Neal Patel, MD
Allen D. Seftel, MD
BASICS
DESCRIPTION
• Anogenital epidermal lesions caused by the transmission of human papilloma virus (HPV)
• The most common viral sexually transmitted infection in the US, they are also called genital warts, or venereal warts
• Most common sites: Penis, vulva, vagina, cervix, perineum, and perianal area.
• Less commonly, urethra, bladder, oropharynx, larynx, and trachea
EPIDEMIOLOGY
Incidence (1)
• Most common STD
• ∼1% of sexually active adults in the US
Prevalence
• Highest prevalence: 18–28 yr olds and exceeds 50%
• HPV DNA can be detected in 10–15% of the US population
• HPV 6 and 11 account >90% of visible genital warts.
RISK FACTORS
• Increased risk with number of sex partners, frequency of sexual activity, early coitus, and presence of condyloma on partners
• Age <25
• Immunocompromised status
• Cigarette smoking and oral contraceptives may be associated with an increased risk.
• Onset of sexual activity at an early age
PATHOPHYSIOLOGY
• HPV is a double-stranded, circular DNA genome consisting of ∼8,000 base pairs. Subtypes 6 and 11 are associated with the majority of genital warts. Types 16, 18 most often associated with potential for malignancy.
• >80 different subtypes can potentially associate with condylomata.
• HPV subtypes associated with malignancy include: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, and 82 (2)
• Transmission is by direct sexual contact.
• Less common mode is autoinoculation from nongenital lesions.
• Basal layer of epidermis is invaded by the virus.
• Latent phase can last months to years.
ASSOCIATED CONDITIONS
• Penile cancer
• Anal cancer
• Cervical cancer
• Buschke-Lowenstein tumor
GENERAL PREVENTION
• Sexual abstinence
• Condoms
• Pre-exposure vaccination (Gardasil, Cervarix, Hepatitis B)
DIAGNOSIS
HISTORY
• Age and sex of patient
• History of recent sexual exposure
• Number of partners and frequency of sexual intercourse
• Visible warts usually seen within 2–3 mo after exposure
• Practice of anal intercourse
• Immunocompromised state
PHYSICAL EXAM
• Lesions are pinkish to red-grayish white cauliflower-like lesions found on moist surfaces, often coalescing.
• Lesions appear pearly white and granular
• Larger lesions may be verrucous or flat in configuration
• With magnifications, a central venule can be seen within each projection.
• Male: Examine penis, meatus, scrotum, perineum, suprapubic, and perianal region
• Female: Vagina, introitus, perineum, cervix, and perianal region
• Examine for evidence of coexisting STD (ulcers, discharge, adenopathy).
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• HPV cannot be readily grown in culture.
• Cytologic testing with Pap smear: Exfoliated genital cells are stained and examined for koilocytosis and neoplasia
• Serologic assays not useful in screening for HPV injection, but may provide prognostic information for patients with abnormal Pap smears
• Histologic analysis from biopsy specimens
• Rapid commercial screening tests available and are fairly accurate: ViraPap, ThinPrep Pap, Hybrid capture II
• If necessary, molecular characterization for diagnosis and serotyping (eg, Southern and/or slot blot hybridization, PCR)
• Consider screening for other associated STDs: HIV, GC, chlamydia, syphilis
Diagnostic Procedures/Surgery
• Magnification with colposcope or 10× handheld magnifying lens of the suspected region after application of 3–5% acetic acid-soaked gauze pad for 5 min allows visualization of nonvisible lesions, but has low specificity. (3,4)
– However, the Centers for Disease Control (CDC) no longer recommends acetic acid soaks to improve diagnosis. The soaks are associated with many false positives.
• Subclinical lesions may appear shiny white.
• Urethroscopy for any patients with suspected urethral warts, with care to occlude proximal urethra to prevent flushing of virus toward bladder
• Proctoscopy for patients at risk for anal condyloma
Pathologic Findings
• Branching, villous, papillary connective tissue stroma covered by epithelium.
• Superficial hyperkeratosis and thickening of the epidermis (acanthosis).
• Clear vacuolization of the prickle cells (koilocytosis), characteristic of HPV infection, is seen.
• There is no evidence of invasion of the underlying stroma
DIFFERENTIAL DIAGNOSIS
• Bowen disease and erythroplasia of Queyrat
• Bowenoid papulosis
• Buschke-Löwenstein tumor
• Condyloma latum (syphilis)
• Extramammary Paget disease
• Fibroepitheliomas
• Herpes simplex virus
• Malignant melanoma
• Molluscum contagiosum
• Nevi
• Pearly penile papules
• Seborrheic keratosis
• Squamous cell carcinoma/basal cell carcinoma
TREATMENT
GENERAL MEASURES (5)
• Diagnosis usually based on observation of characteristic lesions.
• Main goal of treatment is to remove visual presence of warts.
• Current therapies have an equally low effectiveness in preventing wart recurrence and may not reduce disease transmission.
• Vaccine: HPV quadrivalent recombinant (types 6, 11, 16, and 18): Gardasil (Merck) is currently available for administration to females of ages 9–26 for prevention of condyloma acuminata and associated diseases. HPV bivalent Cervarix (types 16 and 18) (GSK)
• Gardasil can also be used in males aged 9–26 to prevent genital warts. Administration to males prior to start of sexual activity is optimal.
• Topical therapy may take up to 3 mo to observe a response.
MEDICATION
First Line
• Podophyllin (Podoben 25%, Podocon, Podofin):
– Applied to lesion (concentration 10–25%) by health care worker once weekly for up to 6 wk
• Podofilox (Condylox):
– Self-application of a 0.5% solution to warts twice daily for 3 days, followed by 4 days without treatment; can be repeated 4–6 times.
• 5-FU (Efudex, Fluoroplex):
– Topical treatment with 5% cream 1–3 times per week for several weeks, as needed. Maybe also used as an intraurethral instillation but not without irritative complications.
• Trichloroacetic acid (Tri-Chlor):
– An 80–90% solution of trichloroacetic acid; apply directly to lesions; repeat weekly
• Imiquimod (Aldara):
– Potent inducer of interferon-α, which enhances cell-mediated cytolytic activity. Available as a 5% cream applied to external lesions 3 times per week up to a maximum of 16 wk
Second Line
Interferon-α IM or intralesional 3 million units 3 times a week for 3 wk
SURGERY/OTHER PROCEDURES
• Electrosurgery (electrodesiccation/loop electrosurgical excisional procedure): To destroy lesions; local anesthesia is usually sufficient
• CO2 laser therapy: Useful for lesions that have not responded to other therapies and for extensive disease. Magnification necessary to maximize efficacy; may produce less scarring
• Holmium laser can be used to remove intraurethral warts via cystoscopy.
• Surgical excision: Often reserved for extensive disease; also effective for isolated warts
• Cryotherapy: Application of liquid nitrogen on patients without extensive disease. This procedure can be repeated at 1- or 2-wk intervals.
ONGOING CARE
PROGNOSIS
• Subclinical infections are probably not curative.
• Women should still undergo routine Pap smears.
• Cervical cancer is associated with HPV infection. HPV infection is not solely responsible for the malignant transformation of genital cells, but it may be a cofactor in development of malignancy. HPV 6 and 11 are low-risk subtypes, and are seldom associated with malignancy.
• Homosexuals are at 25–50 times greater risk for anal cancer.
• Long-term, increased risk of malignancy secondary to HPV infection (HPV types 16, 18, 31, 33, and 51 are at highest risk of anogenital malignancy).
COMPLICATIONS
Malignant transformation: Penile carcinoma, cervical carcinoma, anal cancer, and Buschke-Löwenstein tumor
FOLLOW-UP
Patient Monitoring
• Educate the patient about self-exam.
• Patients should be examined shortly after therapy, to evaluate initial response rates.
• Encourage use of condoms if sexually active.
• Surveillance urethroscopy is recommended 3–6 mo after treatment of intraurethral lesions.
Patient Resources
• Centers for Disease Control and Prevention
– http://www.cdc.gov/std/hpv/default.htm
REFERENCES
1. Workowski KA, Berman S; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010;59(RR-12):1–110.
2. Cogliano V, Baan R, Straif K, et al. Carcinogenicity of human papillomaviruses. Lancet Oncol. 2005;6:204.
3. Naucler P, Ryd W, Törnberg S, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med. 2007;357:1589–1597.
4. Widdice LE, Moscicki AB. Updated guidelines for papanicolaou tests, colposcopy, and human papillomavirus testing in adolescents. J Adolesc Health. 2008;43(4 suppl):S41–S51.
5. Markowitz LE, Dunne EF, Saraiya M, et al. Quadrivalent human papillomavirus vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56(RR-2):1–24.
ADDITIONAL READING
• Beutner KR, Ferenczy A. Therapeutic approaches to genital warts. Am J Med. 1997;102(5A):28–37.
• Chuang TY. Condylomata acuminata (genital warts). An epidemiologic view. J Am Acad Dermatol. 1987;16(2 Pt 1):376–384.
• Leung AK, Kellner JD, Davies HD. Genital infection with human papillomavirus in adolescents. Adv Ther. 2005;22(3):187–197.
• Maymon R, Shulman A, Maymon B, et al. Penile condylomata: A gynecological epidemic disease: A review of the current approach and management aspects. Obstet Gynecol Surv. 1994;49(11):790–800.
See Also (Topic, Algorithm, Media)
• Bowen Disease and Erythroplasia of Queyrat
• Bowenoid Papulosis
• Buschke-Löwenstein Tumor
• Condyloma Latum (Syphilis)
• Fibroepitheliomas
• Herpes Simplex Virus
• Malignant Melanoma
• Molluscum Contagiosum
• Pearly Penile Papules
• Penis, Cancer General
• Penis, Lesion
• Seborrheic Keratosis
• Urethra, Condyloma (Warts)
CODES
ICD9
• 078.11 Condyloma acuminatum
• 079.4 Human papillomavirus in conditions classified elsewhere and of unspecified site
ICD10
• A63.0 Anogenital (venereal) warts
• B97.7 Papillomavirus as the cause of diseases classified elsewhere
CLINICAL/SURGICAL PEARLS
• HPV types 6, 11, 16, and 18 most common subtypes.
• Women who have received the HPV vaccine should still undergo routine screening with Pap smears.
• Eliminating warts may not decrease infectivity or transmission.
• Men along with women may benefit from vaccination.
• Vaccines are not recommended for use in women >26 yr of age.
• In absence of lesions, treatment is not recommended for individuals with subclinical infections.