AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• References

Condylomatous warts of the genital tract and anus have been described as early as the first century AD. The venereal origin of the disease was described in the 1950s. Intracellular virus particles in the wart tissue were demonstrated in 1968. In the 1970s, further work attributed these cellular changes to human papillomavirus (HPV) infection. Simultaneously, molecular hybridization techniques demonstrated the genetic heterogeneity of HPVs.

In the following decades, nearly 100 HPVs were identified by polymerase chain reaction (PCR)–based assays, and the genomes of about 75 HPVs were cloned and sequenced.¹ Of these, more than 30 types infect the genital tract. Recent epidemiologic and molecular studies have conclusively shown the association of HPV types with the development of genital tract and anal cancers.

Problem

Genital and urethral warts are caused by HPV and are easily spread by sexual contact. Subtype HPV 6 is most frequently detected in genital warts. Most of the newly acquired genital HPV infections are subclinical and asymptomatic. Occasionally, the detection of HPV DNA in genital specimens may be the only evidence of current infection. Furthermore, serum antibodies to specific HPV types may be the only indication of past exposure. After a long period of latency, individuals infected with certain HPV subtypes are at risk of developing squamous cell carcinomas.² Immunosuppression is associated with reactivation of HPV, increasing the risk of malignant transformation.

The epidemiologic extent of this disease was underestimated until recent advances in PCR-based assays and DNA hybridization techniques enabled the identification of people who are asymptomatic and infected. In 1991, a study by Bauer et al utilized PCR techniques and demonstrated that 46% of college women undergoing routine pelvic examination were infected with HPV.³ HPV infection is now considered the principal etiologic agent in cervical dysplasia and cervical cancer. HPV 16 has been associated with more than 50% of cervical malignancies. Condylomata have also been linked with squamous cell carcinoma of the penis.

With increased recognition of the problem and better detection methods, the number of patient visits to physicians' offices for genital warts has steadily increased since the 1950s. In the United States, an 8-fold increase in the age- and sex-adjusted incidence of genital warts was reported from 1950-1954 and 1975-1978. A 4.5-fold increase in the number of first consultations for genital warts occurred from 1966-1984.

Current evidence suggests that more than 50% of sexually active adults have been infected with one or more genital HPV types, most of which are subclinical, unrecognized, and benign. This is presently considered a minor sexually transmitted disease (STD) and not reportable, but the asymptomatic nature of the condition and its potential association with malignancy require a high degree of diligence in its diagnosis and management in patients who are at risk. 

In a recent study screening high-risk individuals such as asymptomatic male partners of females with HPV infection, even though they were clinically free of genital warts, 20.3% tested positive for HPV DNA using the hybrid capture 2 (HC2) microplate assay.⁴

Frequency

• United States: Genital warts affect approximately 500,000-1 million patients annually. Approximately 5% of these patients have urethral warts. Recent PCR-based studies detected HPV DNA in 12-16.5% of urethral specimens from healthy young volunteers.
• International: The incidence is similar to that reported in the United States.

Etiology

Urethral warts are caused by HPV. They are primarily sexually transmitted, and transmission is possibly enhanced by the moisture and abrasion of epithelial surfaces. The risk of genital infection increases with each new sex partner. Condoms are not definitely known to provide an effective barrier. Nonsexual transmission through fomites is significant for skin warts but not known in genital warts. Blood-borne transmission has not been reported. Perinatal transmission accounts for cases of condylomata found during the first week of life. Urethral instrumentation such as in cystoscopy or repeated urethral dilatation in patients with pre-existing genital HPV infection has been shown to cause dissemination of HPV into the proximal urethra.⁵

HPV is a DNA virus with several characterized subtypes (see Human Papillomavirus).⁶ Viral types 6,11, 42-44, and 54 are associated with condylomata acuminata and low-grade dysplasia, while types 16, 18, 31, 33, 35, 39, 45, 51, 52, 54, 56, 66, and 68 have a higher association with genital malignancy (especially cervical malignancy). HPV co-infection is also facilitated by immunosuppressed states such as HIV and AIDS. PCR-based methods have shown HPV prevalence rates of 41-74% in women who are HIV seropositive.

Pathophysiology

Cells infected with HPV divide rapidly with duplication of viral particles. These epitheliotropic viruses depend on differentiating squamous epithelium for their replication. Viral capsid proteins and infectious viruses are found in the superficial differentiated cell layers. The disease is transmitted when the viral particles released from the lesions come into contact with another person. Approximately two thirds of the sexual contacts of patients with genital warts develop the same disease. Incubation periods are usually 1-2 months but may extend to several months.

Clinical

A significant proportion of affected men and women are asymptomatic, and their subclinical lesions are not identifiable by simple inspection. When present, the warty lesions are located in moist mucocutaneous surfaces of the perineal and genital areas. A few patients complain of associated symptoms of itching, burning, pain, or bleeding; women may notice a vaginal discharge. Warts occur either singly on a stalk or in broad-based clusters and are soft and friable.

In males, the glans penis, shaft, and prepuce are common sites of infection. Urethral warts are mostly found in the meatus and fossa navicularis but may extend as far as the prostatic urethra. In females, the vulva, vagina, and cervix are common sites of infection. Lesions are also observed at the anal verge and occasionally in the mouth. Bladder involvement is rare.

Generally, condylomata appear in areas subject to physical trauma occurring during sexual intercourse. They may spread to adjacent areas by autoinoculation. Morphologic types include (1) larger cauliflowerlike condylomata, (2) flesh-colored, dome-shaped papular warts that are 1-4 mm in diameter, (3) keratotic warts with a thick crustlike layer resembling skin warts; and (4) flat-topped macular warts. Regional lymph nodes are not enlarged.

Suspect urethral warts when patients with genital warts present with pyuria or urethral discharge. Intraurethral warts may be a cause of recurrent meatal warts. Urethral and bladder involvement with condylomata is often associated with immunosuppression. Gay men who are HIV positive and who practice receptive anal intercourse may present with anal and intra-anal warts. Other groups of immunosuppressed persons (eg, people receiving transplants, people with Hodgkin disease, people with AIDS, people with diabetes) may develop perianal lesions but not intra-anal warts, which are due to transfer of the virus inside the anus.

Carefully assess the external genitalia of patients presenting with a typical sexual history and symptoms suggestive of urethral involvement. Include investigations to exclude other concomitant STDs. Offer current sexual partners of the patients an examination and treatment for macroscopically visible warts and other STDs. If screening of male partners is to be offered, specimens obtained from penile and urethral brushing for HPV DNA detection appear to be the most accurate.⁷ Semen may be alternative to urethral brushing. 

CONTRAINDICATIONS

Section 3 of 10  

• Authors and Editors
• Introduction
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• References

Medical treatments aimed at treating urethral warts should generally be used with caution, and they should be used only when the warts are easily accessible, as in the fossa navicularis.

Podophyllin is contraindicated during pregnancy.

WORKUP

Section 4 of 10  

• Authors and Editors
• Introduction
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• References

Lab Studies

• Currently, tests for HPV DNA detection and typing are probably of clinical value only in the detection and management of cervical intraepithelial neoplasia to reduce the risk of invasive cervical cancer.

Other Tests

• Application of dilute acetic acid solution (3-5%) to the genital area, followed by inspection with a magnifying glass, helps identify subclinical disease.
• • Flat lesions, often not detected on inspection, turn white.
  • A biopsy can then be performed on these acetowhite lesions to confirm the diagnosis.
  • This is usually not applicable for intraurethral lesions.

Diagnostic Procedures

• Biopsy
• • Biopsy is used to confirm that acetowhite lesions are condyloma acuminata before starting treatment because they are not always due to HPV.
  • Biopsy is also used to exclude malignant changes prior to treating large lesions with topical podophyllin because this agent may induce histologic changes suggestive of carcinoma.
• Urethroscopy and/or cystoscopy is appropriate when acetowhite lesions or typical warts are located at the urethral meatus.
• Fluorescence urethroscopy after the instillation of 5-aminolevulinic acid (5-ALA) improves the diagnostic yield of urethral warts not revealed by conventional endoscopy. One hour after urethral instillation of a 0.1% solution of 5-ALA and lidocaine jelly, the urethra is illuminated with blue excitation light with a wavelength of between 375 and 440. The condylomata fluoresce red because of increased accumulation of protoporphyrin IX synthesized from 5-ALA in the epithelial cells, differentiating them from normal mucosa, which fluoresce blue.
• Anoscopy is used for the diagnosis of intra-anal lesions. If the warts are located above the dentate line, sigmoidoscopy is required.

Histologic Findings

Microscopically, condyloma acuminata has an outer layer of keratinized tissue covering papillary fronds supported by connective tissue stroma. The epithelium consists of an orderly arrangement of hyperplastic squamous cells. The dermal papillae are elongated and usually characterized by a lymphocytic infiltrate. Koilocytes are mature squamous cells with an atypical hyperchromatic nucleus surrounded by a large clear perinuclear zone. They are scattered throughout the outer cell layers and are pathognomonic of HPV infection.⁸

TREATMENT

Section 5 of 10  

• Authors and Editors
• Introduction
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• References

Medical therapy

Treatment of urethral warts is aimed at inducing a wart-free state and reducing the amount of infectious virus present. ^{9, 10, 11}

Medical treatment is useful for urethral warts located at accessible sites. Podophyllin resin, an antimitotic plant compound (10-25% solution in ethanol or tincture of benzoin), is applied with a cotton-tipped swab, allowed to dry, and washed off completely after 1-4 hours. Applications may be administered once or twice weekly for as many as 6 weeks. Do not treat pregnant patients with podophyllin.

Podofilox 0.5% solution or gel (purified from podophyllin resin) has a stable shelf life, need not be washed off after use, and is less likely to cause systemic toxicity. Podofilox has not been approved for urethral, rectal, perianal, vaginal, or cervical warts.

Imiquimod 5% cream stimulates the production of interferon and other cytokines and is topically applied 3 times a week for as many as 16 weeks. The treated area is washed 6-10 hours after application of the cream. Imiquimod has not been approved for urethral, rectal, perianal, vaginal, or cervical warts.

Trichloroacetic acid or bichloracetic acid in 80% or 90% solution may be used to treat small moist lesions. The solution is carefully applied to the lesion, avoiding normal tissue, and should be thoroughly washed off in 1-2 hours. Sodium bicarbonate (baking soda) may be applied to the uninvolved surrounding epithelium to remove excess acid.

Cryotherapy with liquid nitrogen and solid carbon dioxide may be suitable for superficial lesions. For each treatment, 1-6 freeze-thaw cycles per wart may be needed. Intraurethral lesions may be difficult to treat.

Applied weekly for 3 weeks, 5-fluorouracil may eradicate urethral lesions.¹² The cream must be worked down into the urethra, avoiding exposure to the scrotal skin. A scrotal support or zinc oxide cream may be useful in this regard. Used as a solution (500 mg in 50 mL normal saline), 5- fluorouracil has also been effective in treating advanced urethral lesions.¹³  

Intralesional interferon alfa-2b has some activity against condyloma and may be used for extensive and recalcitrant lesions.

Reports have shown greater efficacy with combination therapies, using intralesional interferon alfa or topical 5-fluorouracil in conjunction with ablative carbon dioxide or Nd:YAG laser therapy. This reduces the rate of recurrence and is effective in treating recalcitrant lesions.¹⁴

The recent trend toward cost-effective therapies has resulted in a general move toward patient-applied therapies after initial assessment and screening.¹⁵ Compared to provider-applied treatments, which include all of the above, there are currently 2 patient-applied therapy options available: podophyllotoxin and imiquimod. Podophyllotoxin has better efficacy (clearance rates of 68-88% and recurrence rates of 16-34%) than imiquimod (clearance of 40-77% and recurrence of 13-19%). A recent study comparing these home-based treatments seemed to show similar costs.

For warts at the meatus or fossa navicularis, topical 5-ALA photodynamic therapy (ALA-PDT) has been recently shown to be effective, with a complete response rate of 95% after a follow-up of 6-24 months.¹⁶ ALA-PDT also appears to compare favorably to carbon dioxide laser treatments for topical therapy, with lower recurrence.¹⁷

Surgical therapy

Circumcision serves to remove preputial lesions and provides exposure for treatment of urethral meatal warts and subsequent monitoring.

Surgical laser therapy with both carbon dioxide and Nd:YAG lasers has been successful in treating condylomata. An Nd:YAG laser at 15 W power can be applied to the lesion, and a circumferential area of 0.5-1 cm provides excellent control and better tissue penetration than the carbon dioxide laser set at 5 W. Careful follow-up care is required because of the risk of recurrence. For intraurethral lesions, the Nd:YAG laser can be transmitted through a cystoscope, while the carbon dioxide laser is unsuitable because it is directed along a system of mirrors and cannot be used in a liquid medium, precluding its use with a cystoscope.

Better identification of intraurethral lesions with prior application of 5-ALA and subsequent fluorescent diagnostics improves treatment efficacy by appropriately directed Nd:YAG laser therapy, thus reducing the incidence of recurrences.

Transurethral resection of lesions using electrocautery loops (as used for prostatic resections) can be performed for lesions in the prostatic urethra or for solitary lesions in the wider regions of the anterior urethra. The risk of urethral stricture precludes this method in widespread disease of the urethra. The use of a plastic quill as a shield during diathermy destruction of meatal warts minimizes the risk of circumferential thermal injuries and resultant strictures.¹⁸

Surgical excision may be used with urethral lesions inadequately treated endoscopically or that recur after laser or medical therapy. Reconstructive urethroplasty in the form of direct end-to-end anastomosis or graft replacement may be required, depending on the extent of urethra removed.

Follow-up

In patients who are immunocompetent, no follow-up care is required once the warts and possible complications of therapy have cleared.

In patients who are immunosuppressed, periodic cystourethroscopy may be required to identify recurrences.

Follow-up care is also directed at identifying other STDs, as well as the known associated malignancies, eg, penile and cervical intraepithelial neoplasia.

For excellent patient education resources, visit eMedicine's Sexually Transmitted Diseases Center. Also, see eMedicine's patient education article Genital Warts.

COMPLICATIONS

Section 6 of 10  

• Authors and Editors
• Introduction
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• References

• Recurrent disease
• Urethral strictures and related problems
• • Reduced urinary flow/urinary obstruction
  • Infertility due to urethral and ejaculatory duct obstruction
• Associated malignancies
• • Penile and cervical intraepithelial neoplasia
  • Predisposition to bowenoid papulosis (carcinoma in situ of the penis)

OUTCOME AND PROGNOSIS

Section 7 of 10  

• Authors and Editors
• Introduction
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• References

Urethral warts are uncommon. Most genital warts are benign and probably self-limiting. Patients at risk of developing malignancies may benefit from therapy aimed at eradicating these warts.

FUTURE AND CONTROVERSIES

Section 8 of 10  

• Authors and Editors
• Introduction
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• References

Rapid advances in current vaccine research have resulted in the creation of HPV viruslike-particle (VLP) vaccines. HPV16 VLP vaccine was shown to be protective against persistent HPV16 infection in a group of women. Furthermore, a phase 2 randomized, double-blind, controlled trial in 1113 women with a bivalent HPV16/18 VLP vaccine showed a 95% efficacy against persistent cervical infection and 93% efficacy against associated cytological abnormalities.¹⁹ In the future, such vaccines could be used to prevent all types of HPV infections, including urethral infections.

FURTHER READING

Section 9 of 10  

• Authors and Editors
• Introduction
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• References

For more information, visit Medscape’s HPV and Cervical Cancer Resource Center.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• References

1. Koutsky LA, Kiviat NB. Genital human papillomavirus. In: Sexually Transmitted Diseases. 3^rd ed. 1999:347-359.
2. Burmer GC, True LD, Krieger JN. Squamous cell carcinoma of the scrotum associated with human papillomaviruses. J Urol. Feb 1993;149(2):374-7. [Medline].
3. Bauer HM, Ting Y, Greer CE, Chambers JC, Tashiro CJ, Chimera J, et al. Genital human papillomavirus infection in female university students as determined by a PCR-based method. JAMA. Jan 23-30 1991;265(4):472-7. [Medline].
4. Hadjivassiliou M, Stefanaki C, Nicolaidou E, Bethimoutis G, Anyfantakis V, Caroni C, et al. Human papillomavirus assay in genital warts--correlation with symptoms. Int J STD AIDS. May 2007;18(5):329-34. [Medline].
5. Sumino Y, Mimata H, Nomura Y. Urethral condyloma acuminata following urethral instrumentation in an elderly man. Int J Urol. Oct 2004;11(10):928-30. [Medline].
6. Smotkin D. Virology of human papillomavirus. Clin Obstet Gynecol. Mar 1989;32(1):117-26. [Medline].
7. Giovannelli L, Migliore MC, Capra G, Caleca MP, Bellavia C, Perino A, et al. Penile, urethral, and seminal sampling for diagnosis of human papillomavirus infection in men. J Clin Microbiol. Jan 2007;45(1):248-51. [Medline].
8. Schneider V. Microscopic diagnosis of HPV infection. Clin Obstet Gynecol. Mar 1989;32(1):148-56. [Medline].
9. Beutner KR, Ferenczy A. Therapeutic approaches to genital warts. Am J Med. May 5 1997;102(5A):28-37. [Medline].
10. Beutner KR, Wiley DJ, Douglas JM, Tyring SK, Fife K, Trofatter K, et al. Genital warts and their treatment. Clin Infect Dis. Jan 1999;28 Suppl 1:S37-56. [Medline].
11. Carpiniello VL, Schoenberg M. Laser treatment of condyloma and other external genital lesions. Semin Urol. Aug 1991;9(3):175-9. [Medline].
12. Dretler SP, Klein LA. The eradication of intraurethral condyloma acuminata with 5 per cent 5-fluorouracil cream. J Urol. Feb 1975;113(2):195-8. [Medline].
13. Wen YC, Wu HH, Chen KK. Pan-urethral wart treated with 5-fluorouracil intraurethral instillation. J Chin Med Assoc. Aug 2006;69(8):391-2. [Medline].
14. Zaak D, Hofstetter A, Frimberger D, Schneede P. Recurrence of condylomata acuminata of the urethra after conventional and fluorescence-controlled Nd:YAG laser treatment. Urology. May 2003;61(5):1011-5. [Medline].
15. Langley PC, Tyring SK, Smith MH. The cost effectiveness of patient-applied versus provider-administered intervention strategies for the treatment of external genital warts. Am J Manag Care. Jan 1999;5(1):69-77. [Medline].
16. Wang XL, Wang HW, Wang HS, Xu SZ, Liao KH, Hillemanns P. Topical 5-aminolaevulinic acid-photodynamic therapy for the treatment of urethral condylomata acuminata. Br J Dermatol. Oct 2004;151(4):880-5. [Medline].
17. Chen K, Chang BZ, Ju M, Zhang XH, Gu H. Comparative study of photodynamic therapy vs CO2 laser vaporization in treatment of condylomata acuminata: a randomized clinical trial. Br J Dermatol. Mar 2007;156(3):516-20. [Medline].
18. Shaw MB, Payne SR. A simple technique for accurate diathermy destruction of urethral meatal warts. Urology. May 2007;69(5):975-6. [Medline].
19. Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A, et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet. Nov 13-19 2004;364(9447):1757-65. [Medline].

Article Last Updated: Feb 11, 2008