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.

Keratosis follicularis (Darier’s disease)

Pearl

• Dyskeratotic keratinocytes in Hailey–Hailey disease have a red rim around the nucleus, while those in Darier’s disease usually have blue or clear rim.

Fig 9-10 Darier’s disease

Fig 9-11 Darier’s disease, corps ronds and grains

The acantholysis results in suprabasal clefts (lacunae) that contain projections of papillary dermis covered by a single layer of basal cells (villi). There are two types of dyskeratotic cells. The granular layer and horny layer contain corps ronds, round dyskeratotic cells with pyknotic nuclei, a clear perinuclear halo, and pale to bright eosinophilic cytoplasm. Grains are seen in the granular layer as flattened basophilic dyskeratotic cells.

Darier’s disease is an autosomal-dominant disorder with greasy, yellow-brown crusted and hyperkeratotic lesions in the seborrheic areas. Other cutaneous findings include cobblestone papules of the mucosa, palmoplantar pits, verrucous lesions on the dorsal hands and feet (acrokeratosis verruciformis of Hopf) and red and white longitudinal nail streaks with distal “V” nicking. Similar to Hailey–Hailey disease, the gene responsible, ATP2A2, encodes a calcium pump.

Differential Diagnosis

The differential diagnosis of acantholytic dyskeratosis includes the Darier’s type of Grover’s disease where the degree of dyskeratosis is less extensive and more localized. The acantholysis and dyskeratosis of warty dyskeratoma are isolated to a solitary, cup-shaped, follicular configuration. Acantholytic dyskeratosis unrelated to Darier’s disease may occur in the genital region.

Transient acantholytic dermatosis (Grover’s disease)

Key features

• Darier’s pattern with acantholysis and dyskeratosis

• Hailey–Hailey-like full-thickness acantholysis

• Pemphigus pattern with partial-thickness acantholysis

• Spongiotic pattern with rare acantholytic cells

Fig 9-12 Darier-type Grover’s disease

More than one of these patterns may be found in the same specimen. The clinical presentation, the mixture of histologic patterns, and the focal nature of the lesions help distinguish the disease from the histologic mimics. Eosinophils, if present, aid in differentiation from Darier’s disease. Direct immunofluorescence is typically negative, in contrast to pemphigus.

Grover’s disease is an acquired, pruritic disorder most commonly affecting older men on the trunk. Typically there is a sudden onset of discrete, crusted papules. Despite the name, the eruption may or may not be transient. Heat, fever, and sweating precipitate this disorder. Despite the histologic similarity to some genodermatoses, Grover’s disease is not an inherited disorder.

Fig 9-13 Paraneoplastic pemphigus with intraepidermal acantholysis and interface dermatitis

Fig 9-14 Paraneoplastic pemphigus

Paraneoplastic pemphigus

Paraneoplastic pemphigus demonstrates a wide variety of histologic patterns. The most common form represents a hybrid of classic pemphigus (intraepidermal acantholysis) and erythema multiforme (lichenoid lymphocytic infiltrate with interface reaction and necrotic keratinocytes). In one single study, 27% of cases had only suprabasilar acantholysis alone.

Multiple autoantibodies have been detected in paraneoplastic pemphigus, including those directed at: desmoglein 1 (160 kD), desmoglein 3 (130 kD), desmoplakin I (250 kD), bullous pemphigoid antigen 1 (230 kD), envoplakin (210 kD), periplakin (190 kD), and an unnamed 170-kD antigen. Paraneoplastic pemphigus is more severe and recalcitrant to treatment than is pemphigus vulgaris. The disease often remits with cancer remission, and recurs with cancer recurrence.

Subepidermal vesiculobullous disorders: pauci-inflammatory subepidermal conditions

Porphyria cutanea tarda

Fig 9-15 Porphyria cutanea tarda (PCT)

Fig 9-16 PCT: caterpillar bodies

Porphyria cutanea tarda is the most common form of porphyria in the USA. It is commonly associated with hepatitis C, alcohol ingestion, and iron overload. Inherited types result from reduced activity of uroporphyrinogen decarboxylase, an enzyme involved in heme synthesis. Blisters, erosions, and milia occur on the hands and other photo-exposed locations.

Pseudoporphyria results in essentially identical clinical and histopathologic changes, but is instead due to an exogenous medication. Naproxen sodium causes the majority of cases. No disturbance of porphyrin synthesis has been detected in pseudoporphyria. Pseudoporphyria may occur in young patients, and solar elastosis may not be demonstrated. Limited evidence suggests that occasional eosinophils may be more common in pseudoporphyria and festooning of the papillary dermis may not be as prominent.

Epidermolysis bullosa acquisita

Key features

• Subepidermal vesiculation

• Fibrin deposition in the floor of the blister cavity

• Some cases may show neutrophils within the papillary dermis, while other cases are histologically indistinguishable from bullous pemphigoid

• Dermal fibrosis (scar) may be present in the dermis

• Milia formation may be seen in late lesions

• Direct immunofluorescence of adjacent skin demonstrates linear deposition of IgG and C3 at the dermoepidermal junction in a u-serrated pattern; IgA has been demonstrated in a significant number of cases

Fig 9-17 (a) Epidermolysis bullosa acquisita. (b) Epidermolysis bullosa acquisita, DIF showing characteristic u-serrated pattern (arrow).

Epidermolysis bullosa acquisita (EBA) is caused by an antibody to type VII collagen, a major component of the anchoring fibrils. It is thought that deposition of immune complexes leads to the neutrophilic inflammation present in some specimens.

The histology may overlap with bullous pemphigoid, and indirect immunofluorescence on salt-split skin is sometimes used to distinguish the conditions when the typical u-serrated pattern of EBA is not apparent on DIF. In bullous pemphigoid, the immunoreactants are deposited within the basement membrane zone and highlight the roof of salt-split skin. Conversely, in epidermolysis bullosa, the immunoreactants mark the floor of salt-split skin.

Toxic epidermal necrolysis/Stevens–Johnson syndrome

Key features

• Subepidermal vesiculation/sloughing with confluent necrosis of the epidermis

• Minimal inflammatory infiltrate

• Some cases may show a sparse superficial perivascular inflammatory infiltrate

• Overlap between toxic epidermal necrolysis and Stevens–Johnson syndrome exists

• Immunofluorescence is negative

Fig 9-18 Toxic epidermal necrolysis

Fig 9-19 Stevens–Johnson syndrome

Inflammatory subepidermal conditions

Bullous pemphigoid

Fig 9-20 Bullous pemphigoid

Bullous pemphigoid usually occurs in older patients, although children are occasionally affected. The disease is associated with autoantibodies to bullous pemphigoid antigen I (230 kD) and/or bullous pemphigoid antigen II (180 kD). The latter antigen is most clearly linked to pathogenesis. The subepidermal vesiculation results in firm and tense blisters. Intensely pruritic urticarial plaques, without clinically apparent vesiculation, may predate frankly bullous lesions (“urticarial pemphigoid”). Mucosal involvement is sometimes present, but, unlike pemphigus, it is rarely the first site of involvement.

Pemphigoid gestationis (also known as herpes gestationis) is a related vesiculobullous condition occurring in gravid women; it has essentially identical histopathologic and immunohistologic findings.

Fig 9-21 Urticarial pemphigoid

Fig 9-22 Direct immunofluorescence of bullous pemphigoid showing linear deposition of IgG at the dermal–epidermal junction

Cicatricial pemphigoid

Key features

• Subepidermal vesiculation

• Variable degree of inflammation in the dermis

• Neutrophilic microabscesses in the dermis may be identified in new lesions

• Cicatricial pemphigoid usually demonstrates fewer eosinophils than bullous pemphigoid

• Direct immunofluorescence of adjacent skin demonstrates linear deposition of IgG and C3 along the dermoepidermal junction in 80% of cases (also seen along appendageal structures)

Fig 9-23 Cicatricial pemphigoid

Cicatricial pemphigoid refers to a heterogeneous group of scarring, subepidermal blistering disorders caused by a variety of autoantibodies. Tense bullae that heal with scarring are a common theme. Most subtypes involve oral or ocular mucosa. Recurring lesions may demonstrate extensive dermal scarring. Paraneoplastic variants have been described in the literature.

Dermatitis herpetiformis

Key features

• Subepidermal vesiculation

• Neutrophilic abscesses in tips of dermal papillae

• Slight fibrin deposition in the tips of dermal papillae at points of vesiculation

• DIF demonstrates granular deposition of IgA within dermal papillae ± along dermal–epidermal junction. Granules have a vertical “picket fence” appearance.

Fig 9-24 Dermatitis herpetiformis

Dermatitis herpetiformis is an intensely pruritic vesiculobullous disorder. Lesions are common upon the elbows, knees, buttocks, and scalp. Recent research indicates that epidermal transglutaminase-3 is the autoantigen in dermatitis herpetiformis. The disease is highly correlated with celiac sprue. Essentially, all patients have some level of gastrointestinal pathology, even if it is subclinical. Strict gluten-free diets prevent clinical manifestations of disease activity.

The granular deposition of IgA distinguishes dermatitis herpetiformis from linear IgA bullous dermatosis. Deposition is most marked in perilesional skin, with the densest deposits within dermal papillae. A vertical “picket fence” granule pattern may be apparent. Other immunoglobulins may be present in dermatitis herpetiformis; IgM is identified concurrently in up to 30% of cases.

Pearl

The differential diagnosis for neutrophils within dermal papillae or subepidermal collections of neutrophils:

• Linear immunoglobulin A

• Dermatitis herpetiformis

Fig 9-25 Direct immunofluorescence of dermatitis herpetiformis showing granular deposition of IgA in the dermal papillae

Linear IgA bullous dermatosis

Key features

• Subepidermal vesiculation

• Neutrophils are the predominant inflammatory cell

• Some cases may demonstrate scattered eosinophils and a mild perivascular lymphocytic inflammatory infiltrate

• Direct immunofluorescence of adjacent skin demonstrates linear deposition of IgA along the dermoepidermal junction (the only immunoreactant present in 80% of cases)

Fig 9-26 Linear IgA bullous dermatosis

Linear IgA is a heterogeneous subepidermal vesiculobullous disorder. In children, the disease is referred to as chronic bullous dermatosis of childhood. Both disorders are caused by autoantibodies targeting proteins (97–120 kD) that form as degradation products of bullous pemphigoid antigen II. Classically, the disease results in grouped annular lesions of tense bullae which have been likened to a “string of pearls.” Drug-induced cases have been described with vancomycin.

By light microscopy, linear IgA bullous dermatosis overlaps significantly with dermatitis herpetiformis. It may be difficult to separate the two conditions without direct immunofluorescence examination.