Title: The role of histological presentation in erythroderma

Running head: Histology in erythroderma

Authors: M. Megna1, A.A. Sidikov2 D.V. Zaslavsky2, I.N. Chuprov3, E.A. Timoshchuk2, J.

Braegelmann 4, J. Wenzel4, R.A. Nasyrov 2.

Affiliation: 1Department of Dermatology, University of Naples Federico II, Corso Umberto I,

40, 80138 Napoli, Italy; 2St. Petersburg State Pediatric Medical University Litovskaya str., 2, St.
3
Petersburg, 194100, Russia; North-Western State Medical University by the name I.I.

Mechnikov str, kirochnaya, 41, St. Petersburg, 191015, Russia; 4University clinic of Bonn,

Sigmund Freud Str. 25, D 53105 Bonn, Germany

Funding Sources: none declared

Conflicts of Interest: none declared

Key words: erythroderma; histology; diagnosis; aetiology

Word counts:

Figure: 0

Tables: 5

Corresponding Author: …………………

Department of Dermatology – University of Naples Federico II

Via Pansini, 5 80131 Napoli, Italy

Tel: +39 - 081 -7462457 Fax: +39 - 081 - 7462442

E-mail:…………………………….
Abstract:

Erythroderma is an acute and serious medical condition characterized by inflamed red skin

affecting over 90% of the skin surface. Erythroderma can be the common presentation of

different diseases with psoriasis, eczema, cutaneous T-cell lymphoma and drug reactions being

its most common underlying causes. However, despite their differing pathomechanisms, clinical

diagnosis of erythroderma cases can be problematic. Controversial data are reported in literature

regarding the diagnostic value of histological examination in erythroderma subjects.

Nevertheless, erythroderma is a potential life treating disease, it is still poorly investigated in

literature. The aim of this retrospective is to evaluate the accuracy of histopathologic

examination in erythroderma diagnosis, highlighting the diverse microscopic features which

characterize different erythroderma etiologic subtypes.

Introduction

Erythroderma is defined as a diffuse redness of the skin accompanied by a variable degree of

scaling, involving more than 90% of the body surface. Despite it is potentially a life-threatening

condition with high rate of mortality due to both the primary disease causing erythroderma as

well as the pattern of the resulting metabolic alterations, it is still poorly studied in literature.

Erythroderma does not represent a defined entity, possibly being the clinical presentation of

numerous different diseases [1,2]. Indeed, its etiology is very diverse including a variety of

inflammatory dermatoses (atopic dermatitis, eczema, pityriasis rubra pilaris, psoriasis, etc.),

cutaneous T-cell lymphoma (mycosis fungoides and Sezary Syndrome), as well as drugs induced

forms, hematological or internal malignancies, and other diseases [1,2]. Therefore, histological

investigation represent a fundamental aid in the differential diagnosis of erythroderma, being

often mandatory. However, in erythroderma subjects the results of histological examination can

be nonspecific, only showing hyperkeratosis, parakeratosis, acanthosis, chronic inflammatory

infiltrate with or without eosinophils [3-8]. Conflicting views about the diagnostic value of skin

biopsy in the investigation of erythrodermic patients exist. Literature has previously underlined

the possibility to have non diagnostic biopsies even in erythrodermic patients with definite

history of pre-existent dermatosis [10] and clinical and pathological correlation in erythroderma

may be a very complicated task [4]. On the other hand, Rothe et al. highlighted the necessity to

combine clinical data with the histo-pathological features of multiple biopsies over time [6]

whereas in 2 different studies regarding 40 patients with erythroderma and a total of 56 skin

biopsies, a group of dermatopatologists achieved a high mean of diagnostic accuracy (53-66%)

only relying on histological examination [9,11].

Since the data regarding the value of histological examination in erythroderma subjects are

opposing, the aim of this retrospective is to evaluate the accuracy of histopathologic examination

in erythroderma diagnosis, highlighting the diverse microscopic features which characterize

different erythroderma etiologic subtypes.

Material and Methods

A retrospective study, investigating on histological skin specimens of patients admitted with a

clinical diagnosis of erythroderma at the Department of Dermatology of State Pediatric Medical

University of Saint-Petersburg from 2001 to 2014, was performed. The study population

involved 82 erythrodermic patients whose skin samples were taken from the archives of the

Department of Dermatology of State Pediatric Medical University of Saint-Petersburg.

Histopathology examination (through standard haematoxylin and eosin and periodic acid–Schiff

staining) was performed in each case by a pathologist with a special interest in skin disease who

was blind to any clinical information as well as to final diagnosis (established on the basis of

combined clinical and laboratory data and response to therapy). Therefore, a diagnosis only

based on objective microscopic data through a detailed checklist of dermal and epidermal

abnormalities (table 1), which were registered for each case. This blinded histological diagnosis

was compared with final non-blinded diagnosis in each case.

Results

The study population consisted of 82 patients (55 men and 27 women), with a mean age of 73

years (range 25-95). A total of 95 skin biopsies have been analyzed since 11/83 patients had

yielded more than one specimen. Blinded histopathology examination alone was able to give the

correct diagnosis in 61% (n=50/82) of cases when compared to final diagnosis established on the

basis of combined clinical and laboratory data and response to therapy. Particularly, a diagnosis

of psoriasis was performed in 23.2% (n=19/82) of subjects, spongiotic dermatitis/eczema in

20.7% (n=17/82), mycosis fungoides in 8.5% (n=7/82) and drug eruption in 8.5%; histological

diagnosis was inconclusive or not matching with the final diagnosis when available in the

remaining 39.1% of cases (n=32/82). As regards psoriatic sub-group of patients (n=19, mean age

70.2 years, 18 male 1 female), the most common observed histological feature, apart from the

unspecific presence of inflammatory lymphocytes in dermis, was psoriasiform acanthosis

(n=17/19; 89%), followed by the presence of neutrophilis > 50 cells in both epidermis and

dermis (n=16/19; 84%), diffuse parakeratosis (n=11/19; 58%), and diffuse hypogranulosis

(n=11/19; 58%). Other histological features observed in this group of patients are showed in

table 2.

The second most common diagnosis was spongiotic dermatitis / eczema (n=17, mean age 74.2

years, 10 male and 7 female) . The unspecific presence of inflammatory lymphocytes in dermis,

mainly as superficial infiltrate, and exocytosis were registered in all patients (n=17/17, 100%).

Other frequent histological features of this group of patients were represented by irregular

acanthosis (n=14/17; 82%), the presence of eosinophilis < 50 cells in dermis (n=13/17; 76%) and

diffuse spongiosis (n=9/17; 53%). However, without differentiating between local and diffuse

spongiosis, this condition was registered in all cases (table 3).

Regarding the 7 patients with mycosis fungoides (n=7, mean age 77.8 years, 6 male and 1

female), the diagnosis was strongly suggested by the presence of atypical lympochytes in

epidermidis (lympocytic microabcesses), linear arrangement of lymphocytes in basal layer,

atypical lymphocytes > 50 cells in dermis and epidermotropism which were found in all cases

(table 4). In 4 from 7 skin biopsies (57%) a superficial and deep infiltrate in derma was noted

whereas in 3 patients (28%) there was a moderately dense infiltrate. A total absence of any signs

of histologic eczematous patterns of inflammation was registered.

Regarding the fourth group of patients, it comprised 7 cases of drug eruption / drug induced

erythroderma (n=7, mean age 70.8, 4 male and 3 female). Histological features in this group

were the ones distinctive of interface (vacuolar type) dermatitis: hydropic degeneration of the

basal layer of epidermis, the presence of inflammatory lymphocytes in the basal layer of

epidermis, presence of colloidal cells (apoptotic cells) in the epidermis, exocytosis, superficial

infiltrate in dermis, and infiltration of lymphocytes > 50 cells in dermis were observed in all

cases (table 5). Moreover, the presence of apoptotic cells <50 in epidermis was observed in 5/7,

71% of patients.
Discussion

Erythroderma is a rare but severe condition that may lead to severe systemic manifestations and

may be life-threatening, therefore needing prompt diagnosis and treatment [12]. Since it can the

consequence of several conditions, mainly skin disorders, drug consumption and more rarely,

some malignancies, it is of indisputable importance to know the aetiology to facilitate its

management [1]. However, despite these factors, erythroderma is still poorly studied in literature.

Erythroderma patients usually undergo skin biopsies even if conflicting views about the

diagnostic value and utility of skin biopsy in the investigation of erythrodermic patients still

exist. Indeed non diagnostic biopsies may be possible in erythroderma subjects [10] and clinical

and pathological correlation may be a very complicated task [4]. Conversely, other authors

highlighted the importance of histo-pathological examination, even with multiple biopsies over

time [6], suggesting a high mean of diagnostic accuracy (53-66%) [9,11]. For all these reasons

with the current study we aimed to evaluate the real value and accuracy of histopathologic

examination in erythroderma patients, trying also to highlight the diverse microscopic features

which characterize different erythroderma etiologic subtypes. We showed that blinded

histological examination alone was able to elucidate the underlying cause of erythroderma in the

majority of the cases (61%, n=50/82), confirming histological examination as a first useful and

obligated step in the road to erythroderma diagnosis. In this context, our findings also showed

that inflammatory skin diseases, including psoriasis and spongiotic dermatitis / eczema, were

responsible for the majority of erythroderma cases followed by drug reactions and cutaneous T-

cell lymphoma, being in line with literature [11,13,14]. Particularly, a diagnosis of psoriasis was

performed in 23.2% (n=19/82) of subjects, spongiotic dermatitis/eczema in 20.7% (n=17/82),

mycosis fungoides in 8.5% (n=7/82), drug eruption in 8.5% whereas histological diagnosis was

inconclusive or not matching with the final diagnosis when available in the remaining 39.1% of

cases (n=32/82). All these data supported the fact that histological examination allowed us to

specific erythroderma diagnosis with high precision at an early stage, being able to guide define
adequate medical tactics as fast as possible and consequently, to improve the immediate and

remote results of the treatment. Identification of histologic patterns of erythroderma is also

important as most of patients arrive in a serious condition, with signs of systemic metabolic

disturbances and other associated diseases. Therefore, in such patients early administration of

etiologic specific treatment allows to compensate manifestations of cardiovascular insufficiency,

disorders of electrolytic balance, considerably improving the prognosis. The specific histological

features which characterized the main subgroup of erythroderma patients are showed in table 2-

5. When examining a skin biopsy from an erythroderma patients histological features such as

acanthosis, diffuse parakeratosis, diffuse hypogranulosis, and the presence of neutrophils both in

epidermis and in dermis strongly supported a diagnosis of psoriasis providing a possibility for

the early beginning of specific therapy, and avoiding complications of eventual systemic

glucocorticostreoides treatment. Indeed, acanthosis was observed in 89% of psoriasis subjects

group, the presence of neutophils in both epidermis and dermis in 84%, while diffuse

parakeratosis and hypogranulosis were present in 58% of cases.

On the other hand, the diagnosis of spongiotic dermatitis / eczema was defined by histological

signs such as exocitosis (100% of cases), superficial lymphocytic infiltrate (100%), spongiosis

(100%, diffuse 53% and local 47%), irregular acanthosis (82%) and the presence of eosinophils

<50 cells in dermis (76%).

At the same time, the identification of features of interface dermatitis such as hydropic

degeneration of a basal layer of epidermis, lymphocytes in a basal layer of epidermis, colloid

bodies (apoptotic cells), pointed out the diagnosis of drug induced erythroderma, being present in

100%, 100%, 71% of cases, respectively . Exocitosis and superficial lymphocytic infiltrate were

observed in all cases as in spongiotic dermatitis / eczema group, therefore appearing as generic

and unspecific findings for both conditions.

Finally, the detection of lymphocytic microabscesses (100%), a linear arrangement of

lymphocytes in the basal layer of the epidermis (100%), atypical lymphocytes in the epidermis
and the derma (100%) guided the diagnosis to cutaneous T cell lymphoma/mycosis fungoides

and its diagnostic and therapeutic assessment.

Erythroderma remains a condition difficult to study and treat. Histological examinations may be

enough to guide correct diagnosis and treatment the majority of cases. However, the necessity of

multiple skin biopsies, and of combining clinic-pathologic parameters and response to treatment

represent a mainstay of its diagnostic process. With this basis, we showed that a correct judgment

about the cause of erythroderma can be based on objective histopathological criteria in up to

60% of cases. More studies are needed to try to elucidate further histological and/or

immunohistochemical markers (e.g. interleukin 36-Υ may possibly identify psoriasis) [15] which

could help the clinician in erythroderma aetiololgy diagnostic process.

Table 1. Cheklist of microscopic details documented in each case

Epidermis Derma Inflammatory Inflammatory

infiltrate in infiltrate in derma
epidermis
Orthokeratosis Red blood cell Neutrophils Neutrophils
Hyperkeratosis – local extravasation in papillary Inflammatory Inflammatory
Hyperkeratosis – diffuse dermis lymphocytes in lymphocytes
Parakeratosis – local Dilated blood vessels in basal layer Atypical lymphocytes
Parakeratpsis – diffuse papillary dermis Atypical Histocytes
Parakeratosis – serum Coarse collagen in lympocytes Eosinophilis
Parakeratosis – neutrophils papillary dermis Lymphocytic Melanophages
Acanthosis – regular Odema of papillary layer microabcesses Plasma cells
Acanthosis – irregular Sclerosis of papillary Histocytes Exocytosis
Acanthosis – psoriasiform layer Eosinophilis Epidermotropism
Atrophy or hypoplasia – Linear arrangement Superficial
local of lymphocytes in Superficial and deep
Atrophy or hypoplasia – basal layer Lichenoid
diffuse Moderetely dense
Hypergranulosis – local
Hypegranulosis – diffuse
Hypogranulosis – local
Hypogranulosis – diffuse
Spongiosis – local
Spongiosis – diffuse
Necrotic keratinocytes
Apoptotic cells
Hydropic degeneration
of basal layer

Table 2. Detailed histopathological features of erythroderma patients with a diagnosis of

psoriasis.

Histological N (total n=19) % Histological N (total n=19) %

features features (dermis)
 (epidermis)
Parakeratosis 8 42% Neutrophilis > 50 16 84%
(local) cells

Parakeratosis 11 58% Neutrophils < 50 16 84%

(diffuse) cells

Hypogranulosis 8 42% Dilated blood 14 77%

(local) vessels in
papillary dermis

Hypogranulosis 11 58% Inflammatory 19 100%

(diffuse) lymphocytes

Acanthosis 17 89% Eosinophils 10 53%

(psoriasiform)

Acanthosis 2 11%
(irregular)

Neutrophilis > 50 16 84%

cells

Neutrophils < 50 3 16%

cells

Table 3. Detailed histopathological features of erythroderma patients with a diagnosis of

spongiotic dermatitis / eczema.

Histological N (total n=17) % Histological N (total n=17) %

features features
(epidermis) (dermis)
 Parakeratosis 6 35% Inflam. lymph. 17 100%
(local) > 50 cells

Parakeratosis 3 18% Inflam. lymph. 0 0%

(diffuse) < 50 cells

Parakeratosis 6 35% Eosinophilis > 4 24%

(serum) 50 cells

Parakeratosis 2 12% Eosinophilis < 13 76%

(neutrophils) 50 cells

Acanthosis 3 18% Exocytosis 17 100%

(psoriasiform)

Acanthosis 14 82% Superficial 17 100%

(irregular) infiltrate

Spongiosis 8 47%
(local)

Spongiosis 9 53%
(diffuse)

Inflam. lymph. 8 47%

> 50 cells

Inflam. lymph. 9 53%

< 50 cells

Eosinophilis > 4 24%

50 cells

Eosinophilis < 7 41%

50 cells

Table 4. Detailed histopathological features of erythroderma patients with a diagnosis of

mycosis fungoides.

Histological N (total n=7) % Histological N (total n=7) %

features features
(epidermis) (dermis)
 Atypical 7 100 Atypical lymph. 7 100%
lymphocytes > 50 cells
(lympocytic
microabcesses)

Linear 7 100 Atypical lymph. 0 0

arrangement of < 50 cells
lymphocytes in
basal layer

Atypical 7 100 Superficial and 4 57%

lymphocytes (in deep infiltrate
epidermis)

Epidermotropism 7 100% Moderately 3 28%

dense infiltrate

Table 5. Detailed histopathological features of erythroderma patients with a diagnosis of

drug eruption/ drug induced forms.

Histological N (total n=7) % Histological N (total n=7) %

features features
(epidermis) (dermis)
 Necrotic 0 0% Inflam. lymph 7 100%
keratinocytes > > 50 cells
50 cells

Necrotic 2 28% Inflam. lymph 0 0%

keratinocytes < 50 cells
< 50 cells

Apoptotic cells 8 8% Superficial 7 100%

> 50 cells infiltrate

Apoptotic cells 5 71% Eosinophilis > 3 43%

< 50 cells 50 cells

Hydropic 7 100% Eosinophilis < 3 43%

degeneration of 50 cells
basal layer

Inflammatory 7 100% Exocytosis 7 100%

lymphocytes in
basal layer

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