Urethral Warts

Genital and urethral warts are caused by human papillomavirus (HPV) and are easily spread by sexual contact, with more than 30 strains of HPV infecting the genital tract (subtype HPV 6 is most frequently detected in genital warts). ^[1] However, urethral warts are uncommon, and most genital warts are benign and probably self-limiting.

The majority of 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] Epidemiologic and molecular studies have conclusively shown the association of HPV with the development of genital tract and anal cancers. ^[3] Immunosuppression is associated with reactivation of HPV, increasing the risk of malignant transformation.

Patients at risk of developing malignancies may benefit from therapy aimed at eradicating genital warts. ^{[4, 5, 6, 7]} However, 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.

HPV subtypes

HPV is a DNA virus with several characterized subtypes. ^[8] 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).

Types of HPV-associated warts

Warts arising from HPV infection include the following morphologic types (regional lymph nodes are not enlarged in the presence of these lesions):

• Larger cauliflowerlike condylomata
• Flesh-colored, dome-shaped papular warts that are 1-4mm in diameter
• Keratotic warts with a thick, crustlike layer resembling skin warts
• Flat-topped macular warts

Complications of urethral warts

Complications of urethral warts include the following:

• 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)

Patient education

For patient education information, see the Sexual Health Center, as well as Genital Warts (HPV Infection).

Genital warts affect approximately 500,000-1 million patients in the United States annually. Approximately 5% of these patients have urethral warts. Polymerase chain reaction (PCR) assay studies have detected HPV DNA in 12-16.5% of urethral specimens from healthy young volunteers.

The extent of HPV infection in the population was underestimated until advances in PCR assays and DNA hybridization techniques enabled the identification of people who are asymptomatic and infected.

In 1991, a study by Bauer et al demonstrated that 46% of college women undergoing routine pelvic examination were infected with HPV. ^[9] HPV infection is now considered the principal etiologic agent in cervical dysplasia and cervical cancer, with HPV 16 having 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 to 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 study screening 64 male partners of females with HPV infection, 20.3% tested positive for HPV DNA using the hybrid capture 2 (HC2) microplate assay, even though the males were clinically free of genital warts. ^[10]

Chow and colleagues examined trends in the incidence of genital warts since the introduction of an HPV vaccination program in Australia in 2007. In women younger than 21 years of age, the percentage of individuals with genital warts decreased significantly from 18.4% in 2004/2005 to 1.1% in 2013/2014, but the percentage increased among women older than 32 years, from 4.0% to 8.5%. ^[11]

The odds per year for having a diagnosis of genital warts adjusted for number of sexual partners during the vaccination period were 0.55 for women and 0.63 for heterosexual men younger than 21 years. No change was observed in the adjusted odds of genital warts in men or women older than 32 years. In men who have sex with men, a small annual decline in genital warts was seen (adjusted odds = 0.92). ^[11]

As previously discussed, 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 is but not known for genital warts. Blood-borne transmission has not been reported. Perinatal transmission accounts for cases of condylomata found during the first week of life.

Urethral procedures such as in cystoscopy or repeated urethral dilatation in patients with preexisting genital HPV infection have been shown to cause dissemination of HPV into the proximal urethra. ^[12]

Immunosuppression and HPV infection

HPV co-infection is also facilitated by immunosuppressed states, such as the presence of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS). Polymerase chain reaction (PCR) assay–based testing has shown HPV prevalence rates of 41-74% in women who are HIV seropositive.

Replication and spread of viral particles

Cells infected with HPV divide rapidly, with duplication of viral particles. This epitheliotropic virus depends on differentiating squamous epithelium for replication. Viral capsid proteins and infectious viruses are found in the superficial differentiated cell layers. HPV 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.

HPV 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 found most often 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 during sexual intercourse. They may spread to adjacent areas by autoinoculation.

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. HIV-positive men who practice receptive anal intercourse may present with anal and intra-anal warts. Other groups of immunosuppressed persons (eg, those receiving transplants, and those with Hodgkin lymphoma, AIDS, or diabetes mellitus) 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 sexually transmitted diseases (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. ^[13] Semen may be an alternative to urethral brushing.

Urethroscopy and/or cystoscopy are 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 fluoresces blue.

Anoscopy is used for the diagnosis of intra-anal lesions. If the warts are located above the dentate line, sigmoidoscopy is required.

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 a diagnosis of condyloma acuminata before starting treatment, because such lesions are not always due to HPV. This procedure is usually not applicable for intraurethral lesions.

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.

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 are 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. ^[14]

Currently, 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.

Treatment of urethral warts is aimed at inducing a wart-free state and reducing the amount of infectious virus present. Medical treatment is useful for urethral warts located at accessible sites.

Podophyllin resin and podofilox

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. However, podofilox has not been approved for urethral, rectal, perianal, vaginal, or cervical warts.

Imiquimod

Imiquimod 5% cream stimulates the production of interferon and other cytokines and is topically applied 3 times weekly 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 and bichloracetic acid

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.

5-fluorouracil

Applied weekly for 3 weeks, 5-fluorouracil may eradicate urethral lesions. ^[15] The cream must be worked down into the urethra, avoiding exposure of the drug 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. ^[16]

Interferon alfa-2b

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

Ingenol mebutate gel

There are a number of reported cases of successful treatment of condylomata acuminata (CA) with ingenol mebutate, which has been approved by the US Food and Drug Administration for the treatment of actinic keratosis. However, in a study by Dadras and colleagues on the use of ingenol mebutate gel for treatment of cryotherapy-resistant anogenital warts, although 10 of the 15 patients experienced initial complete clearance, the warts recurred in all 15 patients within 12 months. In addition, all of the patients reported pain and local adverse reactions. ^[17]

Self-applied medications

The trend toward cost-effective therapies has resulted in a general move toward patient-applied therapies after initial assessment and screening. ^[18] Compared with provider-applied treatments, which include all of the above, there are currently 2 patient-applied therapy options available: podophyllotoxin and imiquimod. Imiquimod has generally been found to be more effective than podophyllotoxin for treatment of anogenital warts, but more expensive; this has led to conflicting conclusions regarding cost-effectiveness.

A 1999 United States study recommended initial treatment with imiquimod as the preferred intervention option, ^[18] while a 2003 United Kingdom study found the superiority of imiquimod to podophyllotoxin to be modest and statistically insignificant, and concluded that podophyllotoxin has robust economic superiority. ^[19]  A randomized 2020 UK study found that imiquimod and podophyllotoxin creams had similar efficacy for wart clearance, albeit with a wide confidence interval, and concluded that podophyllotoxin is more cost-effective. ^[20]

Laser therapy

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 treatment. This reduces the rate of recurrence and is effective in treating recalcitrant lesions. ^[21]

An Nd:YAG laser at 15W can be applied to the lesion; a circumferential area of 0.5-1cm provides excellent control and better tissue penetration than does the carbon dioxide laser set at 5W. 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. A carbon dioxide laser is unsuitable for use with a cystoscope because it is directed along a system of mirrors and cannot be used in a liquid medium.

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

Blokker and colleagues compared clinical outcomes in a retrospective study of men with condylomata acuminata on the external genitalia or within the urethra who were treated with either the Nd:YAG laser (n=76) or the Thulium laser (n=39). Both treatments were effective and safe, with similar rates of recurrence and complications. ^[22]

Cryotherapy

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

Photodynamic therapy

For warts at the meatus or fossa navicularis, topical 5-ALA photodynamic therapy (ALA-PDT) has been shown to be effective, with a complete response rate of 95% after a follow-up of 6-24 months. ^[23] ALA-PDT also appears to compare favorably with carbon dioxide laser treatments for topical therapy, with lower recurrence. ^{[24, 25, 26]}  A systematic review comparing treatment for urethral condyloma reported that ALA-PDT was the most common treatment and produced the lowest recurrence rate (7.5%). However, adverse effects were significantly higher (69%) among those treate with ALA-PDT compared to laser therapy (28%) and topical treatments (30%). ^[27]

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

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 diathermic destruction of meatal warts minimizes the risk of circumferential thermal injuries and resultant strictures. ^[28]

Surgical excision may be used with urethral lesions that were not adequately treated endoscopically or that recurred 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.

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 known associated malignancies, such as penile and cervical intraepithelial neoplasia.

One HPV vaccine, Gardasil 9 (9vHPV) is currently available in the United States. It provides coverage of 9 HPV subtypes: 6, 11, 16, 18, 31, 33, 45, 52, and 58. It is approved by the US Food and Drug Administration (FDA) for prevention of HPV-associated genital warts (condyloma acuminata) in males and females aged 9 through 45 years. ^{[29, 30]}  A UK study that compared the efficacy and cost-effectiveness of imiquimod or podophyllotoxin cream, either alone or in combination with the older quadrivalent HPV vaccine (no longer available in the US) in patients with anogenital warts did not demonstrate a statistically significant benefit from the vaccine with respect to increasing anogenital wart clearance or preventing recurrence. ^[20]