• Clinical science

Human papillomavirus infection

Abstract

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.

Etiology

Human papillomavirus

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]

Anogenital manifestations

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

Condylomata acuminata (anogenital warts)

  • HPV types 6 and 11: responsible for ∼ 90% of genital warts
  • Location
  • 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; or immune response modifiers
    • Cryotherapy: freezing external warts with CO2, N2O, or N2
    • In case of numerous warts: curettage, laser surgery, or electrocoagulation

Flat condylomata

  • Particularly HPV types 16 and 18
  • 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]

Nonanogenital manifestations

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:

Flat warts (verruca plana)

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

References:[7][4]

Pathology

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

Differential diagnoses

The differential diagnoses listed here are not exhaustive.

Prognosis

  • High rate of recurrence
  • Infection with high-risk types may transition to precancerous or malignant lesions after several years.

References:[4][9]

Prevention

  • 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.
    • Sexual abstinence (statistically reduces the risk of infection, however, this is not a recommendation) or a monogamous relationship (with a non-infected partner)

References:[4][9][12]

Special patient groups

Pregnancy

  • Vertical transmission to the fetus is rare but may lead to:
    • Laryngeal papillomatosisairway obstruction
    • Conjunctival papillomatosis
  • Treatment/Prevention
    • Vaccination should be avoided during pregnancy.
    • Trichloroacetic acid; is preferred; cryotherapy and surgical interventions are also safe.
    • Cesarian section is indicated if the birth canal is obstructed by large genital warts.

References:[12][2]