Human papillomavirus (HPV) is one of the most prevalent sexually transmitted infections in the world and rarely may affect the urethra and bladder. This article describes two cases of bladder HPV infection managed at our institution and summarizes literature describing the management of lower urinary tract HPV lesions published in PubMed (MEDLINE) since 2010. Articles were selected after performing a scoping literature review using the search terms “human papillomavirus”, “condyloma”, “bladder” and/or “urethra”. Thirty-five articles were included in the review with treatment options including surgical excision, ablative therapy, photodynamic therapy, and topical agents. 

Keywords: bladder, urethra, HPV, condyloma, treatment, photodynamic therapy, ablative therapy

HPV, Human papillomavirus; CA, condyloma acuminata; MeSH, medical subject heading; VIN, vulvar intraepithelial neoplasia; UTIs, urinary tract infections; PDT, photodynamic therapy

The Human Papilloma Virus (HPV) is one of the most common sexually transmitted infections in the world. In the United States alone, approximately 14 million people acquire HPV each year.¹ The infection is usually asymptomatic and effectively cleared by the host’s immune system. However, some infections result in condyloma acuminata (CA) or warty growths. Infection involving the bladder and/or urethra is rare and primarily occurs in immune-compromised individuals.¹ Symptoms of CA of the lower urinary tract include frequency, urgency, weak stream, and a feeling of incomplete emptying.²

CA often resolves on its own. However, approximately 30% of all genital lesions recur leading to increased frequency of clinic visits, increased cost to the healthcare system, and psychosocial consequences for patients.¹ The oncogenic properties of HPV also lead to an increased risk of malignancy, particularly squamous cell carcinoma. The relationship between HPV and bladder cancer is not yet fully understood. Current data describes an association between urothelial carcinoma and HPV with one study reporting an odds ratio of 4.24 for the development of urothelial carcinoma in patients with HPV infection.^3,4

Treatment of urethral and bladder CA varies depending on patient factors and the number, size, and site of the lesions involved. Additionally, given the rare nature of urethral and bladder CA lesions, a consensus on appropriate treatment does not exist. The purpose of this article is to describe our experience with two cases of bladder CA and provide a narrative review of current treatment options for bladder and urethral CA described in the literature since 2010. 

Two women treated at our institution for bladder CA were retrospectively analyzed through chart review. Demographic and clinical characteristics including age, gender, past medical history, presentation of CA, and treatment(s) performed were documented. Operative reports and intraoperative pathology reports were additionally reviewed where appropriate.

Literature review

A scoping review of world literature on urethral and bladder HPV/CA was conducted by two researchers to identify articles utilizing any treatment modality for urethral or bladder HPV between 2010 and 2021. This search was completed using PubMed (MEDLINE). A Boolean search was conducted using the Medical Subject Heading (MeSH) terms “urethra” and “bladder” followed by the operator “AND” and the additional MeSH terms “condyloma” and “human papillomavirus”. 

Thirty-five studies were identified and reviewed for study design, number of patients, treatment method, and clinical outcomes. Urethra and bladder CA lesions are rare which is generally limiting to the performance of high-quality studies requiring larger sample sizes. Thus, studies of varying quality (including case reports) were considered for inclusion in this review. No specific outcome measures were required for study inclusion. Articles were excluded if they were not in English or if the full article was not available. Table 1 includes a summary of select studies included in this review. Small case series are considered exempt by the institutional review board (IRB) at our institution.

Case series

Case 1: This is a 36-year-old female with type 1 diabetes mellitus status post pancreatic and renal transplant and vulvar intraepithelial neoplasia (VIN) presenting with symptoms of stress urinary incontinence, recurrent urinary tract infections (UTIs), and a prolapsing urethral lesion. Examination in the office was consistent with a prolapsing urethra and cystourethroscopy was performed which additionally identified a small urethral polyp near the bladder neck at 6 o’clock (Figure 1a). She subsequently underwent surgical excision and repair of her urethral prolapse 10 weeks later. Repeat cystourethroscopy at the time of surgery identified diffuse white, frondular lesions within the urethra with a normal bladder survey. Exam under anesthesia revealed a peri-clitoral lesion which was excised. Pathologic examination of the urethral tissue demonstrated high-grade squamous dysplasia arising from condyloma with p16 and ki67 positivity. 

A surveillance cystoscopy was performed six months postoperatively and demonstrated a well-healed urethra with a new CA lesion near the bladder neck at 5 o’clock. The patient was also evaluated by gynecologic oncology who performed a repeat biopsy of the peri-clitoral lesion and recommended a wide local excision when the pathology returned as high-grade dysplasia. The ongoing plan was to perform a resection of the bladder neck lesion as a combined case with oncology.

Case 2: This is a 32-year-old female with a history of systemic lupus erythematosus (SLE), end-stage renal disease requiring two renal transplants, and anogenital CA status post partial vulvectomy who presented with recurrent UTIs, dysuria, frequency and urge incontinence. Cystourethroscopic examination demonstrated a polypoid lesion emanating from 11 o'clock at the proximal urethra. There was also a 1 cm broad-based growth at the right trigone with fluffy white spicules and a second smaller lesion at the left lateral sidewall of a similar appearance (Figure 1b). Her implanted ureteral orifice was normal in appearance. Cystourethroscopy under anesthesia was performed and three <1 cm raised sessile lesions were noted: left lateral bladder wall, midline trigone, and at 11 o’clock position at the proximal urethra. Transurethral resection of the lesions was successfully performed. Pathologic evaluation demonstrated positivity for p16 with ki67 staining consistent with HPV. A repeat cystoscopy three months later did not show evidence of recurrent disease. 

Figure 1 Urethral and bladder condylomata acuminata (CA).

The most common treatment modalities for bladder CA included resection, ablation, photodynamic therapy, topical agents, and vaccination. The breakdown of studies that employed each treatment modality is as follows: resection (n=15), ablation (n=7), photodynamic therapy (n=10), topical agents (n=10), and vaccination (n=1). Several studies described the use of multiple treatment modalities as CA lesions are notoriously difficult to treat and recurrence is common. 

Surgical excision

Surgical excision is the most common treatment option for the management of bladder and urethral CA with the various techniques described.^5–11 Additionally, surgical excision or cryotherapy is the only recommended treatment options for lesions of the urethral meatus according to the Centers for Disease Control.¹² Currently, there are no Centers for Disease Control (CDC)-supported recommendations for the treatment of intraurethral or intravesical CA.

Surgical techniques vary based on the characteristics and location of the lesion. Open techniques are often chosen when endoscopic excision or ablation either fail or the lesions are so large that these modalities would be unsuccessful.¹³ Endoscopic techniques such as transurethral resection (TUR) have been increasingly used in recent years, particularly for internal lesions.^7-9,14–17 Monopolar or bipolar electrocautery may be used for endoscopic lesion resection. Regardless of the technique used, visual eradication of CA and sufficient resection depth are essential, especially given the increased risk of carcinoma.¹⁸

For thz treatment of distal urethral lesions, an open technique may be appropriate. Nordsiek et al² described the resection of a urethral mass performed in a similar fashion to urethral caruncle excision. In the event that primary closure is not possible, several skin flap techniques have been described including the Cohney, Blandy-Tresidder, Brannen, and De Sy.¹³ Surgical devices such as the harmonic scalpel may also be used for open CA resection.¹¹ For all surgical methods, the most concerning complications are urethral stricture and scarring and thus close follow-up is warranted.

Ablative therapy

Laser therapy is a less invasive option for the treatment of CA when compared to surgery and has been described for nearly 50 years. While many laser types are available, the Nd:YAG laser has been most frequently described in the treatment of bladder and urethral CA, perhaps because it has a deeper penetration effect than Thulium or other commonly used lasers. Lesion location also influences laser selection, as all lasers with the exception of CO₂ easily pass through an endoscope, thus limiting the application of the CO₂ laser to external lesions.

Blokker et al. conducted a retrospective analysis comparing treatment with Nd:YAG to Thulium laser in 115 male patients with genital or urethral CA. All subjects were successfully treated and recurrence rates were comparable (33 vs 34%, respectively) in both groups.¹⁹ A prospective study of 92 patients assessing the efficacy of diode laser vaporization in genital lesions described a 70% response rate and an 18% recurrence rate. However, only four of the lesions described in this study involved the urethra.²⁰ One case report described the successful use of the CO₂ laser on a large periurethral CA lesion.²¹

In addition to laser ablation, cryotherapy has been used in the treatment of CA. This therapy is performed with the use of a metallic cryoprobe or topical application of liquid nitrogen. The low boiling point of the liquid nitrogen results in rapid heat transfer, thus destroying the cells to which it is applied. Few studies published in PubMed since 2010 have used cryotherapy as a treatment modality for bladder or urethral HPV. We describe one study evaluating cryotherapy as part of combination therapy below. Frequently described complications associated with laser therapy include urethral strictures, meatal stenosis, edema, and scarring. Cryotherapy may result in skin irritation and pigmentation changes.

Photodynamic therapy

Photodynamic therapy (PDT) is a two-step treatment modality consisting of the application of a photosensitizing agent followed by light exposure. 5-aminolevulinic (ALA) is an amino acid photosensitizer commonly used in PDT that functions by creating reactive oxygen species with subsequent cellular apoptosis when exposed to a specific wavelength of light.¹³ 

Generally, one cycle of treatment consists of the application of a 20% ALA solution to the lesion for 3 hours followed by 20 to 30 minutes of PDT. The number of cycles and frequency of treatment are determined by the severity of the disease. Xie et al used ALA-PDT in 21 patients with urethral CA and achieved 100% remission after four cycles.²² Additional studies support that ALA-PDT has success rates approaching 100% when two or more cycles are performed.^23,24 Recurrence rates were low with most patients achieving complete remission after additional PDT was performed.

Ablative techniques have been described as an effective adjunct to ALA-PDT. One case series described the utilization of the CO2 laser for lesions of the distal urethra and urethral meatus with no recurrence at a 6-month follow-up.²⁵ Another case study described a male patient with intraurethral CA in whom the ALA solution was dissolved in a gel and administered intraurethral via a catheter. >95% of his lesions were cleared with PDT and the remaining lesions were treated with the Holmium laser.²⁶ Another case study described CA lesions removed with radiofrequency cauterization followed by PDT.²⁷

Cryotherapy has also been described in conjunction with ALA-PDT. Mi et al performed a randomized clinical trial comparing ALA-PDT with cryotherapy versus cryotherapy alone in lesions of the anus, genitalia, and urethra.²⁸ In their protocol, combined therapy consisted of an 8-second topical application of liquid nitrogen to the CA lesions for two rounds followed by ALA-PDT. Combined therapy was statistically superior to cryotherapy alone with 100% of urethral CA lesions responding to combined therapy after two treatments. Recurrence rates were also statistically significantly lower in the combined therapy group (9.4% vs 39.4%, p<0.05) at 12weeks. Another case report by Chen et al had similar findings.²⁹

Side effects of PDT include burning at the treatment site, edema, and dysuria.^23,24,30 One study reported two patients who went into urinary retention and required short-term catheterization likely secondary to periurethral edema.³⁰

Topical agents 

5-fluorouracil (5-FU) is an anti-metabolite drug that works by inhibiting the normal function of DNA and RNA.³¹ Weekly application of a 1-5% solution or gel for six weeks followed by a 6-week holiday was the most common protocol described prior to 2010.¹³ More recent data were primarily case reports with protocols ranging from once a nightly application for one month to once weekly for eight weeks and variable response rates were reported.^32–35 Regimens included in-office and at-home topical applications. Side effects included mild irritative symptoms and dysuria.

5-FU has been examined as an adjunct to surgical and laser therapy.^36,37 One case series described Holmium:YAG laser ablation followed by two 6-week cycles of 5-FU in the treatment of intraurethral CA in 25 male patients.³⁷ Although three participants required a repeat cycle of treatment, the response rate was 100% without relapse over an average follow-up of six months. Policresulen is a polymolecular organic acid that stimulates regeneration and re-epithelialization while imiquimod is an immune system activator that stimulates the targeting of tumor cells. One case report described alternating intraurethral application of a 36% policresulen solution and 5% imiquimod cream used over a 6-week period with no recurrence after six months.³⁵

Ingenol mebutate (IM) is a component of milkweed (Euphorbia peplus) sap and is Food and Drug Administration (FDA) approved for the treatment of actinic keratosis. It is thought to function by mediating immune responses that rapidly induce cell death. Low and high-dose topical application methods have been described. Two case reports including a total of four male patients with lesions of the urethral meatus described the complete resolution of the lesions within a matter of two to three weeks after IM therapy initiation.^38,39

Cidofovir is an antiviral intravenous solution FDA-approved for the treatment of cytomegalovirus retinitis. Its mechanism of action is the suppression of viral replication through the inhibition of DNA polymerase. One case series included two male patients with intraurethral CA and utilized a 0.5% cidofovir cream which was delivered intraurethral via catheter over 28 sessions.⁴⁰ One patient had complete resolution of his urethral CA while the other had two recurrent lesions six months after discontinuing therapy.

Vaccination 

The 9-valent HPV vaccine is prepared from purified virus-like particles and is intended to provide protection from HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 and is currently the only option available in the United States. The CDC recommends routine vaccination at age 11 or 12, with catch-up vaccination through age 26. Earlier vaccination is recommended as the vaccine is intended primarily as a preventative measure rather than for treatment of active infection. One study described vaccination as a treatment modality for genital lesions although only one subject in this study had urethral CA while one case report used vaccine administration as an “immunomodulator” in a patient who underwent surgical resection.^6,41

This is a scoping review of studies only available through PubMed (MEDLINE) published and therefore is not intended to be a comprehensive review of all literature published on the management of bladder or urethral CA. Additionally, we only included treatment modalities utilized since 2010, therefore all possible modalities used for the treatment of bladder and urethral CA are not included in this review. Review articles are limited by the quality of literature considered for inclusion. As >50% of the studies included in this review were case studies or case series, further research is necessary to draw any meaningful conclusions regarding the efficacy or safety of the therapies described.

Early and effective treatment may lead to the eradication of bladder and urethral CA and  reduce the risk of progression to malignancy. Utilization of several treatment modalities or repeat therapy may be necessary as recurrence is common. Surgical resection is the most frequently described treatment for bladder and urethra CA in the literature and may be used for the treatment of internal and external lesions. Laser ablation may be used internally or externally depending on the laser available and has promising response rates. PDT may also be utilized in lesions involving the external and internal urethra but is not viable for use within the bladder. While topical solutions have been extensively used for anogenital lesions, newer evidence supporting their use in urethral and bladder CA is generally of poor quality. Vaccination may provide protection against the development of CA if administered early, although patients should be counseled that vaccination is a preventative rather than a therapeutic measure.

None.

The authors declared that there are no conflicts of interest.

None.

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