Diagnosis and management of vulvar cancer: A review AndreaTan,BS,AmyK.Bieber,MD,JenniferA.Stein,MD,PhD,andMiriamK.Pomeranz,MD New York, New York Vulvar malignancies represent a serious gynecologic health concern, especially given the increasing incidence over the past several decades. Squamous cell carcinoma and melanoma are common subtypes, although other neoplasms, such as basal cell carcinoma and Paget disease of the vulva, might be seen. Many vulvar cancers are initially misdiagnosed as inflammatory conditions, delaying diagnosis and worsening prognosis. It is essential that dermatologists are familiar with characteristic findings for each malignancy to ensure appropriate diagnosis and management. Herein, we review the unique epidemiologic and clinical characteristics of each major vulvar malignancy, as well as discuss their respective prognoses and current management recommendations. ( J Am Acad Dermatol 2019;81:1387-96.) Key words: basal cell carcinoma; melanoma; Paget disease; squamous cell carcinoma; vulva; vulvar cancer. ver the past few decades, the overall subdivided into 2 categories. Usual-type VIN was O incidence of vulvar cancer has increased associated with human papillomavirus (HPV) and by an average of 4.6% every 5 years; vulvar observed mostly in younger women, and differenti- cancer caused 1200 deaths in 2018, and 6190 new ated VIN (dVIN) was HPV-independent and pre- cases are estimated to occur every year.1,2 Although dominantly seen after menopause.5,6 historically vulvar cancer peaks during the 7th In 2015, the terminology was modified to be decade of life, recent trends have been largely driven consistent with other HPV-associated lesions of the by increasing incidence of vulvar squamous cell lower genital tract.7 Under the current classification, carcinoma (SCC) in younger women.3,4 HPV-associated precursors (formerly usual-type SCC is by far the most common vulvar malig- VIN) are called vulvar high-grade squamous intra- nancy, followed by melanoma.3 Less commonly epithelial lesions (HSILs), and non-HPVeassociated seen vulvar neoplasms include basal cell carcinoma precursors remain designated dVIN. Flat lesions (BCC) and Paget disease of the vulva. Diagnosis can associated with basal atypia and koilocytic changes be challenging, but early identification and manage- (condyloma or HPV effect) are termed vulvar low- ment of these clinical entities is essential, as prog- grade squamous intraepithelial lesions (LSILs).7 nosis is generally favorable if diagnosed at an early Vulvar HSILs are associated with risk for invasive stage. Herein, we review the epidemiology, clinical SCC development in younger women because of its characteristics, prognosis, and treatment of major oncogenic HPV-related pathway. However, dVIN, vulvar malignancies. which arises in the background of chronic inflam- matory dermatoses, such as lichen sclerosus, is associated with an even higher risk for invasive SQUAMOUS CELL CARCINOMA malignant progression.7 Terminology Vulvar carcinoma encompasses both invasive SCC and its precursor lesions. In the older nomenclature, Epidemiology precursor lesions (including high-grade premalig- Vulvar SCCs (vSCCs) represent 90% of vulvar nant disease and SCC in situ) were referred to as cancers and occur in 2-7 of every 100,000 women.8,9 vulvar intraepithelial neoplasia (VIN)5 and were As mentioned, the incidence of vSCC has been From the The Ronald O. Perelman Department of Dermatology, Reprint requests: Miriam K. Pomeranz, MD, 530 1st Ave, Ste 7R, New York University School of Medicine. New York, NY 10016. E-mail: [email protected]. Funding sources: None. Published online July 23, 2019. Conflicts of interest: None disclosed. 0190-9622/$36.00 Accepted for publication July 16, 2019. Ó 2019 by the American Academy of Dermatology, Inc. https://doi.org/10.1016/j.jaad.2019.07.055 1387 1388 Tan et al JAM ACAD DERMATOL DECEMBER 2019 increasing in younger women, with in situ lesions Historically, the gold standard for treatment of increasing at a faster rate than invasive SCC.8,10 vSCC was en bloc radical vulvectomy with bilateral Proposed explanations for this trend include tempo- inguinofemoral lymphadenectomy. Given the signif- ral shifts in sexual practices, changes in disease icant morbidity of this procedure, current practice classification, and screening tests.11 Vulvar HSILs, involves wide local excision and sentinel lymph associated with oncogenic HPV subtypes in younger node biopsy with possible lymphadenectomy, women, account for 43%-60% of vSCC.12,13 Risk which has comparable efficacy with decreased factors for progression morbidity.12,20 Adjuvant include immunosuppres- chemotherapy and radiation CAPSULE SUMMARY sion, smoking, and history are also considered on an of cervical cancer. individualized basis, espe- d Many vulvar cancers are initially cially in patients who cannot Clinical presentation and misdiagnosed as inflammatory be treated surgically. pathogenesis conditions, delaying appropriate Treatment of vulvar LSILs Grossly, vSCC (including treatment. Given the steadily increasing and HSILs varies depending invasive and premalignant incidence, misdiagnosis represents a on classification. As vulvar disease) can present as a serious gynecologic concern. LSILs have low risk of malig- raised, flat ulcerated plaque- d Dermatologists should be familiar with nant transformation, treat- like, polypoid, or warty mass vulvar malignancies and maintain a high ment is symptomatic or to on the vulva (Fig 1). Lesions threshold for suspicion during skin prevent autoinoculation and might be skin-colored, examinations. Early treatment and sexual transmission. For white, erythematous, or pig- intervention generally lead to more vulvar HSILs, surgical exci- 12 mented. Although many favorable prognosis. sion, ablative therapy, and patients are asymptomatic at topical imiquimod are all diagnosis, some experience comparable in efficacy.7,21 pruritus, burning, pain, or Surgical excision remains bleeding, especially with invasive disease.12,14 the treatment of choice for dVIN, given its higher Vulvar HSILs tend to be multifocal, slow-growing, risk for malignant transformation.15 and have the potential for spontaneous regression.15 Current preventative efforts focus on immuniza- The histologic subtypes are warty, basaloid, or tion with the quadrivalent or 9-valent HPV vaccine, mixed. If presenting as multicentric, 3-5 mm viola- which has been demonstrated to decrease the risk of ceous or erythematous papules, Bowenoid papulo- vulvar HSILs; the quadrivalent vaccine is protective sis (which frequently self-resolves) might be against HPV genotypes 6, 11, 16, and 18 and the 9- suspected.16 In contrast, dVIN arises in the setting valent vaccine against 6, 11, 16, 18, 31, 33, 45, 52, and of chronic inflammatory dermatoses and has a higher 58.7,22 As of October 2018, the 9-valent vaccine is recurrence rate, worse prognosis, and more rapid approved by the US Food and Drug Administration progression to invasive vSCC than vulvar HSILs.6,15,17 for women and men aged 9-45 years. Addressing vSCC is thought to have 2 distinct pathogeneses other risk factors, such as smoking and chronic related to its subclassification. In HPV-positive vSCC, vulvar dermatoses, also plays an important role in oncoproteins E6 and E7 lead to inactivation of tumor preventing vSCC. suppressor proteins p53 and Rb, respectively, and cell cycle protein p16ink4a is overexpressed.18 In contrast, in HPV-negative vSCC, p16ink4a is not MELANOMA overexpressed, and p53 is expressed.15,18 Epidemiology After vSCC, vulvar melanoma is the second most Prognosis and management common vulvar cancer, accounting for 5%-10% of all vSCC has a combined clinical, surgical, and vulvar malignancies.23 Incidence has been reported pathologic staging system on the basis of the at \0.2 cases/100,000 women.23 Though the vulva American Joint Committee on Cancer and the represents just 0.7% of total body surface area, ;2% International Federation of Gynecology and of all melanomas in female patients occur on the Obstetrics staging systems.19 Lymph node involve- vulva, making the vulva ;2.5 times more likely to ment is the most significant prognostic indicator. develop a melanoma than other locations of the Because of the prognostic implications of HPV same surface area.24 White women are most infection, initial workup should include immunohis- commonly affected, usually in their 5th to 7th tochemical staining for p53 and p16ink4a. decades of life.23 JAM ACAD DERMATOL Tan et al 1389 VOLUME 81, NUMBER 6 Abbreviations used: BCC: basal cell carcinoma dVIN: differentiated vulvar intraepithelial neoplasia EMPD: extramammary Paget disease HPV: human papillomavirus HSIL: high-grade squamous intraepithelial lesion LSIL: low-grade squamous intraepithelial lesion SCC: squamous cell carcinoma VIN: vulvar intraepithelial neoplasia vSCC: vulvar squamous cell carcinoma Fig 1. Invasive vulvar squamous cell carcinoma. Clinical presentation and pathogenesis Vulvar melanoma commonly presents as a macule, papule, or nodule [6 mm in length, with markedly irregular borders and coloration (Fig 2).24 Pruritus, bleeding, discharge, ulceration, or lymph- adenopathy might occur.23 The labia majora and clitoral area are the most common sites. In a study of 219 cases, nearly half of vulvar melanomas occurred on mucosal skin, 12% on hair-bearing skin, and 35% at the junction between mucosal and hair-bearing skin; 25% of cases were clinically amelanotic and more frequently in mucosal than hair-bearing skin.24