Human papillomavirus

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%	Continued up to 8 weeks Fewer local skin reactions than 5% cream Best outcomes in women with perianal, perineal, vulvar, and inguinal warts, and in men with glans, scrotum, inguinal, and penile warts
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)	Continued to clearance of lesions More local skin reactions than 3.75% cream Cannot be directly compared to 3.75% due to differences in study design
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%	Used up to 4 weeks (in 1-week cycles) Protect surrounding skin with petroleum jelly Does not need to be washed off Use with caution near urethral meatus Contraindicated in pregnancy
sinecatechins 10% ointment applied 0.5 cm strand tid	48% (men), 65% (women)	6.5%	Used up to 16 weeks Does not need to be washed off

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