Vulvar Dermatoses and Infections

Published on 30/06/2015 by admin

Filed under Pathology

Last modified 30/06/2015

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 5 (1 votes)

This article have been viewed 3275 times

Vulvar Dermatoses and Infections

Chapter Outline

Introduction

The most common diseases affecting the vulva are dermatologic,17 but the clinicians caring for patients with these complaints are usually gynecologists or family practitioners who may lack sophisticated diagnostic and therapeutic skills in skin diseases. Conversely, dermatologists may have interest and expertise in a subset of diseases in this organ. In summary, no single specialist is generally well trained to care for the full spectrum of vulvar diseases. Multidisciplinary clinics, to which different specialists bring their expertise, are often the best forum to efficiently diagnose and treat acute or chronic vulvar diseases.8,9

In response to the complexity of vulvar disorders, the International Society for the Study of Vulvovaginal Disease (ISVVD) was founded with one objective: to facilitate clear communication between clinicians and pathologists caring for patients with neoplastic and non-neoplastic vulvar diseases. Accordingly, it discarded its 1987 classification, replacing it in 2006 (Table 3.1) with an entirely different classification based on histopathology.10,11 And in 2011, a new clinical based classification of inflammatory vulvar diseases was published to assist the clinician to reach a diagnosis based only on clinical findings (see glossaries at the end of this chapter). Currently, the ISSVD considers both classifications as complementary of each other.

Table 3.1

2006 ISSVD Classification of Vulvar Dermatoses:10,11 Pathologic Subsets and Their Clinical Correlates

image

This chapter utilizes a multidisciplinary approach. The diseases are organized in order of frequency and classified with a clinical perspective using the type of lesion (patch, papule, nodule, etc.) and the symptoms produced (itch, etc.), combined with the histopathologic pattern of inflammation (Figure 3.1). Both vulvar and extravulvar manifestations are covered. Not uncommonly, the latter features are the key to a correct diagnosis.

The brief glossary of clinical dermatological terms at the end of this chapter defines some of the more commonly used terms in dermatology and dermatopathology. To further enhance this chapter, the common dermatopathologic terms used are also defined in a separate glossary divided into terms that apply to the three main layers: the surface keratin layer, the epidermis, and the dermis.

Common Dermatoses Affecting the Vulva

Spongiotic Dermatitis (Eczemas)

Eczema or spongiotic dermatitis encompasses a variety of diseases with spongiosis as a common histologic finding at some stage. The spongiotic tissue reaction shows intracellular and intercellular edema leading to expanded spaces among keratinocytes. Eczema is the leading cause of chronic genital itching. All forms of endogenous and exogenous spongiotic dermatitis can affect the vulva, where they may present acutely or chronically. The location, pattern, and extent of the lesions help to define the different types of eczemas.

General Clinical and Pathologic Features of Spongiotic Dermatitis

Acute Spongiotic Dermatitis.

The term ‘eczema’ derives from the Greek ekzein ‘to boil over,’ reflecting the clinical appearance of acute lesions. Clinically, it exhibits erythematous macules, papules, and plaques (Figure 3.2). With increasing degrees of spongiosis, lesions become vesicular or bullous and begin to weep or to ooze. The vesicles frequently progress to rupture, and their contents dry to form a surface crust. In the biopsy specimen the epidermis shows a variable amount of spongiosis, hyperkeratosis and parakeratosis, and exocytosis of inflammatory cells. If the spongiosis is considerable, the fluid will collect in intraepidermal vesicles that may contain lymphocytes, neutrophils, eosinophils, and Langerhans cells. Mild papillary dermal edema leading to separation of collagen fibers can be seen in association with telangiectatic vessels. The superficial vascular plexus shows a perivascular mixed inflammatory infiltrate consisting of lymphocytes, neutrophils, and eosinophils. This basic pattern of acute spongiotic dermatitis is altered by scratching or superimposed infections (impetiginization). The former produces excoriations or lichen simplex chronicus (see the following section); the latter is associated with neutrophils in the stratum corneum. Acute inflammation in the stratum corneum should prompt the pathologist to request special stains for bacterial (Brown–Brenn) and fungal (periodic acid–Schiff, PAS, and Gomori methenamine silver, GMS) forms.

Chronic Spongiotic Dermatitis.

Clinically the skin exhibits a leathery appearance with accentuation of skin markings (lichenification). The skin also changes from red (characteristic of acute spongiotic dermatitis) to brown or hyperpigmented, particularly in racially dark individuals. Scratching from intense pruritus produces excoriations where the surface has been traumatized. Histologically there is variable hyperplasia of the epidermis (acanthosis) with overlying hyperkeratosis and parakeratosis. The elongated rete ridges are separated by a papillary dermis with prominent capillaries and thick collagen fibers arranged perpendicular to the surface. Lymphocytes predominantly are found around upper dermal vessels. In certain biopsy specimens, in the previously described background of chronic dermatitis, there are features associated with acute inflammation, specifically a notable degree of spongiosis. This coexistence of acute and chronic histologic findings is called subacute spongiotic dermatitis (Figure 3.3).

Clinical Patterns of Vulvar Spongiotic Dermatitis

Endogenous Vulvar Spongiotic Dermatitis.

The two most common endogenous dermatitides are atopic dermatitis and seborrheic dermatitis. Both diseases can show the entire spectrum of eczematous lesions ranging from erythematous scaly areas to oozing to vesicle formation, ending in lichenification. Few physicians see the acute phase. Most patients seek medical attention only during the subacute to chronic phase. Commonly, the correct diagnosis depends on identifying more distinctive extragenital lesions.

Atopic Dermatitis

is a chronic, pruritic inflammation of the skin that affects individuals with personal or family history of atopic diathesis (atopic eczema, asthma, allergic seasonal rhinitis). Among the major diagnostic criteria are the presence of pruritus, chronicity, history of atopy, and lesions with typical morphology such as flexural distribution. Although the etiology and pathogenesis are still unknown, IgE-mediated late phase responses, cytokine imbalances, and cell-mediated reactions may all play important roles. Genetic factors also appear to be involved. One candidate gene is located on chromosome 11q13.5 (note that the gene for the β-subunit of the FCγRI, the high-affinity receptor for IgE, is localized to chromosome 11q12–13). Another gene implicated in the pathogenesis of this disease is on chromosome 16q11–p13 (associated with the IL4R gene).

Patients with atopic dermatitis experience pruritus rather than soreness or irritation when suffering from inflamed skin. The rubbing and scratching in turn stimulate and perpetuate the itch in an ‘itch–scratch cycle.’ Adult women are prone to experience genital eczema in the form of red to hyperpigmented areas, often with subtle changes of excoriation and scale due to the moisture of the area. Biopsies are rarely necessary. The diagnosis is confirmed by the excellent response to therapy, mainly corticosteroid medications.

Seborrheic Dermatitis

is a chronic and recurrent dermatitis that manifests as minimally symptomatic, thin, reddish plaques with greasy yellowish scale involving areas of increased sebum production. Genital lesions frequently occur in association with lesions localized in seborrheic areas with skinfold involvement, especially axillae. Malassezia furfur, the causative organism of pityriasis versicolor, may play a role in seborrheic dermatitis by inducing an allergic reaction. Seborrheic dermatitis of the external genitalia is prominent in the skinfolds. It affects the hair-bearing skin of the labia majora and perineum. The diagnosis is reached by identifying red scaling plaques on the scalp, central face, and skinfolds, and the absence of Candida in cultures of skin scrapings. Similar to atopic dermatitis, the response to therapy confirms the diagnosis.

Exogenous Vulvar Spongiotic Dermatitis.

The two most common forms of spongiotic dermatitis with an exogenous cause are irritant contact dermatitis and allergic contact dermatitis.1216 The acute clinical presentations of allergic and irritant contact dermatitis have significant overlap and with time both evolve to lichen simplex chronicus.

Irritant Contact Dermatitis

occurs when damage to the cutaneous barrier function exceeds the skin’s repair mechanisms.1214 This dermatitis is an inflammatory reaction to direct toxic effects of a chemical, physical, or mechanical agent. Irritants may remove surface lipids and water-holding substances, damage cell membranes, denature keratins, exert direct cytotoxic effects, liberate cytokines, etc. Vulvar tissue structure, hydration, occlusion, and friction may increase its propensity to inflammation.17 Irritant contact dermatitis of the vulva occurs most commonly in the form of diaper dermatitis due to urine; this can also occur in adult women experiencing stress incontinence. The most common contact irritants causing vulvar dermatitis are listed in Table 3.2. Contact irritant dermatitis clinically presents with sharply demarcated, erythematous papules and plaques that may be weeping (Figures 3.3 and 3.4) and eroded if acute, or lichenified in chronic cases (see the section Lichen simplex chronicus).18 The diagnosis is confirmed when the culprit is eliminated and the rash disappears.

Allergic Contact Dermatitis

is a cell-mediated type IV delayed hypersensitivity reaction.12,16 The rash develops 48–72 hours after exposure to the allergen. After sensitization, the patient develops allergic contact dermatitis upon each subsequent exposure. Although one exposure may be sufficient to develop the initial dermatitis, most frequently clinical reactivity becomes manifest only after repetitive exposures. The dermatitis lasts for about 2–3 weeks. As a general rule, infants under five and elderly persons are less liable to develop allergic contact dermatitis as their immune systems tend not to develop type IV hypersensitivity reactions to antigens. If episodes are continuous, a patch test may be useful to study the reactants. Table 3.3 lists the common causes of vulvar allergic dermatitis.

Hints on Histopathologic Interpretation of Vulvar Spongiotic Dermatitis

Biopsy is rarely obtained on acute lesions of either irritant or allergic contact dermatitis. In such cases, the pathologist’s main contribution is to confirm the clinical suspicion of spongiotic dermatitis, and to rule out any other underlying dermatoses such as candidiasis or psoriasis. Performance of fungal stains for vulvar dermatitis can virtually always be justified. Rarely can the histopathologist distinguish the exogenous from the endogenous types with certainty.15 The cause is more likely to be identified after a detailed clinical history and an expert dermatologic examination. However, certain histologic features may point toward a particular entity such as the following:

• Keratin changes. Parakeratosis, particularly when also containing the nuclear remnants of neutrophils, should suggest psoriasis, seborrheic dermatitis, or a fungal infection. The location of parakeratosis around the follicular ostia, and spongiosis accentuated in the epithelium of the follicular infundibula, point toward seborrheic dermatitis.

• Keratinocytes. Focal keratinocyte ballooning and apoptosis suggests irritant contact dermatitis. Extensive keratinocyte necrosis, however, suggests erythema multiforme, fixed drug eruption, or dermatitis artefacta.

• Spongiosis. Exocytosis of eosinophils into the epidermis suggests fungal infection, allergic contact dermatitis, atopic dermatitis, or drug reaction (or, more rarely, cicatricial pemphigoid or pemphigus vegetans). Neutrophils suggest fungal infection or psoriasis. Increased numbers of Langerhans cells suggest allergic contact dermatitis.

• Dermal infiltrate. Eosinophils suggest allergic contact dermatitis. Marked dermal edema and dilatation of lymphatics suggest an urticarial reaction to systemic or topical drugs.

Chronic Dermatitides

Lichen Simplex Chronicus (Formerly Squamous Cell Hyperplasia or Hyperplastic Dystrophy)

Clinical Features

Lichen simplex chronicus is now considered to be equivalent to squamous cell hyperplasia by the ISSVD.19 Lichen simplex chronicus manifests as thick, scaly plaques arising after rubbing and scratching in response to pruritus. The areas most frequently affected are the mons pubis and labia majora. These cutaneous changes may be the end point of various types of eczematous dermatitis or be superimposed upon other inflammatory processes (lichen planus, psoriasis, lichen sclerosus, etc.). Sometimes the original process that started the chronic itch/scratch cycle, perpetuating the lichen simplex chronicus changes, may have resolved by the time of the biopsy (i.e., an episode of allergic contact dermatitis, an infection with Candida, etc.). Clinically, the presence of thick skin with enhanced cutaneous markings (Figure 3.5) is encompassed by the term ‘lichenification,’ referring to the rough surface of lichen overgrowing smooth-surfaced rocks. Excoriations and secondary infections may result from the scratching. The pathogenesis of this disorder remains incompletely understood.

Microscopic Features

The histologic features of lichen simplex chronicus are epidermal acanthosis with superficial dermal fibrosis and variable chronic inflammation (Figure 3.6). Hyperkeratosis and parakeratosis may be present. The dermal collagen bundles are thickened and tend to be vertically oriented. There is an inflammatory infiltrate, predominately of lymphocytes in the superficial dermis. The changes are otherwise nonspecific, and the diagnosis is made by exclusion of other dermatoses. When inflammatory exocytosis is marked, special stains for fungal forms (PAS and GMS) or bacteria are particularly recommended.

Psoriasis

Psoriasis (psoriasis vulgaris) is a chronic, relapsing, inflammatory dermatosis affecting 1–2% of the American population.20 Psoriasis is inherited as an autosomal dominant trait (diathesis) with incomplete penetrance. Four main genetic loci appear associated with this disease (on chromosomes 17q, 4q, 1q, and 6p).

Clinical Features

The most typical clinical presentation is as well-demarcated, red to salmon-colored plaques with loosely adherent, silver scales affecting the extensor surfaces of the extremities (elbows and knees), sacral region, scalp, and nails. The vulva and perineum are involved frequently in combination with typical lesions elsewhere on the body. Psoriasis is infrequently confined solely to the vulva with a reported incidence of 2–5% of psoriatic patients.20 In the vulva and other intertriginous areas, the silvery scales are lost.21 The disease affects hair-bearing areas (mons pubis and labia majora), whereas the labia minora are spared. The intense erythema and the well-demarcated borders help to separate psoriasis from eczema. The lesions frequently are symmetric and may persist for years. Persistent, painful intergluteal and perianal fissuring can be a serious complication. Often the diagnosis is established with certainty after typical lesions develop elsewhere on the body.

Microscopic Features

The epidermal changes are hyperkeratosis, parakeratosis, and elongation of the rete ridges to an even length with club-shaped tips of rete ridges, hypogranulosis, and collections of polymorphonuclear leukocytes within the stratum corneum (Munro abscesses) and epidermis (spongiform pustules of Kogoj). Mitotic figures are found at different levels of the epidermis reflecting the significantly increased rate of epithelial turnover. The papillary dermis shows edema with irregularly dilated vessels with a minimal lymphocytic infiltrate and scattered neutrophils (Figure 3.7). Coexistence of staphylococcal infection, repeated scratching, trauma, and chronicity, as well as partial treatment with topical steroids, can affect the histologic features.

Less Common Dermatoses That Frequently Involve the Vulva

Lichenoid Dermatoses

The two most common conditions in this category are lichen sclerosus and lichen planus.

Lichen Sclerosus

Lichen sclerosus, one of the most common chronic anogenital dermatoses, manifests as thickened and sclerotic dermal collagen.1 Most patients are middle-aged and elderly women.22 Sometimes it is familial.23 Childhood presentation is uncommon, but it is important to remember that it does occur lest it be confused with signs of sexual abuse.2426 One-fifth of patients show extragenital involvement as hypopigmented wrinkled patches. Extragenital lesions as a rule do not undergo malignant degeneration. On the other hand, genital lesions may coexist with or subsequently develop squamous cell carcinoma.2730 In the vulva the frequency with which squamous cell carcinoma is associated with long-standing lesions of lichen sclerosus is 3–4%,30 compared with 5.8% in penile lesions (balanitis xerotica obliterans), most of them associated with human papillomavirus (HPV) infection.31

Clinical Features

The clinical presentation of lichen sclerosus is protean. The initial lesions consist of flat, ivory to white papules that coalesce to form plaques of varying sizes and shapes. The early erythematous lesions with an edematous center impart a white color, and with time transform to the classic sclerotic lesions. The ‘cigarette paper’ atrophy in these lesions refers to the progressively wrinkled, flat or slightly depressed surface (Figure 3.8). The symmetrically involved vulva and anus form the classical ‘figure-of-eight’ or ‘hourglass.’ In the vulva, lichen sclerosus extends to Hart’s line in the vestibule, with the vaginal mucosa uninvolved. Vulvar lesions may combine atrophic and hypertrophic areas, or may develop lichenification secondary to pruritus-related scratching. Early stage of lichen sclerosus may be difficult to separate from lichen planus and some patients with lichen sclerosus may develop introital lichen planus.32 This clinical overlap parallels a similar cytokine response between these two diseases.33

Lichen sclerosus usually causes severe, intractable itch.24,25 Occasionally, the condition is asymptomatic and discovered incidentally during a routine pelvic examination. Over time, variable degrees of scarring occur at an unpredictable pace and extent. Often the labia minora partially resorb (Figure 3.8). In severe cases, vulvar stenosis, effaced anatomy, and clitoral phimosis occur. Dyspareunia is common.

Early diagnosis and adequate treatment can prevent the distressing symptoms and severe vulvar deformities. Close surveillance facilitates early detection of squamous cell carcinoma.34,35 Biopsy has a double role: first to confirm the diagnosis and second to help exclude a malignancy.

Etiology and Pathogenesis

Although the etiology of lichen sclerosus is still unknown, infection may play a potential role, an argument based on the presence of CD8+ and CD57+ lymphocytic infiltrates, a profile usually associated with viral diseases and autoimmune disorders. Direct immunofluorescence studies have shown a deposit of fibrin along the dermoepidermal junction in most of the specimens studied.36 With an indirect fluorescent technique, IgM and C3 were concentrated along the basal lamina of the epithelium.36 Studies of the T-cells within lichen sclerosus have identified monoclonal T-cells that are predominantly cytotoxic CD8+ responsible for the destruction of basal keratinocytes.37 Lichen sclerosus is associated with autoimmune disorders such as vitiligo, pernicious anemia, thyroid disease, etc.3841 Individual HLA types (DQ7, DQ8, and DQ9) have been detected more frequently in patients with lichen sclerosus.38

Tissue studies of glucose metabolism as well as alkaline phosphatase and adenosine triphosphatase have shown a surprisingly high rate of activity equal to that seen in hyperplastic specimens and greater than that found in normal menopausal skin. The cell cycle protein Ki-67 is present in the basal and many parabasal epithelial cells involved by lichen sclerosus.42 Collagen metabolism is abnormally active and the number of capillaries is reduced.

Microscopic Features

Lichen sclerosus affects the epidermis and upper dermis. The microscopic findings can vary considerably depending upon the age of the lesion, scratching, excoriation, and treatment. The main features include a thin epidermis with loss of the rete ridges, an underlying zone of homogeneous collagenized edema of variable thickness, and a band of lymphocytic infiltration beneath this zone (Figures 3.9 and 3.10).43 The squamous epithelium is thinned, but hyperkeratosis may result in some cases from superimposed lichen simplex chronicus. The dermal–epidermal junction may show focal vacuolar change and the basement membrane may fragment, leading to the formation of PAS-positive clumps in the subjacent dermis. Spongiosis may be evident. Mitotic figures are rare or absent. The homogeneous dermal zone usually shows absence of elastic fibers. Both the absence of melanosomes in the keratinocytes and the disappearance of melanocytes contribute to the white clinical appearance.

Clinical Behavior

Lichen sclerosus is a relentless and progressive disease when presenting in most adults, but not uncommonly spontaneously regresses in girls once they reach menarche. Lichen sclerosus sometimes is associated with vulvar squamous carcinoma; however, it is not considered to be a premalignant intraepithelial neoplasm.2729 In a report of vulvar squamous cell carcinoma, 61% of the patients had lichen sclerosus.44 Symptomatic lichen sclerosus is preceded by carcinoma by a mean of 4 years. Among patients with symptomatic vulvar lichen sclerosus, 9% developed vulvar intraepithelial neoplasia (VIN) lesions and 21% invasive squamous cell carcinoma. Differentiated (simplex) type VIN and non-HPV-related squamous cell carcinoma have been associated with vulvar lichen sclerosus.45 Increased basal expression of Ki-67 appears to identify those cases with high risk of evolving into squamous cell carcinoma.46,47 Also, aneuploidy has been reported, which correlates with elevated p53 expression.27 Traditional management has relied on the long-term topical application of testosterone or progesterone. Currently, strong topical corticosteroids produce symptomatic relief and, in some cases, resolution of lichen sclerosus.48

Lichen Planus

Lichen planus is a chronic, inflammatory disease of skin and mucous membranes, which occurs most commonly in women older than 40 years of age.1,15,49 Vulvar pruritus and burning are common symptoms; however, the patient may be asymptomatic.50,51 White, lace-like plaques (Wickham striae) involving the oral and vaginal mucosa also may be present (Figure 3.11).52,53 Patients with this condition experience vulvar pain, dyspareunia, and burning. Lichen planus can result in severe introital and vaginal adhesions, scarring, and stenosis.5456

Lichen planus has been associated with immunodeficiency states, internal malignancy, primary biliary cirrhosis, and ulcerative colitis among other conditions. Whereas lichen sclerosus does not affect the vagina, lichen planus can manifest as desquamative vaginitis.

Clinical Features

Half of the women and one-fourth of the men with cutaneous lichen planus have genital involvement. Unfortunately, it is frequently missed, for several reasons. As a mucocutaneous interface, the vulva can be affected by cutaneous, mucosal, or combined patterns. Thus, the clinical appearance may be highly variable ranging from delicate reticulated papules to an erosive desquamative process involving the vagina and vulva (Figure 3.12).54,55 Within the vulva, the erosive process is typically confined to the vulvar vestibule and commonly involves the vagina. With advancing disease, there is loss and agglutination of the labia minora and prepuce, associated with thinned epithelium, and shrinkage with stenosis of the vaginal introitus.

Pathology

The histopathologic diagnosis of vulvar lichen planus is often difficult. First, mucous membrane lesions may differ considerably from those occurring on vulvar skin. Second, lichen simplex chronicus frequently coexists, and sometimes there is also associated lichen sclerosus. Finally, the erosive pattern, where the epithelium is lost, may be extremely difficult to diagnose due to sampling problems, secondary infection, and inflammation from topical applications. In the skin, two typical microscopic features help in the histologic diagnosis: a band-like chronic inflammatory infiltrate that is predominantly lymphocytic, with rare plasma cells. The inflammation typically involves the upper dermis and immediate overlying epidermis; and liquefaction necrosis of the basal epithelial cells. These cells appear admixed with chronic inflammatory cells, and degenerated keratinocytes result in the formation of colloid bodies (Civatte bodies) (Figures 3.13 and 3.14).

The fully developed epidermal changes usually seen in classic cutaneous lichen planus (saw-tooth pattern, hypergranulosis, orthokeratosis, etc.) are rarely present in vulvar lesions. Accurate diagnosis is important since the erosive form may require immunosuppressive therapy. Also, the presence of chronic lichen planus in the vulva is a risk factor for squamous cell carcinoma.35,57,58 The differential diagnosis includes lichenoid drug reactions, which should be suspected if eosinophils are present.

Immunofluorescent studies often reveal fibrin deposition at the dermal–epidermal junction and, occasionally, granular IgM; rarely, C3 and IgG deposits are also present. The clusters of necrotic keratinocytes (colloid bodies) are positive for IgM in up to 87% of cases and, sometimes, C3 and IgG deposits may be helpful for the diagnosis.59

The epithelial changes are variable within mucous membranes and include thinning of the epithelium, with ulceration and bullous formation. In contrast to the findings within the skin, plasma cells may be evident with mucosal involvement.

The skin lesions resolve in most cases within 1–2 years, but mucosal lesions may persist longer. Hyperpigmentation is a common sequela after resolution, especially in darker skinned patients.

Bullous Disorders

The vesiculobullous disorders result from the congenital or acquired formation of antibodies against components involved in the adhesion of keratinocytes.60 Many of the blistering diseases that affect the skin also involve mucosal sites.61 In the vulva, friction and trauma foster the development of the blistering disorders, which typically present clinically as soggy, weeping, or erosive to ulcerative lesions. Clinical suspicion needs to be high in patients with erosions. Besides a detailed clinical history and careful physical examination, biopsies of the lesion for light microscopy plus perilesional skin for direct immunofluorescence are important. The most significant primary bullous skin diseases affecting the vulva are the following (Table 3.4):

Pemphigus Vulgaris

Pemphigus vulgaris is an acquired, autoimmune blistering disease representing 80% of all pemphigus cases.15 Autoantibodies develop against the desmosomal protein, desmoglein 3, at intercellular sites between keratinocytes, leading to acantholytic blisters that break easily and form erosions.62,63

Clinical Features

Most patients have oral blisters that precede cutaneous involvement by weeks to months. The vulvar lesions consist of erythematous, moist, eroded plaques, at the edge of which intact blisters may briefly be seen. The classical skin lesions consist of flaccid blisters on a normal or erythematous base. The blisters break easily leading to eroded and crusted areas. Trunk, groins, axillae, scalp, and face are frequently involved. These lesions extend if pressure is applied to the top of the bullae (positive Asboe-Hansen sign). They heal without scarring. The disease activity can be followed by enzyme linked immunosorbent assay (ELISA) titers of circulating antibody to desmoglein 3. The principal cause of death is infection secondary to corticosteroid treatment. The mortality rate is 5–15%. There are reported cases of cervical and vulvar microinvasive squamous cell carcinoma in association with pemphigus vulgaris.64

Microscopic Features

The squamous epithelium shows a suprabasal bulla with scattered neutrophils and eosinophils. Because the disease targets an adhesion protein joining keratinocytes, but not between keratinocytes and basement membrane, the basal keratinocytes remain attached to the dermis, imparting a ‘tombstone appearance.’ Dermal changes are nonspecific. Unfortunately, the separated upper layers of the epidermis frequently fall off during the biopsy process and all that remains is the dermis with the single layer of intact basal keratinocytes. Thus, a useful histologic clue is the presence of clefts extending deep into adnexal structures. A biopsy that includes the edge of the blister increases the chances of finding some surviving acantholytic keratinocytes. Direct immunofluorescence usually shows IgG, especially IgG1 and IgG4, in the intercellular spaces (Table 3.4).59

Therapy includes high systemic doses of corticosteroids and cytotoxic agents, plasma pheresis, and supportive measures.

Pemphigus Vegetans

Clinical Features

This rare variant of pemphigus shows well-demarcated, warty erythematous plaques with a moist, ulcerated surface that preferentially involves the pubic, perineal, and perianal areas (Figure 3.15). Rarely, blisters are found at the edges of the plaque. As with pemphigus vulgaris, oral lesions are invariably present, and frequently the presenting feature. ‘Vegetans’ alludes to the warty appearance of these lesions that may mislead the clinician to diagnose condyloma acuminatum or even squamous cell carcinoma.

Microscopic Features

The microscopic as well as immunofluorescent and immunologic findings are similar to pemphigus vulgaris except for the presence of intraepidermal eosinophilic microabscesses (Figure 3.16) and marked epidermal hyperplasia. The presence of eosinophils and the localized and self-limited character of the disease distinguish it from pemphigus vulgaris. The extreme acanthosis may even suggest squamous cell carcinoma (Figure 3.17). Circulating antibodies of the IgG2 and IgG4 subclasses, with strong complement fixation, are commonly present in pemphigus vegetans (Table 3.4).

Bullous Pemphigoid and Cicatricial Pemphigoid

Bullous pemphigoid is a chronic, subepidermal, acquired, autoimmune blistering disease.6569 Multiple, tense blisters typically occur on erythematous plaques or normal skin in elderly patients. These patients develop autoantibodies that target basal cells’ basement membrane attachment plaque (hemidesmosome).61 Cicatricial pemphigoid or benign mucous membrane pemphigoid is a chronic bullous disease that affects predominantly oral and ocular membranes and results in scarring and stenosis.70,71 Anogenital region involvement occurs in 20% of patients. Both bullous and cicatricial pemphigoid can be the result of a drug hypersensitivity reaction. Severe cicatrization with shrinkage may suggest lichen sclerosus or lichen planus;72 however, in contrast to lichen sclerosus or lichen planus, cicatricial pemphigoid is associated with small blisters and a positive Nikolsky sign, i.e., formation of blisters in unaffected tissue by application of light pressure.70,71

Microscopically, there are subepidermal blisters and a mixed inflammatory cell infiltrate within the dermis. Eosinophils are numerous. In cicatricial pemphigoid the lesions evolve to scars. Perilesional direct immunofluorescence usually shows a linear band of IgG with or without C3 at the dermoepidermal junction (Table 3.4). IgA is found in 20% of cases. Systemic corticosteroids and immunosuppressive drugs may be helpful.

Chronic Bullous Dermatosis of Childhood and Adult Linear IgA Bullous Dermatosis

This is an immunobullous disorder of unknown etiology in which linear deposits of IgA are detected in subepidermal blisters. There are two clinical variants that are commonly regarded as different expressions of the same entity. One is the chronic bullous dermatosis of childhood and the other is the adult linear IgA bullous dermatosis. In the first years of life, chronic bullous dermatosis presents with the abrupt onset of large, tense bullae or ‘cluster of jewels’ that have a propensity for perioral and perigenital areas, but extend to thighs and lower abdomen. Initially the blisters fill with clear fluid, but secondary infection results in pustules (Figure 3.18). Commonly, this disease resolves in several months. In adults, the clinical presentation is protean and mimics other bullous disorders. Amiodarone, vancomycin, lithium, and nonsteroidal anti-inflammatory drugs (NSAIDs) can induce this immunobullous disorder.

Histologically, there are subepidermal blisters with neutrophilic microabscesses in the papillary dermis, a finding indistinguishable from that seen in dermatitis herpetiformis. Fibrin with leukocytoclasis in the tip of the papilla favors dermatitis herpetiformis, while the presence of neutrophils parallel to the dermal–epidermal junction points toward linear IgA dermatosis (Figure 3.19). However, only immunofluorescence definitively separates these two diseases. Bullous pemphigoid is distinguished from IgA dermatosis by the linear IgG basement membrane deposits (Table 3.4).

Inherited Dermatoses

Hailey–Hailey Disease

Hailey–Hailey disease is an acantholytic dermatosis involving flexural areas that usually starts in the late teens.73,74 It is inherited as an autosomal dominant trait and the responsible gene called ATP2CL

Buy Membership for Pathology Category to continue reading. Learn more here