Human Papillomavirus-Related Diseases in Urology: Diagnosis, Treatment, Prevention, and Clinical Considerations for Healthcare Providers

1. Global and National Male Disease Burden

Worldwide, HPV-related diseases in men include approximately 15 million cases of anogenital warts annually [8], approximately 28,500 HPV-positive OPCs, 17,500 anal cancers, and 13,000 penile cancers each year [1] (Fig. 1A). The HPV-attributable fraction is especially high for anal cancer (approximately 88%) and OPC (approximately 72%), making these effectively preventable diseases in men through vaccination [1,3]. In the United States, HPV-positive OPC incidence in men surpassed cervical cancer in absolute numbers by the mid-2000s [3].

Fig. 1.

Global and national male disease burden related to HPV. (A) Global annual HPV-attributable disease burden in males. (a) Annual new cases (log scale): anogenital warts (~15 million), oropharyngeal cancer (~28,500), anal cancer (~17,500), penile cancer (~13,000). (b) HPV-attributable fractions. Data sources: de Martel et al. [1]; Chaturvedi et al. [3]. (B) Trends in anogenital wart patients in Korea, 2010–2022. Annual numbers of male, female, and total patients from HIRA national claims data. Male patient numbers increased approximately threefold from 2010 to 2021; female patient numbers stabilized after the 2016 female-targeted NIP launch. HPV, human papillomavirus; HIRA, Health Insurance Review and Assessment Service; NIP, National Immunization Program. Data reconstructed partly based on Chung et al. [9] and Kim et al. [10] based on HIRA national claims data.

In Korea, Health Insurance Review and Assessment Service (HIRA) claims data document a 3.34-fold increase in male anogenital wart prevalence, from 132.83 per 100,000 in 2007 to 443.57 per 100,000 in 2018, with the 25- to 29-year age group consistently most affected (1,492.15 per 100,000 in 2018) [9] (Fig. 1B). Surgical treatment rates for male anogenital warts approximately tripled over the same period [10]. Penile cancer increased from 216 cases in 2010 to 324 cases in 2021 [11]. By contrast, female anogenital wart prevalence peaked in 2012 and has since declined, possibly reflecting early herd effects of the female-targeted NIP introduced in 2016.

2. HPV Genotype Distribution and Disease Spectrum

More than 200 HPV genotypes have been identified, of which approximately 40 infect the anogenital tract. These are classified as low-risk (nononcogenic) or high-risk (oncogenic) based on carcinogenic potential, a distinction that directly governs clinical risk stratification and vaccine selection (Table 1; Fig. 2). In men, low-risk types 6 and 11 account for approximately 90% of condyloma acuminata and are the causative agents of juvenile-onset recurrent respiratory papillomatosis (JORRP) [12]. High-risk types 16 and 18 together drive the majority of HPV-attributable malignancies in men—including most penile, anal, and HPV-positive OPCs—and are classified as group 1 carcinogens by the International Agency for Research on Cancer [2]. Five additional oncogenic types (31, 33, 45, 52, 58) are covered exclusively by the nonavalent vaccine and account for a further 15%–20% of HPV-associated cancers not targeted by the quadrivalent formulation.

Table 1.

HPV genotype classification, associated diseases, and vaccine coverage

Fig. 2.

Disease spectrum of HPV by genotype risk category. Low-risk types 6/11: condyloma acuminata and JORRP. High-risk types 16/18: cervical, oropharyngeal, penile, anal, vulvar/vaginal cancers. Types 31,33,45,52,58: covered by nonavalent vaccine. HPV, human papillomavirus; HPV+, HPV-positive; JORRP, juvenile-onset recurrent respiratory papillomatosis.

3. HPV Natural History in Men

HPV infection in men is highly prevalent. The landmark HPV in men (HIM) cohort study documented a new genital HPV infection incidence of 38.4 per 1,000 person-months in sexually active men aged 18–70 years [13]. Per-contact sexual transmission risk from an infected partner is estimated at approximately 40%–60% [12], and most men acquire HPV infection within years of sexual debut. The clinical spectrum ranges from asymptomatic infection and condyloma acuminata to invasive malignancy in the setting of persistent high-risk infection. Spontaneous clearance of HPV infection—defined virologically as 2 consecutive type-specific negative tests at least 6 months apart—occurred in the HIM cohort with a median duration of 7.52 months for any type and 12.19 months for HPV 16 [13]. Clearance rates in men are generally slower than in women. Proposed biological mechanisms include differences in mucosal immune surveillance: the keratinized epithelium of the penile shaft is a relative barrier to T-cell trafficking compared with the squamocolumnar junction of the cervix; Langerhans cell density and CD4+ T-cell-mediated responses differ by anatomic site; and male innate and adaptive immune responses to HPV antigens appear less robust, possibly reflecting hormonal modulation [14]. Additional determinants of impaired clearance include high lifetime partner number, tobacco use, and immunosuppression [13,14]. For condyloma acuminata, spontaneous regression occurs in approximately 30% of untreated lesions within 4 months and in more than 80% within 18 months [15]; recurrence after treatment is common (20%–50% within 3 months), reflecting viral latency rather than reinfection [12,15].

4. HPV and Male Fertility

Beyond malignancy, HPV infection has a direct impact on male reproductive function. Boeri et al. [4] demonstrated that high-risk HPV detection in semen is significantly associated with reduced progressive sperm motility and elevated sperm DNA fragmentation index in infertile men. Antisperm antibody titers are also increased in men with HPV semen infection [16]. Critically, Garolla et al. [16] showed that completion of prophylactic HPV vaccination in infertile men with HPV-positive semen was followed by recovery of sperm motility, higher natural conception rates, and lower miscarriage rates in their partners at 1-year follow-up. These associations suggest that HPV semen infection may contribute to male-factor infertility; however, causality has not been definitively established, and further prospective studies are needed to determine whether antiviral intervention or prophylactic vaccination can reproducibly improve sperm parameters and reproductive outcomes.

1. Overview of Transmission Routes

While sexual contact accounts for the overwhelming majority of genital HPV infections, the virus can spread through several additional routes that are clinically and occupationally relevant (Fig. 3). HPV is a nonenveloped DNA virus resistant to desiccation [17], capable of surviving for months on environmental surfaces at ambient temperatures, and inactivated only at temperatures above 60°C. This environmental stability underpins the plausibility of fomite transmission and the risk of iatrogenic spread through inadequately disinfected instruments.

Fig. 3.

HPV transmission routes. Five pathways: sexual (~90%); perinatal (<1%); digital/fomite; surgical smoke (primary occupational hazard, dashed border); bloodborne (uncertain). HPV, human papillomavirus; JORRP, juvenile-onset recurrent respiratory papillomatosis.

2. Perinatal and Digital Transmission

Vertical transmission may result in JORRP caused by HPV types 6 and 11. In a Danish registry-based cohort, JORRP developed in approximately 7 per 1,000 births to mothers with genital warts during pregnancy, corresponding to a 231.4-fold higher risk than births without a maternal history of genital warts (95% confidence interval, 135.3–395.9) [18]. Population-based estimates of JORRP incidence in the United States range from 0.36 to 1.11 per 100,000 children aged <18 years [19]. Vertical transmission is rare: the risk of neonatal infection even from an HPV-positive mother is below 1%, and current evidence does not demonstrate that cesarean delivery significantly reduces this already low risk. Accordingly, cesarean delivery is not routinely recommended for the sole purpose of preventing perinatal HPV transmission [12].

Digital (hand-to-genital) transmission has been demonstrated in longitudinal studies of heterosexual couples [20]: high-risk HPV DNA has been detected on the fingertips of more than 50% of sexually active men, with the proposed mechanism involving transfer of infected epithelial cells or secretions during sexual contact and subsequent inoculation of mucosal surfaces via microabrasions [20]. Fomite transmission through inadequately disinfected medical instruments is biologically plausible given HPV's documented environmental persistence [17], with direct implications for instrument disinfection standards in urological practice.

3. Surgical Smoke: The Key Occupational Hazard for Urologists

Surgical smoke generated during electrocautery or CO₂ laser ablation of HPV lesions represents the most clinically significant occupational exposure risk for urologists. Garden et al. [5] first documented HPV DNA in CO₂ laser-generated vapor in 1988. Ferenczy et al. [6] recovered HPV DNA from prefilter canisters in 20% of laser treatment sessions and demonstrated that operator contamination was effectively prevented only when a dedicated smoke evacuator (SED) was properly employed. Wisniewski et al. [7] confirmed in vivo transmission capacity of CO₂ laser debris and reported viral particle deposition on the surgeon's eyeglasses 1 meter from the operative site despite smoke evacuator use—underscoring the need for layered protection. Calero and Brusis [21] reported the first case of laryngeal papillomatosis recognized as an occupational disease in Germany in a gynecological operating room nurse who repeatedly assisted in condyloma ablations. Barrett and Garber [22] concluded that surgical smoke represents a genuine biohazard, and Swerdlow [23] highlighted that smoke evacuation devices remain underused due to insufficient clinician education. A systematic review of virus contamination in surgical smoke published in a urological journal confirmed these findings and identified the surgical treatment of HPV-related lesions, including condyloma ablation, as the setting with the most consistent evidence of HPV aerosolization [24]. Precise incidence estimates for occupational HPV transmission to healthcare workers remain limited by the rarity of confirmed case series and the prolonged latency—potentially months to years—between occupational exposure and clinical disease. Nevertheless, the occupational origin of HPV-associated laryngeal papillomatosis has been formally recognized as a notifiable occupational disease in at least one European health system [21], and documented case reports in operating room personnel who routinely assisted in condyloma ablations without respiratory protection underscore that the risk, while difficult to quantify, is real and legally recognized.

1. The 4-Domain Framework

Infection control related to HPV in urology encompasses 4 interconnected domains: operative safety, instrument disinfection, management of special clinical populations, and vaccination counseling—summarized in Fig. 4.

Fig. 4.

Infection control framework for HPV in urological practice. ① Operative safety (N95, SED, eye protection, ventilated OR); ② instrument disinfection (OPA/H₂O₂ for HLD; ethanol/QAC inadequate); ③ special populations; ④ vaccination counseling. HPV, human papillomavirus; SED, smoke evacuation device; OR, operating room; OPA, ortho-phthalaldehyde; HLD, high-level disinfection; CDC, Centers for Disease Control and Prevention; HIV+, HIV-positive; NIP, National Immunization Program.

2. Operative Safety Recommendations

Based on the aggregated evidence from multiple studies [6,7,21-23], the following protective measures are strongly recommended for all ablation procedures on HPV lesions:

(1) N95 or higher-efficiency respirator for all operating room personnel—standard surgical masks provide inadequate filtration for viral aerosols (expert consensus; randomized trial data specific to urological settings remain limited).

(2) SED with continuous suction positioned at the operative field throughout electrocautery and laser ablation. Ferenczy et al. [6] demonstrated that proper SED use effectively prevented operator contamination.

(3) Adequately ventilated operating room with local exhaust ventilation, as mandated by CDC guidelines [12].

(4) Laser-appropriate protective eyewear; double-glove technique when handling instruments contacting HPV lesions.

Based on the available evidence, these protective measures represent strong evidence-based recommendations for any urological procedure involving ablation, excision, or manipulation of HPV-related lesions. The urological community is encouraged to champion their adoption and to advocate for formal urology-specific infection control guidelines.

3. Instrument and Probe Disinfection

Disinfectant selection is critical because HPV, as a nonenveloped virus, is substantially more resistant to many commonly used agents than enveloped viruses. Table 2 summarizes comparative efficacy data. The evidence base is not uniform: early carrier-based studies using raft-derived native HPV16/18 virions reported that both glutaraldehyde and ortho-phthalaldehyde (OPA) failed to inactivate HPV [25-27], whereas two subsequent independent studies using patient-derived virus and an in vivo infection model demonstrated 3 to >4 log10 inactivation by OPA [28,29], as did a suspension test using HPV16 pseudovirus [30]. Both of the latter studies were supported by a disinfectant manufacturer. Sonicated or vaporized hydrogen peroxide is the agent supported most consistently across all study models [26,29], and ethanol-based hand sanitizers and isopropanol wipes show minimal or no activity against authentic HPV virions in every report [25,29] and should not be used as the sole disinfectant for instruments or endoscopes contacting HPV-infected mucosal surfaces.

Table 2.

Comparative efficacy of common disinfectants against HPV, by experimental model, and guidance for clinical use

Transvaginal and transrectal ultrasound probes present a specific challenge: M'Zali et al. [31] demonstrated that HPV DNA persisted on 13% of probes after routine low-level disinfection with quaternary ammonium wipes, with 7% yielding potentially viable HPV—even when a disposable probe cover was used. High-level disinfection with OPA or hydrogen peroxide solution between patients is required when the probe contacts mucous membranes. A summary checklist of evidence-based infection control recommendations across common urological situations is provided in Table 3 [5-7,21-23,30-32].

Table 3.

Evidence-based infection control checklist for HPV-related procedures in urological practice

1. Classification and Diagnosis

Anogenital warts (condyloma acuminata) have an incubation period of 1–8 months; more than 80% resolve spontaneously within 18 months [15]. The 2023 Korean Sexually Transmitted Infection Guidelines classify lesions as hyperplastic (soft, cauliflower-like; on moist mucosa), sessile keratotic (hard, keratinized; on dry skin), or extensive (requiring surgical excision with evaluation for immune deficiency) [15]. Diagnosis is by visual inspection; biopsy is indicated for atypical lesions—particularly those that are pigmented, indurated, fixed, or treatment- refractory [12]. HPV DNA testing does not guide clinical management [12]. The differential diagnosis of anogenital warts includes several conditions requiring distinction: pearly penile papules (a normal anatomical variant on the coronal sulcus, frequently misdiagnosed and unnecessarily treated); condyloma lata (secondary syphilis—to be excluded serologically); molluscum contagiosum; Fordyce spots; Bowenoid papulosis-flat, pigmented papules that histologically represent penile intraepithelial neoplasia (PeIN), a high-grade squamous intraepithelial lesion with malignant potential, strongly associated with HPV-16, for which biopsy is mandatory and specialist referral is required [33]; and overt HSIL or squamous cell carcinoma. The clinical management algorithm is presented in Fig. 5.

Fig. 5.

Clinical algorithm for diagnosis and management of anogenital warts. Typical → condyloma acuminata; atypical → biopsy (exclude HSIL, Bowenoid papulosis/PeIN, SCC). Treatment by wart characteristics, site, and immune status. All patients receive HPV vaccination counseling. HIV, human immunodeficiency virus; HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial lesion; PeIN, penile intraepithelial neoplasia; SCC, squamous cell carcinoma; TCA, trichloroacetic acid; BCA, bichloroacetic acid; OPA, ortho-phthalaldehyde; HLD, high-level disinfection; STI, sexually transmitted infection; NIP, National Immunization Program.

2. Treatment Regimens

Treatment options fall into 2 categories: patient-applied and provider-administered therapies. Patient-applied agents include imiquimod 5% cream (an immune-response modifier stimulating local innate and adaptive immunity), podofilox 0.5% solution or gel (an antimitotic agent), and sinecatechins 15% ointment (a green tea-derived preparation with antiproliferative properties). Provider-administered options include cryotherapy, trichloroacetic or bichloroacetic acid (TCA/BCA), and surgical or laser removal. No single modality is universally superior; selection depends on wart characteristics, anatomic site, patient preference, and provider experience. Imiquimod demonstrated efficacy as a patient-applied immune-response modifier in a pivotal randomized trial [34]. Shared clinical decision-making improves adherence and outcomes [12]. Spontaneous resolution within 1 year is possible; observation is acceptable in selected patients. Table 4 summarizes recommended regimens [5-7,12,15].

Table 4.

Recommended treatment regimens for external anogenital warts

3. Follow-up and Differential Diagnosis

Follow-up should occur every 1–4 weeks with response assessment at 3 months. Recurrence after treatment is common—reported rates range from 20% to 50% within 3 months—reflecting persistent viral latency in adjacent tissue; patients should be counseled accordingly [12,15].

For HIV-positive and immunocompromised patients, Werner et al. [35] found evidence supporting electrocautery for intra-anal intraepithelial neoplasia and imiquimod for external anogenital warts; a lower biopsy threshold is essential given higher rates of concurrent HSIL and squamous cell carcinoma [12].

1. Vaccine Types and Efficacy

Three HPV vaccines are available in Korea: bivalent (2vHPV), quadrivalent (4vHPV), and nonavalent (9vHPV). The 4vHPV vaccine demonstrated high efficacy against HPV 6/11/16/18-related anogenital disease in both women [36] and men [37], and against anal intraepithelial neoplasia in men who have sex with men [38]. The 9vHPV and 4vHPV vaccines carry approved indications for males in Korea.

2. Korea's 2026 NIP Extension and International Comparisons

Table 5 presents an international comparison of male HPV vaccination policies [8,9,15,39,40]. Korea's 2026 NIP extension to 12-year-old boys (Fig. 6) follows Australia (2013), the United States (2011), and the United Kingdom (2019) in adopting gender-neutral programs [39,40]. A vaccination recommendation algorithm for urological practice is provided in Fig. 7.

Table 5.

International comparison of national HPV vaccination policies for males

Fig. 6.

International timeline of male HPV vaccination milestones. Events alternate above/below axis. Stars (★) mark gender-neutral NIP launches: Australia 2013, UK 2019, Korea 2026. HPV, human papillomavirus; ACIP, Advisory Committee on Immunization Practices; FDA, U.S. Food and Drug Administration; NIP, National Immunization Program; OPC, oropharyngeal cancer; USA, United States America; UK, United Kingdom; 4vHPV, quadrivalent.

Fig. 7.

Male HPV vaccination algorithm. Age 12 (2026→) NIP; ages 13–26 unvaccinated → 3-dose 9vHPV; Immunocompromised → 3-dose any age. Counseling covers wart prevention, cancer risk reduction, fertility, herd immunity. Military personnel: priority catch-up group. HPV, human papillomavirus; NIP, National Immunization Program; 9vHPV, nonavalent HPV vaccine; OPC, oropharyngeal cancer.

3. Cost-Effectiveness of Gender-Neutral Vaccination

Table 6 summarizes key cost-effectiveness analyses of extending HPV vaccination to boys [41-44]. Linertová et al. [41] found that 4 of 9 economic evaluations favored the gender-neutral program, with the most influential parameters being the discount rate of benefits, vaccine price, and inclusion of OPC and penile cancer in outcomes modeled. Mahumud et al. [42] found 9vHPV vaccination cost-effective when female coverage falls below 75%—precisely the situation in Korea, where female coverage is approximately 30%. Population modeling by Ng et al. [43] indicates gender-neutral programs can achieve herd immunity faster, particularly when male coverage exceeds 50%, far above Korea's current male rate of under 5%.

Table 6.

Summary of key cost-effectiveness analyses of extending HPV vaccination to boys

1. Expanding Male Vaccination Coverage and Catch-Up Programs

The 2026 Korean NIP expansion to 12-year-old boys is a critical first step, but the currently unvaccinated cohort of males aged 13–26 years represents the largest nearterm public health opportunity. Proactive catch-up vaccination counseling at every urological clinic encounter is essential; addressing barriers such as low awareness and perceived low personal risk is a key challenge [45]. Data from Australia confirm that gender-neutral programs produce broader and faster declines in anogenital wart incidence across all demographic groups [40,46]. Beyond age 26, whether male catch-up vaccination eligibility should be extended—as has occurred for women to age 45—warrants formal health technology assessment. Most importantly, the large cohort of unvaccinated young Korean males entering or serving in military service represents a uniquely accessible target population for catch-up; the Korean Urological Association and public health authorities should formally advocate for HPV vaccination programs within the military healthcare system.

2. HPV Vaccination for OPC Prevention

In 2021, the U.S. Food and Drug Administration expanded the approved indication of 9vHPV to include the prevention of OPC—a disease that disproportionately affects men and for which no effective screening strategy exists. As Korean national registry data increasingly reflect the HPV-driven rise in male OPC incidence, the clinical and public health case for including OPC prevention as an explicit goal of the Korean male vaccination program will only strengthen [3,47,48].

3. HPV, Male Infertility, and Reproductive Medicine

As noted in Section “HPV and Male Fertility,” HPV semen infection is associated with impaired sperm motility, elevated DNA fragmentation, and potentially reduced natural conception rates [4,16]. Several important research gaps remain unaddressed: the epidemiology of HPV semen infection among Korean infertile men has not been systematically characterized; whether treatment of active condyloma acuminata reduces HPV semen shedding; and whether prophylactic vaccination of HPV-seropositive infertile men reproducibly improves reproductive outcomes. Until such evidence is available, incorporating HPV semen testing into the workup of idiopathic male-factor infertility may be considered on an individualised basis.

4. Establishing Urology-Specific HPV Infection Control Guidelines

Despite the well-documented occupational hazard of surgical smoke for urologists and operating room nurses [21-23], urology-specific HPV infection control guidelines remain absent in Korea and most countries. The urological community is uniquely positioned to develop and champion such guidelines, specifying required personal protective equipment, smoke evacuator standards, endoscope and cystoscope high-level disinfection protocols using agents validated against HPV rather than ethanol- based products [25-30], and standards for ultrasound probe decontamination [31].

5. HPV Screening for Males and Unmet Clinical Needs

No validated HPV screening modality currently exists for males. Urine-based HPV detection methods are under investigation and could transform epidemiological surveillance, facilitate management of HPV semen infection in infertile men, and allow targeted catch-up vaccination of HPV-negative males [4,15]. It should also be noted that male circumcision is associated with a significantly reduced risk of penile HPV acquisition and persistence [49,50], and the declining circumcision rate in Korea reinforces the urgency of vaccination as the primary male-specific preventive strategy.