Human papillomavirus infection

The human papilloma virus (HPV) causes infections of the skin and mucous membranes. The locations and specific manifestations of infection depend on the type of virus and its mode of transmission. Many HPV strains are already spread during infancy and childhood through direct skin-to-skin contact and may remain dormant, while others (especially HPV-1, HPV-2, and HPV-4) can cause common warts (verruca vulgaris). Other strains are sexually transmitted (especially in young adults) and can be further divided into low-risk and high-risk HPV types. Low-risk types (especially HPV-6 and HPV-11) can cause benign anogenital warts (condylomata acuminata) and papillomatous nodules in other genital (e.g., squamous intraepithelial lesions of the cervix) or non-genital (e.g., oral warts, respiratory papillomatosis) mucosal areas. Infection with oncogenic high-risk HPV types (especially HPV-16 and HPV-18) may lead to malignant disease. These high-risk strains account for more than 70% of cervical cancers and can also cause genital, oral, and oropharyngeal squamous cell cancers. Risk factors for infection include skin damage, immunocompromise, early first sexual intercourse, and frequent change of sexual partners. Most HPV infections are asymptomatic and self-limiting, although pruritus, tenderness, and bleeding may occur. Diagnosis is often based on the physical exam alone, but can be confirmed with diagnostic tests (e.g., the acetic acid test), particularly in asymptomatic HPV infections of the cervix. Treatment of condylomas includes the use of local ointments, cryotherapy, and electrocoagulation. However, surveillance is important since recurrence rates are high and malignant transformation is possible. Prevention includes education about safe sexual practices and the proper use of condoms, as well as vaccination of all boys and girls at 11–12 years of age.

Human papillomavirus

• Double-stranded, circular, non-enveloped DNA virus with an icosahedral capsid
• Low-risk types 6 and 11
  • Anogenital warts (condylomata acuminata)
  • Mild cervical cell abnormalities
  • Tumors of non-genital mucosal membranes (e.g., respiratory tract, oral cavity, esophagus, eye)
• High-risk types 16, 18, 31, and 33
  • Cervical cancer (responsible for 70% of cases)
  • High risk of anogenital, oral, and oropharyngeal squamous cell carcinoma
  • Pathomechanism: Inactivation of tumor suppressor genes (HPV-16: E6 gene product inactivates TP53 gene; HPV-18: E7 gene product inactivates Rb gene)
• HPV types 1, 2, and 4: cause skin warts, such as common warts (verruca vulgaris) and plantar warts (myrmecias)

Route of transmission

• Transmission occurs between two epithelial surfaces.
  • Close personal contact: cutaneous warts
  • Sexual contact: anogenital lesions

Risk factors

• Damaged skin/mucous membranes
• Immunodeficiency
• Additional risk factors for genital/mucosal HPV infections include:
  • Unprotected sex
  • Number of lifetime sexual partners
  • Early age at first sexual activity
  • Uncircumcised males

References:^{[1][2][3][4][5][6][7][8][9]}

Epidemiology

• Most common sexually transmitted infection (STI)
• Approx. 50% of new infections affect individuals between 15–24 years of age.
• Prevalence
  • In the US: ∼ 79 million
  • Worldwide: 12% of women with normal cervical cytology test positive for HPV
• Incidence: ∼ 14 million annually in the US
• Sex: ♀ > ♂ (1.4:1)

Genital intraepithelial neoplasms

• Cervical intraepithelial neoplasia (CIN) and cervical cancer
• Vulvar intraepithelial neoplasia (VIN) and vulvar cancer
• Vaginal intraepithelial neoplasia (VAIN) and vaginal cancer
• Squamous cell carcinoma of the penis
• Anal cancer

Condylomata acuminata (anogenital warts)

• HPV types 6 and 11: responsible for ∼ 90% of genital warts
• Location
  • ♀: vulvar, cervix, urethra (rare), anal region
  • ♂: glans penis, foreskin, urethra, anal region
• Diagnosis
  • Visual inspection
  • Application of 5% acetic acid turns lesions white (not a specific finding)
• Clinical findings
  • Exophytic, cauliflower-like lesions
  • Often asymptomatic; may cause pruritus, tenderness, or bleeding in rare cases
• Treatment
  • Pharmacotherapy: local cytostatic treatment; (e.g., 5-fluorouracil, trichloroacetic acid, podophyllin, salicylic acid) or immune response modifiers (e.g., imiquimod, interferon alpha)
  • Cryotherapy: freezing external warts with CO₂, N₂O, or N₂
  • In case of numerous warts: curettage, laser surgery, or electrocoagulation

Flat condylomata

• Particularly HPV types 3 and 10
• Flat, white-brown, slightly elevated, scattered plaques in the anogenital region
• Differential diagnosis: condylomata lata (usually flat, smooth, and moist) in syphilis
• Treatment
  • Curettage or laser surgery
  • Regular checks are necessary because of the high risk of malignancy

Bowenoid papulosis

• Transitional stage between a genital wart and Bowen disease (a squamous cell carcinoma in situ)
• Most commonly HPV-16
• Multiple, flat, red-brown pigmented papules on the external genitalia (particularly the penile shaft, glans, foreskin, vulva, and perianal region)
• Treatment
  • Re-examination every 3–6 months (lesions often regress spontaneously)
  • If persistent: local destructive therapy (see “Treatment” of condylomata acuminata above) followed by surveillance (annual examinations), since lesions may recur
• Malignant transformation occurs in 2.6% of cases.

Giant condylomata (Buschke-Löwenstein tumor)

• Primarily HPV types 6 and 11
• Exophytic, verrucous, locally invasive squamous cell carcinoma without a tendency to metastasize
• Surgical excision

References:^{[4][10][2][3][11]}

Epidemiology

• Most common in infancy, childhood, and adolescence
• Prevalence: ∼ 7–12% in the US
• Sex: ♀ = ♂

Common warts (verruca vulgaris)

• Particularly HPV types 1, 2, and 4
• Skin-colored or whitish, rough, scaly papules or plaques (sometimes with a cauliflower-like appearance) on the elbows, knees, fingers, and/or palms
• Often asymptomatic but may cause tenderness (depending on the location) and pruritus → scratching → bleeding
• Treatment
  • Initially watchful waiting (most skin warts regress within 2 years)
  • Topical agents (e.g., salicylic acid), cryotherapy, or surgical interventions

Plantar warts

• Particularly HPV types 1, 2, and 4
• Rough, hyperkeratotic lesions on the sole of the foot
• Often grow inwardly and cause pain while walking

Nonanogenital mucosal manifestations

HPV types that cause mucosal manifestations in the genital area may also lead to non-anogenital mucosal manifestations, such as:

• Oral warts and oropharyngeal carcinomas
• Laryngeal papilloma
  • Definition: benign tumor of the laryngeal epithelium caused by HPV infection of the throat; associated with strains 6 and 11
  • Clinical features: voice changes (e.g., hoarseness) and, in more severe cases, airway obstruction; white, exophytic cauliflower-like lesions located in the larynx, trachea, and on the vocal cords
• Laryngeal carcinoma
• Respiratory papillomatosis and squamous cell carcinoma (SCC) of the lung
• Conjunctival papillomas and conjunctival carcinoma

Flat warts (verruca plana)

• Particularly HPV types 3 and 10
• Multiple small, flat patches or plaques
• Localization: face, hands, and shins

References:^[7][4]

• Koilocytes
  • Pathognomonic of an infection with HPV
  • Dysplastic squamous cells characterized by well-defined, clear, balloon-like, perinuclear halo and hyperchromasia

• See genital lesions
• Benign tumors, e.g., fibroids, papillomatous dermal nevi
• Malignant tumors, particularly squamous cell carcinomas

The differential diagnoses listed here are not exhaustive.

• Education about possible risk factors and effective preventive measures, such as:
  • HPV vaccination: All boys and girls should be vaccinated at 11–12 years of age.
  • Use of condoms
    • Condoms decrease the risk of infection, but do not provide full protection, as uncovered areas may still be infected.

References:^[4][9][12]