II. Pathophysiology

  1. Human Papillomavirus (HPV) infection of abraded skin
  2. HPV Types 6 and 11 most common visible types
    1. Rarely associated with invasive squamous cell cancer
  3. HPV Types 16 and 18 most aggressive
    1. Associated with Cervical Dysplasia and anal dysplasia
    2. Associated with Head and Neck Cancers (HPV 16)
    3. Other types associated with Squamous Cell Carcinoma (SCC): 31, 33, 35

III. Epidemiology

  1. Prevalence
    1. Clinically evident in 1% of those sexually active in the U.S. (20 Million U.S. adults)
    2. Lifetime risk: 10%
  2. Peak ages in United States
    1. Women: 20 to 24 years old
    2. Men: 25 to 29 years old
  3. Sexually Transmitted
    1. Evaluate for other STDs if present
    2. Penile warts confer 50% transfer risk to Cervix
  4. Incubation Period
    1. Four weeks to more than a year after exposure

IV. Pathophysiology

  1. Human Papilloma Virus types 16, 18
  2. Human Papilloma Virus types 30,31, 34, 35, 39, 48

V. Signs

  1. Characteristics
    1. Flesh colored exophytic lesions on genitalia
    2. Variable appearance
      1. Small, soft, fleshy flat-topped Papules or
      2. Larger cauliflower-like or vegetating masses
    3. Lesion size
      1. Varies from tiny asymptomatic lesions to large Plaques
      2. May interfere with sexual intercourse as well as urination and Defecation
      3. Lesion size is not correlated with cancer risk
  2. Accentuated by:
    1. Acetic acid (3-5%) or white vinegar
      1. Not all acetowhite lesions are warts
    2. Plain water soaks for 10 minutes
  3. Distribution
    1. Penis and Scrotum, vulva, perineum, and perianal mucosa and skin
    2. May spread to Urethra and Bladder
    3. Intra-anal warts may result
    4. May result in Hematuria

VI. Differential Diagnosis

  1. Molluscum Contagiosum
    1. Pearly, flesh-colored Papules with central umbilication
  2. Condyloma Lata (Secondary Syphilis)
    1. Wart-like white to gray Plaques on moist mucosa
  3. Fordyce Spots
    1. Flesh colored Papules, smooth 1-2 mm, on Scrotum or labia
  4. Pearly penile Papule
    1. 1 mm white Papules, circumferentially around the corona of the glans penis
  5. Seborrheic Keratosis
    1. Rough, brown wart-like Plaques
  6. Squamous Cell Carcinoma or Bowen's Disease
    1. Wart-like or sclerotic lesions
  7. Vulvar intraepithelial neoplasia
    1. Pigmented, irregular vulvar Plaque
  8. Lichen Planus
    1. Smooth purple, polygonal Papules and Plaques

VII. Labs: Biopsy Indications

  1. Uncertain diagnosis
  2. Extensive involvement
  3. Immunocompromised status (e.g. HIV Infection, AIDS)
  4. Refractory to standard therapy
  5. Pigmented, indurated, fixed or ulcerated warts
  6. High risk for HPV-related malignancy
    1. See prognosis below

VIII. Management: Overall treatment strategy

  1. Non-Keratinized Warts
    1. First line
      1. Podofilox 0.5% gel applied twice daily for 3 days, off for one day and then repeat cycle 4 times OR
      2. Imiquimod 5% cream applied at bedtyime 3 times weekly (e.g. every other day) for 16 weeks
    2. Alternative
      1. Cryotherapy
    3. Refractory
      1. Podophyllin
      2. Trichloroacetic Acid (TCA)
      3. Ablation
  2. Keratinized warts
    1. First line
      1. Warts <10 mm: Cryotherapy
      2. Warts >10 mm: Surgical excision (or if persistent)
    2. Adjunctive: Imiquimod applied as pretreatment
  3. Warts on mucosal surface (Vagina, Cervix, anal)
    1. First line: Cryotherapy
    2. Alternative: Trichloroacetic Acid
  4. Immunosuppression
    1. Immunosuppression (e.g. HIV Infection, transplant patients) increases risk of Squamous Cell Carcinoma
    2. Biopsy suspicious lesions (e.g. ulcerating, rapid growth, atypical)
  5. Subclinical warts
    1. General HPV screening is not recommended
  6. Anorectal Cancer annual screening (Rectal Exam and anal Pap Smear) Indications
    1. HIV Infection
    2. Men who have Sex with Men
    3. Women with vulvar or Cervical Cancer
    4. Transplant recipients
  7. References
    1. Kodner (2004) Am Fam Physician 70:2335-46 [PubMed]

IX. Management: Pregnancy

  1. Indications for HPV treatment in pregnancy
    1. Treat lesions that would obstruct labor or result in significant bleeding during delivery
    2. CDC does not recommend HPV treatment in pregnancy to prevent neonatal HPV exposure
      1. CDC also does not recommend Cesarean Section to avoid neonatal exposure during delivery
      2. Despite the increased risk of neonatal respiratory papillomatosis
        1. Cesarean Section and Wart Treatment does not reduce risk
      3. Silverberg (2003) Obstet Gynecol 101(4): 645-52 [PubMed]
  2. Contraindicated medications
    1. Absolute contraindications
      1. Avoid Podophyllin, Podofilox, and Fluorouracil
    2. Relative contraindications
      1. Imiquimod is not FDA approved
  3. Agents with relative safety for use in pregnancy
    1. Trichloroacetic acid
    2. Cryotherapy
    3. Surgical excision
    4. Electrocautery
  4. Protocol
    1. Start with Cryotherapy
    2. Consider laser therapy if persistent
    3. Consider Imiquimod or surgical excision for extensive or refractory cases
    4. Avoid Podophyllotoxin-based agents in pregnancy
    5. Genital Warts do not contraindicate Vaginal Delivery unless obstructing pelvic outlet or significant bleeding risk
  5. References
    1. Erlandson (2023) Am Fam Physician 107(2): 152-8 [PubMed]

X. Management: Topical agents applied by patient

  1. Podofilox (Condylox) 0.5% solution or gel
    1. Podophyllotoxin extract applied to wart by patient
    2. Do not use for mucosal lesions
      1. Avoid on perianal, rectal, Urethral, vaginal warts
    3. Works best on moist mucosal skin sites (Does not work on keratinized Epidermis)
    4. Apply twice daily for 3 days, then wait 4 days, then restart application cycle for up to 4 weeks
    5. FDA category C
    6. Similar efficacy to Imiquimod
      1. Complete clearance of Genital Warts in 45-77% with a 4-33% recurrence rate
      2. Buck (2006) Clin Evid (15): 2149-61 [PubMed]
  2. Imiquimod cream 5% (Aldara)
    1. Preferred option among many gynecologists
    2. Do not use on mucous membranes
    3. May cause localized irritation, inflammation or Pruritus
    4. Apply a thin layer on affected lesions every other night for 3 nights per week until resolution for up to 16 weeks
      1. Wash the cream off the area 6 to 8 hours after each application
    5. Effective with 37-62% complete resolution and a 13% recurrence rate
      1. Beutner (1998) J Am Acad Dermatol 38(2 pt 1): 230-9 [PubMed]
      2. Edwards (1998) Arch Dermatol 134(1): 25-30 [PubMed]
  3. Veregen (Sinecatechins)
    1. Green Tea extract (15% ointment) with anti-HPV activity
    2. Apply 0.5 cm strand of ointment three times daily for up to 16 weeks
    3. Very expensive compared with other agents (e.g. Podofilox)
    4. With NNT of 5, no more effective than other agents
      1. As a new medication, no evidence that prevents longterm recurrence
      2. (2012) Presc Lett 19(6): 34
      3. Stockfleth (2012) Expert Opin Biol Ther 12(6):783-93 [PubMed]

XI. Management: Physician Applied Agents

  1. Podophyllin 10-25% in tincture of Benzoin
    1. Apply to each wart up to once weekly for 3-6 weeks; allow to dry
      1. Solution is left on skin for 1-4 hours and then washed off
    2. Similar clearance rates and recurrence to self applied agents listed above
    3. FDA category X
    4. Toxicity risk (deaths have occurred)
      1. Limit application area to <10 cm^2
      2. Limit amount applied to <0.5 ml per treatment
  2. Trichloroacetic acid (TCA) 60-90% compounded solution (or Bichloroacetic Acetic Acid or BCA)
    1. Apply to each wart up to three times weekly until resolution
    2. Allow to dry (lesion will "frost" or turn white)
    3. Solution is liquidy and easily spreads to non-involved skin
      1. If excessive application to normal skin, clean skin with liquid soap or Sodium Bicarbonate
    4. Similar efficacy to other methods

XII. Management: Ablation

  1. Cryotherapy
    1. See Cryotherapy for technique
    2. Apply to each wart up to once every 1-2 weeks
    3. Appears to be safe in pregnancy (although has not been studied)
  2. Surgical excision to dermal-epidermal junction
    1. Risk of painful scarring if excision too deep
    2. Performed under Local Anesthesia
    3. Exercise caution for lesions on the penis or anal verge
    4. Smoke venting equipment and masks are recommended to prevent HPV inhalation into the airway
      1. Using during electrosurgical techniques
    5. Excision Techniques
      1. Electrosurgical (ED&C or LEEP)
      2. Shave excision
  3. Carbon Dioxide laser (CO2 Laser)
    1. Use cautiously to avoid scarring
    2. May be used on mucosal lesions (vagina, Urethra)
    3. Used by specialists

XIII. Management: Agents for refractory warts (specialist use)

  1. Intralesional alpha Interferon
  2. Topical alpha Interferon
  3. Topical 5-FU 2% Solution
    1. No longer recommended due to adverse effects

XIV. Prognosis

  1. Response to topical agents mixed
    1. Response in 60-70% of patients
    2. Recurrence in at least 20-30% (up to 67% in some case studies)
  2. No absolute cure
    1. Warts can be removed, but virus may not be eradicated
  3. HPV-related malignancy risk factors
    1. Chronic Genital Warts
    2. Tobacco Abuse
    3. Cervical Dysplasia history
    4. High risk HPV-type (especially HPV 16 and 18)

XV. Complications: Cancers related to HPV Infection as STD (especially in Immunocompromised patients)

  1. Cervical Cancer
  2. Anal cancer
  3. Vulvar Cancer
  4. Vaginal cancer
  5. Penile Cancer
  6. Oral and pharyngeal cancer

XVI. Prevention

  1. Cervical Cancer Screening (with Pap Smear)
  2. Human Papilloma Virus Vaccine (Gardasil)
  3. Consider annual anorectal cancer screening (Rectal Exam, anal Pap Smear) in high risk patients (see above)
  4. Circumcision
    1. Circumcision reduces transmission rates of HIV, HPV and HSV
    2. Auvert (2009) J Infect Dis 199(1): 14-19 [PubMed]
    3. Tobian (2009) N Engl J Med 360(13): 1298-309 [PubMed]

Images: Related links to external sites (from Bing)

Related Studies