent cream and pulsed dye laser in treatment of a patient with reticular erythematous mucinosis syndrome. Dermatol Online J 2007; 13: 22. 19 Dauden E, Pe~ nas PF, Buezo GF, Fraga J, Garcıa-Diez A. Reticular erythematous mucinosis associated with human immunodeficiency virus infection. Dermatology 1995; 191: 157–160. 20 Dodd HJ, Sarkany I, Sadrudin A. Reticular erythematous mucinosis syndrome. Clin Exp Dermatol 1987; 12: 36–39. 21 Miyoshi K, Miyajima O, Yokogawa M, Sano S. Favorable response of reticular erythematous mucinosis to ultraviolet B irradiation using a 308nm excimer lamp. J Dermatol 2010; 37: 163–166. 22 Chavas P, Polla L, Saurat JH. Paramyxovirus-like inclusions and lymphocyte type in the REM syndrome. Br J Dermatol 1982; 106: 741–742. 23 Bulengo-Ransby SM, Ellis CN, Griffiths CE, Cantu-Gonzalez G, Dubin HV, Voorhees JJ. Failure of reticular erythematous mucinosis to respond to cyclosporine. J Am Acad Dermatol 1992; 27: 825–828.
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24 McNiff JM, Kaplan DH. Plasmacytoid dendritic cells are present in cutaneous dermatomyositis lesions in a pattern distinct from lupus erythematosus. J Cutan Pathol 2008; 35: 452–456. 25 Tomasini D, Mentzel T, Hantschke M et al. Plasmacytoid dendritic cells: an overview of their presence and distribution in different inflammatory skin diseases, with special emphasis on Jessner’s lymphocytic infiltrate of the skin and cutaneous lupus erythematosus. J Cutan Pathol 2010; 37: 1132–1139.
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26 Gambichler T, Genc Z, Skrygan M et al. Cytokine and chemokine ligand expression in cutaneous lupus erythematosus. Eur J Dermatol 2012; 22: 319–323. 27 Izumi T, Tajima S, Harada R, Nishikawa T. Reticular erythematous mucinosis syndrome: glycosaminoglycan synthesis by fibroblasts and abnormal response to interleukin-1 beta. Dermatology 1996; 192: 41–45.
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