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Benign Diseases of the Vulva

  • Demaretta Rush
  • Edward J. WilkinsonEmail author
Living reference work entry

Abstract

The external female genitalia include the mons pubis, labia majora and minora, clitoris, and vestibule. The mons is the portion of hair-bearing skin and associated subcutaneous tissue overlying the pubic symphysis. Inferior to the pubis, the hair-bearing skin of the mons divides into two folds, the labia majora, which join posteriorly at the perineal body, just anterior to the anus. Medial to the labia majora are a second set of folds, the labia minora, each of which divides at the anterior end into two sets of smaller folds. The superior folds fuse in the midline anterior to the clitoris, forming the prepuce, or clitoral hood, and the inferior folds fuse in the midline posterior to the clitoris, forming the frenulum. Posteriorly, the labia minora fuse without further divisions, at the fourchette, posterior to the introitus and anterior to the perineal body. The clitoris consists of a bundle of erectile tissue situated in the midline, with just the tip, or glans, visible between the prepuce and frenulum. Beneath the surface is the body of the clitoris which branches at the base into two crurae running along the pubic rami in the deep soft tissue. The vestibule is a roughly diamond shaped area bounded anteriorly by the frenulum of the clitoris, laterally by the medial edges of the labia minora and posteriorly by the fourchette. Posterior to the frenulum on the vestibule is the urethral orifice, and posterior to that lies the vaginal opening, bounded by the hymen or remnants thereof. The external anatomy is illustrated in Fig. 1.

Anatomy

The external female genitalia include the mons pubis, labia majora and minora, clitoris, and vestibule. The mons is the portion of hair-bearing skin and associated subcutaneous tissue overlying the pubic symphysis. Inferior to the pubis, the hair-bearing skin of the mons divides into two folds, the labia majora, which join posteriorly at the perineal body, just anterior to the anus. Medial to the labia majora are a second set of folds, the labia minora, each of which divides at the anterior end into two sets of smaller folds. The superior folds fuse in the midline anterior to the clitoris, forming the prepuce, or clitoral hood, and the inferior folds fuse in the midline posterior to the clitoris, forming the frenulum. Posteriorly, the labia minora fuse without further divisions, at the fourchette, posterior to the introitus and anterior to the perineal body. The clitoris consists of a bundle of erectile tissue situated in the midline, with just the tip, or glans, visible between the prepuce and frenulum. Beneath the surface is the body of the clitoris which branches at the base into two crurae running along the pubic rami in the deep soft tissue. The vestibule is a roughly diamond shaped area bounded anteriorly by the frenulum of the clitoris, laterally by the medial edges of the labia minora and posteriorly by the fourchette. Posterior to the frenulum on the vestibule is the urethral orifice, and posterior to that lies the vaginal opening, bounded by the hymen or remnants thereof. The external anatomy is illustrated in Fig. 1.
Fig. 1

Anatomy of the vulva. The vestibule is the diamond-shaped area between the medial edges of the labia minora, extending from the frenulum to the fourchette, and containing the urethral and vaginal openings

Histologically, the hair-bearing skin of the mons is similar to the nongenital skin of the rest of the body, consisting of keratinizing squamous epithelium with all of the usual adnexal skin structures, including hair follicles, sebaceous glands, eccrine sweat glands, and sensory receptors. The subcutaneous tissue of the mons is predominantly adipose tissue. The composition of the labia majora is nearly identical, but with an additional component of smooth muscle in the subcutaneous tissue and apocrine sweat glands deep to the epithelium. On the medial portion of the labia majora, the skin becomes hairless, and there is a corresponding absence of hair follicles, as well as an absence of sweat glands, although sebaceous glands remain and may be rather prominent in appearance, forming slightly elevated, pale areas known as Fordyce spots. The epithelium becomes thinner and keratinization decreases on the medial surface of the labia majora as well. The labia minora are composed of connective tissue rich in elastic fibers and blood vessels but without adipose tissue. The mucosa of the labia minora is similar to the medial portion of the labia majora, with which it is continous, with sebaceous glands disappearing towards the medial side. The theoretical line of Hart, which runs along the medial edge of the labia minora, markes the junction between the keratinizing epithelium of the labia minora and the nonkeratinizing squamous mucosal lining of the vestibule. The mucosa of the vestibule is glycogenated in women of reproductive age, or under estrogen influence, and resembles vaginal mucosa. This epithelium merges with the transitional epithelium at the urethral meatus and with the duct openings of the various submucosal glands.

The glandular structures of the vulva are not normally visible on external exam, or even on careful dissection, and many can only be seen microscopically unless enlarged by disease. Aside from the sweat glands in the hair-bearing portions of the vulva, which are no different from those elsewhere on the skin, there are a number of glandular structures specific to the vulvar area. Situated in the interlabial sulcus, surrounding the entire labia minora and clitoris, and on the perineum and surrounding the anus, are specialized apocrine glands, the anogenital mammary-like glands. These glands have a simple columnar epithelium with apical snouts and myoepithelium surrounding the glandular epithelium (van der Putte 1991). They may be located as far as 3.9 mm from the surface (Konstantinova et al. 2017a) and have long and wide coiled ducts that open to the surface. The paired Skene’s glands, homologues of the male prostate, are composed of pseudostratified mucus-secreting columnar epithelium and open to the external surface on both sides of the urethral meatus and along the posterior and lateral aspects of the urethra itself. The ducts are lined by transitional epithelium (Fig. 2). The Bartholin glands are bilateral racemose, tubuloalveolar glands, with acini composed of simple, columnar, mucus-secreting epithelium (Fig. 3). The Bartholin duct, approximately 2.5 cm in length, has three types of epithelial linings depending on the location within the duct. It is lined proximally by mucus-secreting epithelium, distally by transitional epithelium, and, at its exit, just external to the hymen ring of the vestibule posterolaterally, by squamous epithelium. The minor vestibular glands ring the vestibule and extend from the frenulum on both sides of the urethral meatus around the external base of the hymenal ring to the fourchette, lying within 1–2.5 mm of the superficial epithelium and communicating with the vestibular surface. They are composed of acini lined by simple columnar mucus-secreting epithelium.
Fig. 2

Skene gland. The gland is lined by a mixture of urothelium and mucin secreting columnar epithelium

Fig. 3

Bartholin gland and duct. The glandular acini are composed of simple mucin secreting columnar epithelium which merges with the transitional epithelium lining the duct

The major blood supply to the vulva is provided via the anterior and posterior labial branches of the superficial and deep external pudendal arteries, which branch from the femoral artery, and the internal pudendal arteries, which branch from the internal iliac arteries. The clitoris, including the crura and corpora cavernosa, is supplied separately by the deep arteries of the clitoris, whereas the anterior vaginal artery supplies blood flow to the vestibule and the Bartholin glands. The venous return parallels the arterial supply. The nerve supply to the vulva includes sensory nerves, special receptors, and autonomic nerves to the vessels and various glands. The major nerves of the vulva derive from the anterior (ilioinguinal) and posterior (pudendal) labial nerves. The clitoris is innervated by the dorsal nerve of the clitoris and the cavernous nerves of the clitoris, which also supply the vestibule.

The entire vulva, with the exception of the clitoris, drains to the femoral and inguinal lymph nodes. Delicate intercommunicating lymphatic vessels extend to the labia minora, clitoral prepuce, and vestibule, bypassing the clitoris. The lymphatic bed of the labia majora drains in an anterosuperior direction toward the mons, joining the lymphatic vessels from the labia minora and prepuce, and then into the ipsilateral inguinal and femoral nodes. Some contralateral flow also may occur into the superior medial nodes of the femoral group. The superficial inguinal lymph nodes, consisting of 8–10 nodes on each side, divided into a superior oblique and an inferior ventral group, are the major nodes that drain the vulva and therefore are included in a radical vulvectomy. The superior oblique group is found about the Poupart ligament, and the inferior ventral group lies above the junction of the saphenous vein and fascia lata. Lymphatic drainage from the clitoris and midline perineum proceeds bilaterally in more than 67% of cases and may bypass the superficial nodes. A second minor lymphatic pathway from the glans clitoris joins the lymphatics of the urethra, traverses the urogenital diaphragm, and merges with the lymphatic plexus on the anterior surface of the bladder. From there, drainage is into the internal iliac, obturator, and external iliac nodes.

Developmental Abnormalities

Congenital Anomalies

Congenital anomalies of the vulva may include absence, hypoplasia, hyperplasia, or dupilication of various portions of the anatomy. Congenital absence of the clitoris and external genitalia has been described. In Müllerian agenesis, the external genital is largely intact, but the hymen and vagina are absent, usually represented only by a depression in the vestibular area. True hypoplasia of the labia minora occurs infrequently and may be a sign of defective steroidogenesis. Hypertrophy of the labia minora is more common, usually becoming more evident at puberty, and is defined as a measurement of more than 4 cm from the base to the outer edge (Margesson 2006). Clitoral enlargement may be seen in newborns with adrenogenital syndrome or who have been exposed in utero to exogenous maternal androgen therapy, as well as in hermaphroditism and, rarely, with lipodystrophy (Ridley and Neill 1999). Labial fusion may also may be present with intersex disorders, although slight fusion of the labia minora may be seen in infants without apparent cause and typically responds to topical estrogen cream. Urethral anomalies may result in aberrant locations of the urethral opening in the vagina or adjacent to the hymen rather than in the upper portion of the vestibule (Kaufman 1994). Duplication of the vulva is extremely rare and usually is associated with duplication of the internal Müllerian system and rectum as well.

Acquired Abnormalities

Many vulvar conditions may result in altered anatomy later in life. In some cases, labial hypertrophy may develop over time in association with chronic irritation, as from indwelling catheters. Labial fusion may also be an acquired abnormality, secondary to adhesions and scarring in the course of lichen sclerosus, lichen planus, or other inflammatory conditions, or female genital mutilation procedures. Female genital mutilation is practiced in parts of Africa, Asia, and the Middle East and affected patients are increasingly encountered in Western medical practice, where they present with a variety of alterations to the vulvar anatomy which may be complex (Abdul-Cadir et al. 2016). These procedures involve removal of various portions of the vulva and may include reapproximations of the cut margins to partially or completely obscure the vaginal opening. In addition to destroying the normal anatomy, female genital mutilation may lead to complications which can further distort the vulva. Epidermal inclusion cysts of the vulva seem to be a particularly common complication and often present many years after the procedure as large, frequently pedunculated masses which may measure up to 7 cm and may be mistaken for clitoral enlargement due to hormonal factors or neoplasia (Riszk et al. 2007, Osarumwense 2010, Asante et al. 2010). A variety of tumors including granular cell tumors, hemangiomas, and vascular, neural, and smooth muscle tumors may also cause acquired clitoral enlargement.

Infectious Conditions

In developed nations, the most prevalent infections of the vulva are sexually transmitted viral diseases due to human papillomavirus (HPV), herpes simplex virus, and molluscum contagiousum and syphilis, a bacterial disease. Many other pathogens, however, not all of them sexually transmitted, may involve the vulva. Most vulvar infections are readily diagnosed on clinical grounds or by ancillary testing. Biopsies of these conditions are generally performed only when the presentation is atypical or the diagnosis is otherwise in doubt. Although the histopathologic findings are frequently nonspecific, there may be features at least suggestive of a particular etiologic agent, which can guide the selection of additional testing to establish a definitive diagnosis. A summary of the principle vulvar infections presented in this chapter is provided in Table 1.
Table 1

Summary of significant vulvar infections, their clinical manifestations, and suggested ancillary tests to assist in their diagnosis

Infectious conditions of the vulva

Diagnosis

Etiologic agent

Clinical manifestation(s)

Ancillary tests

Bacterial

Syphilis

Treponema pallidum

Primary: Chancre (ulcer)

Secondary: Condyloma lata (papule)

Dark field examination

Immunofluorescence

Immunohistochemistry

PCR

Serology

Granuloma inguinale

Klebsiella granulomatosis

Ulcer

Culture

Warthin-starry or gram stain (“Donovan bodies”)

Lymphogranuloma venereum

Chlamydia trachomatis, types LI, L2, L3

Ulcer, +/− inguinal lymphadenopathy

Serology

Culture

PCR

Chancroid

Haemophilus ducreyi

Ulcer

Culture

PCR

Gram or Giemsa stain

Tuberculosis

Mycobacterium tuberculosis

Ulcers, swellings, exophytic lesions

Culture

Acid-fast stain

Viral

Condyloma acuminatum

Human papillomavirus, usually types 6 and 11

Condyloma acuminatum (genital warts)

None necessary

Herpes

Herpes simplex virus, types I and 2

Ulcers, atypical lesions in immunosuppressed patients

Culture

PCR

Immunohistochemistry

Varicella (vulvar shingles)

Herpes zoster

Unilateral vesicles and ulcers

PCR

Immunohistochemistry

Molluscum contagiousum

Molluscum contagiousum

 

None necessary

Fungal

Various

Various

Scaly plaques (most commonly)

Skin scrapings for KOH prep

PAS or silver stains

Culture

Parasitic

Various

Various

Various

Usually not necessary

Bacterial

Syphilis

For many years, the rates of syphilis infection had been declining in the West, reaching a historic low in 2000, but beginning to to climb again, particularly in the HIV-positive population (Cohen et al. 2013; Hope-Rapp et al. 2010) and in pregnant women, in subsequent years. The disease is caused by Treponema pallidum, a spirochete which does not stain with Gram stain and which cannot be cultured, making it particularly important to be aware of the characteristic clinical and microscopic features.

Clinical Features

The disease manifests in phases. A week to 3 months after initial exposure, the primary lesion, or chancre, appears as a papule which develops into a painless, indurated, shallow, clean-based ulcer with raised edges. Chancres are usually single but may be multiple, especially in HIV-positive patients (Cohen et al. 2013). They may occur on inconspicuous surfaces, such as the cervix, anal mucosa, or oropharynx, and it is not uncommon for the primary lesion to go unnoticed and untreated. Typically, the chancre will heal on its own within 2–6 weeks.

The timing of the development of the secondary stage of syphilis is variable but typically manifests 2–8 weeks after the chancre. At this point, the patient may present with a skin rash that often involves mucous membranes as well as the palms of the hands and soles of the feet, as well as with systemic symptoms of fever, headache, pharyngitis, and lymphadenopathy. Secondary syphilis may be accompanied by new painless cutaneous lesions known as condyloma lata and by mucous patches. Condyloma lata appear as elevated papules or plaques with a velvety papillary surface, involving the vulva, perianal, and inguinal area and measuring up to 3 cm in diameter (Fig. 4), while mucous patches appear as gray-white erosions on the non-hairbearing squamous mucosa of the inner labia. Both condyloma lata and mucous patches are heavily populated with spirochetes and are highly infectious.
Fig. 4

Condyloma lata. The lesions are exophytic, but with a relatively smooth, uniform surface

The tertiary phase of syphilis, which develops after many years of latency, is extremely uncommon today. It’s most significant manifestations involve the cardiovascular and central nervous systems, although cutaneous or mucosal granulomatous lesions, or gummas, may also develop in this phase.

Microscopic Findings

The primary chancre is characterized by ulceration of the epithelium with intense acute and chronic submucosal and perivascular inflammation, characterized by the presence of large numbers of plasma cells. Granulomatous inflammation may also be present.

Histologic examination of condylomata lata reveals marked acanthosis and hyperkeratosis, patchy parakeratosis, and superficial intraepithelial microabscesses. Also present is a chronic inflammatory response within the dermis with a perivascular distribution, similar to that in the primary chancre but with a greater predominance of plasma cells. The arteritis in the lesions of both primary and secondary syphilis may be sufficiently severe to result in obliteration of the smaller vessels. Other patterns of inflammation may also be seen in secondary syphilis, including a psoriasiform pattern, a lichenoid form and a pustular form, in which the prominence of plasma cells in the inflammatory infiltrate and the endarteritis should raise the suspicion for syphilis (Fig. 5).
Fig. 5

(a) Secondary syphilis. This lesion shows prominent pseudoepitheliomatous hyperplasia overlying a dense dermal inflammatory infiltrate containing abundant plasma cells. (b) Deeper in the dermis, the inflammatory infiltrate shows a perivascular distribution

Dieterle, Warthin–Starry, or Steiner stains for spirochetes may be of some use to identify the organisms, which are characteristically located at the dermal-epidermal junction and in a perivascular distribution in the superficial dermis, but these stains may be negative even with active infection. Immunohistochemical staining is now available and considerably easier to interpret (Fig. 6), and the organisms may also be identified on dark-field examination of fresh sera from an active lesion, by a fluorescent conjugated antibody technique, which employs a dried smear preparation, and by PCR. These tests are all much more sensitive and specific for detection of the organisms than silver staining techniques but are also more expensive and may not be available in all clinical settings. For confirmation of the diagnosis, serologic tests, which are widely available and may be used in place of or in addition to microscopic examination of clinical samples, are most commonly used. Serology is very sensitive in secondary syphylis but may be falsely negative in primary syphilis, in which case the test may need to be repeated at a later time.
Fig. 6

Immunohistochemical stain for treponema pallidum in the lesion illustrated in Fig. 5. The organisms are concentrated at the dermo-epidermal junction, and the characteristic spiral structure is evident

Clinical Course and Treatment

Approximately, 30% of patients with primary syphilis will undergo spontaneous remission of the disease. Those who are not treated or who do not achieve spontaneous remission may progress to tertiary syphilis, which, if it continues to go untreated may prove fatal in 10% of those afflicted. Penicillin or another appropriate systemic antibiotic is the treatment of choice for all stages of the disease.

Granuloma Inguinale

Granuloma inguinale, also known as donovanosis or granuloma venereum, is a sexually transmitted disease endemic to Papua New Guinea, South Africa, India, Brazil, and Australia. Occasional local outbreaks of the disease are seen in the West. The disease is caused by a gram-negative, heavily encapsulated rod formerly known as Calymmatobacterium granulomatis, but recently reclassified as Klebsiella granulomatis (O'Farrell and Moi 2016).

Clinical Features

In women, the primary lesions occur on the vulva, vagina, or cervix. The lesions usually appear within 1 week to 1 month of exposure; anal coitus or fecal contamination of the vulva or vagina has been posited as the mode of transmission (Wilkinson and Stone 2008). Four types of lesions have been described: ulcerogranulomatous, hypertrophic, necrotic, and sclerotic/cicatricial, but the typical lesion begins as a papule which develops into an ulcer which then progressively increases in size. Despite its name, granuloma inguinale involves the inguinal region in only 10% of cases (O'Farrell and Moi 2016).

Microscopic Findings

Histologically, the main portion of the lesion consists of granulation tissue associated with an extensive chronic inflammatory cell infiltrate and endarteritis. The ulcer is usually covered with a fibrinous exudate, while the surface epithelium adjacent to the ulcer may show prominent pseudoepitheliomatous hyperplasia. Necrosis and microabscesses may be seen within the epidermis. The granulation tissue is accompanied by a dense mixed inflammatory cell infiltrate, consisting predominantly of plasma cells and mononuclear cells with few lymphocytes, which extends into the dermis.

All of these findings, however, are nonspecific, and the diagnosis cannot be made with certainty without identification of the offending organisms. These show a characteristic bipolar staining pattern, likened to a “safety-pin,” on Warthin–Starry stain or Giemsa stain and are referred to as “Donovan bodies.” They are found within the cytoplasm of large vacuolated histiocytes in the lesion, as well as intracellularly (Fig. 7). Organisms may also be identified by preparing smears from the active lesion or a touch preparation of a biopsy from the edge of the ulcer, allowing the preparation to air dry, then fixing in methanol and staining with Giemsa stain, or by culture.
Fig. 7

Granuloma inguinale. Giemsa stain shows numerous intracytoplasmic “Donovan bodies” with a characteristic halo surrounding the organisms

Clinical Course and Treatment

The lesions of granuloma inguinale grow more rapidly during pregnancy (O'Farrell and Moi 2016) and in patients with concurrent HIV (Basta-Juzbasic and Ceovic 2014), in whom the lesions may persist longer and require a longer duration of treatment. In rare cases, the organisms may disseminate to involve other organs, most commonly liver and bone (O'Farrell and Moi 2016). Treatment with appropriate antibiotics, continued until the lesion is completely healed, is curative.

Lymphogranuloma Venereum

Lymphogranuloma venereum (LGV) is a sexually transmitted disease endemic to Africa, Asia, and Central and South America, caused by Chlamydia trachomatis types L1, L2, and L3. It is uncommon in the West, but sporadic outbreaks have been noted in recent years, principally involving HIV-positive homosexual male patients (French et al. 2005).

Clinical Features

The disease classically manifests in three phases, following an incubation period of 3–30 days. The initial lesion is a painless papule which may progress to an ulcer and heals within a week. Two to 6 weeks later, a second phase may develop, usually characterized by painful inflammation of inguinal lymph nodes which may progress to the development of draining sinus tracts. This classic presentation with inguinal involvement has become increasingly uncommon, however, especially in women (Basta-Juzbasic and Ceovic 2014), with proctitis, vaginitis, and cervicitis accompanied by constitutional symptoms now more frequently observed. A third phase of the disease may develop in patients who continue untreated, consisting of progressively worsening proctocolitis and abscess development with lymphatic obstruction and fibrosis and stricture of the vagina and rectum.

Microscopic Findings
The initial lesion of LGV heals rapidly and is very rarely biopsied. Even if it is, the histology is nonspecific, showing giant cells along with lymphocytes and plasma cells in the inflammatory infiltrate surrounding the ulcer (Fig. 8). Older lesions may exhibit extensive fibrosis of the dermis and sinus tracts. Although the organisms are extremely difficult to identify on light microscopy, evaluation with special stains or other techniques is important to rule out other infectious disease with a similar presentation. The diagnosis rests on the results of serologic testing as well as identification of the organism in culture or by PCR testing.
Fig. 8

Lymphogranuloma venereum. An intense superficial and deep chronic inflammatory infiltrate composed predominantly of lymphocytes and plasma cells is present

Clinical Behavior and Treatment

Treatment is with antibiotics and may also include aspiration or incision and drainage of buboes to prevent progression to deep ulcers and fistulas and aid in healing. Timely treatment will prevent progression to the third, potentially disfiguring, phase of disease.

Chancroid

Endemic in Africa, Asia, and the Caribbean, where it may be responsible for up to 56% of genital ulcer disease (Mohammed and Olumide 2008), chancroid, a sexually transmitted disease caused by Haemophilus ducreyi, is relatively rare in the West.

Clinical Features

The disease presents after a 3- to 7-day incubation period, initially as a small papule which progress to a pustule, and then to a soft painful ulcer. Lesions may be single or multiple and tend to be small, measuring approximately 1–2 mm in diameter, but multiple lesions may coalescence to form ulcers approaching 3 cm in diameter. In women, the ulcers may involve the fourchette, labia, vestibule, clitoris, and perianal area and are often subclinical. In 40–50% of patients, painful inguinal adenopathy develops a few days to 2 weeks following the ulcer (Mohammed and Olumide 2008; Basta-Juzbasic and Ceovic 2014).

Microscopic Findings

Histologic examination of the skin lesions shows a three-layered structure to the ulcer. Superficially, there is an ulcer bed containing abundant neutrophils, beneath which is a layer of granulation tissue. In the deepest part of the lesion is a chronic inflammatory infiltrate consisting primarily of lymphocytes and plasma cells. Gram or Giemsa stains may reveal the gram-negative organisms, which may be present in large numbers in pairs and in parallel chains in the more superficial portion of the lesion, but culture and PCR are more sensitive and specific methods of diagnosis.

Clinical Course and Treatment

Treatment with antibiotics is curative in immunocompetent individuals. The disease is currently much more frequently encountered in HIV-positive patients, however, in whom the lesions are more numerous, heal poorly, and may fail to respond adequately to treatment (Mohammed and Olumide 2008).

Tuberculosis

Tuberculosis of the female genital tract is a common cause of pelvic inflammatory disease and infertility in some parts of the world but is very uncommon in most developed countries. It most commonly afects the fallopian tubes and endometrium (Manoj et al. 2008); vulvar involvement is exceeedingly rare, present in less than 2% of tuberculosis cases with pelvic involvement (Shen et al. 2011; Manoj et al. 2008). It is usually the result of hematogenous spread from a primary pulmonary infection with Mycobacterium tuberculosis, which has often healed by the time the pelvic disease is detected, but autoinoculation is thought to be responsible in some cases. Immunosuppression may play a role in susceptibility, as a case of vulvar tuberculosis has been described in a renal transplant patient (Wilkinson and Stone 2008), and hormones may influence development as well, as most cases present in the reproductive age range (Manoj et al. 2008)

Clinical Features

Vulvar tuberculosis may present as ulcerative lesions or swellings with multiple draining sinuses or as bulky exophytic lesions with associated lymphatic obstruction.

Microscopic Findings

Diagnosis usually can be made by biopsy of the involved tissues, which will reveal the characteristic caseating granulomas with Langhans giant cells. The mycobacteria can be identified on acid-fast stain, but this is far less reliable than isolation of the organism in culture.

Clinical Course and Treatment

Resection of lesions with a 6 month course of antitubercular drugs is curative (Manoj et al. 2008).

Miscellaneous Bacterial Infections

Erythrasma is a superficial skin infection caused by Corynebacterium minutissimum, which presents as an asymptomatic macular pink-brown rash. Because it has a predilection for the skin folds, the vulvar area may be involved, but the diagnosis is generally made on clinical grounds and biopsy is rarely necessary.

Erysepilas is a manifestation of infection of the skin with hemolytic streptocci or Staphylococcus aureus. It presents as a sharply marginated area of erythema, often associated with fever, malaise, chills, and nausea. The infection may progress to involve the subcutis, resulting in cellulitis, in which case the erythema is less well-defined and the involved area becomes edematous and painful.

Skin infection with hemolytic streptococci or Staphyloccuc aureus can also result in impetigo. On the vulva, impetigo is usually restricted to the hair-bearing skin, where it appears as small vesiculopustules which quickly rupture and develop a golden brown crust.

Rare cases of botryomycosis, an ulcerative infection of the skin caused by S. aureus, P. aeruginosa, E. coli, Streptococci, or Proteus species, have been reported to involve the vulva (Elas et al. 2014). This disease is best recognized by examination of the prurulent drainage from the ulcer, in which the characteristic “granules” of bacteria may be identified.

Necrotizing fasciitis may occur in the vulva and perineum in skin damaged by recent surgical intervention or trauma. Most vulvar cases are caused by polymicrobial infection, including anaerobic species (Nakayama and Busse 2010). Predisposing factors include diabetes mellitus, immunosuppression, peripheral vascular disease, increased age, hypertension, obesity, and radiation exposure. Initially, necrotizing fasciitis may appear as mild cellulitis or edema with inflammation, frequently associated with severe pain out of proportion to the degree of apparent tissue damage. Fever may or may not be present. The disease typically progresses rapidly despite treatment with antibiotics and must be recognized quickly, as a delay in diagnosis without therapy carries a nearly 50% mortality rate (Stephenson et al. 1992). Prompt, aggressive surgical debridement radical excision of the infected tissue and broad-spectrum systemic antibiotic therapy offers the only chance of cure, but even with appropriate treatment, mortality rates are reported to range from 20–40% (Sultan et al. 2012).

Viral

Condyloma Acuminatum

Condyloma acuminatum is an exophytic lesion of the skin, or, less commonly, the mucous membranes, caused by infection with low-risk subtypes of human papillomavirus (HPV), most commonly types 6 and 11. The frequency of vulvar condyloma acuminatum varies according to the population but is generally over 1%.

Many risk factors for the development of vulvar condyloma have been identified. As a sexually transmitted disease, the risk of condyloma acuminatum is increased with increasing numbers of sexual partners. The risk is also increased in patients with HPV-related lesions elsewhere in the lower anogenital tract; up to 50% of women with vulvar condyloma acuminatum also have past, concurrent, or subsequent diagnoses of cervical or vaginal squamous intraepithelial lesions (Mittal et al. 2013). Other commonly associated conditions are vaginitis, pregnancy, diabetes, oral contraceptive use, and poor hygiene. Immunosuppression is an increasingly common predisposing condition, and women with HIV, organ transplants, or autoimmune diseases (Santana et al. 2011; Lyrio et al. 2013) often struggle with widespread lesions throughout the lower anogenital tract that can be very difficult to eradicate.

When condyloma acuminatum is detected in a child, sexual abuse must be considered, but other modes of transmission have also been demonstrated. Vertical transmission of the virus, either in utero or intrapartum is possible (Jayasinghe and Garland 2006), and when it occurs, the virus may remain dormant for years before visible lesion develop (Hornor 2004). Many pediatric cases have been shown to contain types 1 and 2, subtypes more common in common skin warts, and frequently the patient or caregiver is found to have common warts (Allen and Siegfried 1998; Stefanaki et al. 2012), suggesting transmission by autoinnoculation and or nonsexual contact. There is some evidence that the disease may also be transmissable by fomites (Jayasinghe and Garland 2006).

Early data on the effects of HPV vaccination strongly suggests that condylomata acuminata may become increasingly less common. In Denmark and Australia, where robust vaccination programs have reached 70–85% of the target population, marked reductions in the diagnosis have already been reported (Ali et al. 2013; Baandrup et al. 2013; Read et al. 2011), and recent data suggests rates are dropping in the USA as well (Flagg et al. 2013).

Clinical Features
The lesions are usually asymptomatic and frequently multiple and multifocal. They often come to clinical attention because of considerable enlargement during pregnancy (Garland et al. 2009; Hoy et al. 2009). Any area of the vulva, as well as the vagina, cervix, urethra, and anal canal may be affected. The lesions may be red, white, gray, or brown and vary in size from millimeters to several centimeters (Fig. 9). Application of a dilute solution of acetic acid will impart a white appearance to the abnormal epithelium, which may aid in identification. On occasion, multiple lesions may coalesce into large plaques, an occurrence more common in diabetic or immunosuppressed patients.
Fig. 9

Perianal condylomata. The exophytic lesions have a corrugated, irregular surface. (Photograph courtesy of Dr. Jaqueline Castagno, University of Florida)

Microscopic Findings
On histologic examination, the lesion consists of complex branching fibrovascular cores covered with acanthotic squamous epithelium, frequently with accompanying hyperkeratosis and parakeratosis (Fig. 10). The pathognomonic feature is koilocytic atypia, characterized by enlarged, hyperchromatic nuclei with irregular, wrinkled nuclear membranes accompanied by a region of perinuclear clearing or “halo,” usually located in the upper third of the epithelium (Fig. 11). These cellular changes are the morphologic manifestation of HPV production in the infected cells but may be minimal to absent in some cases (Medeiros et al. 2005). Basal and parabasal hyperplasia, with increased mitotic figures confined to the lower third of the epithelium, and cytoplasmic maturation beginning to appear in the middle third and relatively normal maturation of the upper third is characteristic, and prominent intracellular bridges may be noted. Dyskeratotic cells may be seen, and a subepithelial chronic inflammatory infiltrate is commonly identified.
Fig. 10

Condyloma acuminatum. This low-power magnification shows the complex papillary architecture, with central fibrovascular stalks lined by thickened epithelium

Fig. 11

Condyloma acuminatum. At higher power magnification, the characteristic koilocytic change, with perinuclear clearing surrounding enlarged, irregularly shaped hyperchromatic nuclei, is seen in the superficial layers of the epithelium

Differential Diagnosis

Other benign exophytic lesions of the vulva, such as fibroepithelial polyp, vestibular papilloma, and seborrheic keratosis will lack the basal hyperplasia and koilocytic atypia typical of condyloma. In cases where the morphology is not sufficiently distinctive, immunohistochemical staining for Ki-67 may also be of further assistance in differentiating these lesions from condyloma. Because HPV infection activates the cell cycle in order to accomplish viral reproduction, a process which occurs in the maturing squamous cells, Ki-67 will be reactive in some cells in the upper levels of the epithelium in LSIL while in normally proliferating epithelium and other benign squamous lesions expression of Ki-67 is limited to the basal and parabasal cells.

Although high-grade squamous intraepithelial lesions (HSIL) and squamous carcinomas with warty morphology may show marked koilocytic atypia in the superficial cells, they are distinguished from condyloma by the presence of abundant, frequently atypical, mitotic figures, particularly if present in the upper layers of the epithelium, and, in the case of carcinoma, the presence of invasion into the underlying tissue.

It should be remembered that, although uncommon, lesions with the typical morphologic features of condyloma can contain areas of associated HSIL. Such lesions are are almost exclusively seen in immunosuppressed patients (Maniar et al. 2013), and for this reason, it is advised that even lesions which appear to be benign condylomata in such patients ought to be biopsied to ensure the absence of a high-grade component. Even when these lesions are biopsied, the extensive condylomatous component may be so distant from other abnormal areas that the high-grade component may be missed on sampling. The same may occur on a microscopic level when a small focus of adjacent high-grade lesion are missed when the slides are examined due to the relative abundance of condylomatous lesion. It is speculated that lesions like these may be responsible for previously reported cases of condyloma containing high-risk HPV.

Clinical Course and Treatment:

Condylomata acuminata may regress spontaneously but usually persist and may increase in size or number over time. They are not considered premalignant and do not progress to high-grade squamous intraepithelial lesions or carcinoma. Topical application of dilute podophyllin, imiquimod, concentrated halogenated acetic acid (trichloroacetic acid), or sinecatechins (Lacey et al. 2013) can be used for the treatment of small vulvar condylomata. Response to therapy may be decreased in immunosuppressed patients and patients with concurrent cervical HPV infection (Koo et al. 2016). Larger lesions and those refractory to topical treatments may be removed or eradicated by electrosurgery, cryosurgery, laser ablation, or surgical excision (Lacey et al. 2013). The overall recurrence rate is reported as 20–30% (Lacey et al. 2013), with higher rates reported in patients with a higher viral load (Koo et al. 2016) and lower rates in patients treated with surgical excision.

Herpesvirus

Genital infection with herpes simplex virus (HSV) was once almost excusively caused by HSV type 2, and HSV type 1 was limited to oral lesions. Today, probably due to changing patterns of sexual behavior, genital infection with type I virus is increasingly common, especially in younger cohorts, comprising approximately half of new cases in some developed countries (Gupta et al. 2007), although vulvar infection with herpes simplex virus (HSV) type 2 is still approximately six times more common than with HSV type 1. Primary genital infection with HSV type 1 is more frequent in women, and more often symptomatic (Fatahzadeh and Schwartz 2007), but also less likely to recur. Antibodies to one type of HSV provide some protection against the other, leading to a decreased frequency of infection with a second type, and may result in decreased severity and duration of the newly acquired infection (Fatahzadeh and Schwartz 2007). Although approximately 20% of the US population has been infected by HSV 2 by age 40, and up to 85% have been infected by HSV 1 by age 60, the frequency of vulvar involvement is unknown, and the majority of infections appear to be subclinical (Fatahzadeh and Schwartz 2007; Maccato and Kauffman 1992; Nettina 1998).

Clinical Features
The disease typically presents 4–7 days after exposure, with a prodrome of constitutional symptoms including fever, headache, muscle aches, and a painful, erythematous swelling of the vulva, followed by the eruption of clusters of papules and vesicles which evolve into exquisitely painful ulcers (Fig. 12). Lesions may involve the anus, urethra, bladder, cervix, and vagina, as well as the vulva, and may be accompanied by dysuria and vaginal discharge.
Fig. 12

Herpes simplex infection of the vulva. Numerous small, shallow ulcers on an erythematous base are visible on the inferior labia majora, labia minora, and perineum

Concurrent HIV infection may drastically alter the presentation of HSV-related disease. HIV-positive patients tend to have more severe and more frequent outbreaks, and to develop more extensive lesions which may take longer to resolve (Domfeh et al. 2012; Fatahzadeh and Schwartz 2007). They may also develop lesions with atypical symptomatology or morphology, including painless lesions, fissures, patchy erythema, furuncles (boils), wart-like lesions, or diffusely and deeply ulcerating lesions (Domfeh et al. 2012; Fatahzadeh and Schwartz 2007). Of most concern to the pathologist may be the hypertrophic, mass-forming lesions sometimes referred to as hypertrophic chronic vegetative lesion (HCVL). Clinically, these lesions present as exophytic masses, measuring several centimeters in greatest dimension (Fig. 13), which may mimic warts or squamous carcinoma clinically (Domfeh et al. 2012; Mosunjac et al. 2009; Gomes do Amaral et al. 2009; Strehl et al. 2012; Tangjitgamol et al. 2013).
Fig. 13

Hypertrophic chronic vegetative lesion and atypical manifestation of herpes infection. The lesion is present on the medial surface of the labia minora and shows minute surface ulcerations. (Reprinted with permission from Selim et al. 2015)

Microscopic Findings
A sample from the margin of the ulcer is most likely to reveal the pathognomonic findings. Infected cells show homogenization of the nuclear chromatin resulting in a “ground glass” appearance, which then progresses to the more typical eosinophilic intranuclear inclusion body. Multinucleation is also a characteristic feature (Fig. 14). Cytologic evaluation of the scraping of the base and edges (Tzank preparation) of a fresh ulcer, or freshly opened vesicle may also show the characteristic cellular changes. Over time, the infected cells undergo karyorrhexis and lysis, and samples taken in the late ulcerative phase may not, therefore, always show the intranuclear inclusions.
Fig. 14

The cellular changes of herpes simplex infection. Several multinucleated forms showing the characteristic homogenized glassy cytoplasm are present at the edge of this herpetic ulcer

The histologic features of the atypical lesions seen in HIV-positive patients significantly different than those of the typical lesion. The large exophytic hypertrophic chronic vegetative lesions show a markedly thickened, hyperkeratotic epithelium, overlying a fibrotic, thickened dermis, with a dense inflammatory infiltrate of plasma cells and lymphocytes. Only small areas of ulceration, in which the characteristic viral changes may be identified, are present in such lesions (Fig. 15).
Fig. 15

Microscopic features of the hypertrophic chronic vegetative herpes lesion illustrated in Fig. 13. There is pseudoepitheliomatous hyperplasia (a) overlying a dense lymphoplasmacytic infiltrate (b). The cytopathologic changes of HSV are seen focally (c), and immunohistochemical stain for HSV confirms the diagnosis (d). (Reprinted with permission from Selim et al. 2015)

Morphologic changes seen with HSV infection are not reliable in separating primary from secondary infection or in distinguishing HSV type I from type II infection, nor can they differentiate the lesions of herpes zoster, which may involve the vulva as well, though only rarely, but immunohistochemical stains can be used to distinguish the type of virus present in tissue, cytologic preparations, or cultures when necessary. Viral culture has a relatively low sensitivity, however, and only about 80% of primary infections and 25–50% of recurrent infections can be identified this way (Gupta et al. 2007). PCR is the preferred method to identify the virus, as it is more sensitive and faster than culture (Fatahzadeh and Schwartz 2007; Gupta et al. 2007; Hope-Rapp et al. 2010).

Clinical Course and Treatment

Untreated, the ulcers of the initial episode heal in approximately 2–6 weeks, after which the virus lies dormant in regional sensory and autonomic ganglia. A 7–10 day course of systemic treatment with the antiviral agents acyclovir, valacyclovir, or famcyclovir can speed healing, decrease viral shedding, and decrease the incidence of new lesions, but these drugs do not prevent or eradicate latent infection, and they are not curative. Periodic reactivation of the virus is likely, leading to subsequent recurrences, the rate of which decreases with time since the primary infection (Gupta et al. 2007). Atypical lesions associated with concurrent HIV-infection may not respond to conventional treatment; these patients may require higher doses of antiviral agents and longer durations of treatment, and some may require the use of alternative antiviral agents. Surgery may also be considered for large atypical lesions refractory to therapy.

Molluscum Contagiosum

Clinical Features

Molluscum contagiosum is a viral infection of the skin which manifests after an incubation period of 14–50 days as small, smooth papules (3–6 mm in diameter) with a central punctum or umbilication. They generally are multiple and separate, although they may be single. Rare plaque formations, made up of 50–100 individual clustered lesions, also have been described. In children, the lesions may develop anywhere in the skin and the route of transmission is from close contact. Genital involvement is unusual in children (Zhuang et al. 2015). In adults, however, the genitals are usually the only site involved and the disease is almost exclusively transmitted by sexual contact (Bast-Juzbasic and Ceovic 2014). On the vulva, the keratinized surfaces of the labia majora, labia minora, and mons are most frequently affected. Lesions are usually asymptomatic, but may be pruritic, and excoriation from excessive scratching may facilitate secondary bacterial infection, which may mask the underlying condition and confound the diagnosis.

Microscopic Findings
Clinical diagnosis usually does not require biopsy, but when biopsy is performed, the histomorphology is distinctive (Fig. 16). The central dimple of the lesion can be seen histologically if the lesion is carefully bisected. Within the dermis, there often is a marked vascular response with endothelial proliferation and perivascular inflammation. In recent infections, the lesions demonstrate marked acanthosis and the characteristic eosinophilic intracytoplasmic viral inclusions (Henderson–Patterson bodies), which may also be identified in scrapings from the interior of the lesions.
Fig. 16

Molluscum contagiosum. The center of the lesion shows the characteristic eosinophilic viral inclusions (Henderson–Patterson bodies)

Clinical Course and Treatment

The lesions are infectious as long as they are present, and although most lesions of molluscum contagiosum regress spontaneously within months to years, many patients are anxious to be rid of them sooner. Numerous treatment options are available to speed resolution, including curettage, cryosurgery, and topical agents. Responses are variable, and more than one treatment modality may be needed to successfully eradicate the disease.

Varicella (Herpes Zoster)

Vulvar shingles, caused by involvement of the vulva by varicella, the etiologic agent of chicken pox, is rare. The lesions represent reactivation of virus which has been dormant in the sacral ganglia. The prodromal vulvar pain, without apparent physical findings, may at first simulate vestibulitis, but the subsequent eruption of vesicles and ulcers soon distinguishes it. Patients are usually postmenopausal and/or immunosuppressed and the vesicles are characteristically unilateral. The histologic and cytologic findings are indistinguishable from HSV, but immunohistochemistry with virus-specific antibody or PCR can differentiate them when necessary.

Cytomegalovirus

Cytomegalovirus (CMV) is a rare cause of ulcerative cervicitis and vulvovaginitis which may mimic HSV infection clinically (Abou and Dallenbach 2013). The histopathologic findings are similar, except that the cytologic changes caused by CMV are both intranuclear and cytoplasmic, multinucleated forms do not occur, and the viral inclusions also may be seen involving vascular endothelial cells, as well as the epithelial cells. The diagnosis can be confirmed in tissue by immunohistochemical staining using specific antibodies to CMV, PCR of swabs collected from active lesions, or by isolation in culture.

Epstein–Barr Virus

Primary infection with Epstein–Barr virus (EBV) is occasionally the cause of ulcerations of the labia minora which may or may not be accompanied by the systemic symptoms characteristic of infectious mononucleosis. The ulcers are usually more than a centimeter in diameter (Halvorsen et al. 2006), necrotic, deep, and painful. The median age of affected patients is 14.5 years old, and in most patients there is no history of recent sexual activity (Halvorsen et al. 2006). Involvement of the vulva is presumed to occur via hematogenous spread, but sexual transmission cannot be completely ruled out in all cases.

The ulcers appear very early in the disease, usually before serology can detect the infection, and heal spontaneously in 3–4 weeks (Halvorsen et al. 2006; Sand and Thomsen 2017; Taylor et al. 1998). Viral culture or PCR may identify the virus (Halvorsen et al. 2006; Sand and Thomsen 2017). Histological findings are nonspecific, and the lesion is extremely unlikely to be encountered as a biopsy specimen.

Fungal Infection

Fungal infection of the vulva may cause chronic inflammatory conditions of the vulvar and perianal skin. The most common agents are Candida species. Recurrent or chronic vulvar candidiasis may cause the involved mucosa to become atrophic and painful, with a glazed red appearance. Painful fissuring in the periclitoral area, interlabial sulcus, and around the introitus may develop and may be a clue to the diagnosis (Margesson, 2006). Dermatophytes are less common, and often of zoonotic origin, with Microsporum canis and Trichophyton mentagrophytes the most commonly encountered (Sand and Thomsen 2017). Dermatophytosis usually involves the hair-bearing skin, producing follicular papulopustular lesions which may coalesce into elevated erythematous scaly plaques. Pityriasis versicolor (tinea versicolor), caused by Malassezia species, has also been reported on the vulva (Day and Scurry 2014). Fungal infections of the vulva rarely require biopsy, and accurate diagnosis generally can be accomplished by microscopic examination of skin scrapings placed in 10% potassium hydroxide, or by appropriate culture methods. When biopsy is performed, the presence of neutrophils in the epidermis may suggest a fungal etiology (Fig. 17), and performance of silver or PAS stain may reveal the organisms. Topical antifungal creams are the usual therapy.
Fig. 17

Fungal infection of the vulvar skin. Numerous intraepithelial neutrophils are present, which can be a useful clue to a fungal etiology. The differential diagnosis includes psoriasis, which can look very similar (see Fig. 18a, b), and definitive diagnosis requires identification of the fungal organisms on special stains

Parasitic Infection

Pediculosis pubis, or pubic lice, caused by infestation of pthirus pubis, is not uncommon, but rarely generates a specimen for histologic examination, as the nits, nymphs, and adult lice may be visualized with the naked eye or with the assistance of a magnifying glass.

Other parasitic infections of the vulva are quite rare. Children infected with enterobius vermicularis (pinworm) frequently experience severe vulvovaginal pruritus, which may awaken them at night, thought to be related to migrating worms. Examination of the vulvar vestibule and vagina in such cases reveals marked inflammation, but only rarely is the parasite identified in the vulvar tissue. A granuloma secondary to Enterobius eggs has been reported involving the vulva (Sun et al. 1991). Skin lesions on the vulva from penetration of the infective cercariae of schistosomiasis, usually Schistosoma mansoni, may be encountered in endemic areas, in which the parasite may be found within the epidermis on biopsied samples. Cutaneous myiasis of the vulva, secondary to infestation of the larval form of the muscoid fly and sarcophaga, has also been reported, and can be diagnosed by recognition of the larva extracted from the vulvar tissues (Cilla et al. 1992; Koranantakul et al. 1991).

Inflammatory Dermatoses

The inflammatory dermatoses are among the most common dermatologic disorders, and vulvar involvement is frequent. The recognition of these disorders, both clinically and histologically, is significantly more difficult on the vulvar skin than in extragenital sites, due, in large part to the particular local conditions. The vulvar skin is confined in an occlusive environment, in which it is subject to high levels of moisture, friction, and other irritations, which frequently combine to induce an aberrant appearance of inflammatory dermatoses in this region. Features which are characteristic on nongenital skin may be obscured or even absent. At the same time, reactive changes and superinfection are much more likely to be superimposed on vulvar lesions, creating a complex tangle of symptoms and findings which can be difficult to tease apart. Biopsies of inflammatory dermatoses of the vulva, consequently, are frequently inconclusive, and arriving at a specific diagnosis often requires careful clinicopathologic correlation as well as observation over time. The job of the pathologist in these cases is not so much to establish an unequivocal diagnosis as to narrow the differential.

Recognition of specific histologic patterns has long been used by dermatopathologists as the first step in classification of dermatologic conditions, leading the ISSVD to establish its first classification scheme based for vulvar dermatoses based on histologic pattern (Lynch et al. 2006). The original 2006 ISSVD classification of the inflammatory dermatoses is simplified to include only those disorders most likely to be encountered on vulvar biopsies, and is the basis for Table 2, which also includes some less common disorders worthy of consideration. Following this framework, the disorders are presented below in groups classified by the dominant histologic pattern.
Table 2

A summary of vulvar dermatoses classified by histologic pattern. The conditions on the left are those included in the 2006 ISSVD classification. On the right are additional conditions presented in this chapter

2006 ISSVD classification of vulvar dermatosesa

Less common entities

(not included in the 2006 ISSVD classification)

Spongiotic pattern

Atopic dermatitis

Allergic/irritant contact dermatitis

 

Acanthotic pattern

Psoriasis

Lichen simplex chronicus (primary or secondary)

 

Lichenoid pattern

Lichen sclerosus

Lichen planus

Fixed drug eruption

Dermal homogenization/sclerosis pattern

Lichen sclerosus

Morphea

Vesiculobullous pattern

Pemphigoid, cicatricial type (mucous membrane pemphigoid)

Linear IgA disease

Bullous pemphigoid

Pemphigoid gestationis

Pemphigus

Bullous SLE

Acanthotic pattern

Hailey–Hailey disease

Darier’s disease

Papular genitocrural acantholysis (papular acantholytic dyskeratosis)

 

Granulomatous pattern

Crohn’s disease

MelkerssonRosenthal disease (granulomatous vulvitis)

Sarcoid

Vasculopathic pattern

Aphthous ulcers

Behçet disease

Plasma cell vulvitis

 

aAdapted from Lynch et al. 2006

Spongiotic Pattern

Epithelial spongiosis is the result of intraepithelial edema. Clinically, spongiotic lesions present as eczematous dermatitides, with a wet, oozing surface. On the vulva, because it is usually closely covered, trapping of the moisture may result in maceration of the surface, which may disguise the underlying condition. Microscopically, spongiosis is evidenced by increased space between epithelial cells, representing the area of fluid accumulation.

Allergic/Irritant Contact Dermatitis

Clinical Features
Contact dermatitis is the most commonly encountered spongiotic dermatitis of the vulva, affecting approximately 15–54% of women (Ball et al. 2015; Connor and Eppsteiner 2014). Vulvar contact dermatitis may be of an allergic type (ACD) or an irritant type (ICD), with the latter being the more common of the two. The allergic type is a cell-mediated response to sensitizing agents, which can include a number of soaps, topical medications and remedies, or components thereof (Moyal-Barracco and Wendling 2014; O’Gorman and Torgerson 2013; Foote et al. 2013; Bauer et al. 2005). The irritant type is due not only to the presence of an irritant, but also to underlying skin damage and subsequent loss of barrier function, as may be seen in urinary incontinence, and occasionally in association with sanitary napkin use during menstruation (Wakashin 2007). A list of selected common potential allergens and irritants is presented in Table 3.
Table 3

Common vulvar allergens and irritants. Many substances can act as either an allergen or an irritant, depending on the sensitivity of the patient

Common vulvar allergens and irritants

Fragrances

Topical anesthetics

Preservatives

Topical antifungals and other antibiotics

Emollients

Metals (nickel, gold)

Body fluids

Soaps and detergents

Lubricants

Excessive heat

The presentation of ICD and ACD is variable, depending on the severity and duration of the process. Acute ICD develops within minutes to hours of the exposure, while those of ACD take 24–48 h to develop. The lesions of ICD tend to be well-circumscribed, confined to the area of contact, more likely to be painful, and less likely to develop vesicles and bullae, while those of ACD are more poorly demarcated, more likely to be pruritic, and more likely to develop vesicles and bullae. Superficial erosion or ulceration may be present in both. Not infrequently, the clinical appearance is normal or only minimally altered (Ball et al. 2015), despite significant symptomatology.

Microscopic Findings

The pathologic findings are also variable and depend on the age of the lesion. Spongiosis may be minimal at first, progressing to pronounced dermal edema with the formation of microvesicles, and regressing again with more time. In long-standing contact dermatitis, lichen simplex chronicus (see section “Lichen Simplex Chronicus”) often supervenes, with prominent acanthosis and hyperkeratosis.

Clinical Course and Treatment

The symptoms of ICD and ACD will continue until contact with the offending agent can be eliminated, a process which may take some time to achieve. All possible exposures must be eliminated by the patient, which can necessitate quite extensive changes and can be quite disruptive, demanding the elimination of every soap, shampoo, laundry product, lotion, lubricant, topical ointments and creams, and even many items of clothing, among other things, until each can be exonerated by the result of patch testing or by slow reintroduction one at a time. A variety of therapies may be used for symptomatic control until the allergen or irritant can be identified. Vaseline or zinc oxide may be used to form a barrier to potential exposures, oral over the counter antihistamines may be used to control itching, and nonsteroidal anti-inflammatory agents may be used to control pain. Sitz baths and cold compresses may also provide relief. Unresponsive pain may be treated with tricyclic antidepressants and anticonvulsants. Finally, topical corticosteroids, or in severe cases localized injection or systemic steroid administration, are also usually part of the management, keeping in mind that in rare cases topical corticosteroids may themselves be the cause of the allergen or irritation.

Atopic Dermatitis

Clinical Features

With 85% of patients presenting before age 5, and the majority of cases remitting by adolescence, atopic dermatitis is predominantly a disease of childhood. The disease first manifests in adulthood in only 2–8% of patients (Arkwright et al. 2013). The disorder may involve the vulvar skin, but very few cases have been reported in the literature to date, and the frequency of vulvar involvement is unknown. The physical findings may be limited to dryness and scaling, but thickening of the skin with localized excoriation may be evident if the vulva has been irritated by scratching.

Microscopic Findings

Because the diagnosis is usually established by clinical findings and the appearance on the nongenital skin, vulvar biopsies are rarely performed on these patients. When they are, the pathologic findings are usually nonspecific. Spongiosis may be present. Within the dermis, lymphocytes and macrophages are present and the density of the infiltrate tends to correlate with the severity and chronicity of the process. Eosinophils and mast cells also may be identified. Most often, superimposed lichen simplex chronicus (see section “Lichen Simplex Chronicus”) has developed in response to the chronic itching and scratching, masking the initiating condition.

Clinical Course and Treatment

Although 70% of children with atopic dermatitis show spontaneous remission before they reach adulthood, a minority of patients suffer lifelong disease with periodic exacerbations. There is no cure for the disease, but most patients’ symptoms can be controlled using emollients and topical corticosteroids. In paients who do not show an adequate response, topical calcineurin inhibitors may be used in place of steroids. Rarely, severe, refractory disease requires systemic treatment with calcineurin inhibitors such as cyclosporine.

Differential Diagnosis of Spongiotic Dermatitis of the Vulva

Histology cannot always distinguish between ICD, ACD, and atopic dermatitis, but certain features favor a specific diagnosis. The presence of balloon cell change and dyskeratosis favors ICD, with the caveat that if such changes are severe fixed drug eruption (see section “Fixed Drug Eruption”) and erythema multiforme (see section “Erythema Multiforme/Stevens–Johnson Syndrome”) must be considered as well. Prominent vesicles containing eosinophils and aggregates of intraepidermal Langhan cells favors ACD (Moyal-Barracco and Wendling 2014; Hoang et al. 2014), although the former may also be seen early in the development of some vesiculobullous disorders, in which case immunofluorescent studies may be used to make the distinction. Spongiosis may be seen as a component of reactions to fungal infection, some drug reactions, arthropod bites, as well as in contact and atopic dermatitis. A careful search for fungal organisms, with the use of special stains such as PAS or silver stains if necessary, will easily establish the presence or absence of infection, and clinical history will help determine whether drug reactions or arthropod bites need to be considered. Spongiosis may also be seen in acantholytic disorders, but as acantholysis is not a feature of atopic or contact dermatitis, this finding will point to a different set of diseases altogether (see section “Acantholytic Pattern”). The differential diagnosis of spongiotic dermatoses is summarized in Table 4.
Table 4

Select features of use in the differential diagnosis of common spongiotic dermatoses of the vulva

Differential diagnosis of spongiotic dermatoses of the vulva

Diagnosis

Pain

Pruritis

Demarcation of lesions

Presence of balloon cell change +/− dyskeratosisa

Formation of vesicles+/− bullaeb

Concurrent involvement of nongenital skin

ACD

Rare

Common

Poor

No

Sometimes (containing eosinophils and Langhans cells)

No

ICD

Common

Rare

Sharp

Sometimes

No

No

Atopy

Rare

Invariably

Poor

No

No

Yes

aRule out erythema multiforme

bRule out vesiculobullous disease

Acanthotic Pattern

Acanthosis refers to thickening of the epithelium, which presents clinically as thick white plaques. Histologically, two patterns of acanthosis may be recognized. In “regular acanthosis,” sometimes also called “psoriasiform hyperplasia,” the rete ridges are uniformly elongated, with all of them having the same length and width. In “irregular” acanthosis,” the rete ridges are variable in length and width from one to the next. Whether regular or irregular, acanthosis takes time to develop and is therefore an indication of a chronic, rather than an acute, condition.

Psoriasis

Clinical Features

Psoriasis is a chronic immune-mediated disease which affects approximately 3.2% of the population of the USA (Young et al. 2017) and involves the genitalia in 30–40% of patients (Andreassi and Bilenchi 2014). The median age of onset in women is 25 years (Young et al. 2017), and the severity of disease often fluctuates with hormone levels, with exacerbations developing in puberty, postpartum, and menopause. Vulvar psoriasis may present in the classic form, most commonly on the mons, with sharply demarcated erythematous papules and plaques covered with silvery scale, which show punctate points of bleeding when the superficial scale is removed (Auspitz sign). More often, however, on other vulvar sites, is the inverse form, in which the scale is absent, and the lesions appear as flat red patches which may also be eroded or ulcerated. Symptoms of vulvar psoriasis may include itching, burning, and pain.

Microscopic Findings
In the classic form, well-developed lesions show the typical diagnostic features of confluent superficial parakeratosis with intraepidermal collections of neutrophils (Munro microabscesses), epidermal hyperplasia, loss of the granular layer, spongiotic pustules, and thinning of the suprapapillary plates (Fig. 18a). In the inverse form (Fig. 18b), diagnostic features may be less prominent or even lacking on biopsy (Andreassi and Bilenchi 2014; Moyal-Barracco and Wendling 2014).
Fig. 18

(a) Classic psoriasis. The epidermis shows regular acanthosis, thinning of the suprapapillary plates, loss of the granular layer, and confluent surface parakeratosis with superficial collections of neutrophils (Munro microsabscesses). (b) Inverse psoriasis. This lesion shows the same features as classic psoriasis but with more even dispersion of neutrophils and a thicker parakeratotic surface

Clinical Course and Treatment

A variety of treatments are available for psoriasis, but none is curative. Mild disease can be treated with a wide variety of topical agents, while more severe disease requires systemic immunosuppressive therapy with agents such as methotrexate or cyclosporine. Phototherapy is another effective adjunctive or alternative to topical agents, but its use on the vulva, where the anatomy may make it difficult, is limited. Newer agents which target directly the cytokines responsible for the aberrant immune response are also available for use in moderate to severe disease, and have significantly improved outcomes.

Lichen Simplex Chronicus

Clinical Features
Lichen simplex chronicus (LSC) is a reactive pattern induced by persistent rubbing or scratching in response to local itching. It may occur without a diagnosed cause of the initial itch (primary lichen sclerosus), or as the end point of many chronic pruritic conditions such as atopic or contact dermatitis, chronic fungal infections, lichen sclerosus, or lichen planus. It most commonly involves the hair-bearing skin of the labia majora, mons pubis, and perianal region and may be confined to a focal area, appearing grey-white or reddened on clinical exam (Fig. 19). The skin markings are often accentuated, a sign of intradermal edema and chronic rubbing; excoriation and fissures are common.
Fig. 19

The gross appearance of lichen simplex chronicus. The left labia majora shows a thickened, grayish surface. (Reprinted with permission from Ball et al. 2015)

Microscopic Findings
In addition to prominent acanthosis of the irregular type, the histopathologic features may include hyperkeratosis and hypergranulosis. Fibrosis of the papillary dermis, characterized by vertical orientation of the collagen fibers, is characteristic, and the capillaries in the papillary dermis also show a vertical orientation (Fig. 20). This orientation of the collagen fibers and capillaries of the papillary dermis is distinctive and a useful clue to the diagnosis (Ball et al. 2015). A chronic inflammatory infiltrate in the superficial dermis is usually present, but the presence of eosinophils and neutrophils is not to be expected. Parakeratosis may be present in LSC but is generally not a prominent feature. These changes are nonspecific, and the diagnosis is usually one of exclusion.
Fig. 20

Lichen simplex chronicus. The epidermis is thickened and shows focal hypergranulosis. The vertical orientation of the collagen fibers and capillaries in the papillary dermis seen here is a characteristic finding. (Reprinted with permission from Ball et al. 2015)

Clinical Course and Treatment

Paradoxically, and much to the frustration of those afflicted, scratching the lesions of LSC only worsens the itch, setting up a vicious cycle which can be very difficult to control. Symptoms can be managed with topical steroids, calcineurin inhibitors, and, of course, avoidance of scratching, but recurrences are frequent.

Differential Diagnosis of Acanthotic Dermatoses of the Vulva

Clinical history will usually confirm a diagnosis of psoriasis, as most patients will have concurrent or previously diagnosed characteristic lesions elsewhere on the skin. In the absence of a clear history, or even when the patient has an established diagnosis of psoriasis, the prominent neutrophilic infiltrate seen in the disease is similar to that seen with fungal infection, and if other histologic feaures are at all equivocal, it is advisable to perform special stains to rule out fungal infection prior to making a diagnosis of vulvar psoriasis. The same should be done for cases of LSC showing significant inflammation, as chronic fungal infections are a common underlying cause of LSC.

Although both psoriasis and LSC are characterized by pronounced acanthosis, they are usually easily distinguished from each other. Again, a clinical history of psoriasis can be extremely helpful, but histologic features are relatively reliable in this distinction as well. The pattern of acanthosis is regular in psoriasis but irregular in LSC, and the granular layer is prominent in LSC but lost in psoriasis. In addition, thinning of the suprapapillary dermis and neutrophilic microabscesses, prominent features in psoriasis, are not present in LSC.

A more difficult problem is to determine whether LSC is of the primary or secondary type. Chronic contact dermatitis commonly evolves to LSC (see section “Allergic/Irritant Contact Dermatitis”), which may be suggested by the presence of associated spongiosis or an inflammatory infiltrate containing eosinophils. When LSC is superimposed on lichen sclerosus (see section “Lichen Sclerosus”) a lichenoid infiltrate or vacuolar changes at the dermo-epidermal junction may suggest the underlying diagnosis, as may the identification of hyalinization of the superficial dermis. The presence of necrotic keratinocytes, which may be numerous in lichen sclerosus but are scarce, if present at all, in LSC (Weyers 2015), may also be helpful in this differential. Acanthosis, hyperkeratosis, and hypergranulosis are common features in intraepithelial neoplasias of the vulva as well, but the presence of cytologic atypia, increased mitotic activity with atypical forms, and abnormal maturation patterns should distinguish them. The differential diagnosis of acanthotic dermatoses of the vulva is summarized in Table 5.
Table 5

Summary of selected features of use in differentiating common acanthotic dermatoses of the vulva

Differential diagnosis of acanthotic dermatoses of the vulva

Feature

Diagnosis

Psoriasis

LSC (primary)

LSC secondary to contact dermatitis or atopy

LSC secondary to LS

Acanthosis pattern

Regular

Irregular

Irregular

Irregular

Granular layer

Lost

Prominent

Prominent

Prominent

Concurrent involvement of extragenital skin

Yes

No

No

No

Spongiosis

No

No

Yes

No

Eosinophils present

No

No

Yes

No

Lichenoid infiltrate

No

No

No

Yes

Basal vacuolar change

No

No

No

Yes

Necrotic keratinocytes

None

Rare

Rare

Common

Lichenoid Pattern

The lichenoid pattern of dermatitis is characterized by a band-like infiltrate confined to the papillary dermis and basal epidermis which obscures the dermo-epidermal junction and causes focal necrosis and vacuolization of the basal keratinocytes. The lesions in this category of vulvar dermatoses may be exceptionally difficult to differentiate from each other on histologic grounds alone.

Lichen Sclerosus

Lichen sclerosus (LS) is more common in the premenarchal and postmenopausal years and is diagnosed in an estimated 1–2% of patients in general gynecologic practice (Goldstein et al. 2005). It is currently considered to be an autoimmune condition, occurring in genetically predisposed patients (Fistarol and Itin 2013; Sherman et al. 2010). On the vulva, it involves the non-hairbearing portions, predominantly affecting the keratinizing epithelium of the medial labia majora, interlabial sulci, labia minora, clitoris, perineum, and perianal area. The disease often begins around the clitoral hood (Fistarol and Itin 2013). Involvement may be limited to a small, single area, or may involve all of these regions in a figure-eight shaped distribution surrounding the introitus and anus. Early lesions may appear as white papules, which typically evolve into white plaques, or as sharply demarcated and slightly elevated erythematous patches with edema. Fissuring may be seen, especially between the clitoris and urethra, in the interlabial sulci and on the perineum posterior to the fourchette (Fistarol and Itin 2013) as well as erosions and ecchymoses. As the lesions age, they typically become dry, hypopigmented and finely wrinkled, an appearance likened to parchment, cellophane, or tissue paper (Fig. 21). The disease does not proceed at the same rate in all areas, so lesions of many different stages may be present in the same patient at the same time. The most common symptom in patients with intact epithelium is pruritus. Patients with associated erosions or fissures may also experience pain, dysuria, and dyspareunia. Only 9% of patients are asymptomatic (Sherman et al. 2010).
Fig. 21

The gross appearance of lichen sclerosis. The skin is thin, shiny, pale, and wrinkled (parchment-like), with focal ecchymosis. There is loss of distinction between the labia majora and minora

Microscopic Findings

Lichen sclerosus was formerly known as “lichen sclerosus et atrophicus,” because on the classic, well-developed lesions, there is striking sclerosis in the papillary dermis and atrophy of the overlying epithelium. It has since become apparent that the microscopic findings of LS are extremely variable, and the classic atrophic, sclerotic appearance, while the easiest pattern to diagnose, is not always present. This accounts for the unique placement of LS into two categories the ISSVD classification of vulvar dermatoses (see Table 2).

Cases of LS with diminished or absent subepithelial sclerosus combined with epithelial hyperplasia rather than atrophy are not uncommon (Fig. 22), and they are significantly more difficult to distinguish from other conditions. It has long been maintained that such lesions, which show a prominent lichenoid infiltrate in the dermo-epidermal junction, with vacuolar changes and intraepidermal lymphocytes in the basal layer and little to no stromal homogenization (lichen sclerosus sine sclerosis) represented early lesions, which would progress in time to more recognizable sclerotic and atrophic lesions. Yet not all cases lacking stromal homogenization necessarily represent early cases, as recent studies have found these features in lesions of long standing (Weyers 2015). Features identified in these cases which may help point to the correct diagnosis include marked thickening of the papillary dermis due to thickening of collagen fibers, lymphocytes in linear formations between the thickened fibers, and the presence of tiny foci of homogenization in the dermal papillae (Weyers 2015).
Fig. 22

Lichen sclerosis with minimal sclerosis. The epidermis shows pronounced hyperparakeratosis, and focal dyskeratotic cells can be seen. There is a dense lymphocytic infiltrate in the dermis, as well as collagen fibrosis, with linear formations of lymphocytes between collagen fibers

Extravasation of red blood cells in the dermis may be seen in LS regardless of the degree of sclerosis or atrophy, which accounts for the ecchymotic appearance sometimes seen. An absence of melanosomes in the keratinocytes and a disappearance of the melanocytes is also a characteristic common to all LS lesions, and this lack of pigment, as well as associated edema, contributes to the white clinical appearance. In long-standing disease, however, postinflammatory pigmentation or melanosis (see section “Postinflammatory Alterations in Pigmentation”) may occur, as well as superimposed lichen simplex chronicus (see section “Lichen Simplex Chronicus”), features which can confound the diagnosis significantly.

Clinical Course and Treatment

Lichen sclerosus diagnosed in childhood may improve somewhat at puberty, but the majority of cases will persist into adulthood (Fistarol and Itin 2013). Untreated, adhesions, and scarring from LS can lead to marked changes in the vulvar architecture, with obliteration and/or fusion of the labia minora, stensosis of the introitus, and obscuring of the clitoris. Timely and adequate therapy is imperative to prevent such changes.

Lichen sclerosus can be controlled with treatment, and symptoms may be relieved, but complete resolution is rare. The majority of patients experience repeated relapses and remissions. Therapy using high-potency topical corticosteroids produces symptomatic relief in a majority of patients, and, in some cases, complete resolution of the disease (Fistarol and Itin 2013). Close clinical follow-up is always necessary, however, regardless of response to treatment, and any area of change developing within the LS should be promptly biopsied, as there is a small but significant risk of vulvar differentiated (simplex) type VIN and subsequent squamous cell carcinoma in postmenopausal women.

Lichen Planus

Clinical Features

Lichen planus (LP) is currently understood as an autoimmune disease, in which T-cells react against basal keratinocytes (Goldstein and Metz 2005). Half of female patients with LP are reported to have vulvar involvement (Moyal-Barracco and Wendling 2014). Most patients are between 30 and 60 year old at onset, with a peak incidence in the 50s (Cooper and Wojnarowska 2006). Vulvar pain, pruritus dyspareunia, and burning are common symptoms, although some patients may be asymptomatic.

Three categories of lesions are described; the classical papulosquamous, the erosive-atrophic, and the hypertrophic, and patients may have more than one type simultaneously. The erosive form is the most common on the vulva, usually involving the labia minor and introitus, and appears as well-delineated, red, eroded areas. The papulosquamous form is uncommon on the vulva, and when it occurs it is usually in the setting of generalized disease, while the hypertrophic form is only very rarely seen on the vulva. Both the papulosquamous and hypertrophic forms, when present on the vulva, are usually associated with the more common erosive lesions as well.

Papulosquamous lesions present as single or multiple poorly demarcated pink, papules, rather than the well-delineated violaceous flat-topped papules typical of the lesions as described on the extragenital skin (Goldstein and Metz 2005). On the vulva, they usually involve the hairbearing skin of the labia majora. Hypertrophic lesions present as single or multiple roughened plaques, usually in the perineal or perianal area. All types of lesion may be associated with a lacy, reticulated appearance of the surrounding epithelium, known to dermatologists as Wickham’s striae.

Microscopic Findings
The histopathologic features of LP, not surprisingly, vary according to the category and location of the gross lesion. Classically, papulosquamous lesions show a sawtooth pattern of rete ridges with a wedge-shaped area of hypergranulosis, usually without hyperkeratosis. There is a dense band-like infiltrate, consisting predominantly of lymphocytes located in the upper dermis and obscuring the dermo-epidermal junction (Fig. 23). Liquefactive degeneration of the basal epithelial cells is present, and scattered necrotic keratinocytes which form eosinophilic colloid or civatte bodies, which can be seen in the basal epithelium and dropping down into the dermis. On the vulva, classic features may be less well-developed.
Fig. 23

Lichen planus, papulosquamous type. The lesion shows hyperkeratosis and hypergranulosis, with irregular acanthosis (“sawtooth” rete ridges) and a band-like inflammatory infiltrate of lymphocytes at the dermo-epidermal junction

Hypertrophic LP is similar to the papulosquamous form, but exaggerated acanthosis is present as well, which may cause significant confusion with LSC clinically and microscopically (Moyal-Barracco and Wendling 2014).

Erosive LP (Fig. 24) frequently lacks diagnostic features on biopsy, particularly if from the central portion of the lesion where the epithelium is entirely absent. If erosive LP is suspected, it is important that the biopsy be from the edge of the eroded area. An attempt to establish a set of diagnostic criteria reached no consensus on any particular indication as being essential to diagnosis (Simpson et al. 2013) but was able to identify several clinical and histologic features considered “supportive” of the diagnosis. The clinical features include location of the eroded areas at the vaginal introitus, the presence of surrounding Wickham’s striae, symptoms of pain and burning, involvement of other mucosal surfaces and the presence of concurrent vaginal inflammation. Histologic features were the presence of a well-defined band of inflammation at the dermo-epidermal junction consisting predominantly of lymphocytes, and signs of basal layer degeneration.
Fig. 24

Lichen planus, erosive type. The epithelium is thin and predominantly eroded, and an obvious lichenoid infiltrate is lacking. (Reprinted with permission from Ball et al. 2015)

Clinical Course and Treatment

Like lichen sclerosus, untreated or unresponsive erosive LP can result in scarring and agglutination of the labia minora, severe introital and vaginal adhesions, and resultant stenosis or even obliteration of the vaginal canal (Lewis 1998). Topical corticosteroids are the first line of treatment for vulvar LP. Occasionally, other topical agents may be preferred. If topical treatments fail, systemic treatment with corticosteroids may be required (Goldstein and Metz 2005). Although treatment provides significant relief of symptoms in most patients, vulvar LP can be difficult to eradicate, particularly the erosive form. Only 9% of patients had complete resolution in one prospective study (Cooper and Wojnarowska 2006). As with lichen sclerosus, there is a risk of progression to differentiated VIN and squamous carcinoma, and close clinical follow-up is essential.

Fixed Drug Eruption

Clinical Features

The vulva is a favored site for fixed drug eruption, a recurrent type IV hypersensitivity reaction (Andreassi and Bilenchi 2014). Classically associated with pyramidone, sulfonamides, antibiotics, and NSAIDs, an increasing number of antibacterial, antifungal, psychoactive, and analgesic drugs are now recognized as potential agents. On the keratinized vulvar skin, fixed drug eruptions are usually single, erythematous, round lesions involving a distinct, clearly delineated area, which may progress to erosion. On the nonkeratinized mucosa, the lesions often appear as erosions with irregular borders. The symptoms are generally mild, consisting of itching and burning.

Microscopic Features

Histologically, the lesions demonstrate spongiotic epithelium overlying a dermis with a perivascular and interstitial infiltrate of lymphocytes admixed with eosinophils and neutrophils. The inflammation may extend upward to involve the basal layer of the epithelium, causing basal vacuolar change. In the nongenital skin, the healing phase is characterized by prominent post inflammatory pigment incontinence, but this is much less common in the vulva.

Clinical Course and Treatment

The lesions typically appear at the same place on reexposure to the responsible agent, often within minutes to hours (Ball et al. 2015). Avoidance of the responsible agent eliminates the condition.

Differential Diagnosis of Lichenoid Dermatoses of the Vulva

It can be very difficult to distinguish early LP of any type from LS without significant atrophy or sclerosis, as both are characterized by a lichenoid inflammatory infiltrate and basal degeneration. This differential diagnosis is summarized in Table 6. Clinical features may be helpful, as lichen sclerosus is rarely painful, only rarely involves the extragenital skin and never involves the vagina or other mucous membranes, whereas lichen planus is usually painful and frequently involves the extragenital skin and mucous membranes as well as the vagina. Useful histopathologic features in this differential diagnosis include the lack of melanophages in LS, which may be numerous in LP, the increased presence of lymphocytes in the epidermis in LS, and the difference in distribution of necrotic keratinocytes, which are confined to the basal layer or upper dermis in LP, but extend from the basal layer up into all layers of the epidermis, sometimes forming clusters, in LS (Weyers 2015). The pattern of acanthosis, if present, may be helpful, as it is irregular in LP but usually regular in LS. Vertical columns of parakeratosis are recently described features of LS not seen in LP (Weyers 2013; Weyers 2015). Parakeratosis of any sort is uncommon in LP.
Table 6

Selected features of use to distinguish lichen sclerosus from lichen planus of the vulva

 

Lichen sclerosus

Lichen planus

Vaginal involvement

No

Yes

Parakeratosis

Common, may be present in vertical columns

Rare

Extravasated red blood cells

Common

Rare

Stromal hyalinization

Common

Rare

Location of necrotic keratinocytes, if present

All layers of the epithelium, clustering may be present

Basal epidermis and upper dermis, no clusters

Table 7

Selected features of use to distinguish between vesiculobullous dermatoses of the vulva

Differential diagnosis of vesiculobullous dermatoses of the vulva

Diagnosis

Location of blister

Typical findings on direct immunofluorescence

Other useful clues

Bullous pemphigoid

Subepidermal

Linear IgG and C3 along basement membrane

Prominent eosinophils

Mucous membrane pemphigoid

Subepidermal

Linear IgG and C3 along basement membrane

Significant scarring

Pemphigoid gestationis

Subepidermal

Linear C3 along basement membrane

Concurrent or recent pregnancy

Linear IgA disease

Subepidermal

Linear IgA along basement membrane

Prominent neutrophilic infiltrate along basement membrane

Pemphigus vulgaris

Suprabasal (intraepidermal)

Intercellular IgG and C3

Acantholyisis in follicular epithelium

Pemphigus foliaceous

Subcorneal (intraepidermal)

Intercellular IgG and C3

 

Pemphigus vegetans

Suprabasal (intraepidermal)

Intercellular IgG and C3

Eosinophilic microabscesses

Bullous SLE

Subepidermal

Linear IgG, IgM, IgA, and C3 along basement membrane (full house)

Other manifestations of SLE

Dermatitis herpetiformis

Subepidermal

Granular IgA at tips of papillary dermis

Fibrin in dermal papillae

With blistering, erosive LP may mimic mucous membrane pemphigoid (see section “Pemphigoid”). Mucous membrane pemphigoid can be distinguished by the identification of the characteristic subepithelial blisters and the presence of abundant eosinophils in the vesicles and in the dermis. Direct immunofluorescence studies will further confirm the diagnosis, showing linear IgG and C3 deposits, which is not a feature of LP.

A lichenoid pattern may also be seen in fixed drug eruption, Stevens–Johnson syndrome, systemic lupus erythematosus, and graft versus host disease. The presence of eosinophils in the inflammatory infiltrate in fixed drug eruption helps to distinguish it from LS and LP, and the other entities are all extremely rare on the vulva and associated with other clinical findings which should establish the diagnosis. Plasma cell vulvitis may mimic a lichenoid dermatitis to a certain extent, but does not demonstrate damage to the basal epithelium, which will aid in this distinction.

Dermal Homogenization/Sclerosus Pattern

In the dermal homogenization/sclerosus pattern, the papillary dermis is thickened by the deposition of dense hyalinized material. Lichen sclerosus is the only entity in this category in the ISSVD 2006 classification (see Table 2).

Clinical Features

Clinical findings are as described for the nonsclerotic type of LS.

Microscopic Findings
When the characteristic features of dermal homogenization and sclerosis are well-developed, the diagnosis is relatively straightforward. The epithelium is typically atrophic, and the rete ridges are lost. Basal vacuolization is common, and there may be sparse lymphocytes in the basal layer. Overlying hyperkeratosis may be present. The dermal homogenization is seen as a subepidermal band of paucicellular, amorphous pink hyaline material, often with edema (Fig. 25), believed to be derived from deposits of protein derived from leaky microvessels with or without inadequate venous and lymphatic drainage (van der Avoort et al. 2010). Beneath the hyaline layer is a band-like infiltrate of lymphocytes which may become less prominent as the lesion ages. As in LS without sclerosis, there may be extravasated red blood cells in the dermis, and melanocytes and melanophages are absent.
Fig. 25

Lichen sclerosus. The well-developed lesion shows the characteristic features of thinning of the epithelium with loss of the rete ridges, and a dense, homogenized layer beneath the epithelium. Deep to the homogenized tissue is the residual layer of chronic (lymphocytic) inflammation

Differential Diagnosis of Sclerotic Dermatoses of the Vulva

The differential diagnosis includes morphea, which is extremely rare in the vulva and in which the dermal fibrosis extends deeper into the reticular dermis, and radiation dermatitis, in which lymphocytes are rare. Occasional neoplasms of the skin may have associated dermal sclerosis, but unless the biopsy is extremely limited, the accompanying features of malignancy should be evident.

Vesicobullous Pattern

The vesicobullous dermatoses are characterized by fluid filled spaces within the epidermis or between the epidermis and the dermis, in the absence of associated acantholysis. These disorders are frequently autoimmune in nature, and immunofluorescence is a necessary tool in their evaluation. On the extragenital skin, vesicobullous lesions are often intact, tense fluid-filled blisters, but on the vulva local conditions are such that most lesions are rapidly ruptured and collapsed, and more likely to present as erosions, which may confound the clinical impression.

Pemphigoid

Clinical Features

Bullous pemphigoid, the most common of the autoimmune blistering diseases, involves the skin and, in a minority of patients, the mucous membranes. A significant number of patients have associated neurologic disease (Schiavo et al. 2013). Mucous membrane pemphigoid, formerly known as cicatricial pemphigoid, is a similar disease, but involves the mucous membranes exclusively. Both are caused by autoantibodies, sometimes developed in the context of a drug reaction, viral infection or other inducing factor, to the components of hemidesmosomes and to type VII collagen, leading to loss of adhesion between the basal epithelium and the basement membrane.

Although bullous pemphigoid is significantly more common than mucous membrane pemphigoid, vulvar involvement is more common with the latter (Moyal-Barracco and Wendling 2014). Patients are usually older women, in the sixth to seventh decades of life, presenting with erosions, erythema, and small blisters of the labia minora, majora, and perianal mucosa which heal with scarring. A positive Nikolsky phenomenon (slippage and detachment of the superficial epidermis from the underlying dermis when the examining finger is slid over the skin surface) may be observed.

Bullous pemphigoid presents with symptoms weeks to months before the eruption of blisters, which may consist of itching, erythema, or urticaria. When the bullae develop on the vulva, they rupture rapidly, leaving shallow erosions. The Nikolsky sign is absent in bullous pemphigoid.

Microscopic Findings
In both types of pemphigoid, microscopic examination shows subepidermal blister formation with the blisters containing variable numbers of eosinophils and neutrophils (Figs. 26 and 27). Bullous pemphigoid shows a mixed inflammatory cell infiltrate within the dermis consisting predominantly of eosinophils with lesser components of lymphocytes and histiocytes. Direct immunofluorescence demonstrates linear IgG and complement C3 along the basement membrane in both types of pemphigoid (Fig. 28), and serologic studies will identify the circulating autoantibodies.
Fig. 26

Bullous pemphigoid. At low power, the separation of the epidermis from the basement membrane is evident

Fig. 27

Mucous membrane pemphigoid. There is separation of the epithelium from the basement membrane, with inflammation in the dermis, but negligible inflammation within the blister itself. (Reprinted with permission from Hoang et al. 2015a)

Fig. 28

Direct immunofluorescence of bullous pemphigoid shows linear deposition of C3 along the basement membrane. (Reprinted with permission from Hoang et al. 2015a)

Clinical Course and Treatment

Bullous pemphigoid is usually a self-limited disease which regresses in months to years. Systemic corticosteroids are the principle treatment, and topical corticosteroids may be an alternative in limited disease (Ruocco et al. 2013b). Immunosuppressive drugs, such as azothiaprine, cyclophosphamide, may be used in combination with or as alternatives to steroids, and dapsone and tetracycline-nicotinamide are also effective alternatives. Intravenous immunoglobulin therapy and plasmapheresis can also be effective but are reserved for severe, refractory cases. If the condition is drug related, the offending medication should be discontinued, which in some cases will allow for complete resolution. In mucous membrane pemphigoid, scarring and fibrosis can result in significant distortion of the vulvar anatomy, similar to advanced vulvar lichen sclerosus or lichen planus, and more aggressive treatments may be required to minimize this risk.

Pemphigoid Gestationis

Pemphigoid gestationis, formerly known as herpes gestationis, is another subepidermal bullous dermatosis, with morphology similar to other forms of pemphigoid, but immunofluorescence which shows predominantly C3, with associated IgG in only a minority of cases. It occurs in approximately one in 40–50 thousand pregnancies, presenting in the second or third trimester or immediately postpartum as an intensely pruritic eruption of small vesicles. It involves the mucosal membranes in 20% of cases, (Kneisel and Hertl 2011), but involves the vulva in only 10% (Hoang et al. 2015a). Treatment is geared toward the control of symptoms and usually consists of topical corticosteroids and oral antihistamines, with addition of systemic steroids for more severe cases (Kasperkiewicz et al. 2012). Most cases resolve shortly after delivery.

Linear IgA Disease

Clinical Features

Linear IgA disease is the most common autoimmune blistering disorder in children, but may also present in adulthood, usually in patients between 20 and 40 years of age or over 60 years old. The disease commonly involves the lower abdominal, pelvic, inguinal, and genital areas, presenting as clusters of annular lesions that usually are pruritic and typically evolve over the course of 24 h into ulcerated, crusted lesions. Mucosal surfaces are involved in 50% of patients (Kneisel and Hertl 2011). In some cases, the eruption is preceded by a bacterial or viral infection (Egan and Zone 1999; Wojnarowska and Frith 1997) and other cases are drug induced, with vancomycin being one of the most commonly implicated agents (Klein and Callen 2000).

Microscopic Findings

Biopsy of an early bullous lesion reveals subepithelial vesicles that contain predominantly neutrophils, sometimes admixed with eosinophils, within the vesicular fluid. Neutrophilic microabscesses may occur within the papillary dermis and epidermis, but more often, the neutrophils are evenly distributed along the basement membrane. The diagnostic finding is the identification of a linear deposition of IgA in the basement membrane on direct immunofluorescence studies.

Clinical Course and Treatment

First-line therapy is usally dapsone or sulfapyridine, sometimes with the addition of prednisone as well, with supplementary topical treatments to prevent superinfection and speed reepithelialization. Refractory cases may be managed with erythromycin, colchicine, flucoxacillin, or intravenous immunoglobulin therapy (Kasperkiewicz et al. 2012)

Pemphigus

Pemphigus is an immunologically mediated blistering disease of the skin caused by autoantibodies directed against desmogleins (Hoang et al. 2015a). About 25% of cases are associated with other autoimmune diseases (Ruocco et al. 2013a) Many factors appear to trigger the development of the autoantibodies in individuals with a genetic predisposition, including drugs, viruses, and others (Ruocco et al. 2013a). Three forms of the disease are recognized: pemphigus vulgaris, pemphigus foliaceous, and pemphigus vegetans, all of which may involve the vulva.

Clinical Features

The vesicobullous lesions of pemphigus vulgaris may involve the skin, oral mucosa, and other mucosal surfaces. Studies have shown 22–44% of patients with pemphigus vulgaris have genital involvement (Kavala et al. 2015; Barbosa et al. 2012), and the vulva is the second most common mucosal site of involvement (Barbosa et al. 2012). In some cases, the genital area is the only site of disease (Barbosa et al. 2012). The labia majora and minora are the most common sites on the vulva (Kavala et al. 2015; Barbosa et al. 2012), and the lesion usually appears as an erosion rather than a blister, due to the location.

Pemphigus foliaceous is similar to pemphigus vulgaris, but involves only the skin, never the mucous membranes. Genital involvement is not uncommon and occurs exclusively on the keratinizing surfaces, involving either the labia minora or majora with equal frequency (Barbosa et al. 2012). Like pemphigus vulgaris, the lesions present predominantly as erosions on the vulva.

A rare variant, pemphigus vegetans, shows a predilection for the flexural areas, and a small number of cases with involvment of the vulva and groin have been reported (Zaraa et al. 2010). The lesions may present as a localized, indurated, inflamed area with oozing vesicles on keratinized skin and as erosive plaques on mucosal surfaces. Most patients have concurrent oral involvement and multifocal disease, but rare cases may involve only one site (Ruocco et al. 2015; Zaraa et al. 2010).

Microscopic Findings
In pemphigus vulgaris, there is an intraepidermal separation in the suprabasilar layer, leaving the basal keratinocytes attached to the floor of the blister lending an appearance likened to a “row of tombstones,” (Fig. 29) and there may be prominent acantholyis in the follicular epithelium (Fig. 30). In pemphigus foliaceous, the separation occurs in the granular layer of the superficial epidermal layers, leading to the development of subcorneal blisters, without associated acantholyisis of follicular epithelium. In both pemphigus vulgaris and pemphigus foliaceous, there is a perivascular and interstitial infiltrate in the dermis consisting of lymphocytes, neutrophils, and, to a lesser degree, eosinophils. Pemphigus vegetans appears similar to pemphigus vulgaris, with the added findings of eosinophilic microabscesses and verrucous epidermal hyperplasia (Fig. 31), and with eosinophils forming a more prominent component of the dermal inflammatory infiltrate (Moyal-Barracco and Wendling 2014). In all three types of pemphigus, direct immunofluorescent studies show intercellular deposition of IgG and C3.
Fig. 29

Pemphigus vulgaris. The acantholysis begins in the suprabasilar epithelium, with basal keratinocytes aligned like “tombstones” along the base of the blister. (Reprinted with permission from Hoang et al. 2015a)

Fig. 30

Pemphigus vulgaris. The acantholysis in this disease involves the follicular epithelium as well, as shown here. (Reprinted with permission from Hoang et al. 2015a)

Fig. 31

Pemphigus vegetans. In this variant of pemphigus, there is marked epidermal hyperplasia (a), with formation of eosinophilic microabscesses (b). (Reprinted with permission from Hoang et al. 2015a)

Clinical Course and Treatment

Untreated, pemphigus may spread to involve increasing amounts of the body surface and may ultimately result in death from fluid and protein loss. With current therapy, the mortality rate is between 5–10% (Ruocco et al. 2013a) and represents a combined effect of the disease and complications of the high doses of systemic glucocorticoids and other drugs used to treat it. The utility of the addition or substitution of additional drugs and treatments such as etretinate, azothiaprine, cyclophosphamide, cyclosporine, and intravenous immunoglobulin to the traditional steroid regimen is still not entirely clear but appears to be useful in reducing the risk of relapse (Atzmony et al. 2015).

Bullous Systemic Lupus Erythematosus

Bullous systemic lupus erythematosus is a very rare manifestion of lupus, seen in less than 5% of patients. Involvement of the vulva is even less common, but rare cases have been reported (Miziara et al. 2013). It develops when autoantibodies to the basement membrane and other anitigens deposit in the skin, resulting in subepidermal blisters similar to those of bullous pemphigoid. The two can be distinguished by immunofluorescence; in lupus, there is a characteristic “full house” pattern on immunofluorescence, showing deposition of IgG, IgM, IgA, and C3 at the dermo-epidermal junction.

Differential Diagnosis of Vesiculobullous Dermatoses of the Vulva

The erosions of he vesicobullous dermatoses may appear similar to the ulcerations caused by many vulvar infections, but judicious use of special stains and cultures for suspected pathogens can easily distinguish them. When intact blisters are present and can be biopsied, establishing the level of separation in the epidermis is the first step in narrowing the differential diagnosis. In pemphigoid and bullous lupus erythematosus, the separation occurs at the basement membrane, while in pemphigus the separation is intraepidermal. Immunofluorescent studies will be of use even when the vesiculobullae are ruptured and will demonstrate distinctive patterns which are usually definitive. The characteristic association with concurrent pregnancy and resolution following delivery should distinguish pemphigoid gestationis from other entities.

Dermatitis herpetiformis very rarely involves the vulva but may mimic other vesicobullous dermatosis, particularly linear IgA disease, as it may also show microabscesses in the papillary dermis. The diagnosis of dermatitis herpetiformis may be suggested by the finding of fibrin deposits in the papillary dermis as well, but it is more definitively identified by its distinctive pattern of granular IgA at the dermal papillae on direct immunofluorescence (Table 7).

The acantholytic disorders can likewise be distinguished from vesiculobullous diseases by the results of direct immunofluorescent studies, which are uniformly negative in acantholytic disorders (see section “Acantholytic Pattern”).

Acantholytic Pattern

Acantholysis occurs when there is deficient cohesion between cells due to loss of desmosomes in the epithelium. Clinically, this dyscohesion manifests as small, flaccid blisters in the epithelium, and microscopically, the cells appear disorganized and separated into clusters or individual cells surrounded by empty spaces. In acantholytic disorders, the basal layers remain attached to the basement membrane, and the disruption is confined to the suprabasal layers of epithelium.

Hailey–Hailey Disease

Clinical Features

Hailey–Hailey disease is caused by a mutation in ATP2C1 and is inherited as an autosomal dominant trait. In approximately one-third of patients, however, the mutation is sporadic, and there is no family history of the disease. The disease typically presents in the second or third decade of life. Intertriginous areas usually are involved, with symmetric distribution, but several cases in which the lesions are confined exclusively to the vulva have been reported (Wieselthier and Pincus 1993). The usual clinical presentation is recurrent clusters of vesicles that develop, rupture, and leave crusted, moist papules that later coalesce to form plaques.

Microscopic Findings
The disease is characterized by intradermal acantholysis involving at least half of the epithelium above a suprabasilar cleft, with resultant suprabasalar lacunae. Acantholytic cells that maintain their nuclear details remain attached to each other in the acantholytic space, giving a dilapidated brick-wall appearance (Fig. 32). Mild dyskeratosis in the acantholytic cells is characteristic, and rarely, corps ronds, distinctive forms of dyskeratosis with pyknotic nuclei and a clear perinuclear halo, are seen in the granular layer. Chronic inflammation in the dermis is prominent, and direct immunofluorescent studies are negative.
Fig. 32

Hailey–Hailey disease. The epithelium shows suprabasilar acantholysis, with clusters of keratinocytes maintaing cohesion within the acantholytic space

Clinical Course and Treatment

The disease runs a chronic, relapsing course. Treatment modalities include oral and topical corticosteroids and antibiotics, cyclosporine, dapsone, and methotrexate for refractory disease (Farahnik et al. 2017), but most patients fail to respond completely. In severe cases, surgery, botulinum toxin, dermabrasion, or laser ablation may be used and can result in long-term remission (Farahnik et al. 2017).

Darier Disease

Clinical Features

Darier disease is a genetic disease closely related to Hailey–Hailey and also inherited as an autosomal dominant trait, although nearly half of cases are sporadic (Takagi et al. 2016), caused by mutation in ATP2A2. Onset of disease occurs by 20 years of age, with a peak during adolescence. Factors which appear to exacerbate disease include high temperature, high humidity, excessive sweating, and mechanical irritation. It is not surprising, then, that vulvar or groin involvement is common (Moyal-Barracco and Wendling 2014). Other areas typically involved are the chest, neck, back, and ears. On clinical examination, the lesions are crusted, hyperkeratotic papules that often appear darker than the surrounding skin.

Microscopic Findings

The microscopic findings include acantholysis of the suprabasal epithelial cells in an acanthotic epidermis, resulting in clefts that extend from the basal layer through the granular layer. Columns of parakeratosis are characteristic, and dyskeratosis is prominent, with the formation of corps ronds and grains, another form of dyskeratotic cell distinguished by an elongated nucleus and scant cytoplasm without a perinuclear halo, throughout the granular layer. Dermal inflammation is usually minimal.

Clinical Course and Treatment

Like Hailey–Hailey, Darier disease is a chronic disease with frequent relapses. Treatment is aimed at controlling the symptoms and may include topical steroids or vitamin D3 ointment, oral retinoids or cyclosporine, topical antibiotics and antifungals to prevent superinfection, and avoidance of exacerbating factors. In severe cases, laser ablation may be used (Takagi et al. 2016).

Papular Acantholytic Dyskeratosis

Clinical Features

Papular acantholytic dyskeratosis, or papular genitocrural acantholysis, is a rare chronic disorder which typically presents in the second to fifth decade of life. It presents as white to skin-colored smooth papules involving the perineum, labia majora, and inguinal folds. The lesions are usually asymptomatic but may be associated with pain or itching.

Microscopic Findings

Histologic examination reveals acanthosis, hyperkeratosis, hypergranulosis, and focal parakeratosis, with suprabasal acantholysis. Dyskeratotic cells are a prominent feature, forming corps ronds and grains throughout the thickness of the epidermis. Some cases may show a superficial dermal perivascular lymphocytic infiltrate as well. The histologic appearance is similar to Hailey–Hailey disease and Darier disease, and there is some evidence of a genetic relationship with Hailey–Hailey disease as well (Pernet et al. 2012; Yu et al. 2016).

Clinical Course and Treatment

Treatment is not required if asymptomatic but may consist of topical steroids or retinoids, tacrolimus, cryotherapy, or laser therapy. Response to treatment is variable. Complete resolution is not usually achieved, but symptoms are greatly reduced (Yu et al. 2016).

Differential Diagnosis of Acantholytic Dermatoses of the Vulva

Clinical features such as family history, age of onset, and whether there is involvement of cutaneous sites outside of the groin and vulva may be useful in differentiation of the acantholytic dermatoses involving the vulva. Histologic features are also useful. The acantholysis is more marked in Hailey–Hailey disease than in Darier disease, and in papular acantholytic dyskeratosis, the acantholysis is localized rather than more diffuse as in Hailey–Hailey or Darier disease. In contrast to Darier disease and papular acantholytic dyskeratosis, there is minimal, if any, dyskeratosis and only very rare corps ronds or grains in Hailey–Hailey disease. Discrete columns of parakeratosis are seen only in Darier disease. Warty dyskeratoma is also characterized by prominent acantholyis, and may enter the differential, but unlike the acantholytic dermatoses, it is a solitary lesion. The differential diagnosis of acantholytic dermatoses of the vulva is summarized in Table 8.
Table 8

Summary of features useful to distinguish between acantholytic dermatoses of the vulva

Differential diagnosis of acantholytic dermatoses of the vulva

 

Hailey–Hailey disease

Darier disease

Papular acantholytic dyskeratosis

Age of onset

2d–3d decade

Before age 20, with peak in adolescence

2d–5th decade

Areas involved

All intertriginous areas

Chest, back, neck, ears, groin

Genital area folds

Columns of parakeratosis

No

Yes

No

Dyskeratosis

Minimal

Prominent

Prominent

Pattern of acantholysis

Diffuse

Diffuse

Localized

Degree of acantholysis

Severe

Moderate

Moderate

Granulomatous Pattern

Granulomatous inflammation is defined by the presence of clusters of epithelioid histiocytes and multinucleated giant cells with an associated inflammatory infiltrate consisting predominantly of lymphocytes. When the skin is involved, the inflammatory process involves the dermis and or subcutaneous tissue, while the epithelium is spared.

Crohn Disease

Clinical Features

Vulvar involvement by Crohn disease may occur as a direct extension of perianal disease continuous with gastrointestinal tract involvement, or, more commonly, as “metastatic” disease, distant and separate from gastrointestinal tract involvement. In most cases, concomitant gastrointestinal involvement is present, but in approximately 25% of patients, particularly in children, vulvar lesions may precede the gastrointestinal diagnosis by many years (Duan et al. 2014; Moyal-Barracco and Wendling 2014).

Four types of vulvar manifestations have been described. The most common is asymptomatic swelling of the labia minora and or majora, reported in 67% of patients in one series (Barret et al. 2013). Deep, linear, “knife-like” ulcerations are also common. Hypertrophic lesions, presumed to be related to impaired lymphatic drainage, may also develop, and may progress to form quite large acquired lymphangiomas (see section “Lymphangioma Circumscriptum”). The least common lesion is chronic suppuration or abscess. Despite the sometimes striking clinical findings, vulvar Crohn disease is typically asymptomatic. Only a minority of patients complain of symptoms, which may include pain, pruritis, discharge, dyspareunia, and dysuria (Barret et al. 2013).

Microscopic Findings

Histologic findings understandably differ according to the type of lesion, but typically include a subacute or chronic inflammatory infiltrate and epidermal ulceration in addition to caseating and noncaseating granulomata which may involve any region of the dermis. Small abscesses of neutrophils may also be present in the dermis. Hypertrophic lesions demonstrate dilation of lymphatic vessels and varying degrees of dermal fibrosis.

Clinical Course and Treatment

The clinical course is unpredictable; lesions may regress spontaneously or may stubbornly persist, requiring surgical resection to finally achieve resolution. The development of fistulas and draining sinus tracts is a common complication, particularly with involvement of the anus and rectum. In addition to the systemic therapy with steroids and immunomodulators used for the management of the intestinal disease, treatment of Crohn disease of the vulva may involve the addition of topical antibiotics and steroids to achieve a local response.

Melkersson–Rosenthal Syndrome and Granulomatous Vulvitis

Clinical Features

MelkerssonRosenthal syndrome is a poorly understood disease typically characterized by orofacial swelling, facial palsy and abnormal furrows of the tongue. Some cases may be accompanied by granulomatous cheilitis, a swelling and inflammation of the lips, or with a similar process on the vulva known as granulomatous vulvitis; only very rarely do both cheilitis and vulvitis manifest in the same patient (Sbano et al. 2007). It is hypothesized that cases of granulomatous cheilitis or vulvitis occurring in the absence of other symptoms of MelkerssonRosenthal syndrome represent formes frustes of the disease. Clinically, granulomatous vulvitis presents with painless erythema and swelling of the labia majora. Unlike Crohn disease, ulceration is very rare.

Microscopic Findings

Histologically, the most striking finding is of non-necrotizing granulomata extending deep into the dermis. The findings may be indistinguishable from Crohn disease, and clinical correlation is imperative.

Clinical Course and Treatment

There is no definitive therapy for the disorder, which runs a chronic, relapsing course. Treatment is similar to that of Crohn disease; systemic corticosteroids and immunomodulating agents alone or in combination with topical or intralesional steroids and antibiotics have all been reported to be effective in treating symptoms (Ghosh et al. 2011). As in Crohn disease, surgery may be required as a last resort for refractory cases (Ghosh et al. 2011).

Sarcoidosis

Clinical Features

Genitourinary involvement with sarcoidosis is very uncommon, and only rare cases of vulvar involvement have been reported (Pereira and Khan 2017). Patients complain of itching, and involved areas may have a papular, nodular or plaque-like appearance. Less commonly, the involved areas are ulcerated.

Microscopic Findings

Histologic examination shows florid granulomatous inflammation in the dermis beneath a mildly acanthotic and hyperkeratotic epithelium. There is minimal inflammation aside from the abundant non-necrotizing granulomata.

Clinical Course and Treatment

Treatment with topical steroids has been effective in other cutaneous sites, but therapy is not necessary for small asymptomatic skin lesions, and lesions may regress on their own in time (Pereira and Khan 2017).

Differential Diagnosis of Granulomatous Dermatoses of the Vulva

The clinical history may explain the findings, as the majority of patients will already have an established diagnosis of a granulomatous disease with systemic involvement. In the absence of such history, granulomatous response to foreign material or keratin from a ruptured epidermal inclusion cyst, a much more common finding on the vulva than granulomatous dermatoses, should be ruled out before these more unusual conditions are considered. Regardless of the clinical history, an investigation to rule out mycobacterial or fungal organisms is warranted to rule out infectious causes. Granulomatous inflammation may also be seen in pyoderma gangrenosum (see section “Pyoderma Gangrenosum”), but the presence of an associated neutrophilic inflammation, not a feature of the granulomatous dermatoses, will readily distinguish this entity. The differential diagnosis of granulomatous inflammation of the vulva is summarized in Table 9.
Table 9

Selected features of use in the diagnosis of granulomatous inflammation of the vulva

Differential diagnosis of granulomatous inflammation of the vulva

 

Infection

Foreign body reaction

Crohn disease

MelkerssonRosenthal syndrome/granulomatous vulvitis

Sarcoid

Usual type of granuloma

Necrotizing

Non-necrotizing

Necrotizing and non-necrotizing

Non-necrotizing

Non-necrotizing

Ulceration

Often

No

Often

No

Occasional

Systemic disease

Sometimes

No

Often (gastrointestinal)

Yes (orofacial)/no

Yes

Other useful features

Organisms identified on special stains or cultures

Presence of foreign material (suture, keratin), multinucleated foreign body-type giant cells

Edema, linear ulcerations

Pruritis

Vasculopathic Pattern

The disorders classified as vasculopathic in the ISSVD 2006 classification present as erosions or ulcerations which are attributed to local disruption of blood supply. Histologic examination in these conditions shows evidence of blood vessel damage in a background of widespread dermal inflammation.

Vulvar Aphthosis

Vulvar aphthosis manifests as painful, shallow, well-demarcated ulcers typically less than 5 mm in diameter with a gray-white base. The most common site is the inner aspect of the labia minora. The onset is acute, and most ulcers heal within 7–10 days. As with oral aphthosis, the etiology is unclear. Risk factors for these ulcers include stress, infections, vitamin deficiency, and family history (Huppert et al. 2006). The lesions are rarely biopsied, and the histologic features are nonspecific, but in the initial stages, a dense neutrophilic infiltrate with a leukocytoclastic vasculitis involving the superficial capillaries may be seen.

Behçet Disease

Clinical Features

Behçet disease is a multisystemic vasculitis of small and large vessels. The onset of disease is typically in the third decade of life, and it very rarely presents in childhood or inpatients over 50 years old (Yazici et al. 2010). Clinical findings may include mucosal ulcers, a variety of cutaneous lesions, arthritis, uveitis, thrombophlebitis and gastrointestinal, and central nervous system lesions. Almost all patients have recurrent oral apthous ulcers, and 50–85% have genital ulcers as well (Mat et al. 2013). Genital ulcers are more common in female patients, and involvement of the vulva alone is thought to occur as a limited form of the disease (Moyal-Barracco and Wendling 2014). The most common location of the vulvar lesions is the labium majus, followed by the labium minus. The ulcers are painful and necrotic, with a sharp border.

Microscopic Findings

Histologic findings are nonspecific. Early lesions show a neutrophilic infiltration, which evolves into a lymphoplasmacytic one. In half of patients, a lymphocytic vasculitis may be seen, but a leukocytoclastic vasculitis is rare in Behçet disease (Mat et al. 2013).

Clinical Course and Treatment

The ulcers heal in 2–4 weeks, and unlike most infectious ulcers, lesions of Behçet disease over 1 cm are likely to leave a scar (Mat et al. 2013; Yazici et al. 2010). The diagnosis is made based on the constellation of clinical findings, and tends to follow a course of repeated relapses and remissions, although in many patients, the disease resolves over time. Active disease is managed based on the systems involved. Genital ulcers are generally treated with topical steroids as needed to control symptoms. More severe disease may be treated with systemic therapies including colchicine, azathioprine, cyclosporine, interferon, and TNF-blocking agents (Yazici et al. 2010).

Plasma Cell Vulvitis (Vulvitis of Zoon)

Clinical Features

Plasma cell vulvitis is relatively rare and typically presents with a single shiney, red to orange-brown plaque, usually of the labia minora or introitus. Most lesions are associated with severe pruritus or burning pain (Virgili et al. 2015). The etiology is unknown, and trauma, viral infection, and autoimmune response have been proposed as possible triggers (Moyal-Barracco and Wendling 2014).

Microscopic Findings
Microscopic examination of early lesions may show slightly thickened epithelium with parakeratosis and a lichenoid lymphoplasmacytic infiltrate. In more advanced lesions, the epithelium is thinned, with flattening of rete ridges and lack of a granular layer or keratinized surface. Spongiosis is a common finding. There may be a neutrophilic infiltrate in the epithelium, with occasional superficial erosion, but ulceration is rare. The more prominent inflammation is in the dermis and consists predominantly, but not exclusively, of plasma cells (Fig. 33). This infiltrate is diagnostic when it consists of 50% plasma cells or more, and the diagnosis is precluded when the infiltrate is less than 25% plasma cells. When the infiltrate is more than 25% plasma cells but less than 50% plasma cells, additional features must be present which support the diagnosis. Prominent dilation of dermal blood vessels with associated intradermal red cell extravasation and hemosiderin-laden macrophages is a particularly useful supportive feature, and this finding is the rationale for its classification as a vasculopathic disorder in the ISSVD system (see Table 2).
Fig. 33

Plasma cell vulvitis. An inflammatory infiltrate composed predominantly of plasma cells is present beneath the epithelium

Clinical Course and Treatment

The clinical course is one of recurrent relapses and remissions. Perineal hygiene, supportive care, and topical and intralesional corticosteroids are the usual treatment (Yoganathan et al. 1994). Other options include etretinate (Robinson et al. 1998) and topical tacrolimus (Virgili et al. 2008). Some patients are fortunate enough to resolve spontaneously, while in others, the disease may be refractory to all treatments, and surgery may be the only option for resolution (Gurumurthy et al. 2009).

Differential Diagnosis of Vasculopathic Dermatoses of the Vulva

The ulcers of vulvar aphthosis and must be distinguished from infectious causes of ulceration, which can be achieved by the use of special stains and cultures when indicated. The perivascular plasma cell infiltrate in plasma cell vulvitis may also be suggestive of syphilis, which can be ruled out with serologic studies, and by the failure to demonstrate spirochetes by the usual techniques. Clinical features are of the most use in distinguishing apthosis from Behçet disease, as the histologic features are variable and nonspecific, but the finding of a leukocytoclastic vasculitis on biopsy favors aphthosis. A summary of the differential diagnosis of vasculopathic dermatoses of the vulva is provided in Table 10.
Table 10

Selected features of use to differentiate vasculopathic dermatoses of the vulva

Differential diagnosis of vasculopathic dermatoses of the vulva

 

Aphthous ulcers

Behcet disease

Plasma cell vulvitis

Ulcerateda

Yes

Yes

No

Leukocytoclastic vasculitis

Yes, in early lesions

No

No

Lymphocytic vasculitis

Yes

Yes

 

Prominent plasma cellsb

No

No

Yes

Mouth ulcers

Yes

Yes

No

Intradermal red cell extravasation, hemosiderin deposition

Rare

Rare

Frequent

aRule out infectious causes, especially viral

bRule out syphilis

Miscellaneous Dermatoses Lacking a Dominant Histologic Pattern

Amicrobial Pustulosis of the Folds

Amicrobial pustulosis of the folds (APF) is a rare neutrophilic dermatosis affecting predominantly young female patients. Most cases develop in patients with a previous diagnosis of some type of autoimmune disease, but cases have been reported in which which APF presented prior to the diagnosis of the autoimmune disease (Marzano et al. 2008), indicating the need for close clinical follow-up and testing of individuals without any previous diagnosis.

The onset of APF is typically sudden, and it follows a course of chronic remissions and relapses. It presents as small pustules, some but not all of which are associated with hair follicles, which may coalesce into erosive, crusting plaques. The anogenital area is always involved, as well as the inguinal or other skin folds. Despite the name, however, involvement is often not limited to the skin folds alone but may involve multiple other areas of the skin as well (Schneider et al. 2016; Wang et al. 2017).

Microscopic examination shows small pustules within the epidermis, with an associated neutrophilic infiltrate in the epidermis, dermis, and perivascular space, often accompanied by pronounced spongiosis. Cultures of closed pustules are uniformly negative, but eroded areas may become superinfected.

The differential diagnosis includes infection, pustular psoriasis, and other blistering diseases of the skin, and these disorders must be ruled out by appropriate studies and clinical correlation to establish a definitive diagnosis. Treatment options include topical and systemic steroids, cyclosporine, and dapsone. Recently, treatment with cimetidine in combination with ascorbic acid has been reported to be effective (Marzano et al. 2008).

Erythema Multiforme/Stevens–Johnson Syndrome

Erythema multiforme is an acute, self-limited hypersensitivity reaction. Vulvar involvement is not uncommon, but the disease is very rarely confined to the vulva. The instigating agent is often infection, particularly with HSV (Schofield et al. 1993) or mycoplasma (Saitoh et al. 1995). Other causes include drug reaction, pregnancy, malignancy, or radiotherapy.

Clinically, erythema multiforme presents as painful red areas that quickly evolve into blisters and culminate in painful vulvar ulcers. The histopathologic features vary according to the age of the lesion. Early lesions show nonspecific changes of dermal edema and chronic inflammation in the dermis, erythrocyte extravasation, and focal interface dermatitis. The fully developed lesion shows marked vacuolar degeneration of the basal layer and necrosis of individual keratinocytes. In the late stages of the lesion, the necrotic epidermis detaches, forming a subepidermal blister which proceeds to ulceration and subsequent reepithelialization.

Stevens–Johnson syndrome, is similar to erythema multiforme, but involves the skin more extensively, as well as the mucous membranes, particularly the oral mucosa and conjunctiva. It is also distinguished by involvment of other organ systems and an association with high fever and other systemic symptoms not seen in erythema multiforme. The most common cause of the Stevens–Johnson syndrome is drug reaction. Vulvar involvement is extremely rare with Stevens–Johnson syndrome, and the histologic findings are identical to those of erythema multiforme.

Pyoderma Gangrenosum

Pyoderma gangrenosum (PG) is a progressive necrotic and ulcerative condition of the skin which appears to be autoimmune in nature (Ahronowitz et al. 2012). Most cases involve the lower extremities, and 50% of cases occur in association with systemic disease, most commonly inflammatory bowel disease or arthritis (Dabade and Davis 2011). In these cases, the associated disease is usually diagnosed prior to the skin disease, but in some cases, the PG precedes or is part of the initial presentation (Ahronowitz et al. 2012). In 25% of cases, the disease arises in an area of recent trauma, and when the vulva is involved, it may present at the site of previous surgery or healed obstetric lacerations (Reed et al. 2013). Occasional cases involving the vulva have been reported to have no other associated disease or previous trauma (Satoh and Yamamoto 2013). Clinically, PG presents as a painful, sharply demarcated and often deep ulceration with a characteristic raised, purple, and undermined margin to the ulceration.

The microscopic findings are not specific, but biopsy is nonetheless advisable if only to rule out infectious causes of ulceration. In addition to the epithelial ulceration with a hyperkeratotic, hyperplastic margin, severe dermal inflammation consisting predominantly of neutrophils may be identified, but infectious organisms are not present in pyoderma gangrenosum. Lymphocytic vasculitis may also be seen.

Treatment of the associated autoimmune disease, if there is one, may lead to resolution of the PG as well, but the activity of the PG is frequently independent of the associated disease, necessitating specific intervention. Treatment usually consists of a combination of local wound care and topical and/or systemic steroids or immunomodulating agents. The lesions are often refractory to treatment and require a trial-and-error appraoch to management until an effective regimen is identified. Surgical treatment may be considered and can be successful, but should be used with caution in patients whose disease appears to have been induced by local trauma, as in these patients, surgery may only worsen the disease (Ahronowitz et al. 2012).

Vulvodynia

Clinical Features

The latest ISSVD consensus definition of vulvodynia is “vulvar pain of at least three months duration, without a clear identifiable cause, which may have potential associated factors” (Bornstein et al. 2016). The ISSVD classification of vulvodynia is based on the site of pain, whether it is localized or generalized, and whether it is provoked, spontaneous, or mixed. Vulvodynia may also be classified as primary, occurring with the first attempt at vaginal penetration, or secondary, developing after a period of normal functioning. The estimated prevalence in the USA is 3–7% (Xie et al. 2012), and the median age of onset is 28 years (Leclair et al. 2011).

The etiology of vulvodynia is not well understood and is likely multifactorial. Patients frequently have a history of chronic or recurrent vulvovaginal infection, with persistent pain following resolution of the infectious process. In older terminology, the disease was commonly called vestibulitis, suggesting an inflammatory etiology, and this term may still be applied in certain cases. However, it has subsequently been recognized that many cases are not associated with significant inflammation, or not solely with inflammation, and are not confined to the vestibule, in which case the term “vestibulitis” is not appropriate.

Whether or not to biopsy patients with significant pain but without visible lesions has been somewhat controversial, particularly as the histologic findings are variable and nonspecific. Currently, it is recommended to biopsy patients unresponsive to empirical therapy and with no definite cause of pain, if only to rule out subclinical infection or inflammatory disease.

Microscopic Features

Recent studies suggest certain findings may be associated with vulvodynia in the absence of other histopathologic findings. The most significant findings include increased numbers of mast cells and neural hypertrophy and hyperplasia, which are suggested to represent evidence of abnormal immune response and neuromodulation leading to abnormal sensory perception in the area (Akopians and Rapkin 2015; Hoffstetter and Shah 2015; Leclair et al. 2011; Regauer et al. 2015). Other reported findings include nonspecific lymphocytic inflammation, increased progesterone receptor expression and lymphoid tissue with germinal center formation (Tommola et al. 2015). The latter finding suggests an altered immune response may play a role in some cases, as such tissue was not found in controls. Changes to central neurologic processing of sensory stimuli in the region have also been hypothesized as an explanation for patients’ symptoms (Akopians and Rapkin 2015).

Clinical Course and Treatment

The combination of the lack of distinctive physical and histologic findings and poorly understood etiology make diagnosis and management of these patients extremely difficult. Treatments aim at symptom reduction and include sitz baths, topical emollients, topical anesthetics, topical and oral antidepressants, oral neuropathic pain medications such as gabapentin, the elimination of possible irritants and allergens, and adjunctive psychotherapy. Often a combination of these interventions is used. Spontaneous remission has been seen in some patients, but the majority does not achieve complete resolution despite multiple attempted therapies (Hofstetter and Shah 2015). Vestibulectomy is undertaken in some women with localized vestibulodynia, and short-term follow-up shows 60–85% of patients so treated experience significant relief (Hofstetter and Shah 2015).

Pigment Disorders and Benign Melanocytic Lesions

Physiologic hyperpigmentation of the vulvar skin, especially of the perineal body, perianal area and the tips of the lateral labia minora and posterior vestibule is usual in adult women. It is thought to occur as the result of hormonal influences and may be more prominent in women with naturally dark complexions. Darkening of the vulvar skin is not, therefore, in itself a cause of concern or an indication for biopsy. Hypopigmentation of the vulva is much less common, but may occur in patients with vitiligo or albinism, or sometimes as postinflammatory change (see below), conditions which rarely necessitate biopsy.

However, pigmented vulvar lesions, which will appear as well-demarcated, focal areas of discoloration are estimated to occur in 10–12% of women (Murzaku et al. 2014)), and these often do require histologic examination for diagnosis. In fact, biopsy is more frequently necessary for the evaluation of localized pigmented lesions on the vulva than for those on the extragenital skin, as the gross appearance of vulvar pigmented lesions is not as reliable an indication of the diagnosis and expected behavior as on other skin sites.

Postinflammatory Alterations in Pigmentation

Both hypo- and hyperpigmentation may occur as postinflammatory changes in healing skin. Biopsy is rarely necessary, particularly in the typical clinical setting. In areas of previous ulceration, recently healed skin will temporarily lack a normal population of melanocytes, a condition referred to as postinflammatory depigmentation, or leukoderma. This disorder is common after herpes infection, syphilitic ulceration, burns, and deep laser or cryotherapy. Histologically, the skin appears thinned and lacks the usual amount of pigment but on careful microscopic inspection, some melanin can usually be identified. Postinflammatory hyperpigmentation is a common finding, especially in patients with chronic inflammatory conditions such as lichen simplex chronicus, lichen sclerosus, and lichen planus. Histologic examination will show pigment-laden macrophages in the dermis or submucosa, as well as extracellularly (pigment incontinence), in addition to chronic changes related to the associated disorder.

Lentigo Simplex

Lentigo simplex, a benign melanocytic proliferation, may occur on the mucous membranes as well as on the skin. It is relatively common in the vulva. The lesion is typically small, 4 mm or less in diameter, flat, and uniformly pigmented. Histologically, lentigo simplex is a localized circumscribed area of slightly hyperplastic epidermis that contains an increased number of normal-appearing melanocytes along the side and tips of the elongated rete ridges associated with basilar hyperpigmentation (Fig. 34). Extreme degrees of epidermal pigmentation may be present, with numerous squamous cells exhibiting cytoplasmic melanin granules, usually in highest concentration near the epithelial–stromal junction. There may be mild acanthosis and slight clubbing of the rete ridges, and heavily pigmented melanophages may be present in the upper dermis. At times, a minimal superficial dermal inflammatory cell infiltrate is noted, but this is by no means constant.
Fig. 34

Lentigo simplex. Increased basilar pigmentation is evident, with abundant melanophages in the superficial dermis

Vulvar Melanosis

Vulvar melanosis, the most common pigmented lesion in women of reproductive age (Murzaku et al. 2014), is characterized by prominent brown to black pigmented macular areas with irregular borders that may be solitary or multiple, ranging from a few millimeters to several centimeters in size. The labia minora are the most common site of involvement (Murzaku et al. 2014), and the hair-bearing portions of the vulva are not affected. The cause is unknown; it is speculated that it may be a form of postinflammatory hyperpigmentation or a defect in melanin transport (Oliveira et al. 2011).

Grossly, the lesions cannot be reliably distinguished from melanoma, and biopsy is imperative. Histologic examination shows a normal or slightly increased number of melanocytes, but with increased dendritic processes and an increased amount of pigment within them, especially at the tips of the rete ridges. There is usually also elongation of the rete ridges and increased dermal melanophages. Unless the lesion is of significant size, a feature favoring melanosis over lentigo simplex, distinction between the two entities may be extremely difficult, both on clinical examination and histologically. The distinction lies in the fact that the melanocytes increase in number in lentigines but not in melanosis, a feature which is not always easily discernable and is somewhat subjective. Of greater import is to distinguish the lesion from melanoma, which is, fortunately, usually considerably easier, as in melanoma, there is an even greater degree of melanocytic proliferation, in addition to cellular atypia, pagetoid upward spread of the pigmented cells, and an infiltrative growth pattern, none of which should be present on melanosis or lentigo.

Common Nevi

Vulvar melanocytic nevi, like those elsewhere on the skin, may be junctional, compound, or intradermal. Clinically, nevi are usually well-defined, papular, uniformly pigmented, and typically less than 10 mm in diameter (Rock et al. 1990). They are most often found on the labia majora, labia minora, and the clitoral hood (Murzaku et al. 2014). These nevi are histologically identical to those found on the non-genital skin.

Most nevi biopsied on the vulva are either compound or intradermal in type. In pure junctional nevi, which are identified relatively infrequently on the vulva, the nevus cells are located within the epidermis and at the dermal–epidermal junction. Histologic examination shows a proliferation of nevus cells, which are somewhat larger than melanocytes and have round or ovoid nuclei. The cytoplasm may contain melanin, or appear clear without granules or fibrils. Dendrites are not present, and intercellular connections are not visible. The cells may lie singly within the dermis, but more commonly they tend to form nests. Individual cells, or cell nests, bulge downward from the tips of the rete ridges. In compound nevi, the nevus cells are located in both the epidermis and the dermis (Fig. 35). The basement membrane of the epidermis surrounding the nests disappears, and collagen and elastic fibers surround the nests, pushing the epidermis upward, accounting for the fact that the lesion is clinically elevated above the level of the surrounding skin. In intradermal nevi, the nevus cells and nests are entirely located within the the connective tissue of the dermis (Fig. 36); no activity is seen at the dermoepidermal junction.
Fig. 35

Compound nevus. Nests of nevus cells, many showing heavy pigmentation, are present at the dermo-epidermal junction and within the dermis

Fig. 36

Intradermal nevus. The nevus cell nests are completely enclosed within the dermis, with no activity at the dermo-epidermal junction

Common vulvar nevi do not demonstrate cellular atypia or architectural distortion, and show a characteristic pattern of zonal maturation, with the cells becoming more spindled and neural-like with deeper penetration into the dermis.

Melanocytic nevi in the setting of lichen sclerosus may display unusual and concerning histologic features worthy of special mention (Edwards 2010; Carlson et al. 2002). Grossly, such lesions are usually very dark and rather small. Histologically, the rete ridges tend to be elongated, with clusters of melanocytes present at the dermo-epidermal junction. Melanocytes trapped in sclerosis may show mild cytologic atypia, and focal pagetoid upward spread of the nests and individual cells, may be seen, mimicking melanoma. A lichenoid inflammatory infiltrate disrupting dermal nests and increased melanophages with pigment incontinence may also be seen, mimicking changes of regressing melanoma. Follow-up of these nevi has shown no evidence of malignant behavior, and recognition that these changes may occur in the setting of LS is important to prevent overcalling such lesions as melanoma.

Atypical Genital Nevi

Atypical genital nevi show a peculiar morphology with features in common with dysplastic nevi, but without any associated risk for developing melanoma. As the name suggests, they are an unusual pigmented lesion occurring only on the genital skin, and they have distinctive histologic features not seen in nevi in other locations. About 5% of vulvar nevi fall into this category (Murzaku et al. 2014). Patients are usually young women, with the reported median age ranging from 21 to 26 years old (Gleason et al. 2008; Ribe 2008). They occur more often on the labia minora than do common nevi, and, especially in children, are prone to develop in mucosal sites (Murzaku et al. 2014). The lesion may be concerning on clinical exam due to the large size, irregular borders, dark pigmentation, or any combination of these features.

On microscopic examination, the lesions usually have a component of a typical common intradermal nevus, which is useful in the diagnosis, but numerous unusual features are also present. The nests of nevus cells are often much larger than those of common nevi (Fig. 37). There may be marked junctional activity, sometimes with a continuous band of nests between the epidermis and the dermis, which can obscure the dermo-epidermal junction (Gleason et al. 2008; Brenn 2011). Often there is cytologic atypia. Other worrisome features, including focal pagetoid spread of single nevus cells, adnexal involvement, nests along elongated rete ridges and dense fibrosis of the papillary dermis, may be seen (Gleason et al. 2008; Ribe 2008; Murzaku et al. 2014; Brenn 2011). These lesions were once thought to be malignant and are still frequently misdiagnosed as such due to these features, but it has since become clear that these lesions are entirely benign and have virtually no risk of malignant transformation. Characteristics that help to distinguish atypical genital nevus from melanoma include the presence of dermal maturation, the sparsity of mitotic activity, and the absence of necrosis or ulceration (Murzaku et al. 2014).
Fig. 37

Atypical genital nevus. An unusually large nevus cell nest with cellular atypia is present at the dermo-epidermal junction

Dysplastic Nevi

Dysplastic melanocytic nevi are seen most often in young women of reproductive age, and may show overlapping gross and microscopic features with atypical genital nevi but are fortunately very rare on the vulva. They present as pigmented, elevated lesions greater than 0.5 cm in diameter with irregular borders. Microscopic examination reveals elongation and bridging of the rete ridges, with nests of large epithelioid or spindle-shaped nevus cells with nuclear pleomorphism and prominent nucleoli. The nests extend into adnexal structures, including hair shafts and the ducts of sweat glands. The low-power impression is frequently that of a large junctional nevus, with a dermal component that has spindle- or epithelioid-type nevus cells in nests or isolated within the papillary and reticular dermis. Lamellar fibrosis of the upper dermis is a characteristic feature. Dysplastic nevi have a variably increased risk of transformation to malignant melanoma, and patients with multiple dysplastic nevi are at higher risk for development of melanoma generally, necessitating careful, lifelong dermatologic surveillance.

Benign Squamous Proliferations

Fibroepithelial Polyp (Acrochordon)

The fibroepithelial polyp, or “skin tag,” is a relatively uncommon benign polypoid tumor of the vulva. Fibroepithelial polyp occurs on the keratinized skin of the vulva and vary in appearance from small, flesh-colored, or hyperpigmented, papillomatous growths resembling condylomata to large pedunculated tumors that often are hypopigmented. On cut section, fibroepithelial polyps are soft and fleshy. Small tumors may resemble intradermal nevi; large lesions may present cosmetic problems but generally are clinically insignificant. They usually arise in hair-bearing skin but may be found on the labia minora.

Histologically, fibroepithelial polyps may be of two types, one that is predominantly epithelial and another that is primarily stromal. The epithelial surface varies from a thickened layer with papillomatosis and hyperkeratosis to an attenuated flattened layer exhibiting multiple primary folds. The connective tissue stalk is composed of loose bundles of collagen with a moderate number of blood vessels. The stroma may be edematous and hypocellular. The stromal cells usually have relatively uniform nuclei; however, marked atypia may be seen in some cases (Carter et al. 1992). They are distinguished from condyloma by the lack of cellular atypia (Fig. 38).
Fig. 38

Fibroepithelial polyp. A fibrovascular stalk is covered by a lining of keratinized squamous epithelium showing no abnormalities of maturation or cellular atypia

Vestibular Papilloma

Vestibular papilloma presents as a small papillary lesion, usually less than 5 mm in length, with a diameter of 1–2 mm, which, unlike condyloma, does not appear white upon application of acetic acid. In contrast to a fibroepithelial polyp, vestibular papilloma typically occurs on the nonkeratinizing squamous mucosa of the vestibule and may be single or multiple. When multiple, the diagnosis is vestibular papillomatosis, a condition found in up to 33% of normal women of reproductive age (Hoang et al. 2015b). Single lesions may be asymptomatic, but vulvar papillomatosis is usually associated with pruritus, pain, and burning (Chan and Chiu 2008; Sangueza and Saenz 2007). The etiology of vestibular papillomatosis is unclear.

On microscopic examination, the squamous papilloma is composed of a delicate fibrovascular connective tissue core covered by nonkeratinized squamous epithelium, which is glycogen-rich in women of reproductive age. They may have a thin keratin layer. Inflammation is rarely present. Distinction from condyloma acuminatum is based on the lack of cellular atypia.

Seborrheic Keratosis

Seborrheic keratosis is a benign exophytic lesion of the skin. Common on the sun-exposed skin of the elderly, they are less commonly seen on the vulva, where they may occur on the hair-bearing skin of the labia majora or mons. The lesions are frequently pigmented and well-demarcated from the surrounding skin, often described as appearing to be “stuck on” the surface, giving the impression they could be easily dislodged.

On microscopic examination, there is prominent acanthosis and pronounced surface hyperkeratosis. Pigmentation, if present, is usually evident in the basal and parabasal cells. Follicular plugging with hyperkeratosis is a typical feature, as is the formation of “horn cysts,” accumulation of hyperkeratotic scale in intraepithelial spaces formed by invaginations of the surface epithelium (Fig. 39a). “Squamous eddies,” clusters of squamous cells which give the impression of swirling currents are another characteristic feature (Fig. 39b).
Fig. 39

(a) Seborrheic keratosis. The thickened epithelium shows several horn cysts. Cytologic atypia is absent. (b) A squamous “eddy” is shown at the center of this rete ridge

The papillary architecture and hyperkeratosis of seborrheic keratosis can be suggestive of condyloma, particularly at low power. In fact, as seborrheic keratoses are frequently found to contain HPV DNA (Gushi et al. 2003; Bai et al. 2003), some authors have maintained that these lesions are variants of condyloma (Li and Ackerman 1994), although this remains controversial. The absence of koilocytic atypia in seborrheic keratosis and of keratin horn cysts in condylomata will usually resolve the diagnosis. The acanthosis and irregularity of the epithelium may also suggest a squamous intraepithelial lesion, but the lack of significant nuclear atypia or mitotic activity in seborrheic keratosis should distinguish it. The lesions may be treated with topical agents, destructive treatments, or excision.

Keratoacanthoma

Keratoacanthoma presents as a rapidly growing, firm, dome-shaped lesion with central umbilication. Like seborrheic keratosis, it is common on the sun-exposed skin of the elderly, but rarely reported on the vulva (Chen and Koenig 2004; Gilbey et al. 1997; Ozcan et al. 2006; Nascimento et al. 2005). On microscopic examination, the lesions show an endophytic growth pattern, with a broad, pushing border. A collarette of epidermis surrounding a central keratin-filled crater corresponds to the central umbilication seen grossly. Towards the center of the crater, the squamous cells are larger, containing abundant amounts of eosinophilic glassy cytoplasm. During the early stage of rapid growth, there may be mild to moderate nuclear atypia, and mitotic figures may be numerous. As the lesion matures, however, these features regress, with only minimal atypia remaining in a well-developed lesion. A dense inflammatory infiltrate is usually present at the base of the lesion. Occasionally, small, irregular nests of cells may be present focally adjacent to the pushing border. Less commonly, perineural or intravascular invasion may be apparent. These features have led many to believe that keratoacanthoma may actually be a low-grade variant of squamous carcinoma (Karraa and Khachemoune 2007; Schwartz 2004; Weedon et al. 2010), but in the absence of other features, particularly on the vulva, where malignant behavior has never been reported, a more conservative interpretation is advisable.

Untreated, keratoacanthoma typically increases rapidly in size over a period of weeks to months and then may persist for months until finally undergoing spontaneous involution, usually within 6 months of eruption. Alternatively, excision may be performed and is usually curative, with rare recurrences reported.

Cysts

Epithelial Inclusion Cyst

Epithelial inclusion cysts frequently develop on the vulva. They may arise from occluded sebaceous glands that have undergone squamous metaplasia or as a complication from previous surgical intervention. They may develop anywhere on the vulva but are more common on the labia majora and clitoris. Epithelial inclusion cysts of the clitoris may be pedunculated and become quite large, with lesions measuring 8 cm or more (Al-Ojaimi and Abdulla 2012), causing them to be mistaken clinically for malignancy. Such lesions are more commonly seen as sequelae of female genital mutilation procedures, usually developing in adolescence (Asante et al. 2010; Riszk et al. 2007). It is believed that the hormonal milieu may play some role in the growth of the lesions at this time. The phenomenon is not limited to patients with a history of genital mutilation, however, as numerous similar cases have also been reported in women and girls without such a history, in patients ranging from very young children to the elderly (Anderson-Mueller et al. 2009; Cetinkursun et al. 2009; Paulus et al. 2010; Schober et al. 2014).

On gross examination, excised lesions are found to contain thick white to yellow, grumous or cheesy material. On microscopic examination, the cyst lining appears as a relatively flattened, stratified squamous epithelium lacking adnexal structures (Fig. 40). Foreign body-type giant cells may be seen in the tissue adjacent to the cyst wall, a response to keratinous material leaking into the adjacent dermis.
Fig. 40

Epidermal inclusion cyst. The lining of the cyst is thinned, and abundant kertotic debris fills the cystic cavity

Epithelial inclusion cysts are benign lesions, although rare cases of squamous carcinoma may arise in within them. Treatment of asymptomatic small cysts usually is not necessary; however, surgical excision may be necessary for diagnosis or if the cyst is enlarging, symptomatic, or secondarily infected.

Bartholin Cyst and Abscess

The estimated lifetime risk for the development of a cyst or abscess of the Bartholin gland is 2% (Marzana and Haefner 2004), with abscess being approximately three times more common than cysts (Lee et al. 2014). The lesions develop as a result of obstruction of the vestibular orifice of the Bartholin ducts, leading to subsequent accumulation of secretions and associated cystic dilation of the duct.

The normal Bartholin duct contains three types of epithelium: mucinous columnar epithelium distally, transitional epithelium centrally, and squamous epithelium towards the orifice. This accounts for the variable appearance of the epithelial lining of a Bartholin gland cyst, in which any of the three types may appear, often in combination (Fig. 41). A case of melanocytic colonization, in which melanocytes with cytoplasmic pigment were found in the cyst lining has been reported (Nigam et al. 2017), but pigmentation is not a usual finding. As in other cystic lesions, in some cases the lining may be flattened and not classifiable. If the cyst is not infected, there is minimal, if any, inflammatory response within the adjacent tissue. Secondary infection of the cyst is common, however, in which case the lesion is classified as a Bartholin gland abscess, and associated inflammation may be a prominent feature.
Fig. 41

Bartholin gland cyst. The lining of this cyst shows a mixture of mucinous, transitional and squamous epithelium, mirroring the normal structure of the Bartholin gland duct

Marsupialization, drainage, and antibiotics, if infected, are the initial treatments of choice. Lesions which are not excised may recur, necessitating additional treatment and surgical excision may be performed for definitive treatment and to preclude further recurrence.

Mucous Cyst

Mucous cysts of the vulva are most commonly seen in the vestibule or labia minora (Heller 2015). Their origin is unclear and may be different for different sites. It has been proposed that at least some lesions develop from occlusion of minor vestibular glands, but other proposed origins include Mullerian heterotopia or metaplasia, Wolffian or urogenital sinus remnants, and the Bartholin gland (Heller 2015).

The cysts are lined by a single layer of mucin-secreting cuboidal to columnar epithelium resembling endocervix. Squamous metaplasia may be present. Special stains may distinguish these cysts from those of mesonephric origin, as the epithelium stains with both Alcian blue and Mayer mucicarmine, whereas the epithelial lining of cysts of mesonephric origin does not (Newland and Fusaro 1991), although this distinction is not critical, as neither lesion is of particular clinical significance.

Excision is usually performed for diagnostic purposes or to relieve associated symptoms, and is curative.

Ciliated Cysts

Cysts lined with ciliated epithelium of tuboendometrioid type may also occur on the vulva. They are usually found in the vulvar vestibule and labia minora. Patients are typically between 25 and 35 years old and present with cysts measuring 1–3 cm (Kuniyuki et al. 2008). The proposed origin of the cysts is heterotopic Mullerian epithelium, a concept which is supported by the finding of estrogen and progesterone receptor expression in them (Kuniyuki et al. 2008). They are distinguished from endometriosis by the absence of associated endometrial stroma or hemosiderin-laden macrophages. As with mucinous cysts, excision is not necessary, unless the lesion is symptomatic, but is usually performed to establish a diagnosis.

Gartner Duct Cyst

Gartner duct cysts, presumably derived from remnants of the mesonephric (Wolffian) ducts, are encountered occasionally on the lateral aspects of the vulva and the vagina. They are thin walled, translucent, and contain clear fluid. The lining epithelium is cuboidal to columnar and is not ciliated, and they are filled with eosinophilic secretions.

Mammary-like Cysts (Hidrocystoma)

Hidrocystoma originates in the anogenital mammary-like glands and is found in the distribution of those glands, predominantly in the interlabial sulcus. It is characterized by a peripheral basal layer of myoepithelial cells and a luminal layer of cuboidal to columnar cells showing apical decapitation secretion, typical of apocrine glands. Anogenital mammary-like glands and dartos muscles may be identified in the surrounding tissue.

Cysts of the Canal of Nuck

The canal of Nuck is formed by the peritoneum of the processus vaginalis which accompanies the round ligament through the inguinal canal to its insertion in the deep vulvar tissue. Cysts of the canal of Nuck are generally found in the superior aspect of the labia majora or inguinal canal and are believed to arise from inclusions of the peritoneum at the inferior insertion of the round ligament into the labia majora. As such, they are analogous to the hydrocele of the spermatic cord. These cysts can achieve substantial size and must be distinguished from an inguinal hernia, with which they are associated in approximately one-third of cases (Schneider et al. 1994). Microscopic examination reveals a cyst lining of flattened mesothelial cells.

Skene Gland Cyst

Cysts derived from the paraurethral Skene’s glands are most common in women of reproductive age (Heller 2015). Though often asymptomatic, they may present with a sizeable mass or associated pain, discharge, dysuria or urinary obstruction. Histologically, the cysts are lined by transitional or squamous epithelium.

Benign Glandular Lesions of the Vulva

The various glands of the vulvar region may all develop hyperplastic or neoplastic mass lesions. Occasionally, also, glandular epithelium may be found to replace the squamous epithelium, producing a sharply demarcated, red velvety area (Coghill et al. 1990; Horn et al. 2014). The phenomenon is not well-understood and can lead to significant diagnostic difficulty. Most patients are postmenopausal at the time of diagnosis (Horn et al. 2014). Vaginal adenosis with extension to the vestibule may explain some cases, but lesions confined to the vestibule or other vulvar sites at the time of presentation require a different explanation. The presence of mucinous epithelium on the vulva has been reported in association with re-epithelialization following Stevens–Johnson syndrome, topical medications like 5-fluorouracil, or laser treatment, and some cases of plasma cell vulvitis (Coghill et al. 1990; Heller 2015; Marquette et al. 1985), but other patients have no history of any sort of predisposing factor. Possible explanations which have been proposed include metaplastic changes or embryonic displacement of stem cells (Horn et al. 2014). Very rarely, glandular epithelium with an intestinal phenotype, is identified on the vulva, possibly of cloacogenic origin (Horn et al. 2014), and this may be the origin of rare tubulovillous adenomas and gastro-intestinal-like carcinomas reported arising on the vulva (Vitrey et al. 2003; Fox et al. 1988).

Lesions of the Anogenital Mammary-like Glands

The presence of mammary-like tissue in the vulva was once widely held to be ectopic in nature, representing caudal remnants of the embryonic “milk-line” thought to extend from the axilla and pectoral region through the abdomen and pelvis, terminating in the vulvar region. Subsequent work has cast doubt on this theory, and it is now well-established that mammary-like tissue found in the vulva is derived from the anogenital mammary-like glands (El-Khoury et al. 2016; Kurashiga et al. 2014; Konstantinova et al. 2017a, b; van der Putte 1991; van der Putte 1994). These glands are morphologically and immunohistochemically remarkably similar to breast tissue except for the lack of a lobular architecture and a greater frequency of frequent columnar cell change and columnar cell hyperplasia. Normally, the glands are small and not clinically visible, but they are the source of a number of proliferative lesions, most often benign, which produce palpable subcutaneous masses.

By far the most common lesion of the anogenital mammary-like glands is hidradenoma papilliferum, which is also the most common benign glandular lesion of the vulva (Baker et al. 2013). Patients with hidradenoma papilliferum range in age from 25–90 years in age, with an average age of 49–52 years (Konstantinova et al. 2016; Scurry et al. 2009). The lesions are found in the distribution of the anogenital mammary-like glands, with the majority arising in the interlabial sulcus and involving the labia majora or minora. They may be cystic, solid, or pedunculated and are usually asymptomatic, although some patients may present with bleeding, pruritus, or complaints of an enlarging mass. Only rarely are the lesions painful. Grossly, the lesions present as an elevated area with a palpable subcutaneous mass, and may appear red, blue, or skin-colored (Scurry et al. 2009). All but one of the reported cases have been solitary (Konstantinova et al. 2016) and usually small, ranging in size from 1–20 mm in greatest dimension with a mean size of 6–7 mm (Konstantinova et al. 2016; Scurry et al. 2009). Rare cases may exceed 2 cm in size (Konstantinova et al. 2016).

Microscopically, there is considerable heterogeneity in the appearance of these tumors, though all invariably consist of a mixture of papillary and tubular structures (Fig. 42) The tubules and papillary structures are lined by predominantly cuboidal to columnar epithelial cells surrounded by myoepithelial cells, often reminiscent of intraductal papilloma of the breast (Fig. 43). The myoepithelial cells are most often flattened and inconspicuous and may require immunohistochemical stains such as SMA, S100, calponin, or p63 to distinguish them (Fig. 44). Less commonly, the myoepithelial cells are rounded and demonstrate clear cytoplasm. Detection of the myoepithelial cell layer, with immunohistochemical confirmation, if necessary, is critical to the diagnosis and important to distinguish it from malignant glandular entities. The appearance of the epithelial cells can be quite variable, showing a spectrum of changes analogous to fibrocystic change of the breast, but typically there is at least some part of the lesion showing the typical apocrine features of columnar cells with eosinophilic cytoplasm and prominent apical snouts. Oxyphilic (apocrine) metaplasia is very common, and less commonly the epithelium may show clear or foamy cells. Squamous metaplasia and mucinous metaplasia have also been reported but are not common findings (Konstantinova et al. 2016; Scurry et al. 2009). Architectural features are similarly variable, with areas of solid or streaming growth of the epithelium, intraluminal tufting, arching, or micropapillary formations occurring admixed with the papillary fronds and tubules. Mitoses may be seen in both the epithelial and myoepithelial cell components, and may be as high as 13 per 10 high power fields, but even such high mitotic counts have no impact on clinical behavior (Sington et al. 2006), which is always benign, with no reported cases of recurrence or metastasis.
Fig. 42

Hidradenoma papilliferum. At low magnification, the lesion is seen as a subcutaneous mass with a tubulopapillary architecture

Fig. 43

Hidradenoma papilliferum. A high-power magnification of the cells lining the tubules and papillae shows a distinct two layers; an outer myoepithelial layer and an inner layer of columnar cells with apical “snouts”

Fig. 44

Hidradenoma papilliferum. Immunohistochemical staining for p63 highlights the myoepithelial cell layer

Many other benign glandular lesions may arise in the anogenital mammary-like glands, most of which closely resemble lesions of the breast, and are termed accordingly. These include lactating adenoma, fibroadenoma, phyllodes tumor, pseudoangiomatous stromal hyperplasia, tubular adenoma, and erosive adenomatosis (Kazakov et al. 2011; Konstantinova et al. 2009; Scurry et al. 2009). Lesions diagnosed as syringocystadenoma papilliferum are presumably derived from the anogenital mammary-like glands as well (Steshenko et al. 2014).

Lesions of Sweat Gland Origin

Occasional cases of nodular hidradenoma, eccrine hidrocystoma, poroma, spiradenoma, and syringoma have also been reported on the vulva (Baker et al. 2013; Dereli et al. 2007; Kazakov et al. 2010a; Ozcan 2009; Hoang and Kazakov 2015). They may arise from the anogenital mammary-like glands or other eccrine and apocrine sweat glands in the region, and the clinical and histologic features are identical to those of cases presenting on the nonvulvar skin. Syringoma, a benign tumor of eccrine origin, is the most common of these lesions and reportedly the second most common adnexal lesion of the vulva (Baker et al. 2013). Syringoma presents as multiple papules on the labia majora, often with associated pruritis. Histologic examination reveals a small, well circumscribed lesion in the upper dermis, consisting of small solid nests and ductal structures, often with a characteristic comma or tadpole shape, embedded in a collagenous stroma (Fig. 45).
Fig. 45

Syringoma. Comma-shaped glandular structures are seen in the fibrotic dermis

Solid Lesions of Bartholin Gland Origin

The most common benign solid lesion of the Bartholin gland is nodular hyperplasia (Kazakov et al. 2007). The lesions are usually asymptomatic, but may be associated with mild pain, and present as a firm, sometimes lobulated mass measuring from 2–4 cm, which appears gray on cut sections. Histologic examination demonstrates a an irregular but not encapsulated proliferation of glandular acini composed of cuboidal or columnar cells with abundant mucin filled cytoplasm, which maintain a normal acinar-duct relationship. Nuclei are basally located and without atypia. Associated dilated ducts filled with inspissated secretions form a lesser component of the lesion.

Less common than nodular hyperplasia is the Bartholin gland adenoma. The distinction between nodular hyperplasia and adenoma of the Bartholin gland is not well-defined or uniformly accepted. In fact, the diagnosis of Bartholin gland adenoma itself is not universally accepted, and it remains a question whether such lesions are better considered as hamartomas than neoplasias (Heller and Bean 2014). Compounding the issue is the finding that one case of nodular hyperplasia of the Bartholin gland has been found to be monoclonal (Kazakov et al. 2007). The proposed distinction is that an adenoma is encapsulated, sharply circumscribed and lacks the normal acinar-duct relationship.

Rare cases of pleomorphic adenoma (mixed tumor of the vulva) have been reported arising in the Bartholin gland (Heller and Bean 2014), as have malignant tumors of salivary gland type suggesting that reports of the finding of salivary gland-like tissue in the vulva (Marwah and Bergman 1980) may also be derived from the Bartholin gland and are the source of such tumors.

Prostate-like Tissue and Solid Lesions of Skene’s Gland Origin

Prostatic-type tissue has been described in the vulva, typically as an incidental finding presenting as a lobular arrangement of glands and nests located in the superficial dermis (Kazakov et al. 2010b; Kelly et al. 2011). The tissue stains positively for markers of prostatic differentiation on immunohistochemistry. The origin of this tissue is not entirely clear, but recently “misplaced” Skene’s glands have been proposed as a possible explanation (Kelly et al. 2011). Eutopic Skene’s glands may also develop adenomomatous hyperplasia, leading to nodular masses of prostatic-type tissue in the paraurethral area (Kazakov et al. 2010b).

Adenoma of Minor Vestibular Glands

Adenoma of minor vestibular glands is a rare benign tumor. The lesions are small, ranging from 1–2 mm to 1 cm, and composed of multiple lobular clusters of small glands lined by mucin-secreting columnar epithelium. Most cases have been found incidentally in vestibulectomy specimens excised for vulvar vestibulitis (Prayson et al. 1995)

Endometriosis

Endometriosis, in which endometrial glands and stroma are present in areas outside of the endometrial cavity, is uncommon on the vulva. Most reported cases have developed in the area of a previous episiotomy (Heller 2015; Li et al. 2015). In such cases, it is presumed that the endometrial tissue became implanted in the incision at or near the time of delivery. The disease has also been reported in the areas of vulvar incisions for other procedures (Buda et al. 2008), and rare cases of spontaneous perineal endometriosis with no previous surgical therapy have been reported (Nasu et al. 2013). In one unusual case, bilateral endometriomas developed in the Bartholin glands with no history of prior intervention (Aydin et al. 2011).

Endometriosis involving the vulva, while unusual, looks no different histologically than endometriosis anywhere else, and the observation of benign-appearing endometrial glands and stroma is diagnostic. Associated fibrosis, hemosiderin-laden macrophages and lymphocytic inflammation are commonly present. Excision with a wide margin is usually curative.

Benign Lesions of Folliculo-Sebaceous Origin

Benign lesions of follicular origin are rare on the vulva and necessarily identified only on the hair-bearing skin of the labia majora and mons. Trichoepithelioma, trichofolliculoma, pilomatricoma, cylindroma, and warty dyskeratoma have all been reported on the vulva (Baker et al. 2013; Heller et al. 2009; Lora et al. 2015). Their appearance and behavior do not differ from that of such lesions identified elsewhere on the body.

Benign sebaceous lesions are even more rare on the vulva. Sebaceous glands encountered in the vulvar tissue are most likely to represent Fordyce spots; sebaceous hyperplasia is reportedly extremely rare on the vulva (Baker et al. 2013), and sebaceoma is also only rarely reported (Baker et al. 2013).

Benign Lymphovascular Lesions

Hemangiomas

Cavernous hemangiomas are the most common type of hemangioma on the vulva (Hoang and Sangueza 2015). Small capillary hemangiomas are also reported to be common on the vulva, especially in elderly patients (Heller 2015). Arteriovenous hemangiomas occur less commonly. All of these lesions present as well-circumscribed collections of blood filled vessels involving the reticular dermis (Fig. 46), morphologically identical to those occurring in other body sites.
Fig. 46

Capillary hemangioma. The dermis is filled by lobules of capillaries, while the overlying epithelium is uninvolved

Pyogenic granuloma, or lobular capillary hemangioma, although common in the vagina, is very rare on the vulva (Abreu-dos-Santos et al. 2016), and those that do arise are usually associated with pregnancy. Histologically, a thin ulcerated epidermis is noted covering a mass of granulation tissue. Capillaries are numerous, and secondary inflammatory changes frequently are found within the stroma (Fig. 47). Around the periphery of the lesion, there may be a downward growth of the epidermis producing a “collarette.” The overall architecture appears lobulated with a few thickened fibrous septae separating the vascular proliferation.
Fig. 47

Pyogenic granuloma. This hemangioma variant is characterized by inflammation in the loose connective tissue between the proliferation of capillaries

Angiokeratoma

Angiokeratoma is a variant of hemangioma quite common on the vulva. The usual site of involvement is the labia majora, where the lesion appears as a red, purple, or black, slightly elevated area. They may be solitary or multiple, and unilateral or bilateral (Nomelini et al. 2010; Yigiter et al. 2008). They are rarely symptomatic but may result in bleeding, pain or pruritus. Most patients are under 50 years of age. Their peculiar appearance often prompts excisional diagnostic biopsy, often for concern for melanoma.

Histologic examination reveals endothelial-lined and blood-filled dilated channels, separated by strands and cords of squamous epithelial cells representing downgrowth from the overlying epithelium, which is often hyperkeratotic (Fig. 48). Varying degrees of acanthosis and papillomatosis are present, along with a mild inflammatory reaction in the deep dermis.
Fig. 48

Angiokeratoma. Strands of squamous epithelium surround endothelial-lined vascular spaces containing red blood cells

Lymphangioma Circumscriptum

Almost all lesions of the lymphatic derivation on the vulva are acquired, secondary to obstructed lymphatic flow which may result from chronic inflammatory conditions, surgery, radiation treatment, trauma, infection, or obesity (Chang et al. 2016; Heller 2015; Lawrance et al. 2015; Zhu et al. 2014). Unlike in other areas of the body, acquired lymphangioma circumscriptum of the vulva tends to be markedly exophytic and hyperplastic and may grossly suggest warts or even carcinoma (Lawrance et al. 2015). The surface of the lesion is usually covered in small oozing vesicles, and secondary infection may result in ulceration, pain, and cellulitis, which may confound the underlying diagnosis.

Microscopic examination reveals dilated, tortuous thin-walled lymphatic vessels in the papillary and reticular dermis (Fig. 49). The overlying epithelium usually is unremarkable but may be eroded or hyperkeratotic.
Fig. 49

Lymphangioma. Dilated lymphatic channels are prominent in the superficial dermis

Treatment includes surgical excision, laser therapy, cryotherapy, electrocautery, or radiotherapy (Chang et al. 2016), but eradication may be difficult, especially with persistence of the underlying cause.

Miscellaneous Tumor-like Lesions

Verruciform Xanthoma

Verruciform xanthoma is an uncommon benign lesion of mucosal surfaces occasionally reported on the vulva. Clinically, the lesion may be concerning for condyloma or squamous carcinoma. In reported cases, most patients have been postmenopausal, and most have been single lesions involving the labia minora or majora, clitoris or fourchette (Fite et al. 2011; Frankel et al. 2011). Grossly the lesions present as asymptomatic, slow growing, sharply demarcated plaques with a verrucous surface and a yellowish-orange hue, with reported dimensions ranging from 2 to 20 mm (Fite et al. 2011). Most patients have had associated disorders of the vulvar epithelium, usually lichen sclerosus, but also lichen planus, Paget disease and radiodermatitis. It is hypothesized that the lesions may be a reactive condition developing in response to damage at the dermo-epidermal junction (Fite et al. 2011).

Histologically, the lesion shows acanthosis and parakeratosis of the epithelial layer, with elongated rete ridges and the diagnostic finding of collections of foamy histiocytes (xanthoma cells) in the papillary dermis. There may be a varying degree of acute or chronic inflammation in the dermis as well. The lesion does not respond to topical steroids or topical wart treatments, and may recur if incompletely removed.

Idiopathic Vulvar Calcinosis

Vulvar calcinosis is a rare benign condition which presents as firm, bilateral, subcutaneous nodules measuring 2–5 mm, involving the labia majora or fourchette, which may develop cystic change progressing to draining sinuses. Histologic examination demonstrates normal-appearing overlying epithelium with basophilic acellular superficial subcutaneous nodules measuring from less than 0.1 mm to approximately 2 mm, sometimes associated with a chronic inflammatory infiltrate, mast cells, and foreign body giant cells (Fig. 50). The acellular material stains with Von Kossa stain and contains acid mucopolysaccharides (Balfour and Vincenti 1991). The etiology is unclear; the disease has been reported in patients with abnormal calcium metabolism and without (Biswas et al. 2007; Tomazzini et al. 2008), and never with evidence of calcium deposition in other sites.
Fig. 50

Calcinosis. A well-circumscribed nodule of calcification is present in the superficial dermis

Vulvar Amyloidosis

Localized vulvar amyloidosis is extremely rare, and almost always occurs in association with a high-grade squamous intraepithelial lesion. The amyloid deposits have been found to consist mainly of cytokeratins (Quddus et al. 2014).

Benign Lesions of the Urethra

Urethral Prolapse

Prolapse of the urethral mucosa may occur at any age, but it is most common in premenarchal children and in postmenopausal women. Redundancy of the mucosa and laxity of the supporting periurethral fascia contribute to the formation of prolapse, which is aggravated by increased abdominal pressure; it may be related to relative lack of estrogen. The prolapsed urethra may present as a large red polypoid mass covered with urethral mucosa with edematous vascular submucosa, protruding from the urethra and mimicking a urethral neoplasm. Histologically, the urethral mucosa may exhibit ulceration, and the underlying connective tissue is generally filled with an inflammatory infiltrate. Vascular engorgement usually is present. Cryosurgery is an effective method of treatment (Kaufman 1994).

Urethral Caruncles

Caruncles are fleshy, friable, sessile, or polypoid masses that arise in the posterior urethra near the meatus. Most patients are postmenopausal, with an average age of 68 years, but cases have been reported in adult women of all ages (Conces et al. 2012). Caruncles often are asymptomatic but may cause bleeding or dysuria. The lesions may be quite large, up to 3 cm in size, but the average lesion is less than 1 cm (Conces et al. 2012). Superficial ulceration is present in over one-third of lesions (Conces et al. 2012).

On histologic examination, the epithelium is typically a mixture of urothelial and squamous. Invagination of the epithelium into the stroma, producing rounded nests or gland-like spaces, is a common finding, and helps to distinguish a caruncle from urethral prolapse, which is otherwise very similar on gross and microscopic appearance. The stroma contains a variable amount of chronic inflammation and may be fibrotic or edematous, containing prominent blood vessels which are frequently dilated and congested. The etiology is unknown; like prolapse, estrogen deficiency is believed to play a role. Other possible factors include irritation, trauma, and local congestion (Conces et al. 2012).

Malacoplakia of the Urethra

Malakoplakia of the urethra is a chronic granulomatous inflammatory process which presents as a polypoid mass at the urethral meatus. When the urethra is involved, it is usually as a result of spread from bladder involvement. On microscopic examination, the lesion contains foamy histiocytes, lymphocytes, granulocytes, and plasma cells. The diagnostic Michaelis–Gutmann bodies are seen within the cytoplasm of the histiocytes as inclusions having a blue-gray color. The inclusions may appear laminated or targetoid. With PAS stains, the Michaelis–Gutmann bodies usually stain pink to red. Many of the adjacent histiocytes also contain PAS-positive cytoplasmic material. Excision may be diagnostic and curative for small lesions within the urethra, although recurrences are not uncommon. Antibiotics also may be of value.

Urethral Condyloma Acuminatum

Condyloma acuminatum may involve the urethra, and the presentation may mimic urethral prolapse, caruncle, or urethral carcinoma. Urethral condyloma, however, is usually seen in women of reproductive age and is rare in postmenopausal women. It is usually associated with condyloma acuminatum of other anogenital sites, particularly the vulvar vestibule. When condylomata acuminata are present in the mid or upper urethra, patients may have associated symptoms of urethritis, but otherwise the lesions are usually asymptomatic. The histologic appearance is the same as in other locations in the lower anogenital tract.

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Authors and Affiliations

  1. 1.Department of PathologyBanner University Medical CenterTucsonUSA
  2. 2.Department of Pathology, Immunology and Laboratory MedicineBanner University Medical CenterGainesvilleUSA

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