DermatologyTier 1Disease (DEADMAN)

Viral infections - human papilloma virus

Description

Non-enveloped double-stranded DNA virus; >200 genotypes; infects basal keratinocytes via microtrauma
Replication tied to keratinocyte differentiation -> no viraemia, no cell lysis -> poor innate immune signalling

Genotype groups

Group	Types	Disease
Low-risk mucosal	6, 11	Anogenital warts, recurrent respiratory papillomatosis
High-risk mucosal	16, 18 (+31/33/45/52/58)	Cervical, anal, vulval, vaginal, penile, oropharyngeal SCC
Cutaneous	1, 2, 4	Common, plantar, plane warts
Beta-HPV	5, 8	Epidermodysplasia verruciformis; SCC in immunosuppressed

HPV16 + 18 cause ~70% of cervical cancer; HPV16 alone causes ~90% of HPV-positive oropharyngeal cancer

Commonest STI worldwide - lifetime risk of genital HPV >80%
Peak incidence soon after sexual debut
~90% of new infections clear within 2 years - persistence is the oncogenic step
Australia:
- Genital warts in young women fell >90% after the 2007 NIP vaccination program (herd effect in heterosexual men too)
- On track to be among the first countries to eliminate cervical cancer as a public health problem (<4/100,000)
Oropharyngeal SCC is rising while other head and neck SCC falls; M>F (~3:1), 40-60 yrs, non-smokers

Persistent high-risk infection -> integration of viral DNA into host genome
- Disrupts E2 (the repressor) -> unopposed E6 and E7
- E6 -> degrades p53 -> loss of apoptosis
- E7 -> inactivates Rb -> releases E2F -> unchecked S-phase entry
- -> genomic instability -> dysplasia -> invasive carcinoma
p16INK4a over-expression is the surrogate marker of E7 activity -> p16 immunohistochemistry = the practical test for HPV-driven tumours
Latency period: infection to cancer typically 10-20 years

Cofactors for persistence/progression

Smoking, immunosuppression (HIV, transplant), high parity, long-term COC, other STI (chlamydia, HSV)
Anal cancer risk highest in men who have sex with men living with HIV

Clinical

Anogenital warts - condyloma acuminata; clinical diagnosis, biopsy only if atypical, pigmented, fixed or refractory
Cutaneous warts - thrombosed capillaries as black dots, loss of dermatoglyphics (distinguishes plantar wart from callus)

Cervical screening - Australia (NCSP)

HPV test (not cytology) every 5 years, ages 25-74
Self-collected vaginal swab available to everyone eligible - equivalent sensitivity for high-risk HPV; removes the main access barrier
Result-driven pathway:
- HPV 16/18 detected -> direct colposcopy regardless of cytology
- Other high-risk HPV -> reflex LBC; HSIL/possible HSIL -> colposcopy; negative/low-grade -> repeat at 12 months
- HPV not detected -> return in 5 years
Exit testing at 70-74
Cytology alone is no longer a screening test

Other sites

Anal: no national program; targeted digital anorectal exam +/- anal cytology/HRA in high-risk groups (HIV-positive MSM)
Oropharyngeal: no screening test. Presents as an asymptomatic cystic neck node in a non-smoker
- p16 IHC positive = HPV-associated; confirm with HPV DNA/RNA if equivocal
- HPV-positive oropharyngeal SCC is staged separately (AJCC 8th) because prognosis differs so markedly

Tests not to do

HPV typing on warts, and HPV testing in men or under-25s - no clinical utility

1. Prevention - the dominant intervention

Gardasil 9 (types 6/11/16/18/31/33/45/52/58) on the National Immunisation Program
- Single dose at age 12-13 (school program); single dose suffices for immunocompetent people aged 9-25
- 3 doses (0, 2, 6 months) if significantly immunocompromised, at any age
- Catch-up to age 25 free; available (privately) to 45
- Recommended for MSM and people living with HIV irrespective of prior exposure
Vaccination does not replace screening - vaccinated women still screen on the same schedule
Condoms reduce but do not eliminate transmission (skin outside the covered area)
Smoking cessation

2. Anogenital warts - treat by lesion and patient

Patient-applied: imiquimod 5% cream (3x/week, up to 16 wks) or podophyllotoxin 0.5% solution (contraindicated in pregnancy)
Clinician-applied: cryotherapy (first-line in pregnancy), trichloroacetic acid, electrosurgery, curettage, laser
No treatment eradicates the virus - all aim at lesion clearance; recurrence ~30%
Screen for other STIs; warts are not an indication for a partner's cervical screening outside the usual schedule

3. Cutaneous warts

Most resolve spontaneously (~2/3 within 2 years in children) - observation is legitimate
Topical salicylic acid +/- cryotherapy; duct tape occlusion
Refractory/immunosuppressed: intralesional bleomycin, candida antigen, topical 5-FU

4. Cervical abnormalities

Colposcopy-directed biopsy; LLETZ/cone for HSIL (CIN2/3)
- Excision increases risk of preterm birth in subsequent pregnancy - counsel young women
Treat HPV-related cancer per site-specific oncology pathways

5. Immunosuppressed patients

Higher persistence, multifocal disease, faster progression
Transplant and HIV cohorts need more intensive surveillance and lower threshold for biopsy
In HIV, antiretroviral therapy reduces but does not abolish the excess risk

Cervical cancer - HPV is a necessary cause; ~99.7% of cases
Anal, vulval, vaginal, penile SCC
Oropharyngeal SCC (tonsil, base of tongue) - HPV16 now the leading cause in high-income countries, having overtaken tobacco/alcohol
Recurrent respiratory papillomatosis (HPV 6/11, vertical transmission)
Epidermodysplasia verruciformis - beta-HPV, inherited EVER1/EVER2 defect, cutaneous SCC
HIV and other immunosuppression
Smoking
Bowenoid papulosis, Buschke-Löwenstein (giant condyloma)

90% clear spontaneously within 2 years; persistence beyond 2 years is the risk state
Progression: persistent high-risk HPV -> CIN1 -> CIN2/3 -> invasive cancer over 10-20 years
- CIN1 regresses in ~60%; CIN3 progresses to cancer in ~30% over 30 years if untreated
HPV-positive oropharyngeal SCC has substantially better prognosis than HPV-negative tobacco/alcohol-related disease
- Better radiosensitivity; de-escalation of therapy is under trial, not yet standard
Genital warts: recurrence common irrespective of modality; psychological impact often exceeds the physical
Vaccinated cohorts: falling high-grade cervical abnormalities and wart presentations in Australia

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