Background
- Oncogenic double-stranded DNA virus in the Papillomaviridae family, with hundreds of genotypes
- Infection with one genotype does not confer immunity to others
Epidemiology
- Transmission is from direct contact (including during sexual encounters) or vertical (before or during birth)
- Lifetime prevalence is 70% in North America
- HPV infection is the primary risk factor for cervical cancer
- About 400 women die from cervical cancer annually
Risk Factors
Anogenital Lesions
- For women:
- Directly related to the number of male sex partners
- Male partners' number of female sex partners
- Sex with a new partner
- Vaginal and anal intercourse
- For men:
- HIV infection
- Current and past sexual behavior
- Number of sex partners
- Absence of condom use
- Prior sexually transmitted infection
- Race and ethnicity
- Circumcision status
Pathophysiology
- Virus enters via a breach in the epithelium and binds to heparan proteoglycans on the basement membrane and basal cell
- Replication within the basal cell, which differentiates as usual and releases virions
- The condyloma are formed when viral replication causes proliferation of all layers of the epidermis except for the basal cell
- In high-grade lesions, viral DNA is usually integrated into the host genome, where it interferes with tumour suppression genes
Clinical Manifestations
- Incubation period 3 to 4 months (range 6 weeks to 2 years)
- Most commonly associated with warts (including genital warts), cervical cancer, and penile cancer
- Most warts resolve within 24 months without treatment
| Disease | Common Genotypes | Uncommon Genotypes |
|---|---|---|
| Plantar warts | 1, 2, 27 | 4, 26, 28, 29, 41, 57, 63, 65, 77, 117, 125, 128, 129, 130, 131, 132, 133, 148, 149, 179, 184 |
| Common warts | 1, 2, 4, 27 | |
| Warts of meat, poultry, and fish handlers | 2, 7 | 1, 3, 4, 10, 28 |
| Flat and intermediate warts | 3, 10 | 27, 28, 38, 41, 49, 75, 76, 126 |
| Epidermodysplasia verruciformis | 5, 8, 9, 12, 14, 15, 17 | 19, 20, 21, 22, 23, 24, 25, 36, 37, 38, 47, 49, 50, 75, 93 |
| Condylomata acuminata | 6, 11 | 16, 18, 26, 31, 33, 35, 40, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 58, 59, 66, 68, 70, 153, 175, 178, 180, 200, 201, 202 |
| Intraepithelial neoplasia (unspecified) | 26, 30, 34, 39, 40, 53, 57, 59, 61, 62, 67, 68, 69, 71, 81, 83 | |
| Intraepithelial neoplasia (low-grade) | 6, 11 | 16, 18, 31, 33, 35, 42, 43, 44, 45, 51, 52, 54, 61, 70, 72, 74 |
| Intraepithelial neoplasia (high-grade) | 16, 18 | 6, 11, 31, 33, 34, 35, 39, 42, 44, 45, 51, 52, 56, 58, 66, 67 |
| Cervical carcinoma | 16, 18 | 26, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 67, 68, 73, 82 |
| Recurrent respiratory papillomatosis | 6, 11 | 16, 18, 31, 33, 35, 39 |
| Focal epithelial hyperplasia of Heck | 13, 32 | 18, 33, 45 |
| Conjunctival papillomas and carcinomas | 6, 11, 16 |
Cutaneous Warts
- Includes deep plantar warts, common warts, and plane warts
- Usually asymptomatic, though they can bleed and cause pain
- Usually spontaneously resolve within a few months to a few years
- Common warts (verrucae vulgaris) are well-demarcated, exophytic, hyperkeratotic papules with a rough surface
- Can occur on back of hand, between fingers, around nails (periungual), palms, soles, and (rarely) mucous membranes
- Can coalesce into larger lesions
- Mosaic warts are when they coalesce into a cobblestone appearance
- Filiform warts occur on the head
- Vegetating warts can occur on the hands of butchers, fish handlers, and meat packers
- Plane warts (verrucae planae) are more common on children
- Multiple, slightly elevated papules with irregular margins and smooth surface
- Can occur on face, neck, and hands
- When more elevated, they are called intermediate lesions
- Plantar warts (verrucae plantaris or myrmecia) is most common in adolescents and young adults
- When grouped in clusters, they are called mosaic warts
- May be painful
- Can also occur on the palms
Anogenital Warts
- Hyperkeratotic, exophytic papules that are either pedunculated or sessile
- In men, mostly involves the cavity of the prepuce if uncircumcised, or the shaft if circumcised
- Can also occur on meatus and within the distal urethra
- Very rarely involve proximal urethra or bladder
- Perianal warts are more common in men who have sex with men
- In women, they are most commonly found on the posterior introitus, the labia majora and minora, and the clitoris
- Can also occur on the perineum, vagina, anus, cervix, and urethra
Recurrent Respiratory Papillomatosis
- Papillomas appear most commonly in larynx, but also trachea, bronchi, and lungs
- Hoarseness, dysphonia, airway obstruction, respiratory distress, and stridor
- In lungs, can cause nodules, atelectasis, and secondary bacterial pneumonia, with eventual bronchiectasis and vacitation
- Can progress to invasive squamous papillomatosis or even squamous cell carcinoma
- Genotypes 6 and 11 most commonly implicated
- In children it is caused by perinatal vertical transmission and can be life-threatening (juvenile-onset recurrent respiratory papillomatosis)
- 25% present by 1 year, 50% by 5 years, and 100% by 11 years
- Occurs in 1 in 4000 live births to women with HPV infection
- In adults, most commonly seen in ages 20 to 40 years
HIV Coinfection
- HIV infection is associated with increased risk of acquiring HPV infection
- Risk is decreased by HIV treatment
- HPV infection is associated with increased risk of acquiring HIV infection
- Coinfection is associated with a higher risk of progression of HPV lesions
Infection in Children
- Genital warts can be acquired from contact with warts on caregiver's hands or on children's own hands
- Vertical transmission can also occur
Associated Malignancies
- HPV is the underlying cause of:
- Almost 100% of cervical cancer
- 50% of vulvar and penile cancer
- Over 90% of anal cancer
- Also contributes to oropharyngeal and nasopharyngeal cancers
Differential Diagnosis
- Condyloma latum (secondary syphilis)
- Seborrheic keratosis, localized hyperpigmented lesions that are rarely associated with malignancy
- Molluscum contagiosum, caused by a poxvirus, highly infectious, and common in immunodeficiency; lesions are usually umbilicated
- Pearly penile papules, angiofibromas that occur at the penile corona and are normal variants
- Dermatitis
- Neoplasm
- Bowen disease, in situ squamous cell carcinoma confined to the epidermis and can occasionally become invasive
- Bowenoid papulosis
- Squamous cell carcinoma
- Buschke-Lowenstein tumor, a rare and highly differentiated genital carcinoma
- Vulvar intraepithelial neoplasia
- Benign nevus
- Dysplastic nevus
Diagnosis
- Cutaneous and anogenital warts are usually diagnosed clinically
- For cervical and rectal lesions, soaking with 3 to 5% acetic acid for 3 to 5 minutes followed by colposcopy improves diagnosis of those lesions
- Acetic acid will cause whitening of the lesions
Cervical Cytology
- Cervical cytology with Papanicolaou testing
- Uses ASCCP system to describe grade
- Atypical squamous cells of undetermined significance (ASCUS)
- Atypical squamous cells for which a high-grade squamous intraepithelial lesion cannot be excluded (ASCH)
- Low-grade squamous intraepithelial lesion (LSIL)
- Includes koilocytic or condulomatous atypia, mild dysplasia, and cervical intraepithelial neoplasia (CIN) 1
- High-grade squamous intraepithelial lesion (HSIL)
- Includes moderate and severe dysplasia, CIN 2, CIN 3, and carcinoma in situ (CIS)
- Squamous cell carcinoma
Management
Cutaneous Warts
- Since many lesions will spontaneously resolve, can watch and wait
- Most common treatment is topical salicylic acid, often sold over-the-counter and applied daily for up to 12 weeks
- Before applying treatment, need to do hot water soak and abrasion in order to remove the cornified layer
- Another common treatment is cryotherapy with topical liquid nitrogen
- Most effective with a sustained 10 second freeze, which can cause pain and blisters
- Frequently needs multiple treatments, spaced every 2 weeks
- Another treatment is occlusive duct tape application (occlusive therapy)
- Less evidence for glutaraldehyde, formaldehyde, podofilox, and cantharidin
Anogenital Warts
- 10 to 20% will spontaneously resolve within 3 to 4 months
- Up to 90% will clear them by 2 years
- No great evidence in favour of any specific treatment
- May be either physician-applied or patient-applied
Patient-Applied Therapy
- Imiquimod 3.75% or 5% cream
- Podofilox (podophyllotoxin) 0.5% solution applied twice daily for 3 days followed by 4 days off, for up to 4 weeks
- Veregen 15% ointment applied three times daily for up to 16 weeks
- Green tea extract that contains a number of possibly active ingredients
- Causes local erythema, pruritus, pain, and ulceration
- Trichloroacetic acid 10 to 90% solution applied weekly
- Causes ulcers
- Safe in pregnancy
| Treatment | Clearance | Recurrence | Comments |
|---|---|---|---|
| imiquimod 3.75% cream applied daily at bedtime, washed off after 8 hours | 16% (men), 36% (women) | 17% |
|
| imiquimod 5% cream applied three times weekly at bedtime (MWF), washed off after 6 to 10 hours | 33% (men), 72% (women) | 6% (men), 19% (women) |
|
| podofilox 0.5% solution applied to washed and dried skin with a cotton swab every 12 hours for 3 days (followed by 4 days off) | 53-78% | 17-79% |
|
| sinecatechins 10% ointment applied 0.5 cm strand tid | 48% (men), 65% (women) | 6.5% |
|
Physician-Applied Therapy
- Cryotherapy, as for cutaneous lesions, applied every 1 to 2 weeks
- Very effective, and safe in pregnancy
- Surgical or electrosurgical resection
- May result in scarring
- CO2 laser therapy
- Previously: 5-fluorouracil (5-FU) and intralesional interferon
Prevention
Vaccination
- Uses viral-like particles that express L1 capsid protein with aluminum as an adjuvant
| Vaccine | Genotypes | Schedule | |||||
|---|---|---|---|---|---|---|---|
| Girls and Women | Boys and Men | ||||||
| 9 to 15 years | ≥15 years | Immunocompromised | 9 to 15 years | ≥15 years | Immunocompromised | ||
| Cervarix | 16, 18 | 2 or 3 dose | 3 dose | 3 dose | not indicated | ||
| Gardasil | 6, 11, 16, 18 | 2 or 3 dose | 3 dose | 3 dose | |||
| Gardasil-9 | 6, 11, 16, 18, 31, 33, 45, 52, 58 | ||||||
- Two-dose schedule
- Only indicated for children aged at least 9 to less than 15 years
- Given at 0 and 6 months
- Three-dose schedule
- Indicated for everyone, including children 9 years and older, men and women 15 years and older and immunocompromised people
- HPV-2: given at 0, 1, and 6 months
- HPV-4: given at 0, 2, and 6 months
- HPV-9: given at 0, 2, and 6 months
- Vaccination with quadravalent vaccine covers about 70% of cervical cancer genotypes, and the nonavalent about 65%
- Vaccination of genotypes 6 and 11 cover about 90% of genital warts
- Not recommended in pregnancy, but does not appear to be harmful
