Spongiosis associated with epidermal eosinophilic infiltration was first described in 1968 as a pre-acantholytic inflammatory change observed in both pemphigus vulgaris and foliaceus, often preceding its typical clinical and histological presentation.2 ES may be the sole alteration or may appear adjacent to acantholytic areas.

Later, ES was considered a relevant histological aspect of pemphigus herpetiformis (PH), an unusual clinical variant of pemphigus.3 PH clinically resembles dermatitis herpetiformis, and is characterized by pruritic urticarial erythema with vesicobullous eruption in about 50% of cases (Fig. 1). Acantholysis may not be evident by histopathology, but ES is invariably present; immunofluorescence studies with intraepidermal intercellular deposits confirm the diagnosis of PH3,4 (Fig. 2).

Figure 1.

Clinical presentation of pemphigus herpetiformis (A). Annular urticarial plaques (B) and peripheral vesicles (C) in herpetiformis pattern on posterior trunk.

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Figure 2.

Pemphigus herpetiformis. (A) Eosinophilic spongiosis, without prominent acantholysis (Hematoxylin & eosin, x400). (B) Direct immunofluorescence with linear, intercellular, and intraepithelial IgG deposits.

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There were 27 cases of PH diagnosed at the Department of Dermatology of Hospital das Clínicas – University of São Paulo Medical School in the last 15 years, corresponding to 5% of all pemphigus patients under follow-up at this clinic. Among them, ES was the main anatomopathological feature (present in 100% of the cases) and was considered by the authors as a mandatory criterion for PH, with or without concomitant evidence of acantholysis.

ES was also described as the initial histological finding in one case of paraneoplastic pemphigus.5 Additionally, pemphigus vegetans may display ES commonly associated with supra-basal acantholysis and epidermal hyperplasia.1,6

In bullous pemphigoid (BP), ES is a prominent feature, even in the absence of adjacent subepidermal detachment. It is especially observed during the pre-bullous phase, when urticarial lesions, eczema, or even isolated pruritus prevail (Figs. 3 and 4).6,7 This finding may not be fortuitous, as previous studies demonstrated the role of eosinophils in the pathogenesis of BP. It seems that the release of toxic proteins by eosinophils can contribute to blister formation.7 It is hypothesized that chemokines released by keratinocytes after epidermal damage induce eosinophilic migration into epidermis in BP, including IL-8 and eotaxin.7

Figure 3.

Urticarial (A) and bullous (B) phases of bullous pemphigoid.

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Figure 4.

Bullous pemphigoid. (A) Focal eosinophilic spongiosis adjacent to subepidermal clefting (Hematoxylin & eosin, x400). (B) Direct immunofluorescence with linear deposits of IgG in the basement membrane zone.

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Ruiz et al. observed that among 150 patients with ES, 24% had an underlying AIBD, emphasizing BP as the main cause.8 Mucous membrane pemphigoid and pemphigoid gestationis are less frequently associated with ES. During pregnancy, the occurrence of ES in urticarial lesions may support the diagnosis of pemphigoid gestationis and help to distinguish it from polymorphic eruption of pregnancy.6

Even though ES is traditionally associated with AIBD, it has been accepted as a consistent histological feature of other inflammatory skin disorders, notably spongiotic dermatitis.6 Although lymphocytes are the main inflammatory cells, ES can occur adjacent to other epidermal alterations in eczema, such as in contact, atopic, or nummular dermatitis.6,9 Ruiz et al. found that most patients with isolated ES had either eczematous dermatitis or AIBD without concomitant vesicles or blisters.8 In such cases, immunofluorescence studies are required to distinguish both disorders.1

Arthropod bite reactions, urticaria, drug reactions, and scabies represent other causes of ES.1,6,9 Prominent dermal edema and mixed inflammatory infiltrate are classically seen in insect bite reactions and urticarial lesions.1,6 Nevertheless, the urticarial phase of an AIBD must be excluded. In scabies, the presence of the mite in stratum corneum may confirm the diagnosis.6 Id reactions secondary to fungal or other infections may also cause ES.8

The vesicular phase of incontinentia pigmenti, a rare X-linked dermatosis, may also exhibit ES along with dyskeratotic keratinocytes, and has distinctive histopathological features.1,6 ES is seldom observed in lichen sclerosus, polycythemia vera, porokeratosis, Meyerson's nevi, Still's disease, and Wells syndrome.1,6,9 Additional histopathological alterations provide more specific evidence to support the diagnosis. In eosinophilic follicular pustular folliculitis (Ofuji folliculitis), ES is found in the hair infundibulum and sebaceous duct.1,9

ES cases with specific clinical and histological features may provide evidence to an accurate diagnosis. In contrast, those with unusual clinical presentation and/or without additional histopathological alterations may represent a diagnostic challenge. (Fig.5)

Figure 5.

Diagnostic management of eosinophilic spongiosis. DIF, direct immunofluorescence; (−), negative; (+), positive; BP, bullous pemphigoid; MMP, mucous membrane pemphigoid; PG, pemphigoid gestationis.

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A careful analytic approach and clinicopathological correlation are often necessary for etiological elucidation. This includes the evaluation of associated epidermal and dermal alterations from several histological serial sections. Acantholysis, dyskeratosis, intense dermal edema, inflammatory infiltrate, basement membrane zone alterations, and the presence of microorganisms may be observed and aid in the diagnosis.

The diagnosis of early AIBD requires ancillary testing. Immunofluorescence (IF) studies are the gold standard for the diagnosis of AIBD to demonstrate the presence of autoantibodies against intra-epidermal or basement membrane zone antigens in vivo.10 Direct IF detects tissue-bound autoantibodies, whereas indirect IF quantifies circulating autoantibodies. Deposits of fluorescent antibodies are detected in all pemphigus and BP patients, and may be determinant in atypical cases.10