Blistering Disorders and Acantholytic Processes Affecting the Epidermis of the Vulva


Subcorneal blister

Staphylococcal scalded skin syndrome

A microbial pustulosis of the folds (Chap. 3)

Pemphigus foliaceus

Intraepidermal blister

Pemphigus vulgaris

Papular acantholytic dyskeratosis of vulvocrural area

Hailey–Hailey disease

Darier’s disease

Erythema multiforme/Stevens–Johnson syndrome (Chap. 3)

Herpesvirus infection (Chap. 6)

Subepidermal blister

Bullous pemphigoid and mucous membrane (cicatricial) pemphigoid

Pemphigoid gestationis

Linear IgA disease/chronic bullous disease of childhood

Epidermolysis bullosa

Bullous lichen planus (Chap. 5)

Bullous lichen sclerosus (Chap. 5)




Table 4.2
Summary of clinical and histopathologic features











































































































 
Genital involvement

Mucosal involvement

Age group commonly involved

Level of separation

Type of inflammatory infiltrate

DIF

Pemphigus foliaceus
   
Adults

Subcorneal
 
Intercellular IgG and C3

Pemphigus vulgaris

80 %
 
Adults

Intraepidermal
 
Intercellular IgG and C3

Bullous pemphigoid

9 %

Uncommon

Elderly, rarely in children

Subepidermal

Eosinophils

Linear IgG and C3 at BMZ

Mucous membrane pemphigoid

55 %

Always with associated scarring

Adults

Subepidermal

Neutrophils and eosinophils

Linear IgG and C3 at BMZ

Pemphigoid gestationis

5 %

Rarely
 
Subepidermal

Eosinophils

Linear C3 at BMZ

Linear IgA disease

60 %

Common

Children and adults

Subepidermal

Neutrophils

Linear IgA at BMZ

Epidermolysis bullosa

Rarely

Rarely

Infants

Subepidermal

Minimal
 

SSSS
 
Rarely

Children

Subcorneal

Minimal

Negative

Papular acantholytic dyskeratosis
   
Adults

Intraepidermal

Minimal

Negative

Hailey–Hailey disease

Common
 
Adults

Intraepidermal

Neutrophils

Negative

Darier’s disease
   
Adults

Intraepidermal

Minimal

Negative


DIF direct immunofluorescence examination, SSSS Staphylococcal scalded skin syndrome, BMZ basement membrane zone




Subcorneal Blister



Staphylococcal Scalded Skin Syndrome


Staphylococcal scalded skin syndrome (SSSS) is caused by exfoliative (or epidermolytic) toxins produced by coagulase-positive group II Staphylococcus aureus (especially strain 71) [1]. These organisms are responsible for a preceding conjunctivitis or upper respiratory tract infection. Most cases of SSSS are associated with exfoliative toxins A and B [2]. The exfoliative toxins (ETs) induce epidermal blistering through the cleavage of desmoglein-1, the cell–cell adhesion molecule that is expressed by keratinocytes in the stratum granulosum [2]. Currently, the role of exfoliative toxins in the pathogenesis of SSSS is not well defined [3].


Clinical Features


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].


Histopathology and Differential Diagnosis


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.

A313723_1_En_4_Fig1_HTML.jpg


Fig. 4.1
Staphylococcal scalded skin syndrome. A subcorneal blister with minimal inflammatory infiltrate is seen (Courtesy of Dr. M. Angelica Selim, Department of Pathology, Duke University Medical Center, Durham, NC)


A313723_1_En_4_Fig2_HTML.jpg


Fig. 4.2
Staphylococcal scalded skin syndrome. Stratum corneum and granular cells comprised the blister roof


Summary





  • Clinical Presentation



    • Skin tenderness and erythema in flexural skin, then widespread exfoliation


    • Caused by infection of exfoliative toxin-producing Staphylococcus aureus


  • Histologic Features



    • The exfoliative toxin causes subcorneal blister at the granular layer.


  • Differential Diagnosis



    • Bullous impetigo


    • Pemphigus foliaceus


Takeaway Essentials





  • Clinically Relevant Pearls



    • The exfoliative toxins induce epidermal blistering through the cleavage of desmoglein-1 that is expressed by keratinocytes in the stratum granulosum.


    • Diagnosis may be reached by identifying the detached epidermis in frozen section analysis; the presence of stratum corneum and superficial epidermis confirms the diagnosis of SSSS.


  • Pathology Interpretation Pearls



    • Subcorneal blister at the granular layer


    • Minimal dermal inflammation


    • Minimal acantholysis in contrast to bullous impetigo


Pemphigus Foliaceus and Pemphigus Vulgaris


Pemphigus vulgaris, a rare acquired immunobullous disorder of the skin and mucosa, and pemphigus foliaceus are caused by autoantibodies against desmoglein 3 [7] and desmoglein 1 [8], respectively. Recently, endemic pemphigus foliaceus (fogo selvagem) has been suggested to be triggered by environmental antigen with molecular mimicry with desmoglein 1 [9].


Clinical Features


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 [1012]. 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.

A313723_1_En_4_Fig3_HTML.jpg


Fig. 4.3
Pemphigus vulgaris. Superficial ulcers seen on an erythematous base (Courtesy of Dr. Agustin Alomar, Department of Dermatology, DERMADEX, Instituto Universitario Dexeus, Barcelona, Spain)


A313723_1_En_4_Fig4_HTML.jpg


Fig. 4.4
Pemphigus vulgaris. Flaccid bullae and abundant secretions related to vaginal involvement [12] (Courtesy of Dr. Carlos Ferrándiz, Department of Dermatology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain)


A313723_1_En_4_Fig5_HTML.jpg


Fig. 4.5
Pemphigus vegetans. Slightly raised plaques and small ulcerations (Courtesy of Dr. Isabel Bielsa, Department of Dermatology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain)

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].


Histopathology


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).

A313723_1_En_4_Fig6_HTML.jpg


Fig. 4.6
Pemphigus vulgaris. Suprabasilar acantholysis is noted (Courtesy of Dr. M. Angelica Selim, Department of Pathology, Duke University Medical Center, Durham, NC)


A313723_1_En_4_Fig7_HTML.jpg


Fig. 4.7
Pemphigus vulgaris. Acantholysis can be prominent within follicular epithelium (Courtesy of Dr. M. Angelica Selim, Department of Pathology, Duke University Medical Center, Durham, NC)


A313723_1_En_4_Fig8_HTML.jpg


Fig. 4.8
Pemphigus vegetans. (a) Marked epidermal hyperplasia resembling a verrucous process. (b) Eosinophilic microabscesses containing acantholytic cells are seen within the epidermis (Courtesy of Dr. M. Angelica Selim, Department of Pathology, Duke University Medical Center, Durham, NC)


A313723_1_En_4_Fig9_HTML.jpg


Fig. 4.9
Pemphigus foliaceus. Subcorneal separation and acantholysis are seen

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].

A313723_1_En_4_Fig10_HTML.jpg


Fig. 4.10
Pemphigus vulgaris. Direct immunofluorescence examination demonstrates intercellular IgG deposition within the epidermis


Differential Diagnosis


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].


Summary





  • Clinical Presentation



    • Pemphigus vulgaris often presents with cutaneous flaccid bullae in association with painful mucosal erosions and/or flaccid bullae in the mouth or nasal mucosa.


    • Vulvar superficial ulcers and erosions are the second most frequent form of mucosal disease.


    • Pemphigus foliaceus presents with recurrent crops of flaccid bullae that rupture readily resulting in shallow erosions and crusted erythematous plaques.


    • Pemphigus vegetans characteristic warty erythemaous plaques affect the labia and they are associated with extragenital bullae.


  • Histologic Features



    • Acantholysis at the granular layer in pemphigus foliaceus


    • Intraepidermal blister with suprabasilar acantholysis in pemphigus vulgaris


    • Verrucous epidermal hyperplasia and intraepidermal eosinophilic microabscesses containing acantholytic cells in pemphigus vegetans


    • Intercellular IgG and C3 depositions are seen on DIF studies for both pemphigus foliaceus and vulgaris


  • Differential Diagnosis



    • For pemphigus foliaceus: bullous impetigo, staphylococcal scalded skin syndrome, dermatophytosis, and IgA pemphigus


    • For pemphigus vulgaris: Hailey–Hailey disease, Darier’s disease, and acantholysis of the vulvocrural area


Takeaway Essentials





  • Clinically Relevant Pearls



    • Endemic pemphigus foliaceus is triggered by environmental antigen with molecular mimicry with desmoglein 1.


  • Pathology Interpretation Pearls



    • Acantholysis noted in hair follicular epithelium for pemphigus vulgaris and vegetans but not pemphigus foliaceus


    • In 20 % of pemphigus foliaceus, direct immunofluorescence staining is seen in the upper third of the epidermis.


    • Intraepidermal subcorneal and suprabasal acantholysis can be seen on histologic sections due to EMLA (eutectic mixture of local anesthetics) application.


  • Immunohistochemical/Molecular Findings



    • IgG4 immunostaining on paraffin-embedded tissue may be a new sensitive and specific test.


Intraepidermal Blister



Papular Acantholytic Dyskeratosis of the Vulvocrural Area



Clinical Features


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].


Histopathology


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.

A313723_1_En_4_Fig11_HTML.jpg


Fig. 4.11
Papular acantholytic dyskeratosis. Acantholytic, dyskeratotic cells including corps ronds and grains are seen within the epidermis (Courtesy of Dr. M. Angelica Selim, Department of Pathology, Duke University Medical Center, Durham, NC)


Differential Diagnosis


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.


Summary





  • Clinical Presentation



    • Solitary or grouped, flesh-colored papules


  • Histologic Features



    • Intraepidermal acantholysis, dyskeratotic cells including corps ronds and grains


  • Differential Diagnosis



    • Darier’s disease


    • Hailey–Hailey disease


Takeaway Essentials





  • Clinically Relevant Pearls



    • Consider diagnosis in any case of asymptomatic and eruptive genitocrural papules


  • Pathology Interpretation Pearls



    • Presence of corps ronds and grains rules out pemphigus.


    • A broad zone of acantholysis is present in Hailey–Hailey disease rather than focal area as seen in papular acantholytic dyskeratosis of genitocrural area.


  • Immunohistochemical/Molecular Findings



    • Negative direct immunofluorescence studies also speak against immunobullous disease.


Hailey–Hailey Disease


Hailey–Hailey disease (benign familial pemphigus) is an autosomal dominant acantholytic genodermatosis whose pathogenesis is thought to involve mutations in a calcium pump, ATP2C1, which encodes the human secretory pathway Ca2+/Mn2+ APTase protein 1. The latter is a part of an adhesion complex between desmosomal proteins and tonofilaments [27]. The mutation is thought to weaken the intracellular junctions. Although the disease is familial, up to one-third of patients have no family history of the disease. Hailey–Hailey disease often occurs during the second and fourth decades with frequent remissions and relapses and tends to improve with age.


Clinical Features


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].

A313723_1_En_4_Fig12_HTML.jpg


Fig. 4.12
Hailey–Hailey disease. Eroded and crusted whitish plaques involving the genital area and inguinal folds (Courtesy of Dr. Carlos Ferrándiz, Department of Dermatology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain)


Histopathology


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.

A313723_1_En_4_Fig13_HTML.jpg


Fig. 4.13
Hailey–Hailey disease. Acantholysis involving the entire epidermis is seen


Differential Diagnosis


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.


Summary





  • Clinical Presentation



    • Predilection of the disease for flexural or intertriginous areas such as neck, axillae, and groins


    • Start as pruritic erosions that spread centrifugally to surrounding skin with associated crust and foul odor


  • Histologic Features



    • Intraepidermal acantholysis involving at least half of the epidermis above a suprabasilar cleft


    • Marked surface crust, epidermal acanthosis, and dermal inflammation


    • Negative direct immunofluorescence studies

    Differential Diagnosis



    • Pemphigus vulgaris


Takeaway Essentials





  • Clinically Relevant Pearls



    • Crusts predominate with some small peripheral vesicles.


  • Pathology Interpretation Pearls



    • Diffuse acantholysis and mild dyskeratosis are characteristic.


    • Corps ronds and grains are infrequent.


  • Immunohistochemical/Molecular Findings



    • Negative DIF studies rule out pemphigus group of disorders.


Darier’s Disease


Darier’s disease in an uncommon genodermatosis whose pathogenesis is thought to be due to mutation of a gene on chromosome 12q encoding a calcium pump protein, ATP2A2 [33]. Although it can be autosomal dominant, only half of the cases in a large series have a positive family history [34].


Clinical Features


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.

Only gold members can continue reading. Log In or Register to continue

Nov 11, 2017 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Blistering Disorders and Acantholytic Processes Affecting the Epidermis of the Vulva
Premium Wordpress Themes by UFO Themes
%d bloggers like this: