204.1 🎓 醫孞生版

204.1.0.1 📌 䞀頁重點

  • Virus: dsDNA, Papillomaviridae, non-enveloped, ~ 8 kb genome
  • > 200 types; ~ 40 infect anogenital tract
  • Risk classification:
    • Low-risk: 6, 11 — anogenital warts (condyloma acuminata), RRP (recurrent respiratory papillomatosis)
    • High-risk: 16, 18 (cause ~ 70% cervical CA), 31, 33, 45, 52, 58, 35, 39, 51, 56, 59, 66, 68
  • Diseases:
    • Cervical cancer (#1 HPV-associated; HPV essentially necessary cause)
    • Anal cancer (MSM + immunocompromise + women with cervical disease)
    • Oropharyngeal cancer (rising — HPV-16 driven; tonsil + base of tongue)
    • Vulvar, vaginal, penile cancer
    • Anogenital warts (HPV 6, 11)
    • Recurrent respiratory papillomatosis (RRP) — perinatal acquisition; HPV 6, 11
  • Transmission: sexual + skin-to-skin + perinatal
  • Universal exposure by mid-20s in sexually active adults
  • Most infections clear spontaneously within 2 years
  • Persistent high-risk HPV = pre-cancer + cancer risk
  • Vaccines (2024 standard):
    • Gardasil 9 (9vHPV) — covers HPV 6, 11, 16, 18, 31, 33, 45, 52, 58 (cancers ~ 90% + warts)
    • 2-dose series for 9-14 yr (0 + 6-12 mo)
    • 3-dose series for ≥ 15 yr (0 + 2 + 6 mo)
    • Universal vaccination 9-26 yr ACIP; shared decision 27-45 yr
    • High efficacy (95%+) prevention of vaccine-type HPV
    • Cancer prevention demonstrated in Sweden + Australia cohorts (cervical CA reduction)
  • Cervical screening (USPSTF + ACS 2024):
    • Age 25-65: HPV primary testing q5y preferred; OR HPV + cytology q5y co-test; OR cytology alone q3y
    • Age 21-24: cytology q3y (limited HPV given high prevalence + spontaneous clearance young)
    • High-risk groups (HIV, immunocompromise): more frequent
  • Treatment:
    • Genital warts: imiquimod, podophyllin, cryotherapy, surgical
    • Cervical pre-cancer (CIN 2-3): LEEP (loop electrosurgical excision) or cold knife cone
    • Anal pre-cancer (AIN 2-3): ablation, surgery
    • Cervical cancer: surgery + chemoradiation; HPV-driven oropharyngeal CA — chemoradiation + immunotherapy

204.1.0.2 1⃣ Virology

  • dsDNA, ~ 8 kb genome, ~ 8 open reading frames
  • Non-enveloped, capsid proteins L1 + L2
  • Replicates in nucleus of squamous epithelium
  • Productive replication in differentiated cells
204.1.0.2.1 Genes
  • E6, E7: oncoproteins
    • E6 binds + degrades p53 → impaired apoptosis
    • E7 binds + inactivates Rb → cell cycle dysregulation
    • High-risk HPV E6/E7 → cancer
  • E1, E2 (replication, transcription regulation)
  • L1, L2 (capsid)
204.1.0.2.2 Classification

  • 200 types

  • α-papillomaviruses (mucosal, anogenital)
  • β, γ-papillomaviruses (skin)
  • High-risk α-PV: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68
  • Low-risk α-PV: 6, 11

204.1.0.3 2⃣ Diseases

204.1.0.3.1 Genital Warts (Condyloma Acuminata)
  • Low-risk HPV 6, 11 (~ 90%)
  • Soft, cauliflower-like papules
  • Anogenital, perianal, urethral
  • Self-limited many cases (months-years)
  • Cosmetic / discomfort indications for treatment
  • Differential: condyloma lata (syphilis, broad-based), molluscum (umbilicated), seborrheic keratosis
204.1.0.3.2 Cervical Cancer
  • HPV 16 + 18 cause ~ 70%
  • Other high-risk types: ~ 25%
  • Non-HPV: < 5%
  • Persistent infection > 2 yr = pre-cancer / cancer risk
  • Progression: HPV infection → CIN 1 → CIN 2 → CIN 3 → invasive cancer (decades)
  • Most regress (immune clearance)
  • Screening + vaccination = preventive
204.1.0.3.3 Anal Cancer
  • HPV 16 most common (~ 80%)
  • Risk groups: HIV + (especially MSM), women with cervical disease, immunocompromise
  • Anal pap (cytology), HRA (high-resolution anoscopy)
  • 2024 ANCHOR study: AIN 2-3 treatment reduces cancer in HIV+
204.1.0.3.4 Oropharyngeal Cancer
  • Rising incidence — HPV-16 driven (90%+)
  • Tonsil + base of tongue
  • Younger, non-smoker / non-drinker patients (changing from traditional H&N CA)
  • Better prognosis than HPV-negative H&N CA
  • Treatment: chemoradiation + immunotherapy in advanced
204.1.0.3.5 Vulvar / Vaginal / Penile Cancer
  • HPV 16 main
  • Less common but rising
  • HPV vaccination prevents
204.1.0.3.6 Recurrent Respiratory Papillomatosis (RRP)
  • HPV 6, 11 perinatally acquired
  • Juvenile-onset: recurrent throat / larynx papillomas
  • Adult-onset (less common)
  • Hoarseness, airway obstruction
  • Multiple surgical resections needed
  • Cidofovir + bevacizumab off-label
204.1.0.3.7 Bowenoid Papulosis
  • Penile / vulvar in situ
  • HPV 16 main
  • Treatment: cryotherapy, excision

204.1.0.4 3⃣ Vaccines

204.1.0.4.1 Gardasil 9 (9vHPV)
  • Covers HPV 6, 11, 16, 18, 31, 33, 45, 52, 58
  • L1 virus-like particles (VLPs)
  • 6 +/- AS04 (alum) adjuvant
204.1.0.4.2 Schedule (ACIP 2024)
Age Schedule
9-14 2 doses 0 + 6-12 mo
15-26 3 doses 0 + 2 + 6 mo
27-45 Shared decision-making — 3 doses
204.1.0.4.3 Efficacy
  • > 95% efficacy preventing HPV-type infection + cervical pre-cancer in clinical trials
  • Cancer prevention demonstrated in Swedish cohort (Lei et al. NEJM 2020):
    • 88% reduction cervical cancer with vaccination < 17 yr
    • 53% reduction with vaccination 17-30 yr
  • Anogenital warts → near elimination in Australia (universal vaccination)
  • Herd immunity benefits
204.1.0.4.4 Safety
  • Site reaction, mild flu-like
  • Syncope (give seated)
  • No proven serious adverse events despite media controversies (extensively studied)
204.1.0.4.5 Status (2024)
  • Most countries ≥ 1-dose HPV vaccine programs
  • WHO 2030 goal: 90% girls vaccinated by 15 yr
  • 2024: Australia + UK + Sweden tracking toward elimination
  • Pediatric + adolescent + young adult primary targets

204.1.0.5 4⃣ Cervical Cancer Screening

204.1.0.5.1 USPSTF + ACS 2024 Updates
Age Preferred Strategy
21-24 Cytology q3y
25-65 HPV primary testing q5y preferred; OR HPV + cytology co-test q5y; OR cytology q3y
≥ 65 with adequate prior screening Discontinue
Hysterectomy (cervix removed) for benign Discontinue
HIV / immunocompromise More frequent (annual after diagnosis)
204.1.0.5.2 HPV Primary Testing
  • Detect high-risk HPV DNA (regardless of cytology)
  • Higher sensitivity than cytology
  • Negative HPV → long screening interval (5 yr)
  • 16/18 partial genotyping: if + → colposcopy regardless of cytology
  • Other high-risk + cytology: triage with reflex cytology
204.1.0.5.3 Cervical Cancer Risk Stratification
  • HPV + cytology + colposcopy + biopsy → CIN 1, 2, 3, AIS
  • CIN 2-3 → LEEP or cold knife cone
  • AIS → cone (if margin negative); hysterectomy (if family complete)
204.1.0.5.4 Co-Testing Algorithm
  • HPV - + cytology - → 5 yr screening
  • HPV + + cytology - → repeat 1 yr or 16/18 genotype + colposcopy
  • HPV + + cytology + → colposcopy
  • HPV - + cytology + (ASCUS or LSIL) → repeat 3 yr or HPV test

204.1.0.6 5⃣ Anal Cancer Screening (Emerging)

  • 2024 ANCHOR trial: AIN 2-3 treatment reduces anal cancer in HIV+
  • HIV+ MSM: anal cytology + HRA screening
  • HIV+ women: anal screening (depending guidelines)
  • General population: screening not standard yet
  • Vaccination prevents

204.1.0.7 6⃣ Treatment

204.1.0.7.1 Genital Warts
  • Imiquimod 5% cream (self-applied, 3×/wk × 16 wk)
  • Podophyllotoxin 0.5% solution (self-applied)
  • Cryotherapy with liquid nitrogen
  • TCA / BCA (trichloroacetic acid) — provider-applied
  • Surgical: excision, electrocautery, laser
  • HPV does NOT clear with topical Tx — only lesion clearance
  • Partners: examine + treat if visible warts; no routine partner Tx for occult
204.1.0.7.2 Cervical Pre-Cancer
  • CIN 1: observation (most regress)
  • CIN 2-3: LEEP (loop electrosurgical excision) or cold knife cone
  • AIS: cone with margin negative
  • Hysterectomy if family complete or persistent disease
204.1.0.7.3 Cervical Cancer
  • Surgery (early stage)
  • Chemoradiation (cisplatin + radiation) for locally advanced
  • Bevacizumab for advanced
  • Pembrolizumab + chemotherapy for advanced (KEYNOTE-826 trial)
204.1.0.7.4 Anal Pre-Cancer / Cancer
  • AIN 2-3: ablation (cryotherapy, infrared coagulation, electrosurgery) or topical (imiquimod, fluorouracil)
  • Anal cancer: chemoradiation (mitomycin + 5-FU + radiation) — sphincter preservation
204.1.0.7.5 Oropharyngeal Cancer
  • Chemoradiation (cisplatin + radiation)
  • Surgery (transoral robotic surgery) for selected
  • Immunotherapy (pembrolizumab, nivolumab) for advanced / recurrent
204.1.0.7.6 Bevacizumab + Cidofovir for RRP
  • Off-label use to reduce surgical recurrence
  • Systemic + topical / intralesional approaches