General
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• HPV associated carcinoma occuring in younger population (35-65 years) than squamous cell carcinoma (55-85 years)

Alternate terminology
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• Basaloid / warty carcinoma are often considered together due to common HPV etiology

Epidemiology
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• Usually affects younger women - mean age at diagnosis is 54 years
• Risk factors include multiplicity of sex partners, early age at initiation of sexual intercourse, and history of abnormal Pap smears
• Rarely is multifocal
• Patients may have synchronous or metachronous (not synchronous) malignancies of cervix and vagina

Pathophysiology
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• Tumors arise from cutaneous or mucosal epithelia of vulva
• Most commonly due to infection by high risk HPV; usually type 16, also types 33 and 18 (Eur J Cancer 2013;49:3450)
• Begins with vulvar intraepithelial neoplasia (VIN)

Clinical features
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• Pruritus and pain are most common presenting symptoms
• May have local discomfort, bleeding, mass, ulcer or swelling, or be completely asymptomatic
• Better disease-free and overall survival in HPV vs. non HPV associated carcinomas

Radiology
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• MRI, CT, PET/CT and ultrasound can assess extent of tumor, involvement of normal tissues and surrounding organs, presence of lymph node metastasis
• Whole body FDG-PET/CT is useful for initial work up and for assessing response to chemoradiotherapy

Prognostic factors
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• Early diagnosis and regular follow up for residual and recurrent lesions are the most important prognostic factors
• Presence of perineural invasion can predict local recurrence
• Metastasis is common in patients with lymphovascular space invasion

Case reports
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• 2 young women with single large inguinal lymph node metastases (Gynecol Obstet Invest 2009;67:42)
• 25 year old woman with coexisting VIN III and high-grade cervical SIL (Eur J Gynaecol Oncol 2007;28:131)
• 32 year old woman with synchronous HPV related neoplasm of cervix, vulva, oral cavity and oropharynx (Radiother Oncol 2009;92:138)
• 53 year old woman with groin metastasis after extensive microinvasive vulvar cancer (J Reprod Med 2007;52:78)

Treatment
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• Surgical resection
  • Partial or total vulvectomy or conservative wide excision with or without sentinel lymph node biopsy
  • Inguinofemoral lymph node dissection may be considered for deep or large tumors
• Neoadjuvant radiotherapy or chemotherapy
• Palliative radiation therapy

Gross description
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• Lesions can be vegetating, ulcerated, infiltrative, nodular or pigmented

Micro description
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• Hallmark of tumor is immature squamous epithelium
• Cells are arranged in variably sized solid nests, cribriform lobules with comedonecrosis and peripheral palisading of nuclei
• Occasionally infiltrative cords, nests or trabeculae are present, surrounded by densely hyalinized stroma often containing thin walled vessels
• Tumor is composed of basaloid cells with scant basophilic cytoplasm, high nuclear to cytoplasmic ratio
• Nuclei are oval to round, with coarsely granular chromatin, resulting in a stippled appearance
• Mitotic figures are frequent and atypical mitotic figures can be easily identified
• Small foci of keratinization may be identified in some tumors
• Perineural invasion may be common and extensive
• Vulvar intraepithelial neoplasia-grade III is frequently associated with the invasive component
• Admixture of warty architecture is not uncommon

Micro images
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Large lobular nests

 

Comedonecrosis

Surface ulceration and background undifferentiated VIN

 

Perineural invasion

Smaller nests

Focal squamous differentiation

HPV-positive vulvar squamous cell carcinomas

Positive stains
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• Epithelial cells: p16 (Am J Surg Pathol 2006;30:1347), p63, 34βE12, EMA (focal), CEA (focal minimal), Ki67 in suprabasal layers (Gynecol Oncol 2002;84:94)
• In situ hybridization demonstrates HPV16 in 70%, with a nuclear dot-like pattern

Negative stains
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• CD56, NSE, synaptophysin, chromogranin

Electron microscopy description
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• Usually not performed

Differential diagnosis
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• Clinical differential diagnosis: Squamous cell carcinoma
• Histological differential diagnosis:
  • Basal cell carcinoma with neuroendocrine differentiation
  • Merkel cell carcinoma
  • Poorly differentiated squamous carcinoma
  • Sebaceous carcinoma
  • Small cell carcinoma

References
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• J Natl Cancer Inst Monogr 2003;14, Am J Clin Oncol 2013;36:415, Biomed Res Int 2014;2014:480573, J Clin Pathol 1984;37:1201, Clin Exp Dermatol 2009;34:e965, Blaustein's Pathology of the Female Genital Tract - pg.291

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