Blistering diseases

Subcorneal vesiculobullous disorders

Pemphigus foliaceus

• Acantholysis (loss of attachments between keratinocytes)

• Dyskeratosis may occur within the granular layer

• Direct immunofluorescence demonstrates “net-like” deposition of immunoglobulin (Ig) G and C3 between keratinocytes in upper epidermis

Fig 9-1 Pemphigus foliaceus

Pemphigus foliaceus is a subcorneal vesiculobullous disorder caused by autoantibodies directed at an intercellular keratinocyte adhesion protein, desmoglein 1 (160 kD). The disease usually presents with superficial crusted erosions upon the face and upper trunk. The superficial nature of the blisters makes them fragile and most patients lack intact bullae.

The presence of a subcorneal blister, with acantholytic cells and scattered eosinophils, is highly suggestive of pemphigus foliaceus. Direct immunofluorescence (DIF) is diagnostic and demonstrates intercellular IgG and C3 deposition, primarily confined to the upper half of the epidermis. The split occurs in the granular layer, as in staphylococcal scalded-skin syndrome. Pemphigus foliaceus may demonstrate neutrophils within the vesicle, making distinction from bullous impetigo difficult. A tissue Gram stain may be helpful, but the presence of an impetiginized crust does not rule out pemphigus foliaceus.

Pemphigus erythematosus blends the immunohistologic findings of pemphigus foliaceus with lupus erythematosus. Patients often have a positive serum antinuclear antibody. Immunofluorescence yields both an intercellular deposition of immunoreactants and a “lupus band” of immunoreactants along the basement membrane zone.

Fig 9-2 Direct immunofluorescence of “net-like” staining in the upper epidermis of pemphigus foliaceus

Subcorneal pustular dermatosis (Sneddon–Wilkinson disease)

Key features

• Subcorneal pustule

• Pustule “sits” upon the epidermis without depressing it

• Superficial mixed perivascular infiltrate with occasional neutrophils

• Dyskeratosis is uncommon

• Immunofluorescence is negative (distinguishing it from IgA pemphigus)

Fig 9-3 (a) Subcorneal pustular dermatosis. (b) “Subcorneal pustular dermatosis” type of IgA pemphigus

Cases of subcorneal pustular dermatosis with intercellular deposition of IgA have been reclassified as IgA pemphigus. Subcorneal pustular dermatosis may represent a subclass of pustular psoriasis, although mitotic figures within the underlying epidermis, common to psoriasis, are not identified in subcorneal pustular dermatosis. The classic patient is an older woman with annular or polycyclic lesions of the trunk or groin with pustules at the periphery.

Acute generalized exanthematous pustulosis

Key features

• Subcorneal or superficial epidermal pustules

• Mild spongiosis in the surrounding epidermis

• Superficial mixed infiltrate in an edematous papillary dermis

• Occasional eosinophils within the dermal infiltrate

• Immunofluorescence is negative

Fig 9-4 Acute generalized exanthematous pustulosis

Acute generalized exanthematous pustulosis is an uncommon reaction to exogenous medications. Beta-lactam antibiotics are most often implicated, but a myriad of drug associations have been described. The presence of eosinophils in the inflammatory infiltrate helps distinguish the condition from pustular psoriasis. Early pustules may be noted in association with hair follicles or sweat ducts.

Intraepidermal vesiculobullous disorders

Pemphigus vulgaris

Key features

• Split immediately above basal layer leaves a “tombstone row” of basal keratinocytes

• Tracking of separation down hair follicles (“follicular extension”)

• Eosinophils may occur in spongiotic foci or within the blister cavity

• Superficial lymphocytic inflammatory infiltrate in dermis

• Eosinophils may be seen within the dermal infiltrate

• Direct immunofluorescence demonstrates “net-like” deposition of IgG and C3 between keratinocytes in lower epidermis

Fig 9-5 Pemphigus vulgaris

Fig 9-6 Direct immunofluorescence of pemphigus vulgaris

Pemphigus vulgaris is an intraepidermal vesiculobullous disorder caused by autoantibodies directed at an intercellular keratinocyte adhesion protein, desmoglein 3 (130 kD). The disease presents with erosions of the skin and mucosa. Often the disease begins in the posterior oropharynx weeks before cutaneous lesions are noted. Most patients lack intact bullae. Erythematous skin shears away easily when lateral pressure is applied (Nikolsky sign).

Clefting above the basal layer, with acantholysis of the remaining basilar keratinocytes, leads to a visual impression likened to “rows of tombstones” sitting upon the dermal papillae. Tracking of the blistering process down adnexal structures is often demonstrated. Direct immunofluorescence is diagnostic and demonstrates intercellular IgG and C3 deposition, primarily confined to the lower half of the epidermis.

Pemphigus vegetans is a related disorder which demonstrates vegetative cutaneous lesions with epidermal hyperplasia and lesser vesiculation. Suprabasilar crypts containing eosinophils may be identified within the acanthotic epidermis in many cases of pemphigus vegetans.

Fig 9-7 Pemphigus vegetans–pseudoepitheliomatous hyperplasia (PEH) and eosinophils

Familial benign chronic pemphigus (Hailey–Hailey disease)

Key features

• An inherited disorder with defective cell–cell adhesion

• Not antibody-mediated

• Acantholysis at all levels of the epidermis resembles a “dilapidated brick wall”

• Acanthosis

• Red dyskeratotic rim surrounds nucleus

• Immunofluorescence is negative

Fig 9-8 Hailey–Hailey disease

Fig 9-9 Dilapidated brick wall for comparison

Hailey–Hailey disease is an autosomal-dominant, inherited disease caused by mutations in the ATP2C1 gene. This gene encodes for a portion of a calcium pump essential for proper keratinocyte differentiation and adhesion. Skin of the intertriginous areas is most prominently affected and yields a clinical appearance likened to “wet tissue paper.” Acantholysis at all levels of the epidermis yields the histologic appearance of a “dilapidated brick wall.” While the disease itself is not immunologically mediated, superinfection of macerated skin by bacteria or yeast may engender an underlying inflammatory infiltrate within the superficial dermis.

Differential Diagnosis

The Hailey–Hailey variant of Grover’s disease has similar histologic findings; however, in contrast to the broad lesions of benign familial pemphigus, there is less extensive and focal involvement in Grover’s disease.

The negative direct immunofluorescence, dyskeratosis and follicular sparing in Hailey–Hailey disease allows distinction from pemphigus vulgaris. The acanthosis of benign familial pemphigus is a feature not typically identified in other blistering disorders.