Inflammatory Diseases of the Vulva

Clinical Features

Atopic dermatitis is a chronic, pruritic process which occurs in individuals (more often men) with a personal or family history of atopic diathesis (including asthma, allergic rhinitis, allergic conjunctivitis). The disease usually first manifests during childhood as an erythematous papulovesicular rash involving the flexural and extensor surfaces of the extremities. The lesions evolve towards scaly lichenified patches and plaques over time. The vulva is infrequently involved.

Microscopic Features

Atopic dermatitis features the classic histologic changes of spongiotic dermatoses. In acute lesions, there is intercellular, and to some extent, intracellular edema of the lower epidermis with epidermal and perivascular infiltration by lymphocytes. Perivascular eosinophils are rare. Subacute lesions exhibit increasing psoriasiform epidermal hyperplasia with parakeratosis ( Fig. 1.1 ), and a decrease in the extent of spongiosis. Chronic lesions display more marked psoriasiform epidermal hyperplasia and lichenification with very mild to absent spongiosis. Further lichenification produces prominent hyperkeratosis with “vertical streaking” of collagen in the papillary dermis, leading ultimately to LSC.

Differential Diagnosis

The distinction between atopic dermatitis, allergic contact dermatitis (ACD), and ICD (drug, ingestant, scabetic infestation, others) is difficult without clinicopathologic correlation. Direct immunofluorescence can be performed if there is a vesiculobullous lesion associated with eosinophils, to rule out pemphigus vegetans or bullous pemphigoid . Chronic lesions can resemble psoriasis histologically. Unlike the regular pattern of epidermal hyperplasia found in psoriasis, the rete ridges in advanced stages of a chronic eczematous dermatitis are generally irregular in both length and width.

Prognosis and Treatment

Most cases of atopic dermatitis resolve spontaneously by the age of 30. Treatment is aimed towards hydration of the skin, minimizing triggering factors and symptoms, and decreasing inflammation. The latter is usually achieved with topical steroids. Nonsteroidal immunosuppressive agents such as tacrolimus are also considered as they have fewer disadvantages compared with chronic steroid use.

Clinical Features

ACD is more frequent in females and in white persons. Common findings include a pruritic papulovesicular eruption, discretely patterned crusted plaques, or, occasionally, bizarre-appearing patterns, depending on the extent of contact with the agent.

Microscopic Features

In acute episodes, the spongiosis is limited to the lower epithelium, and the stratum corneum remains uninvolved. With persistent allergen exposure, there is formation of coalescing vesicles at various levels of the epidermis, imparting a “Swiss-cheese” appearance ( Fig. 1.2 ). Intraepithelial inflammatory cells are usually lymphocytes (rarely eosinophils). Chronic forms feature progression from a spongiotic to a lichenoid pattern like in atopic dermatitis.

Differential Diagnosis

See atopic dermatitis section.

Prognosis and Treatment

Removal of, or protection from the offending agent is paramount. Without it, the disease will persist, leading to longer and more severe episodes, and to complications such as infection. In addition, treatment includes short-term topical corticosteroid therapy to reduce inflammation, and emollients to allow the reestablishment of the barrier function of the skin.

Clinical Features

Females are more frequently affected than males, with no particular genetic predisposition. A large range of clinical appearances may be seen, including erythema, eczematous changes, vesiculobullous lesions, and epidermal necrosis. Lesions tend to be confined to the areas of contact with the offending agent, thus often sparing the genitocrural folds.

Microscopic Features

In contrast to ACD, the agent responsible for ICD produces direct injury to the epidermis. The degree and severity of the epidermal injury varies based on the nature, potency, and concentration of the irritant. Histologically, common changes include ballooning degeneration of the surface keratinocytes with subsequent necrosis and surrounding epidermal spongiosis. Neutrophil infiltration is seen in areas of epidermal necrosis ( Fig. 1.3 ). The underlying superficial dermis contains perivascular inflammation composed of lymphocytes, macrophages and, frequently, neutrophils. Interstitial edema and vasodilatation are also present ( Fig. 1.4 ).

Differential Diagnosis

See atopic dermatitis section.

Prognosis and Treatment

Removal of, or protection from, the offending agent is paramount to prevent recurrences. Management aims to restore the skin’s barrier function. Topical applications containing ceramides may be particularly helpful. Corticosteroids and immune modulators are in general not recommended.

Clinical Features

Seborrheic dermatitis is a common eczematous dermatitis occurring in areas of the skin that have the greatest number of sebaceous glands (scalp, face, chest, upper back, axillae, and anogenital skin). Not surprisingly, men are more commonly affected than women. Most patients present during the fourth to fifth decade; however, an infantile form (in babies during first three months) has been described. The affected vulvar skin, more commonly the genitocrural folds, is erythematous with scaling “bran-like” papules and plaques with a “greasy yellow” appearance. Immunosuppressed patients, especially those with human immunodeficiency virus (HIV) infection, have a higher prevalence of this disease. The pathogenesis is unknown; however, Malassezia species (Pityrosporum) has been implicated as an etiologic factor; in many patients, flares of the disease correlate with proliferation of Malassezia spp. and respond to antifungal agents. It is thought that the yeast triggers an immunologic response affecting the hair-bearing epidermis.

Microscopic Features

In its acute form, seborrheic dermatitis features mild spongiosis with a parakeratotic scale crust containing scattered neutrophils ( Fig. 1.5 ). The papillary dermis is mildly edematous with a mixed perivascular inflammatory infiltrate (composed of lymphocytes, histiocytes and, rarely, neutrophils) involving the superficial plexus. As lesions progress, psoriasiform hyperplasia appears and becomes extensive with parafollicular accentuation of the parakeratotic scale (“shoulder parakeratosis”) ( Fig. 1.6 ). Neutrophils are commonly observed within the scale crust and within spongiotic foci. In chronic lesions, the psoriasiform hyperplasia is prominent and the parakeratotic scale crust may extend into the interfollicular epidermis.

Differential Diagnosis

The presence of neutrophilic parakeratosis and psoriasiform epidermal hyperplasia raises consideration of psoriasis . Features in favor of seborrheic dermatitis are irregular elongation of the epidermal rete, accentuation of parakeratosis and scale crusts about the follicular ostia, and predilection of the follicular and epidermal spongiosis toward the upper layers of the epidermis. However, distinction can be difficult. Neutrophil-rich parakeratosis is also a feature observed in many impetiginized eczematous dermatitis . A tissue Gram stain is a helpful adjunct in excluding this possibility.

Prognosis and Treatment

Seborrheic dermatitis generally exhibits a mild chronic clinical course with little discomfort. Treatment is directed towards removal of the scales with keratolytics, followed by sparing use of topical corticosteroids. Topical antifungal agents (i.e., ketoconazole, ciclopirox) constitute an important adjunct in therapy and tend to reduce or eliminate the need for steroid therapy over time when used consistently. Resistance to therapy may be a sign of immunodeficiency, particularly HIV infection.

Clinical Features

Psoriasis is a chronic dermatitis characterized by a hyperproliferative epidermis. It is a common disorder, affecting 2%–4% of whites (less frequently other ethnicities). The disease usually manifests during early adulthood. Vulvar involvement can be a manifestation of the classic, generalized form or of the so-called inverse psoriasis which affects intertriginous areas. The most common clinical vulvar presentation is a pruritic, bilaterally symmetrical, erythematous, well-demarcated, nonscaly, macular eruption or plaque, as opposed to patches and plaques with a “silvery” scale typical of other anatomic regions. The anatomic distribution is wide, and most patients that present with a vulvar psoriasiform lesion will have evidence of lesions elsewhere on the body. These lesions tend to concentrate in areas of persistent trauma or friction (elbows, knees, sacrum, scalp, and intertriginous areas). Other triggers include drugs and infections. Superinfection by yeast, fungi, and bacteria is possible.

Microscopic Features

Psoriasis, like many other dermatoses, has a range of microscopic changes that evolve over time. Early lesions have a nonspecific spongiotic epidermal reaction pattern that includes superficial dermal vascular congestion, edema, and lymphocyte-rich perivascular inflammation. As lesions progress, a characteristic (“psoriasiform”) pattern of epithelial hyperplasia appears, characterized by regular acanthosis, elongation of the rete ridges, thinning of the suprapapillary plates, and loss of the granular cell layer (hypogranulosis) ( Fig. 1.7 ). Other typical findings include mounds of neutrophil-rich parakeratosis and increased basal mitotic activity. Confluence of neutrophilic aggregates within the parakeratosis is seen in mature lesions. Intraepidermal neutrophil collections located in the stratus corneum are termed “Munroe microabscesses,” whereas those in the spinous layer are called “spongiform pustules of Kogoj” ( Fig. 1.8 ). The accompanying epidermal hyperplasia has a regular appearance, characteristically with intervening thinned suprapapillary plates and subjacent dilated capillaries, frequently in immediate apposition to the overlying epidermis ( Fig. 1.9 ).

Differential Diagnosis

Late-stage lichen simplex chronicus can be distinguished from psoriasis by the presence of thicker suprapapillary plates, hypergranulosis, and thickened vertically oriented collagen bundles within the papillary dermis. Distinction of psoriasis from seborrheic dermatitis can be very difficult, particularly at early stages; the presence of spongiosis involving the rete ridges is not typical of psoriasis, and favors seborrheic dermatitis instead. Chronic candidiasis and dermatophytoses may feature neutrophil exocytosis and psoriasiform epidermal hyperplasia. Therefore, special stains should be routinely considered to exclude the presence of fungal elements.

Prognosis and Treatment

Psoriasis is a chronic condition characterized by frequent relapses. Complications include psoriatic arthritis (seen in up to 30% of patients) and infections. Thus, long-term management is required, focusing on balancing the extent of disease involvement with the potential side-effects of therapy. Topical treatment, in the form of emollients, corticosteroids, tars, vitamin D analogs, and tacrolimus, is utilized for localized plaques. Systemic therapies for severe disease include methotrexate, retinoids, and cyclosporine. Phototherapy and photochemotherapy (psoralen with ultraviolet A) are also used.

Clinical Features

LSC is a condition in which scaly plaques are formed in response to repetitive irritation of affected sites by rubbing or scratching. Women are more commonly affected, usually between the third and fifth decades of life. Anatomic sites of predilection include the perianal and genital regions, and the posterior neck, forearms, and pretibial areas. Within the vulvar region, LSC can present as a primary or secondary condition. Heat, sweat, and friction can be a primary cause of skin irritation that can ignite the itch/scratch cycle leading to the features of LSC ( Fig. 1.10 ). Secondary causes can be numerous and are important for the pathologist to identify as the underlying cause of LSC, especially when premalignant or malignant in nature.

Microscopic Features

LSC is characterized by epidermal acanthosis (hyperplasia) with psoriasiform appearance. The epithelium shows broad compact orthokeratosis with hypergranulosis; parakeratosis is present, often with a patchy distribution ( Fig. 1.11 ). Focal erosion or ulceration is common. The rete ridges are thick without suprapapillary plate thinning. A characteristic feature is the presence of thickened eosinophilic bundles of collagen arranged in vertical streaks within the papillary dermis ( Fig. 1.12 ), although compared to the skin this feature is less developed in the mucocutaneous surfaces of the vulva and perineum.

Differential Diagnosis

Superimposed changes of LSC can be observed in virtually all dermatoses, therefore careful evaluation to exclude a primary dermatosis is essential before rendering a diagnosis of idiopathic LSC; this particularly applies to instances in which primary treatment is unsuccessful. Superimposed LSC on high grade squamous intraepithelial lesion / vulvar intraepithelial neoplasia of usual type (HSIL/u-VIN) , a human papillomavirus (HPV) associated premalignant skin lesion, is an important differential. Close examination of the lower epithelial layers is key: nuclear enlargement, hyperchromasia, loss of polarity, overlapping, and loss of maturation with mitoses above the basal membrane are features indicative of HSIL. Importantly, HSIL with superimposed LSC will show rather abrupt maturation of the dysplastic epithelium, which may lead to not only misinterpretation as idiopathic LSC but also as a low-grade squamous intraepithelial lesion (LSIL/VIN1) or differentiated VIN. A VIN3 lesion with superimposed LSC can also resemble a VIN2 lesion, but this distinction may not carry clinical consequences. In equivocal cases, strong, nuclear, and cytoplasmic block staining of p16 immunohistochemistry will help point to a diagnosis of HSIL. Atypical verruciform lesions of the vulva also present with hyperkeratotic lesions that show irregular epidermal hyperplasia. Verruciform proliferations of the vulva, including the so-called verruciform LSC, are rare and still poorly understood. Importantly, some are regarded as neoplastic in nature. The most important is verrucous carcinoma , which is locally aggressive. Unlike LSC, verrucous carcinoma presents clinically as a large exophytic mass. Histologically, they show expansile invasion into the vulvar stroma in the form of bulbous nests with broad-fronts and smooth edges. While LSC, if tangentially sectioned, may give this appearance, the depth and complexity of the growth of verrucous carcinoma are usually obvious and exceed that of tangential cutting. Other verruciform lesions that deserve distinction from LSC include entities historically known as vulvar acanthosis with altered differentiation (VAAD) and atypical verruciform hyperplasia , recently grouped into the term differentiated vulvar intraepithelial lesion (DEVIL) . DEVIL presents clinically as plaques or areas of exophytic cauliflower-like growth, corresponding histologically to epithelial acanthosis with verruciform growth lacking cytologic atypia (see Chapter 2 ). The finding of frequent PIK3CA mutations and absence of TP53 mutations, added to the observation of DEVIL-type lesions preceding or accompanying verrucous carcinoma, has led to consideration of this constellation of atypical verruciform proliferations as a third category of squamous preinvasive neoplasia. It is important to note that verrucous carcinoma and DEVIL have bland cytomorphology throughout, and their distinction from LSC must be based on the severity and distribution of the epithelial proliferation. The distinction between DEVIL-type lesions and LSC can be quite difficult. In fact, the term “verruciform LSC” has been used to describe LSC lesions with prominent exophytic growth, and these lesions have been found to harbor PIK3CA mutations linking them to DEVIL. From the diagnostic perspective, it is important to suspect DEVIL if the lesion is exophytic and produces verruciform growth, and if it persists despite treatment or recurs over time. Complete excision and close monitoring may be prudent in this scenario.

Prognosis and Treatment

Identification and treatment of any underlying process, and cessation of the traumatic stimulus, are imperative in the treatment of this condition, something that may be quite difficult in the long-term. Emollients, topical steroids, and simple barrier occlusion may help break the itch–scratch cycle. Behavioral modification and psychological/psychiatric intervention can be beneficial, particularly if no underlying etiologic factor is identified and medical management is not effective.

Clinical Features

Lichen planus (LP) is a T-cell mediated inflammatory dermatosis that affects keratinized and nonkeratinized epithelium. While idiopathic in nature, LP is sometimes associated with other disorders such as ulcerative colitis, hepatitis B/C, immunodeficiency, cirrhosis, and peptic ulcer disease. Several clinical variants exist, but there are three most important to the vulva: classic (papulosquamous), hypertrophic, and erosive, each with its own unique clinical and histologic features ( Table 1.4 ). Erosive lesions are a more common presentation at anogenital sites; they appear clinically as ulcerated and friable patches in the mucosa. Other types of LP clinically appear as reticulate lacy lesions. When chronic, erosive lesions may evolve to scarring.

Microscopic Features

Evolved lesions of classic (papulosquamous) LP feature a band-like infiltrate composed of lymphocytes with an admixture of macrophages, which adhere to the basal aspect of the epidermis ( Fig. 1.13 ). The associated basal cell damage is seen as abrupt maturation (“squamatization”) of basal keratinocytes, dyskeratotic cells throughout the epidermis (Fig.1.14), and eosinophilic colloid bodies in the papillary dermis. The infiltrate does not obscure the interface and does not extend into the suprabasilar epidermis. Plasma cells may be prominent in mucosal epithelium or at mucocutaneous interfaces. Other hallmarks of LP include irregular acanthosis, hyperkeratosis, “ wedge-shaped ” hypergranulosis (adjacent to acrosyringia or acrotrichia), and clefts which appear at the dermoepidermal junction (“ Max–Joseph” spaces). Importantly, parakeratosis is not a feature of LP and its presence should suggest other disorders. As chronicity ensues, dermal fibrosis becomes apparent and the epidermis becomes progressively flattened and thinned. Hypertrophic LP features the same lichenoid infiltrate with accompanying hypergranulosis and acanthosis. The latter can sometimes be quite exuberant, producing the so-called “pseudoepitheliomatous hyperplasia,” which can be mistaken for a premalignant or malignant process. Erosive LP , as the term implies, exhibits a superficial ulcerative surface with a lichenoid stromal infiltrate. If present, the edge of the lesion will show changes of classic LP ( Fig. 1.15 ).

Ancillary Studies

Immunofluorescence shows irregular fibrin deposits in the DEJ. IgM deposits around necrotic keratinocytes are common and, when prominent, are helpful to confirm the diagnosis of LP. IgG, C3, and IgA deposits can also be present.

Differential Diagnosis

The differential diagnosis of LP in the vulva depends on the variant of LP . Classic/papulosquamous LP features a band-like infiltrate and attention should be drawn to the epidermal reaction pattern and composition of the infiltrate because, although uncommon in flexural or mucosal sites, lichenoid drug eruptions may be histologically indistinguishable from LP. Helpful clues in favor of lichenoid drug eruption are: presence of eosinophils within the infiltrate, involvement of the deep vascular plexus, and the presence of parakeratosis. Early lesions of LS are virtually indistinguishable from LP, and a descriptive diagnosis of “lichenoid dermatosis” followed by a differential may be prudent. The diagnosis of LS can, nonetheless, be raised if signs of chronicity are identified (effacement and flattening of the rete pegs, homogenization of the papillary dermis). If the infiltrate is rich in plasma cells, plasma cell (zoon) vulvitis may be considered; however, in this disorder the epithelium displays atrophy and hypogranulosis, unlike LP.

Hypertrophic LP may raise the differential diagnosis of a neoplastic proliferation such as a squamous cell carcinoma due to their overlying pseudoepitheliomatous hyperplasia and lichenoid-type host response. The presence of epithelial atypia and irregular inward growth should raise the possibility of malignancy. Long-standing lesions may overlap morphologically with LSC; the presence of basal cell damage, particularly at the base of the rete ridges, is indicative of LP. Lichenoid keratosis or LP -like keratosis is a solitary lesion that is essentially a T-cell-mediated regression of a variety of benign “keratoses” including warts , seborrheic keratosis , and lentigines . These may be present alongside the inflammatory infiltrate and be a helpful histologic clue to the diagnosis. As a pitfall, the inflammation associated with regression of pigmented lesions (including melanoma ) and atypical keratinocytic proliferations (including squamous cell carcinoma in situ and basal cell carcinoma ) may have a striking lichenoid appearance. Any lichenoid infiltrate containing numerous melanophages should be treated with caution, and additional level sections and immunohistochemical stains for melanocytic markers may be useful in evaluating a clinically ambiguous lesion. Likewise, the presence of large epithelioid cells or keratin plugs should prompt consideration for epithelial markers to exclude epithelial neoplasia.

Erosive LP requires distinction from other ulcerative lesions, particularly aphthous ulcers and infections (fungi, syphilis, herpes). In addition to correlating with the clinical history, it is very important to examine the edge of the eroded area to identify classic LP changes, or microorganisms or viral cytopathic changes in the epithelium. A dense plasma cell infiltrate should raise the possibility of syphilis. A neutrophilic perivascular infiltrate is more in keeping with aphthous ulcers.

Prognosis and Treatment

Most cases of LP have a self-limiting course; indeed, over two-thirds of patients experience spontaneous remission in the 12–18 months following diagnosis. Treatment is largely symptomatic and consists of immunosuppressive agents, either topical or intralesional steroids (for local to regionally confined lesions), or systemic corticosteroids, retinoids, and cyclosporine (for cases with widespread involvement).