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Causes of acquired erythroderma in adults presenting to a tertiary care centre in Cairo, Egypt

Shalaby, Suzana; El-Nabarawy, Eman A.a; Assaf, Magdab; Abdel Halim, Mona R.E.a

Journal of the Egyptian Women's Dermatologic Society: September 2015 - Volume 12 - Issue 3 - p 162–169
doi: 10.1097/01.EWX.0000464741.27105.23
Original articles
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Background Erythroderma is a morphologic presentation of a variety of cutaneous and systemic diseases.

Objective To study the causes of acquired erythroderma in adults presenting to a tertiary care centre in Cairo, Egypt, during the period between April and December 2011.

Patients and methods Thirty erythrodermic patients were subjected to thorough clinical and pathological evaluation. Immunophenotyping was performed for selected cases. A constellation of findings was used to define the underlying cause.

Results Causes of erythroderma in this series included 15 (50%) cases of erythroderma due to a pre-existing dermatosis, seven (23.3%) cases of drug-induced erythroderma, one (3.3%) case of papuloerythroderma of Ofuji, and seven (23.3%) cases of erythrodermic cutaneous T-cell lymphoma [one (3.3%) case] of Sézary syndrome and six (20%) cases of erythrodermic mycosis fungoides (MF).

Conclusion A pre-existing dermatosis was the most common cause of erythroderma. Meticulous clinical and pathological evaluation remains the cornerstone in identifying the underlying cause of erythroderma in countries with limited resources for auxiliary investigations.

aDermatology Department, Faculty of Medicine, Cairo University, Cairo

bPathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Correspondence to Eman A. El-Nabarawy, MD, 1007 Korneich El-Nile, 15411 Cairo, Egypt Tel: +20 100 196 5072; e-mail: emannabarawy@gmail.com

Received February 10, 2015

Accepted March 17, 2015

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Introduction

Erythroderma/exfoliative dermatitis reflects a severe state of skin irritation with many possible metabolic complications 1. It represents a morphologic presentation of a variety of cutaneous and systemic diseases, making identification of its cause very challenging. A thorough workup is essential in order to reach a definite diagnosis or the underlying cause 2,3.

Several studies were conducted to identify the incidence of different causes of erythroderma 4, but to the best of our knowledge, no studies were conducted on Egyptian patients. The current work aimed to study different causes of acquired erythroderma in adults presenting to a tertiary care centre in Cairo, Egypt, during the period between April and December 2011.

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Patients and methods

This cross-sectional study was conducted at the Outpatient Clinic of the Dermatology Department, Faculty of Medicine, Cairo University Hospital (Kasr Al Aini), during the period between April and December 2011. It was approved by the Dermatology Research Ethical Committee, and an informed consent was signed by the patients for participation in the study and photography.

Thirty patients with erythroderma were recruited. Exclusion criteria included patients less than 18 years old and congenital causes of erythroderma.

In order to identify the underlying cause, a thorough workup was carried out for each patient. This included retrieval of clinical data according to a predesigned detailed clinical sheet covering several aspects in history, general and cutaneous examination, and laboratory investigations (Table 1). In addition, two 4-mm punch biopsies were taken from each participant. Biopsies were fixed in 10% neutral buffered formalin, followed by embedding in paraffin. Routinely stained hematoxylin and eosin (H&E) slides were prepared for all 30 cases, and thorough light microscopic evaluation was carried out guided by a predesigned pathological assessment sheet (Table 2). When needed, additional slides were stained according to the technique described by Shi et al.5 using mouse monoclonal anti-CD2 (MS-1074-S0), -CD4 (MS-1528-S0), -CD5 (MS-393-S0), -CD7 (CM158 AK, BK, CK), and -CD8 (MS-457-S0 antibodies, supplied by Biocare Medical (Orange County, California, USA). This was also performed on lymph node biopsies when needed. T-cell gene rearrangement studies by PCR were planned to be restricted only to suspected cutaneous T-cell lymphoma (CTCL) cases with a nonspecific skin histology in which immunophenotyping failed to show a neoplastic profile.

Table 1

Table 1

Table 2

Table 2

A final diagnosis (cause of erythroderma) was reached in each case on the basis of a careful constellation of clinical, pathological, and other findings (when needed) and was guided by features described in the literature for the diagnosis of different diseases causing erythroderma 6–20.

Data were coded and entered using SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, Illinois, USA) version 17 and Microsoft Excel 2007 (Microsoft Corporation, New York, USA). Data were summarized using mean±SD for quantitative variables and the % for qualitative variables. Comparisons between groups were done using χ2-tests for qualitative variables. P value<0.05 was considered statistically significant.

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Results

The current study included 30 adult patients with erythroderma: 16 (53.3%) were male and 14 (46.7%) female, with an average male-to-female ratio of 1.14 : 1. Ages ranged from 18 to 73 years, with a mean of 43.9±1.49 years. The duration of erythroderma ranged from 2 weeks to 2 years with a mean of 4±4.48 months.

Clinical and pathological data of the studied cases are illustrated in Tables 3 and 4, respectively. Some features are illustrated in Figs 1–3. A lymph node biopsy was carried out in the six cases that presented with generalized lymphadenopathy. In three (50%) cases, reactive dermatopathic lymph nodes were detected. In the remaining three (50%) cases, pathological evidence of lymphoma was detected in the lymph nodes: they included two cases of erythrodermic mycosis fungoides (MF) and one case of Sézary syndrome. Absolute lymphocytosis was detected in these three cases, whereas Sézary cells were detected in one case (Sézary syndrome) only. In cases with CTCL, the CD4 : CD8 ratio in the blood was determined: only one case (Sézary syndrome) showed a significant elevation in the ratio (30 : 1).

Table 3

Table 3

Table 4

Table 4

Figure 1

Figure 1

Figure 2

Figure 2

Figure 3

Figure 3

Immunophenotyping was carried out for two cases: a case of Sézary syndrome (where skin pathological features were controversial between CTCL or lichenoid drug reaction) and a case of late-onset atopic dermatitis (where pathological examination revealed a few lymphocytes in the dermal infiltrate with hyperconvoluted nuclei). The Sézary syndrome case showed a typical neoplastic profile (CD4 positive, CD8 negative with loss of CD7 and partial loss of CD2 and CD5, both in the skin and in lymph node biopsies). In contrast, the case of late-onset atopic dermatitis showed no loss of pan T-cell markers and a CD4-negative CD8-positive pattern consistent with inflammatory conditions.

The final diagnoses of the studied cases included 15 (50%) cases of erythroderma due to a pre-existing dermatosis, namely 12 (40%) cases of psoriasis, two (6.7%) cases of atopic dermatitis, and one (3.3%) case of pemphigus foliaceus. The remaining 15 cases were diagnosed as drug-induced erythroderma in seven (23.3%) cases, one (3.3%) case of papuloerythroderma of Ofuji, and seven (23.3%) cases of erythrodermic CTCL, which included one (3.3%) case of Sézary syndrome and six (20%) cases of erythrodermic MF.

Following the establishment of the diagnoses in our cohort, we performed retrospectively a statistical evaluation to determine clinical and histopathological features that were significantly associated with a particular diagnosis. Results are illustrated in Tables 5 and 6 respectively.

Table 5

Table 5

Table 6

Table 6

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Discussion

As reported by others 1,4,21, pre-existing dermatoses followed by drugs were the most common causes of erythroderma in this series. The tertiary care nature of our hospital and the increased awareness of CTCL may explain the relatively higher incidence of this disorder in our study in comparison with others 4.

In agreement with Akhyani et al. 22 and Karakayli et al. 23, we found that the history of pre-existing dermatoses and recent drug intake as well as the pattern of onset and duration of erythroderma are key points in establishing a final diagnosis.

Although the cutaneous features of erythroderma are usually nonspecific and most studies did not correlate with the clinical picture with the etiology 21,24, we agree with Sehgal et al. 1 and Kraft and Lynde 11 that the clinical picture of erythroderma is usually modified according to the underlying disorder, wherein proper clinical evaluation usually yields specific clues that help in reaching the underlying cause.

Fiery red erythema, or what has been described as deep red to salmon pink erythema 13, has been considered as a sign favoring psoriasis and as a cause of erythroderma. In contrast, we noticed a peculiar dusky erythema in our CTCL cases, a finding not reported before up to our knowledge. Hair fall was previously reported in all cases of longstanding erythroderma; cicatricial alopecia was said to be present mainly in cases of MF 25; however, in our CTCL cases, we found diffuse alopecia with some cicatricial areas.

All our cases that presented with peripheral blood eosinophilia were cases of drug-induced erythroderma. Pal and Haroon 26 reported these laboratory finding to be significantly associated with drug-induced erythroderma, whereas others reported eosinophilia as a nonspecific finding in 20% of the erythrodermic patients 10 and in cases of eczema and MF 21.

An integral part of the general examination in erythrodermic patients that provides important clues to the underlying cause is lymph node examination. Six (20%) of our cases had generalized lymphadenopathy, and three (50%) of them had lymphoma. It has been reported that 50% of the erythrodermic patients may have dermatopathic lymphadenopathy, and a lymph node biopsy is advised only when lymph nodes exhibit lymphomatous characteristics (large size and rubbery consistency) or when the cause of erythroderma is undetermined 25,27.

In five of our cases, no specific clinical clues pointed toward a specific diagnosis or the underlying cause (undetermined erythroderma), and the final diagnosis depended entirely on the histopathological examination, wherein two turned out to be MF and three turned out to be lichenoid drug reaction. Most previous reports of undetermined erythroderma appeared to represent reactions to drugs not recalled by the patient 28 or MF cases starting without a pre-existing patch/plaque stage and showing no specific cutaneous clues 29.

In contrast to Ram-Wolff et al. 20, we noticed that specific histopathological features of psoriasis such as subcorneal neutrophilic collections, spongiform pustules, and suprapapillary thinning are not necessarily present. The most encountered pathological features in this group were psoriasiform hyperplasia, hypogranulosis, and superficial infiltrate. This can be explained by the more subtle histopathological manifestations of psoriasis in the context of erythroderma with more spongiosis mimicking spongiotic dermatitis 21,30.

Drug-induced erythroderma showed pathological features known to occur with any form of drug reactions, mainly interface vacuolar changes. In agreement with others, not all of our drug-induced cases showed necrotic keratinocytes 20 or eosinophils in the infiltrate that were reported in other conditions such as spongiotic dermatitis and MF 17,30,31.

In agreement with Nagler et al. 3, Ram-Wolff et al. 20, and Vonderheid 29, the presence of evident disproportionate epidermotropism and atypical lymphocytes in the dermal infiltrate was a specific clue to diagnose CTCL. In addition, we found irregular hyperplasia, dense infiltrate, and wiry papillary dermal fibrosis in such cases.

One of the histopathological conflicts that is encountered in the context of erythroderma is the difficulty encountered sometimes in differentiating between epidermotropic lymphocytes of CTCL and interface vacuolar changes and interface lymphocytes of drug reaction, especially in the presence of activated lymphocytes 17,30,31. Clinical correlation and immunohistochemical evaluation may help to settle the diagnosis in such controversies, especially in cases of Sézary syndrome, where a typical neoplastic profile (CD4-positive, CD7-negative cells of more than 40% in two sites: skin, blood, and/or lymph nodes) 3,29,32 is usually detected as in our case of Sézary syndrome. Other tools such as TCR gene rearrangement studies are sometimes needed in such cases to establish a final diagnosis; however, this technique still has its limitations with possible false-positive or false-negative results 33.

Another reported problematic issue is the differentiation between late-onset atopic dermatitis presenting as erythroderma and MF 34. This was encountered in one of our cases: a young male patient was clinically favored to have late-onset atopic dermatitis, but on the histopathological level, a few lymphocytes in the dermal infiltrate were perceived as atypical cells. Immunophenotyping revealed an inflammatory immunoprofile 29 that favored a benign nature. It is noteworthy here to mention that the characteristic cerebriform nucleus of atypical lymphocytes found in MF can also be found under benign dermatologic conditions such as atopic dermatitis and others 35 and loss of CD2 and CD5 (pan T-cell markers) can be detected in benign erythrodermas 36,37.

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Conclusion

The diagnosis of cases of erythroderma and the identification of its underlying cause is a challenging process necessitating a proper constellation of clinical and pathological findings. The main value of clinical evaluation is identifying cases related to a pre-existing dermatosis and drug-induced cases. Histopathological evaluation is the cornerstone in the diagnosis of neoplastic cases and in confirming the diagnosis of drug-induced cases. Multiple biopsies from different sites should be carried out. Also, repeating the biopsy in chronic persistent cases is recommended. Although immunohistochemistry and other studies are sometimes needed, clinicopathological correlation is mandatory and remains the backbone of diagnosis, especially in countries with limited resources for sophisticated auxiliary investigations.

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Acknowledgements

The authors thank all residents of the Dermatology Department, Faculty of Medicine, Cairo University, for their significant help in the collection of cases.

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

clinical; cutaneous T-cell lymphoma; drug reaction; eczema; erythroderma; histopathology; MF; psoriasis

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