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 inside the cell, 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., PCR), 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 persons 9–26 years of age.

Human papillomavirus ^[1]

• Double-stranded, circular, nonenveloped DNA virus with an icosahedral capsid
• Low-risk HPV types 6 and 11
  • Anogenital warts (condylomata acuminata) ^[2]
  • Mild cervical cell abnormalities
  • Tumors of nongenital mucosal membranes (e.g., respiratory tract, oral cavity, esophagus, eye)
• High-risk HPV types 16, 18, 31, and 33
  • Cervical cancer (responsible for 70% of cases) ^[3]
  • High risk of anogenital, oral, and oropharyngeal squamous cell carcinoma
• 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 ^[3]

• Damaged skin/mucous membranes (e.g., maceration, trauma, herpes simplex virus infection)
• Immunodeficiency (e.g., HIV infection, chemotherapy)
• Additional risk factors for genital/mucosal HPV infections include:
  • Unprotected sex
  • Number of lifetime sexual partners
  • Early age at first sexual activity
  • Uncircumcised males

Pathogenesis

• HPV expresses the following oncoproteins
  • E6 → inhibition of p53 protein → inhibition of the intrinsic apoptotic pathway and inhibition of p21 protein
  • E7
    • Inhibition of retinoblastoma protein (pRb) → increased activity of E2F-family of transcription factors
    • Inhibits p21 and p27 (CDK inhibitors) → increased activity of cyclin-dependent kinase

6 comes before 7 and P comes before R: E6 inhibits P53 and E7 inhibits pRb

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

Epidemiology

• Most common sexually transmitted infection (STI) ^[4]
• Approx. 50% of new infections affect individuals between 15–24 years of age. ^[5]
• Prevalence: ∼ 79 million in the US ^[1]
• Incidence: ∼ 14 million annually in the US ^[1]

Genital intraepithelial neoplasms

• Pathogen: HPV types 16 and 18
• Classification
  • Squamous intraepithelial lesion (SIL): low-grade (LSIL) or high-grade (HSIL) ; ^[6]
    • Cervical intraepithelial neoplasia (CIN)
    • Vulvar intraepithelial neoplasia (VIN)
    • Vaginal intraepithelial neoplasia (VaIN)
    • Penile intraepithelial neoplasia (PeIN)
    • Perianal intraepithelial neoplasia (PAIN)
    • Anal intraepithelial neoplasia (AIN)
  • Squamous cell carcinoma
    • Cervical cancer
    • Vulvar cancer
    • Vaginal cancer
    • Carcinoma of the penis
    • Anal cancer

Bowenoid papulosis

• Description: : An HSIL that resembles squamous cell carcinoma in situ on histology but tends to occur in younger individuals and has a lower risk of malignant transformation ^[6]
• Pathogen: : most commonly HPV-16
• Location
  • ♀: vulvar
  • ♂: glans penis, foreskin, shaft, perianal region
• Clinical features: multiple, flat, red-brown pigmented papules on the external genitalia
• Diagnostics
  • Visual inspection
  • Biopsy: shows focal epidermal hyperplasia and epidermal dysplasia
• Treatment
  • Reexamination every 3–6 months (lesions often regress spontaneously)
  • If persistent: local destructive therapy (see “Treatment” of “Condylomata acuminata”) followed by surveillance (annual examinations), since lesions may recur

Condylomata acuminata (anogenital warts)

• Pathogen: HPV types 6 and 11 (responsible for ∼ 90% of genital warts) ^[2]
• Location
  • ♀: vulvar, cervix, anal region, urethra (rare)
  • ♂: glans penis, foreskin, urethra, anal region
• Clinical features
  • Exophytic, cauliflower-like lesions
  • Often asymptomatic; may cause pruritus, tenderness, or bleeding in rare cases
• Diagnostics
  • Visual inspection
  • Application of 5% acetic acid turns lesions white (not a specific finding)
  • Biopsy indications ^[7]
    • Immunodeficiency (e.g., HIV infection)
    • Warts with atypical features (e.g., affixed to underlying tissue, pigmented, indurated, bleeding)
    • Warts refractory to treatment
• Treatment
  • Pharmacotherapy: local cytostatic treatment ; (e.g., 5-FU, 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

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

Giant condylomata (Buschke-Löwenstein tumor)

• Pathogen: primarily HPV types 6 and 11
• Clinical features: exophytic, verrucous, locally invasive squamous cell carcinoma without a tendency to metastasize
• Diagnostics
  • Visual inspection
  • Biopsy
• Treatment: surgical excision

Epidemiology

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

Common warts (verruca vulgaris)

• Pathogen: : particularly low-risk HPV types 2 and 4
• Clinical features
  • Lesions are plaques or papules
    • Skin-colored or whitish
    • Usually firm, often with a rough and scaly surface
    • Sometimes have a cauliflower-like appearance
    • Located 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) ^[8]
  • Topical agents (e.g., salicylic acid), cryotherapy, or surgical interventions

Plantar warts (verruca plantaris)

• Pathogen: particularly HPV types 1
• Clinical features
  • Rough, hyperkeratotic lesions on the sole of the foot
  • Often grow inwardly and cause pain while walking

Flat warts (verruca plana)

• Pathogen: particularly HPV types3 and 10
• Clinical features
  • Multiple small, flat patches or plaques
  • Localized on the face, hands, and shins

Nonanogenital mucosal manifestations

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

• Oral warts and oropharyngeal carcinomas
• Laryngeal papilloma: benign tumor of the laryngeal epithelium caused by HPV infection of the throat
  • Associated with HPV type 6 and 11
  • Appear as white, exophytic cauliflower-like lesions located in the larynx, trachea, and on the vocal cords
  • Usually single lesions in adults and multiple in children
  • Can cause voice changes (e.g., hoarseness) and, in more severe cases, airway obstruction
• Laryngeal carcinoma
• Respiratory papillomatosis and squamous cell carcinoma (SCC) of the lung
• Conjunctival papillomas and conjunctival carcinoma

• See “Genital lesions.”
• Benign tumors, e.g., fibroids, papillomatous dermal nevi
• Molluscum contagiosum
• Malignant tumors, particularly squamous cell carcinomas

The differential diagnoses listed here are not exhaustive.

• There is no treatment for the infection itself.
• In most cases the infection clears up without any treatment
• Several factors guide the choice of the treatment of anogenital warts, including wart characteristics (i.e., size, number, and anatomic site), patient preference, and potential adverse effects.
• Treatment options of HPV–related anogenital warts
  • Routine clinical monitoring
  • Local treatment with one of the following:
    • Podophyllotoxin
    • Imiquimod
      • Mechanism of action: toll-like receptor 7 agonist → activates immune cells (i.e., macrophages, monocytes, dendritic cells)
      • Indication: actinic keratoses, superficial basal cell carcinomas, herpes simplex infections, and anogenital warts
      • Adverse effects: burning pain at application site, dermal rash, pruritus
    • Trichloroacetic acid
  • Cryotherapy
  • Surgical removal (e.g., tangential scissor, shave excision, curettage, laser, electrosurgery)
• Evidence of malignancy should always be excluded on HPV–related cervical lesions via cytological and histological monitoring.
• For treatment options of HPV–related cervical lesions, see “Treatment” in “Cervical cancer.”

Reference:^[9]

• High rate of recurrence
• Infection with high-risk types may transition to precancerous or malignant lesions after several years. ^[3]

• Education about possible risk factors and effective preventive measures, such as: ^[3]
  • HPV vaccine: human papillomavirus 9-valent vaccine ; ^[10][11]
    • A 9-valent inactivated vaccine that is made from the L1 protein of the human papillomavirus types 6, 11, 16, 18, 31, 33, 45, 52, and 58
    • Provides protection against genital warts and cervical cancer.
    • See the “ACIP immunization schedule” for scheduling details.
  • Use of condoms: Condoms decrease the risk of infection but do not provide full protection, as uncovered areas may still be infected. ^[3]

Pregnancy ^[1]

• Transmission
  • Vertical transmission to the fetus is rare but may lead to:
    • Laryngeal papillomatosis → airway obstruction
    • Conjunctival papillomatosis
• Treatment/prevention
  • Vaccination should be avoided during pregnancy.
  • Trichloroacetic acid is preferred
  • Cryotherapy and surgical interventions are also safe.
  • Podophyllin, 5-FU, and interferon are teratogenic and contraindicated in pregnancy.
• Delivery
  • Cesarean section does not prevent vertical transmission of HPV.
  • Cesarean section is indicated only if the birth canal is obstructed by large genital warts.

Condylomata acuminata in children

• Transmission
  • Autoinoculation
    • Transmission of HPV from other cutaneous or mucosal sites of infection (e.g., transmission from the anogenital region to the hands)
    • Most common form in children
  • Heteroinoculation: transmission of HPV from close skin contact (e.g., bathing, diaper changing)
  • Sexual: transmission from sexual abuse ^[12]
  • Perinatal transmission (e.g., during vaginal delivery) or prenatal transmission (e.g., due to ascension of HPV into the uterus)
  • Fomite transmission (e.g., contaminated towels)
• Diagnostics
  • The possibility of sexual abuse should always be considered.
  • See “Diagnostics” in “Condylomata acuminata” above for details.
• Management
  • Watchful waiting: Most lesions resolve spontaneously within a few years. ^[13]
  • If warts persist or lesions become symptomatic (e.g., pruritus, bleeding, pain):
    • Topical agents (e.g., imiquimod, podophyllotoxin)
    • Surgical or laser therapy for extensive or large warts (≥ 1 cm)