SSSS often starts as skin tenderness and erythema in flexural skin and with mucous membrane sparing. Vulva was the presenting site in one rare case of SSSS in a child [4]. Subsequently large flaccid blisters with positive Nikolsky’s sign develop which rupture readily. Widespread exfoliation which can involve most of the body surface (Ritter’s disease) is caused by toxins produced from infections at distant site and reaches the cutaneous target via hematogenous spread. Significant skin sloughing can result in poor thermoregulation, delicate fluid balance, and susceptibility to superinfection. SSSS mainly affects neonates and children less than 6 years of age likely due to an immature immune system and less effective renal toxin clearance [5]. In children spontaneous healing occurs after several days with mortality less than 5 %. In contrast, staphylococcal septicemia may develop in adult patients with mortality up to 60 % [6].

Subcorneal blister is present containing occasional acantholytic cells and few neutrophils (Fig. 4.1). On frozen section of sloughed skin, one would see only the granular cells attached to the stratum corneum (Fig. 4.2). Only a sparse dermal infiltrate is seen, in contrast to a heavier infiltrate in bullous impetigo and pemphigus foliaceus. DIF studies are negative.

Vulvar lesions were the second most frequent site of mucosal pemphigus vulgaris, with a frequency of approximately 22–51 % [8, 10], affecting labia majora and minora followed by vagina. Rarely genital lesions can be the sole manifestation of the disease especially in young age [10–12]. The two variants of pemphigus vulgaris described in the pediatric population, childhood, and juvenile types have increased incidence of genital lesions than the adult counterpart. Involvement of the uterine cervix and vagina is not uncommon in genital pemphigus vulgaris [10]. These patients often present with painful mucosal erosions (Fig. 4.3) and/or flaccid bullae (Fig. 4.4) involving the mouth or nasal mucosa, associated with round to oval bullae in non-erythematous skin with predilection for scalp, face, axillae, and groins. In the vulvar, as in non-genital skin, blisters have a short duration leading to superficial ulcers and erosions [8, 12]. Nikolsky’s sign is present. Rarely the clinical, histologic, and antibody profile may change from pemphigus vulgaris to pemphigus foliaceus [13]. In pemphigus vegetans, a vegetative variant of pemphigus vulgaris, hypertrophic or warty vegetations develop (Fig. 4.5) in association with the bullae in inguinal, perianal, umbilical, mammary, axillary, and scalp [14]. The localized and self-limited character of pemphigus vegetans distinguishes it from pemphigus vulgaris.

Pemphigus foliaceus presents with recurrent crops of flaccid bullae that rupture readily resulting in shallow erosions and crusted erythematous plaques. Mucous involvement is rare. Of interest, a recent series from Brazil documented genital involvement by pemphigus foliaceus for the first time in 4/15 (27 %) patients [8].

In pemphigus vulgaris, acantholysis results in intraepidermal blister with basilar cells aligned at the floor of the blister resembling a row of “tombstones” (Figs. 4.6 and 4.7). There are no brightly eosinophilic dyskeratotic cells. The roof of the blister shows scalloping of cells due to acantholysis. In addition to the mentioned histologic features, verrucous epidermal hyperplasia, intraepidermal eosinophilic microabscesses containing acantholytic cells, and dermal infiltrate of lymphocytes and eosinophils are also seen in pemphigus vegetans (Figs. 4.8a, b) [15]. Acantholysis is noted only at the granular layer in pemphigus foliaceus (Fig. 4.9). The characteristic cell is a dyskeratotic granular layer cell. In some cases there is a mid-epidermal cleft with acantholytic cells. However, there is no evidence of suprabasilar acantholysis, ruling out a variant of pemphigus vulgaris. A moderately dense and mixed infiltrate comprising of lymphocytes, neutrophils, and scattered eosinophils is seen around the dermal blood vessels and also interstitially in both pemphigus foliaceus and pemphigus vulgaris. Neutrophils can be prominent in both lesions. For pemphigus vulgaris and pemphigus vegetans, acantholysis can be prominent within follicular epithelium; however, eosinophils would be prominent within the inflammatory infiltrate for pemphigus vegetans (Fig. 4.8).

For all three types of pemphigus, intercellular IgG and C3 depositions are seen on direct immunofluorescence (DIF) studies (Fig. 4.10). Circulating autoantibodies to epidermal intracellular spaces can be detected with indirect immunofluorescence (IIF) method against monkey esophageal epithelium; and the titer correlates with the clinical activity of the disease. Not long ago, IgG4 immunostaining has been shown to be a sensitive and specific test for diagnosing pemphigus in the setting of active lesions when additional frozen tissue is not available for DIF examination [16]. In addition, it has recently been reported that DIF can be performed on plucked hair follicles as an alternative test [17].

Although Hailey–Hailey disease, Darier’s disease, and acantholysis of the vulvocrural area are in the histologic differential diagnosis for pemphigus vulgaris, the DIF studies are negative in these entities. The follicular involvement noted in pemphigus vulgaris is not seen in these other intraepidermal acantholytic disorders; whereas, dyskeratosis is not a feature of pemphigus vulgaris. Marked dermal inflammation would be seen in Hailey–Hailey disease in contrast to the paucity of it in pemphigus vulgaris. Infection is in the differential diagnosis for pemphigus vegetans due to the marked epidermal hyperplasia and inflammation. Special stains, cultures for microorganisms and mmunofluorescent tests are useful tools to differentiate these two diseases. DIF studies would be negative in bullous impetigo, dermatophytosis, and SSSS—entities with similar histologic features to pemphigus foliaceus. In addition, Gram and periodic acid–Schiff (PAS) stains would highlight the intracorneal bacteria and fungal hyphae in bullous impetigo and dermatophytosis, respectively. An intercellular IgA deposition on DIF would be seen within the epidermis for IgA pemphigus. Of interest, intraepidermal subcorneal and suprabasal acantholysis can be observed on histologic sections due to EMLA (eutectic mixture of local anesthetics) application, and these changes can pose a potential diagnostic pitfall [18].

Papular acantholytic dyskeratosis of the vulvocrural area or papular genitocrural acantholysis often presents as solitary or grouped, flesh-colored papules on the vulva and perianal region, with extension to the thigh and perineum in some cases [19, 20]. However, a spectrum of clinical presentations includes vesicles, bullae, patches, and plaque [20, 21]. A rare case in pediatric age group has been reported [22]. These lesions are generally asymptomatic, but pruritus and burning sensation can be the symptoms in some cases [23].

It has been suggested that some cases of papular genitocrural acantholysis is an allelic variant of Hailey–Hailey disease since heterozygous mutations in intron 5 and exon 24 of the ATP2C1 gene have been reported [24, 25].

Histologic sections show hyperkeratosis, hypergranulosis, epidermal acanthosis, and acantholysis in the spinous zone (Fig. 4.11) [26]. The histologic features of intraepidermal acantholytic, dyskeratotic cells including corps ronds and grains can be indistinguishable from those of Darier’s disease and Hailey–Hailey disease. Corps ronds are cells with pyknotic nuclei with surrounding clear halo in the granular layer of epidermis. Grains are elongated cells with scant cytoplasm and abundant keratohyalin granules. DIF examination is negative.

While Darier’s and Hailey–Hailey diseases are familial, acantholytic dermatosis of the vulvocrural area is often sporadic. Discrete columns of parakeratosis overlying suprabasilar acantholysis are seen in Darier’s disease. A broad zone of acantholysis is present in Hailey–Hailey disease rather than focal area as seen in papular acantholytic dyskeratosis of genitocrural area.

There is predilection of the disease for flexural or intertriginous areas such as neck, axillae, inframammary region, inguinal folds, and perianal and genital region (Fig. 4.12) [27]. Isolated vulvar involvement has been reported [28, 29]. The lesions start as pruritic erosions that spread centrifugally to surrounding skin with associated crust and foul odor. Resolution can result in hypopigmentation but not scarring. More than 70 % have asymptomatic longitudinal white bands affecting the nails [27]. Superinfection with Candida albicans, Staphylococcus aureus, and herpesvirus can be seen, frequently explaining the foul order in these patients [27, 30]. Rarely, squamous cell carcinoma can arise in the setting of Hailey–Hailey disease [31, 32]. Risk factors for development of squamous cell carcinoma such as sun exposure, irradiation, and exposure to carcinogenic agents were not identified in these patients [32].

There is a suprabasilar cleft with at least half of the overlying epidermis showing acantholysis and mild dyskeratosis. The marked acantholysis gives an appearance of “dilapidated brick wall” with irregular spaces between keratinocytes (Fig. 4.13). Surface crust and prominent dermal inflammation are seen. DIF studies are negative in contrast to positive findings in pemphigus vulgaris.

The main histologic differential diagnosis would be pemphigus vulgaris which has absence of scale crust, normal thickness epidermis, suprabasilar acantholysis, follicular epithelium involvement, and minimal dermal inflammation. In contrast to Darier’s disease, corps ronds and grains are infrequently identified.

The disorder often presents at puberty, but can appear later in life, with numerous hyperkeratotic papules usually distributed over the trunk and a “sandpaper” feel. The disease has a seborrheic distribution (chest, neck, back, ears, and groin) and frequently involves the vulva. Localized vulvar presentation has been described [35, 36] and rarely can be associated with squamous cell carcinoma [37]. The associated rash often has a distinct odor and is worsened by humidity, heat, stress, and sunlight. The nails tend to be thin, brittle, and dystrophic and sometimes with characteristic vertical striations. Associated palmar pitting can also be seen. These findings are often helpful clues in diagnosis of the disease. Superinfection with bacteria, virus, or fungus is common.