Genital diseases in the mature woman

    Genital Diseases in the Mature Woman Natalie Matthews, Vivian Wong, Joe Brooks, George Kroumpouzos PII: DOI: Reference:

S0738-081X(17)30202-X doi: 10.1016/j.clindermatol.2017.10.012 CID 7208

To appear in:

Clinics in Dermatology

Please cite this article as: Matthews Natalie, Wong Vivian, Brooks Joe, Kroumpouzos George, Genital Diseases in the Mature Woman, Clinics in Dermatology (2017), doi: 10.1016/j.clindermatol.2017.10.012

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GENITAL DISEASES IN THE MATURE WOMAN

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Natalie Matthews, MPhil,1 Vivian Wong, MD, PhD,1 Joe Brooks, MD,2 George Kroumpouzos, MD, PhD1, 3

Affiliations: 1

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Department of Dermatology, Alpert Medical School of Brown University, Providence, RI, USA

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Arizona Vulva Clinic, AZ, USA

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Department of Dermatology, Medical School of Jundiaí, São Paulo, Brazil

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Keywords: vulvovaginal disease; vaginitis; mature; infection; tumor; management

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Word Count: 6,437 (text) / 147 (abstract) Table Count: 1

Conflicts of Interest: none declared

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Financial Disclosure: none declared

Corresponding Author:

George Kroumpouzos, MD, PhD Rhode Island Hospital 593 Eddy Street, Providence, RI 02903 Phone: 781-812-1078 Fax: 781-812-2748 Email: [email protected]

Figure Count: 9

References: 195

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ABSTRACT Vulvovaginal conditions are common in mature women. This reflects age-related changes in immunity

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and skin barrier function of vulvovaginal tissues. Vaginal atrophy is commonly complicated by dryness and inflammation which makes postmenopausal atrophic vaginitis a virtually ubiquitous condition. The

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differential of vaginitis includes inflammatory, infectious, and malignant diseases, plus drug hypersensitivity. Atrophic vaginitis is treated with estrogen replacement therapy. Vulvovaginal

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malignant melanoma occurs predominantly in postmenopausal women and carries a poor prognosis.

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Similarly, the incidence of vulvovaginal malignancies, such as squamous cell carcinoma and extramammary Paget disease, rises exponentially after 65 years of age. Early diagnosis of these malignancies is of utmost importance. Lichen sclerosus et atrophicus and vulvovaginal candidosis are

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among the most common postmenopausal vulvovaginal conditions. Lichen sclerosus et atrophicus is

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associated with significant morbidity, and its management can be challenging. The incidence of

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INTRODUCTION

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vulvovaginal candidosis increases in patients on estrogen replacement therapy.

Menopause marks a sharp decline in skin barrier function and immunity.1-6 Vulvovaginal tissues are particularly susceptible to these age-related changes.3-5, 7-11 At all stages of life, the vulva and vagina are more sensitive to a wider range of irritants and allergens than other skin sites.4, 12 These changes are heightened after menopause with tissue atrophy and immune decline.7, 13 The histologic, chemical, and immunologic changes that occur with aging increase the risks to post-menopausal women’s vulvovaginal health.1, 7, 8, 14 Vaginal atrophy, lichen sclerosus et atrophicus (LSA), and candidosis are among the most common postmenopausal vulvovaginal conditions.14-16 We review the physiologic vulvovaginal changes, tumors, inflammatory disorders, infections, and other vulvovaginal diseases that are encountered in the mature patient.

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PHYSIOLOGIC POSTMENOPAUSAL VULVOVAGINAL CHANGES

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Following menopause, the labia majora lose subcutaneous fat, and the labia minora, vestibule, and

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vaginal ruggae atrophy.6, 8, 9 The vaginal epithelium becomes pale and easily traumatized.6 At the cytologic level, estrogen-induced parakeratosis of vulvar stratum corneum is highest in the third decade

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of life but rarely seen by the eighth decade.10 Estrogen decline, along with chronologic aging,

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contributes to a decrease in lipid production and a rise in pH in the vulvovaginal skin.17-21 The decline in lipid-producing epithelial cells contributes to diminished stimulation of keratinocyte proliferation and

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slower healing after trauma.9, 12 Lipid production is further decreased by the loss of a normal calcium gradient in the skin with age, which contributes to higher levels of calcium in the stratum corneum.

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Ultimately, the lowered intercellular lipid content facilitates the entry of microbes and irritants into intracellular spaces. A rise in pH facilitated by low estrogen allows for impaired stratum corneum

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antimicrobial action and disrupts cell cohesion.12, 18, 21

Cell-mediated immunity is also diminished starting with menopause. The number of Langerhans cells in

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vulvar tissue decreases by over 50% after menopause.8, 13, 22 This decline is associated with an increased risk of infection and vulvar cancer.8, 13, 22 In addition to the decline in Langerhans cell numbers, there is a decreased response to cytokines with aging. The Langerhans cell activated cytokine response is significantly blunted in an older women.8, 9 Taken together, these changes that occur with age and a decline in estrogen allow for clinically important vulvar skin barrier compromise, decreased cellmediated immunity, microbial colonization, and microbe invasion into the vulvar epithelium.10-12,17,21

In mature patients, multiple contributing factors are common and should be considered; for example, atrophy plus irritation from pads and prolonged sitting, LSA with candidosis or a secondary bacterial

ACCEPTED MANUSCRIPT 4 infection in a diabetic.21, 23-26 Postmenopausal atrophic vulvovaginitis is a virtually universal condition.14,21 Vaginal secretions decrease, reducing lubrication and increasing coital discomfort. Thinned tissue is

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more easily irritated and may be more susceptible to infection.27 When vaginal pH rises, colonization by

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enteric organisms to the urinary tract increases, as well as Candida, thereby increasing the risk for infection.15, 21 Also, with worsening urinary continence that occurs with age, urinary ammonia can

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further increase local pH and activate fecal enzymes that may further compromise skin integrity and

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increase skin susceptibility to microbial infection.28, 29 The immunologic changes that occur after menopause7, 21 may in part contribute to the increased prevalence of LSA among mature women.14, 30

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Among the elderly, LSA is more often associated with squamous cell carcinoma (SCC).24, 31, 32 In fact, the incidence of squamous cell carcinoma in vulvar and vaginal tissues, and other vulvovaginal cancers, such

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as malignant melanoma (MM) and extramammary Paget disease (EMPD), rise exponentially after 65

MALIGNANT TUMORS

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VULVOVAGINAL TUMORS

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years of age.23, 31, 33-36

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Vulvar carcinogenesis is driven by chronic inflammatory conditions, autoimmune dysfunction, and human papilloma virus (HPV) disease. 37, 38 Half of vulvar carcinomas are related to HPV infection and the remainder may be associated with compromised Langerhans cell function.12, 21, 38 Chronic inflammation is characterized by vulvar dystrophy which is a feature of post-menopausal changes. 37 As discussed above, compromised cell-mediated immunity occurs with age and a decrease in estrogen.21 With impaired vulvovaginal immunity, the defense against HPV disease, including SCC, is weakened.7, 21, 37 With these changes that occur after menopause, it is unsurprising that greater than 60% of vulvovaginal SCCs appear after menopause.37, 39-41 The average age for vulvovaginal MM is greater than 60 years.42-44 In EMPD, the median age at diagnosis is between 60-70 years.36

ACCEPTED MANUSCRIPT 5 Malignant Melanoma MM of the female genital tract, including the vulva and vagina (Fig. 1), is rare (2-3%), occurs

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predominantly in older, postmenopausal women.45-48 The median age of vulvar MM is 66 years and for

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vaginal MM is 70 years.33, 42-44 Despite its rarity, vulvar MM is the second most common vulvar malignancy after squamous cell carcinoma and represents 3-10% of all vulvar malignancies.33, 45 The

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prognosis of vulvovaginal MM is very poor, given that there is a high risk of local progression and distant

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metastases.42, 47 Median survival for vulvar MM is 61 months with a 5-year relative survival rate of 60%.35, 49, 50 Women with vaginal MM have a median survival of 19 months and 5-year relative survival

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rate of 18%.35, 50 The worse prognosis of vulvar MMs in comparison to cutaneous MMs may be in part due to the morphologic peculiarity of vulvar skin.19, 34 The subepithelial tissues of the clitoris and labia

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lack a defined papillary dermis which differ in morphology from the rest of the skin of the body. In addition to being at higher risk of vulvovaginal MM, older women are also at increased risk for

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recurrence, with a 26% increase for each decade.33, 35 An association between hormone replacement

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therapy and MM risk or worse prognosis has not been substantiated.51

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There is relatively little that can be done in prevention of vulvovaginal MM beyond early diagnosis. Early diagnosis, particularly before nodal spread, allows for vulvar conservation and improved survival.42 MM subtypes in vulvovaginal tissue include superficial spreading, nodular, and mucosal lentiginous.46, 52 Mucosal lentiginous is the most common subtype in the vulvar region.46, 53 Any pigmented lesion, particularly one that appears to be rapidly growing, should be reported immediately. Genital MM can be pruritic, painful, ulcerate, and bleed.46, 48 Colposcopy with acetic acid may be a helpful diagnostic tool; however, any lesion that raises concern should be excised for biopsy.35 Genital MM should be differentiated from benign pigmented lesions, like lentigo simplex, vulvar melanosis, melanocytic nevi, and seborrheic keratosis. S-100 and HMB-45 immunohistochemistry are helpful tools for differentiating MM from other vulvovaginal malignancies, such as vulvar intraepithelial neoplasia, SCC, and EMPD.37

ACCEPTED MANUSCRIPT 6 Like cutaneous MM, vulvovaginal MM can be staged, using the AJCC system.37, 54, 55 While Breslow thickness has been shown to correlate with prognosis in patients with cutaneous MM, such microstaging

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does not reliably apply for the vulva and labia, which lack a well-defined papillary dermis.35 The primary

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site can also affect prognosis in patients with vulvar MM. For example, women with a central primary lesion, compared to those with a lateral lesion, are at greater risk for having groin node involvement and

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recurrence.35 For vaginal MM, only tumor size has been found to correlate with survival. Women with

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lesions smaller than 3 cm have experienced significantly better survival rates than women with lesions equal or larger in size.37, 42, 56, 57 Historically, the recommended surgical treatment for vulvar MM has

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been radical vulvectomy with bilateral inguinofemoral lymphadenectomy, regardless of lesion size, thickness, or depth of invasion; however, many investigators note that radical surgery does not improve

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the survival of patients with early disease when compared to local excision. Radical surgery can be disfiguring and is associated with severe morbidity (lymphedema, secondary disabilities). 34, 35, 46, 57

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Conservative surgery or hemivulvectomy is often preferred for localized lesions. In most cases, given the

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aggressive nature of these tumors and often late stage of diagnosis, adjuvant immunotherapy, or

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combined immunochemotherapy, is also pursued.37, 56, 57 There have been reported cases of melanoma in the cervix, uterus, and ovaries. These MMs are exceedingly rare, are essentially incurable, and carry an extremely poor prognosis. The 5-year survival rate of primary MM of the cervix uteri is only 14% despite radical tumor surgery. 49, 58 The worst prognosis belongs to MM with primary localization of the ovaries, which can present as abdominal pain and ascites.52 Squamous Cell Carcinoma SCC is the most common malignancy of the lower female genital tract and cervix.39, 41 Lower genital SCC often manifests after the fifth decade of life in women, and approximately 60 % of vulvar SCC appears

ACCEPTED MANUSCRIPT 7 after menopause, between 50 and 80 years of age.37,59 SCC often develops from one of two different mechanisms from premalignant lesions. One of these is the HPV-dependent pathway, which is more

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commonly seen in younger women (< 50 years old) usually with vulvar intraepithelial neoplasia (VIN).

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The HPV-independent pathway is seen more often in the elderly and results in differentiated VIN lesions and chronic inflammatory vulvar dystrophy or LSA.59, 60 Despite the high prevalence of LSA in the elderly,

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between 3-7% of vulvovaginal SCCs develop from it. 32 Conversely, of those who have SCC, greater than

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30% of women have also been found to have LSA. 32 When SCC does occur from preexisting LSA, it often manifests 10 years after LSA diagnosis. Although the exact carcinogenic mechanism of LSA is still

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debated, an association between LSA and SCC is well-established.59, 61 Regardless of the HPVindependent or dependent pathway, postmenopausal women are still the population at greatest risk for

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SCC.37, 59

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Lower genital SCC often presents as a vulvar lump or mass (Fig. 2). Rarely, patients present with a large, fungating mass. The lesion can be raised and may appear fleshy, ulcerated, leukoplakic, or warty. Most

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SCCs are unifocal and occur on the labia majora.37, 60 Approximately 5% of cases are multifocal, and the

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labia minora, clitoris, or perineum may be involved as primary sites.60 Very often patients will experience pruritus. Less commonly, they may present with vulvar bleeding, discharge, dysuria, and pain.62 Therapeutic options are primarily surgical. There is no evidence that radical resection and prophylactic lymphadenectomy improves the survival rate or decreases the risk of recurrence.62 The most important factor for survival is the depth of invasion.37,63 The 10-year survival rate of vulvovaginal SCC is 64.5 %, which is almost double that of MM.64, 65 Extramammary Paget Disease EMPD is a rare adenocarcinoma of apocrine gland-bearing skin.66 It accounts for 10% of all cases of Paget disease.67, 68 The prevalence of EMPD is unknown; however, it is thought to be most common in

ACCEPTED MANUSCRIPT 8 postmenopausal white women. The most common site of EMPD is the vulva, accounting for 65-80% of cases.68, 69 Of all vulvar malignancies, EMPD accounts for 2%.66, 70 EMPD manifests as erythematous to

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gray-white, sharply demarcated plaques with fine scale that are often asymptomatic (Fig. 3).69 It may be

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asymptomatic or present with various degrees of burning sensation and pruritus. EMPD may lead to the appearance of excoriations, ulcerations, and lichenification. In later stages, it may become infiltrated.66, This disease is usually multifocal with subclinical extension. The distribution of the lesion can mimic

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67, 69

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other lesions such as chronic candidal intertrigo, contact dermatitis, seborrheic dermatitis, tinea cruris, inverse psoriasis, and in situ squamous cell carcinoma.66, 69 A skin biopsy should be considered in

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patients with persistent eczematous plaques that do not respond to therapy in order to rule out EMPD.69 When diagnosed with EMPD, up to 29% of patients are found to have a co-existing internal

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malignancy.66 Genital EMPD is often associated with genitourinary carcinomas, while perianal EMPD is more frequently associated with gastrointestinal carcinomas.66 A thorough workup should be

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conducted at time of diagnosis for other underlying malignancies.

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Treatment of EMPD is surgical, requiring a 2 to 3 cm margin.71 Other therapies, including interferon

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alpha, topical fluorouracil, imiquimod, CO2 laser ablation, and photodynamic therapy, have been tried with variable success. Despite available treatment modalities, the recurrence rate is high (20 to 60%).66, 70

EMPD usually remains confined to the epidermis, but it can evolve to invasive adenocarcinoma, and

when it does, the most commonly observed sites of metastasis are to the lymph nodes and bone.66, 69 Prognosis depends on the depth of invasion. While the prognosis for primary EMPD in situ is excellent, that of invasive primary EMPD is poor. The median 10-year survival rate of EMPD with positive lymph node involvement is 20-25%.66, 69

ACCEPTED MANUSCRIPT 9 Bartholin Gland Carcinoma Bartholin gland carcinoma (BGC) is a rare tumor and accounts for <1% of all female genital malignancies,

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and <5% of all vulvar malignancies.72 The median age of occurrence is 50 years old.72, 73 Infections of the vulva and Bartholin glands are thought to predispose women to BGC, but the exact pathogenesis

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remains unknown. BGC is associated with HPV infections, particularly of the subtype 16.74 Due to the deep location of Bartholin glands and the lack of early clinical symptoms, BGC is commonly under and

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misdiagnosed. The diagnosis of BGC is dependent on histopathology. BGC histology subtypes include adenocarcinoma, squamous, adenoid cystic, keratosis gland, transitional cell, and undifferentiated

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carcinomas.72, 75 While the traditional management of BGC is surgery, clinical studies have demonstrated that multimodal therapy with chemoradiation may be a more effective strategy.75, 76 The prognosis of

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BGC is poor due to delayed treatment that results from underdiagnosis or misdiagnosis.72

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Verrucous Carcinoma (Buschke-Löwenstein Tumor)

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Verrucous carcinoma of the anogenital region, also called giant condylomata acuminata of Buschke and Löwenstein, may involve primarily the rectum, or extend to groin, perineal, penile, or vulvar areas.77

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Characteristic lesions consist of a warty plaque or cauliflower-like tumor that can ulcerate and become extremely large.78 Buschke-Löwenstein tumors have been linked to HPV-6 and less often to HPV-11 infection.79 Wide local excision is a consistently effective therapy, and skin grafts may be necessary in some cases. Chemotherapy and radiation should only be administered in nonresectable or recurrent disease cases.77, 80-82

ACCEPTED MANUSCRIPT 10 BENIGN TUMORS A variety of benign tumors, especially epidermal and vascular, can affect the vulvovaginal area.

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Epidemiologic data are scarce, but it seems that the prevalence of benign tumors increases with age.

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Common benign tumors are discussed below.

Seborrheic keratoses become more prevalent with age, particularly in individuals after their fifth decade

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of life, without any sexual predilection.83 On the vulva, seborrheic keratoses can resemble melanoma, HPV-associated VIN, and genital warts.84, 85 In fact, in one study 0.5% of vulvar seborrheic keratosis-like

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lesions were actually melanomas on biopsy; 86 therefore, it is important to biopsy any pigmented lesion that is not absolutely typical morphologically.87 Symptomatic lesions can be treated with cryotherapy,

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shave excision, or light curettage.84, 87 Epidermal inclusion cysts are commonly seen on the vulva (Fig. 4),

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and should be differentiated from other benign lesions such as vulvar lipomas. Other cysts, such as Bartholin gland cyst, Skene’s gland cyst, and hydrocele, are less often encountered. Giant fibroepithelial

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polyps (skin tags) of the vulvar area have been exceptionally reported.88 Hidradenoma papilliferum, a

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benign neoplasm of the apocrine sweat gland or anogenital mammary-like gland origin, occasionally occurs on the vulva or perineum in adult women.89 Urethral caruncle is a fleshy red protruberance that arises from the distal urethra and may represent an eversion of the urethral mucosa as a result of postmenopausal shrinkage of the surrounding vaginal epithelium. They are found almost excusively in postmenopausal women and are generally asymptomatic.28 Urethral prolapse is a rare condition that can manifest in postmenopausal white patients as round doughnut-shaped mucosa protruding from the urethral opening.90

Capillary hemangiomas (senile hemangiomas) can appear on the vulva with increasing incidence with age.91 Vulvar angiokeratomas are uncommon but may be seen in the context of radiotherapy.92

ACCEPTED MANUSCRIPT 11 Cavernous hemangiomas and venous malformations of the lower genital tract are exceedingly rare.93, 94 Acquired lymphangioma circumscriptum (LC) more commonly occurs in the vulvar region.95 It is often

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caused by trauma to the region, such as pelvic surgery or radiation.96 Inflammation and infection, such

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as from Crohn’s disease and tuberculosis, can also increase the risk for LC.97, 98 These lymphatic malformations do not communicate to the normal lymphatics.99 LC most commonly occurs on the chest,

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mouth, axillae, and tongue; rarely does it present on the vulva.99 The etiology of LC is unknown;

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however, various growth factors and their receptors have been implicated in its development.98, 99 Malignant transformation of LC is rare and is usually related to radiotherapy at corresponding sites.100

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Treatment options include surgical removal, sclerotherapy, cryotherapy, radiotherapy, pulsed dye laser

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surgery, and electrodessication.99 Recurrence is common.91

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VAGINITIS

With the natural decline in estrogen after menopause, vaginal tissue is more susceptible to irritation and

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infection.12 Interestingly, prior to the Women’s Health Initiative, when systemic estrogen replacement

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was more commonly prescribed, vaginitis was rarely diagnosed;101 now, vaginitis is considered one of the most common conditions seen among the mature female population.14 Vaginitis is characterized by vaginal pruritus, burning, and increased discharge.102 Vaginitis in the mature patient is caused by numerous and varied disease processes ranging from physiologic, like atrophic vaginitis, to infectious, like Trichomonas vaginalis. Postmenopausal women should always be screened for sexual history when they present with symptoms. Vulvar dystrophy and dysplasia can also be pruritic, as well as vulvar malignancies. Many conditions can cause vaginitis, ranging from serious malignancies and drug hypersensitivities; etiologies for vaginitis are outlined in Table 1. The differential for vaginitis should also include vulvodynia, desquamative vaginitis, and vulvar vestibulitis for symptoms of dyspareunia and vulvovaginal discomfort.101

ACCEPTED MANUSCRIPT 12 Table 1. Etiologies of vaginitis. Physiologic Inflammatory

Infectious

Immunobullous Drug Malignancies Hypersensitivity

Atrophic vaginitis

Desquamative inflammatory vaginitis

Candida vaginosis

Mucous membrane pemphigoid

Vestibulodynia/vulvar vestibulitis Erosive lichen planus

Trichomonas vaginitis Bacterial vaginitis Herpes simplex virus infection

Pemphigus vulgaris

Extramammary Paget disease

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Squamous cell carcinoma

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Pemphigus vulgaris

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Atrophic vaginitis is the most common noninfectious vaginitis.14 For establishing a diagnosis of vaginitis,

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it is prudent to obtain a thorough history of menopause, estrogen use (topical vs. systemic), vaginal fluid

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wet mount and cultures, evaluation of extragenital skin/mucosal disease, and tissue biopsy.8, 103, 104 Threshold for performing a biopsy should be low for any pigmented or ulcerated vulvar lesion. Note that

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for women on hormone therapy the presentation vaginal symptoms may vary. For example, increased

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vaginal discharge without itching or burning may merely represent improved vaginal lubrication;105 however, hormone replacement therapy can also increase the risk for candida vaginosis. Atrophic Vaginitis

Atrophic vaginitis or urogenital atrophy is a common disorder characterized by vaginal dryness and inflammation. It is encountered in 10% to 40% of all postmenopausal women.106 It is thought to be related to estrogen deficiency, which is associated with endometrial thinning, reduction of vaginal secretions, and increased vaginal pH;8 therefore, use of an antiestrogenic medication and hypoestrogenic states, such as menopause, immune disorder, chemotherapy, radiation therapy, and oophorectomy, predispose postmenopausal women to atrophic vaginitis. Symptoms and signs include

ACCEPTED MANUSCRIPT 13 vaginal dryness, pruritus, burning, dyspareunia, burning leucorrhea, yellow-whitish malodorous discharge, dysuria, and hematuria. Atrophic vaginitis increases the risk of urinary tract and vaginal

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infections. Recent literature has termed this constellation of vaginal symptoms, along with sexual

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symptoms with a lack of vaginal lubrication, sexual discomfort or pain, impaired sexual function, and urinary symptoms with recurrent infections, dysuria and urgency, as the genitourinary syndrome of

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menopause.107 The differential diagnosis includes conditions outlined in Table 1. Clinically, atrophic

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vaginitis presents as pale, shiny labial and vaginal patches with thinning and patchy erythema and petechiae. A pap smear may demonstrate immature squamous epithelial cells with enlarged nuclei

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admixed with inflammatory cells and basophilic granular debris. Round amorphous basophilic structures, known as “blue blobs,” are characteristic findings. Management for atrophic vaginitis can be

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challenging; however, symptomatic relief is an important goal. First-line therapies include vaginal moisturization and topical vaginal estrogen supplementation. Vaginal lubricants may be used during

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sexual intercourse. Engagement in sexual activity could be helpful, as it may enhance blood circulation.8

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Estrogen replacement therapy (ERT), topical or systemic, can be helpful in relieving the

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symptoms.106,108,109 While systemic ERT is no longer recommended for atrophic vaginitis symptoms in postmenopausal women,110 several additional systemic therapies have become available. In particular, selective estrogen receptor modulators, such as lasofoxifene, ospemifene, and bazedoxifene, and conjugated estrogen combinations are helpful treatments. Systemic ERT should not be provided in patients with a history of cancer. Also, systemic ERT is not recommended for treatment of atrophic vaginitis without systemic menopausal symptoms due to its suboptimal safety profile (e.g. it can worsen sexual and urinary symptoms), and lack of effectiveness in 10-15% of all atrophic vaginitis cases.

ACCEPTED MANUSCRIPT 14 Desquamative Inflammatory Vaginitis Desquamative inflammatory vaginitis (DIV) is found in both pre- and postmenopausal women.101 DIV is

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characterized by vaginal and introital erythema, and edema of the labia minora. Erosions, ulcers, and synechiae are absent. There is often irritation at the introitus, burning, dyspareunia, and yellow to

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green/grey alkaline (pH increased; i.e. > 5) vaginal discharge.6 While the etiology of DIV is unknown, there is an association between DIV and infectious vaginitis, such as Candida or bacterial vaginosis, as

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well as pelvic inflammatory disease.101 DIV is also more common among women on HRT.101 The differential diagnosis includes generalized vulvodynia, vestibulodynia, infectious vaginitis lichen planus,

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and LSA. The wet mount reveals parabasal cells, increased leukocytes, and an absence of lactobacilli, causative organism, and signs of estrogen deficiency.101 Cultures can sometimes yield S. agalactiae or E.

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coli. Treatment options include topical clindamycin cream and topical corticosteroids.101

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IMMUNOBULLOUS DISORDERS

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Mucous Membrane Pemphigoid

Anogenital disease occurs in a third of patients with mucous membrane pemphigoid (MMP). It is typically seen in elderly women, between ages 60 to 80 years, and can manifest with vulvar pain, pruritus, dysuria, atrophic scarring, and anogenital stenosis.101 The lesions present clinically as flaccid pustules or bullae on the genital skin. The disease can resemble genital erosive lichen planus and other blistering diseases, such as pemphigus vulgaris. The oral and conjunctival mucosae are often involved as well, with desquamative gingivitis and conjunctivitis, respectively. Cutaneous involvement with scarring may be observed. Confirmation of diagnosis is made via skin biopsy at the edge of a blister and immunofluorescence studies of perilesional normal skin. The disease typically runs a chronic debilitating course. Sexual and urinary complications are common, and treatment is often challenging.

ACCEPTED MANUSCRIPT 15 Pharmacologic treatment is generally the same as in extragenital disease.101 Local care of the vagina, including estrogen replacement, use of vaginal dilators to prevent adhesions, and a high index of

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secondary yeast infections with flares, is extremely important.101 Pemphigus Vulgaris

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Pemphigus vulgaris of vulvovaginal tissue often precedes widespread disease.101 It should be differentiated from cicatricial pemphigoid and lichen planus of vulvovaginal tissues. Routine biopsy from

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the edge of an erosion or blister and direct immunofluorescence on perilesional skin confirm the

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diagnosis. Local care of the vagina in patients with pemphigus vulgaris includes estrogen replacement, when appropriate, use of dilators to prevent synechiae, and evaluation for infections while on

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immunosuppressive therapy.101 Systemic pharmacologic treatment is largely similar to that of

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oropharyngeal disease.Topical steroids can be used for mild vulvovaginal disease.101

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Plasma Cell Mucositis

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INFLAMMATORY DISORDERS

Plasma cell mucositis, or Zoon vulvitis, affects the vulva and rarely the vagina. Its etiology is unknown. This condition is most commonly reported in premenopausal women, but the postmenopausal population is often affected, as well.111 Clinically, it presents as well-demarcated bright red smooth, shiny, moist, friable papules, and plaques (Fig. 5). The lesions may be asymptomatic or associated with pain, pruritus, burning, dyspareunia, and dysuria.112, 113 Differential diagnosis includes lichen planus, pemphigus vulgaris, fixed drug eruption, Paget disease, SCC, herpes simplex virus infection, and venereal infections, such as chancroid, lymphogranuloma venereum, and syphilis. Skin biopsy is key to diagnosis, revealing dermal lichenoid polyclonal lymphoplasmacytic inflammation. This benign condition may run a

ACCEPTED MANUSCRIPT 16 chronic course with relapses. Vegetative and nodular lesions may suggest a poor prognosis. Topical corticosteroids and calcineurin inhibitors have been tried with variable success.114-116 Surgical excision

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may be attempted for recalcitrant cases.112

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Aphthae

Genital aphthae can present on the labia minora (Fig. 6), and less commonly, on the vagina and cervix.117

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Their prevalence is unknown. They are idiopathic in approximately 90% of cases. Patients with recurrent

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aphthous stomatitis may also develop genital aphthae. Genital aphthae are painful crater-like ulcers on the genital mucosa. They are often debilitating, with the larger ones having a potential for scarring.

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Simple aphthosis, with few minor aphthae of the genital mucosa, may prompt no further diagnostic workup; however, sudden onset of numerous aphthae could be secondary to medication use, infections,

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such Epstein Barr Virus, neoplasms, and nutritional deficiencies.117, 118 Aphthous lesions may involve the genital region in conditions including reactive nonsexually related acute genital ulcers, complex

A thorough clinical history and physical examination should be obtained, and appropriate laboratory

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119

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aphthosis, inflammatory bowel disease, myeloproliferative disease syndromes, and Behçet disease.117,

studies should be performed. Treatment is symptomatic, with topical anesthetics, sucralfate and

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corticosteroids being first-line treatment. Recurrent cases typically improve in terms of frequency and severity of episodes with age. Lichen Sclerosus et Atrophicus LSA is a chronic progressive inflammatory disease with a predilection for the anogenital area (80% of cases), but it can occur anywhere on the body (20% of cases).120, 121 This disease increases in incidence after menopause and is most common in women between the fifth to sixth decade of life.30 The incidence is estimated at approximately 14 per 100 000 per annum in women between 50 to 59 years of age.30 No racial predilection is known. The lesions typically involve the vulva region and present as

ACCEPTED MANUSCRIPT 17 atrophic and sclerotic ivory-white plaques (Fig. 7) associated with pruritus, dysuria, and dyspareunia. Vulvar LSA is very rare but has been described.120 Other cutaneous findings include telangiectasias,

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hemorrhagic blisters, erosions, and fissures and have rarely been described developing in the

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background of genital telangiectasias, hemorrhagic bullae, erosions, and ulcers. Lesions may koebnerize.122 While there are no systemic manifestations, the lesions can be extremely debilitating.

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Chronic scarring can lead to functional and sexual impairment as fusion of the labia minor and clitoris

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may occur.

A skin biopsy is essential to diagnosis and shows epidermal atrophy, hydropic basal degeneration, and

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upper papillary dermal pallor with a band of lymphocytic infiltrates.121 Up to 34% of patients have concomitant autoimmune diseases, including vitiligo, alopecia areata, diabetes mellitus, thyroid disease,

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pernicious anemia, and MMP. There can also be an association with LSA. High-grade VIN can occur in

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areas affected by LSA, and can progress into squamous cell carcinoma in 4-5 % of cases.123 Malignant transformation (Fig. 2) is more common in older patients and those with histopathology of epithelial

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hyperplasia.124, 125 Treatment includes high potency topical steroids and pruritus control.126-129 Surgical

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excision may be performed in recalcitrant cases.130 Other therapies, including topical calcineurin inhibitors, systemic androgens, retinoids, photodynamic therapy, laser, systemic immunosuppressants, and biologics have been tried with variable success and side effect profiles.30, 122, 127, 131 Surgical excision may be attempted as a last resort.132 Lichen Simplex Chronicus Lichen simplex chronicus (LSC) is a vicious cycle of intense pruritus necessitating persistent rubbing/scratching that leads to skin thickening (lichenification).133 It is considered an end-stage of the itch-scratch cycle of vulvar dermatitis.134 While it can occur at any age, it is more common in prepubertal children and postmenopausal women (5 to 15 % of all cases).124, 127 Clinically, there is

ACCEPTED MANUSCRIPT 18 lichenification of the labia, perianal area, mons pubis, and upper part of the inner aspect of the thighs skin with erosions and fissuring.22, 135 It is usually more pronounced on one side due to scratching with

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the dominant hand. A skin biopsy can help to make the diagnosis.136 Treatment involves elimination of

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potential irritants and use of topical steroid preparations. Oral or intralesional steroids may be needed for refractory cases.137 Anti-itch medications may help. Breaking of the itch-scratch cycle, e.g. via

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behavioral modification, is key.133 Concomitant infection and contact dermatitis should be treated

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accordingly. Surgical excision is considered as a last resort. Regular follow up is recommended, as there is a 3% to 5 % lifetime risk of vulvar carcinoma development.137

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Contact Dermatitis

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The prevalence of contact dermatitis in women peaks at 10 - 20 and 40 - 50 years of age.138, 139 The vulvar skin is particularly susceptible to contact dermatitis compared with other body sites due to

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impaired barrier function.134, 138 Hypoestrogenic states are associated with a higher risk for vulvar

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dermatitis due to concurrent atrophic vaginitis.140 Concurrent urinary and/or fecal incontinence in mature women adds to the risk for vulvar contact dermatitis. Urine can act as an irritant or increase

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vulvar moisture and thereby enhance penetration of hydrophilic irritants into the skin.28 Additional risk factors include occlusion, malnutrition, and concomitant skin infection.139 Irritant vulvar contact dermatitis is more common than its allergic counterpart.139 Patients present with vulvar irritation and well-demarcated edematous papules and vesicles, which can erode and ulcerate.141 Patients often experience pain and burning. Common culprits include soap, adult or baby wipes, metals, antiseptics, toilet paper, condoms, lubricants, vaginal creams, dyes, emollients, laundry detergents, condoms and other rubber products, topical anesthetics, topical antibiotics, topical medications, and diapers.140, 142-147 Patch testing may be performed to identify a potential allergen.146 It is important to exclude other inflammatory conditions, such as atopic dermatitis, and neoplastic

ACCEPTED MANUSCRIPT 19 diseases, such as EMPD.134, 148 Resolution of contact dermatitis is accomplished via complete avoidance of the irritant or allergen.

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Intertrigo

Intertrigo is often seen in the mature women due to inability to maintain adequate hygiene.28 Erythema

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and excessive moisture can be noted in the genitocrural folds, labia, perineum and lower abdominal folds. Keeping the areas dry and maintaining adequate hygiene usually result in resolution of the

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condition.28

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Hidradenitis Suppurativa

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Hidradenitis suppurativa typically occurs in early adulthood with a gradual decline in prevalence, but mature women can be affected as well. The prevalence in women decreases from 4.53 % in their 30’s to

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0.75% in their 70’s.149 Co-morbidities include, among others smoking, hyperandrogenism, metabolic syndrome and its components, mood disorder, depression, and other inflammatory conditions, including

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Crohn’s disease, SAPHO syndrome, pyoderma gangrenosum, and Behçet disease.150, 151 Clinically,

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hidradenitis suppurativa is characterized by chronic inflammatory comedones, nodules, and cysts, and at later stages, deep-seated abscesses, sinus tracts, ulceration, and scarring. There is a predilection for the intertriginous skin, especially the genitalia, groin, and buttocks. Hidradenitis suppurativa is associated with significant morbidity, as it can lead to significant pain and psychosocial burden.150, 152 There is a significant risk of non-healing wounds and skin cancer development.153 Psoriasis While genital psoriasis represents 4 % of all psoriasis cases, little is known about the incidence as well as the age distribution of genital psoriasis.154, 155 Anecdotal reports suggest that it is more common in prepubertal and postmenopausal women.155 Clinically, it presents as sharply demarcated erythematous

ACCEPTED MANUSCRIPT 20 scaly plaques with scales on the mons pubis, inguinal folds, perianal region, and vulva. As the hairbearing areas are favored, the labia minora are unaffected.154, 156 Silver scales classic for cutaneous

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lesions are typically not conspicuous in the genital counterparts. Patients complain of vulvodynia,

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burning, and dyspareunia.157 The differential diagnosis includes tinea cruris and erythrasma. Treatment with a high potency topical steroid may be attempted. Vitamin D analogs and coal tar products are

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typically too irritating for the anogenital region. Immunomodulators and biologics may be tried,

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especially when there is widespread disease or arthritic symptoms.155

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Lichen Planus

The prevalence for genital lichen planus (LP) is unknown. Genital LP can occur in the setting of

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generalized cutaneous disease, erosive disease, hypertrophic disease, and lichen planopilaris.158 Mucosal disease is typically more persistent than cutaneous disease.137 Fifty percent of women with cutaneous

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involvement have genital disease.159 Approximately 25 % of women, who have oral mucosa-limited

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disease, also have genital involvement.22 Erosive vulvovaginal LP is the most common subtype and may cause significant ulcerations with vaginal adhesions and scarring.160 Hypertrophic and lichen planopilaris

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with genital involvement are the rarest subtypes of genital LP. Symptoms and signs in genital LP include itch, pain, burning, dyspareunia, and post-coital bleeding.161 The vulval-vaginal-gingival syndrome of LP (syndrome of Hewitt and Pelisse) is characterized by desquamative gingivitis and erosive vulvovaginal disease.159, 162 Esophageal involvement may occur, as well 160. Clinically, vulvar LP presents as edematous violaceous or erythematous plaques with erosions (Fig. 8) with a white reticulate border (analogous to the Wickham’s striae noted in oral LP) on hair-bearing areas of the groin and the inner aspects of the vulva and vagina.159, 163 Differential diagnosis includes Stevens-Johnson syndrome/toxic epidermal necrosis, erythema multiforme, and MMP. Diagnosis may be made clinically and confirmed with biopsy. Treatment is with topical steroid or topical calcineurin inhibitor preparations.137, 158 Systemic

ACCEPTED MANUSCRIPT 21 corticosteroid and immunomodulators may be needed for severe disease.162, 164, 165 Surgery may be necessary to treat vaginal adhesions and correct vestibular anatomy.22, 165 Vaginal LP often carries a

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chronic course, and patients should be counseled appropriately.159, 166 Therapies targeted at pain

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management and improvement of sexual function are helpful.101 Because scarring can occur, the

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patient should be monitored for potential development of malignancy.137, 161, 167 Behçet Disease

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Behçet disease is most commonly diagnosed between the second and fourth decade of life.168 It is a

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multisystem neutrophilic vasculitic syndrome with recurrent mucosal ulcerations, ocular disease, and polymorphous cutaneous lesions.169 Recurrent genital and oral aphthae are the most common

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manifestations in mature women. Additional manifestations include erythema nodosum and papulopustular lesions.169, 170 Systemic complications include vision-threatening uveitis, deep vein

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thrombosis, and cerebrovascular accidents. 169, 170, 171 Immunosuppressive therapies are utilized for

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Crohn’s Disease

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moderate to severe disease.172

Crohn’s disease (CD) rarely affects vulvovaginal tissue.173 While prevalence is slightly higher in premenopausal women, cases of CD in genital tissue have been reported in women as old as 64 years of age.173 CD more often occurs in vuvlovaginal tissue from metastatic spread. Gastrointestinal symptoms are absent in 25% of cases.173 It commonly presents with erythema, pruritus, edema, and ulcerations, and lesions can be biopsied for diagnosis. Treatment is largely medical; surgery is reserved for significant disfigurement.173

INFECTIONS

ACCEPTED MANUSCRIPT 22 Candida Vulvovaginosis Candida vulvovaginosis (Fig. 9) is a common infection; most women have at least one lifetime episode.174, Fifteen to 30% of infected hosts are asymptomatic carriers.176 Postmenopausal women may be

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175

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infected with different strains of Candida species from younger women.175 The condition typically decreases in incidence with age (33%).177 Susceptibility increases with estrogen replacement therapy,

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copper-containing intrauterine devices, chronic antibiotic therapy, incontinence, and

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immunosuppression.139

Patients often report pruritus, burning, and irritation, which can be more pronounced in the

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postmenopausal atrophic vaginal mucosa.174 LSC can complicate the infection. Candidosis can be sexually transmitted and is often associated with recurrent infections. Diagnosis can be made when

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either a wet preparation (saline, 10% KOH) or Gram stain of vaginal discharge demonstrates budding

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yeasts, hyphae, or pseudohyphae. If clinical suspicion is high and potassium hydroxide preparation negative, a fungal culture may be sent. Topical or vaginal polyene or imidazole anti-fungals are curative

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in healthy individuals. Oral therapy with a single dose of fluconazole 150 mg daily may be prescribed

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instead.178 For immunocompromised or recalcitrant disease, fluconazole 50 mg to 100 mg daily for 14 days is indicated.174, 179 It is important to discuss proper genital hygiene and potential sexual transmission in recurrent diseases. A prolonged course of antifungal therapy is necessary. Treatment of the sexual partner may be warranted. Other Fungal Infections Dermatophytoses are more prevalent in the elderly than in non-elderly.180 It is estimated that up to 60% of individuals over 65 years of age have onychomycosis or tinea pedis.180 Tinea cruris can spread to the hair-bearing labia majora and surrounding skin. Predisposing factors include obesity and diabetes mellitus.181, 182 Tinea cruris presents as erythematous scaly plaques and, along with candidosis, psoriasis

ACCEPTED MANUSCRIPT 23 inversa, and erythrasma, should be included in the differential diagnosis of vulvar pruritus.180 Deep fungal infections of the vulvar areas, such as kerion and Majochi’s granuloma183, 184 secondary to

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Trichophyton mentagrophytes, have been exceptionally reported.185 Herpes Simplex Virus Infection

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Herpes simplex virus (HSV) infection is the most common cause of vulvar ulcers.186 Asymptomatic viral shedding is the most common mode of transmission. Transmission can also occur via autoinoculation

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from herpes labialis. Genital HSV infection is most commonly found in patients between 13 to 40 years

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of age.187 Its prevalence in the mature female is unknown.186, 187 HSV manifests as grouped eroded macules and papules with vesicles, pustules, and ulcers on the external genitalia, perianal region, and

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buttocks, and upper portion of the thighs. HSV infection in immunocompromised patients may resemble condylomata, fissures, excoriations, and eroded vegetative plaques.186 Stress, such as hospitalization

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and severe illness, can trigger an HSV outbreak. Diagnosis is confirmed via polymerase chain reaction or

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viral culture of active lesions.187 Given that older patients are at greater risk for complications from the infection,7 it is important to include HSV infection in the differential diagnosis for anogenital ulcers and

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perform the appropriate diagnostic testing and treatment promptly. Differential diagnosis include aphthae, candidosis, sexually transmitted diseases (STD) such as lymphogranuloma venereum, syphilis, HIV, Epstein Barr-associated ulcers, bullous dermatoses, and malignancies.186 One should consider STD screening for the patient and any sexual partner. Symptomatic episodes are treated with acyclovir, valacyclovir, or famciclovir. Daily suppressive antiviral therapy is recommended to decrease viral shedding and disease recurrence.187 Erythrasma This superficial cutaneous infection is caused by Corynebacterium minutissimum.188-190 Inguinal erythrasma is more common in the elderly, obese, and diabetics, particularly in warm humid

ACCEPTED MANUSCRIPT 24 environments.190 It presents as red-brown patches or thin plaques with scale distributed in the inguinal, intergluteal, interdigital, or submammary folds. It can exceptionally affect the vulva. Differential

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diagnosis includes psoriasis inversa, dermatophytosis, and candidiosis. The diagnosis is supported by

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coral pink fluorescence under Wood’s lamp examination. Culture of skin scrapings corroborates the diagnosis. Topical macrolides such as erythromycin, or topical imidazoles are commonly used for

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treatment. More extensive infections may require oral erythromycin.188-190

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Scabies

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Close quarters in elderly living facilities and reduced cognitive capacity contribute to the increased prevalence of scabies among geriatric populations.191-193 There is no gender difference in incidence.192

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The classic clinical presentation includes burrows, erythematous papules and severe generalized pruritus that is typically worse at night; however, the clinical manifestations may be blurred in the

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elderly, giving rise to scabies incognito.193 Burrows can be noted in finger webs, on flexural aspect of the

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wrist, elbows or armpits, genitals or breasts.188, 194-196 In elderly individuals, burrows may be found on the head and neck and can manifest as vesicles, pustules or nodules.188, 196 Scabies can present similarly to

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other pruritic eruptions, such as dermatitis, impetigo, tinea corporis, and psoriasis. The diagnosis can be confirmed by microscopic evidence of mites, eggs, or fecal pellets and corroborated by biopsy.192 Permethrin 5% cream or lotion is first-line treatment.192,194 Alternatively, treatment with one or two doses of oral ivermectin (200 μg/kg/dose) one week apart is effective in managing institutional or community outbreaks, and provides rapid reduction of scabies symptoms.194 In addition to treatment, preventative measures are important, especially in nursing homes.193

CONCLUSIONS Physiologic, age-related changes increase a mature woman’s risk for the development of vulvovaginal disease. Vulvovaginal disease is common in the mature population. Atrophy, lichen sclerosus et

ACCEPTED MANUSCRIPT 25 atrophicus, and candidosis are among the most common postmenopausal vulvovaginal conditions. Dermatologists possess the necessary skills to effectively diagnose and treat vulvovaginal disease.

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Health care providers should consider that older women may be reluctant to mention vulvovaginal

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symptoms and, therefore, seek assistance when appropriate. When possible, vulvovaginal examination should be considered in a routine physical evaluation, which may help diagnose these conditions early

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and treat them effectively.

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36. Parker LP, Parker JR, Bodurka-Bevers D, et al. Paget's disease of the vulva: pathology, pattern of involvement, and prognosis. Gynecol Oncol. 2000; 77:183-189.

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surgery for VIN 2/3. Eur Rev Med Pharmacol Sci. 2014; 18:2949-2952. 40. Tristram A, Hurt CN, Madden T, et al. Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT(3)VIN): a multicentre, open-label, randomised,

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phase 2 trial. Lancet Oncol. 2014; 15:1361-1368. 41. Akhtar-Danesh N, Elit L, Lytwyn A. Trends in incidence and survival of women with invasive vulvar

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42. Tcheung WJ, Selim MA, Herndon JE, 2nd, et al. Clinicopathologic study of 85 cases of melanoma of the female genitalia. J Am Acad Dermatol. 2012; 67:598-605. 43. Baderca F, Cojocaru S, Lazar E, et al. Amelanotic vulvar melanoma: case report and review of the literature. Rom J Morphol Embryol. 2008; 49:219-228. 44. Sanchez A, Rodriguez D, Allard CB, et al. Primary genitourinary melanoma: Epidemiology and disease-specific survival in a large population-based cohort. Urol Oncol. 2016; 34:166 e167-114. 45. Irvin WP, Jr., Legallo RL, Stoler MH, et al. Vulvar melanoma: a retrospective analysis and literature review. Gynecol Oncol. 2001; 83:457-465. 46. Gungor T, Altinkaya SO, Ozat M, et al. Primary malignant melanoma of the female genital tract. Taiwan J Obstet Gynecol. 2009; 48:169-175. 47. Murzaku EC, Penn LA, Hale CS, et al. Vulvar nevi, melanosis, and melanoma: an epidemiologic, clinical, and histopathologic review. J Am Acad Dermatol. 2014; 71:1241-1249.

ACCEPTED MANUSCRIPT 29 48. Baiocchi G, Duprat JP, Neves RI, et al. Vulvar melanoma: report on eleven cases and review of the literature. Sao Paulo Med J. 2010; 128:38-41. 49. Ferraioli D, Lamblin G, Mathevet P, et al. Genital melanoma: prognosis factors and treatment

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modality. Arch Gynecol Obstet. 2016; 294:1037-1045.

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ACCEPTED MANUSCRIPT 30 64. Homesley HD, Bundy BN, Sedlis A, et al. Assessment of current International Federation of Gynecology and Obstetrics staging of vulvar carcinoma relative to prognostic factors for survival (a Gynecologic Oncology Group study). Am J Obstet Gynecol. 1991; 164:997-1003; discussion 1003-

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Figure 1. Nodular melanoma on the left labium minorum.

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FIGURE LEGENDS

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Figure 2. Squamous cell carcinoma on the labium minorum developed on the grounds of lichen sclerosus et atrophicus.

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Figure 3. Extramammary Paget disease: well-demarcated erythematous plaque on the vulva. Figure 4. Epidermal inclusion cysts in a chain distribution on the labium majorum.

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Figure 5. Plasma cell mucositis of the vulva manifesting as a well-demarcated bright red smooth, shiny, moist plaque.

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Figure 6. Aphthous ulcer of the vulva: a painful oval ulcer covered by a yellow-white fibromembranous slough.

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Figure 7. Lichen sclerosus et atrophicus: atrophic and sclerotic ivory-white plaques and telangiectasias on the vulva.

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Figure 8. Lichen planus: edematous violaceous or erythematous plaques with a white reticulate border and erosions on the vulva. Figure 9. Vulvovaginal candidosis: white-cheesy, thick odorless discharge, vulvar hyperemia and edema.

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Figure 9