Penile warts are the most common sexually transmitted disease in men and are caused by the human papillomavirus (HPV). Penile warts typically present as soft, flesh-colored to brown plaques on the glans and shaft of the penis.
To provide an update on the current understanding, diagnosis and treatment of penile warts, a review was conducted using key terms and phrases such as "penile warts" and "genital warts. "The search strategy included meta-analysis, randomized controlled trials, clinical trials, observational studies, and reviews.
Epidemiology
HPV infection is the most common sexually transmitted disease worldwide. Infection with HPV does not mean that a person will develop genital warts. It is estimated that 0. 5 - 5% of sexually active young adult men have genital warts on physical examination. The peak age of the disease is 25 - 29 years.
Etiopathogenesis
HPV is a non-enveloped capsid double-stranded DNA virus belonging to the genus Papillomavirus of the Papillomaviridae family and infects only humans. The virus has a circular genome of 8 kilobases in length, which encodes eight genes, including the genes for two encapsulating structural proteins, namely L1 and L2. The virus-like particle containing L1 is used in the production of HPV vaccines. L1 and L2 mediate HPV infection.
It is also possible to become infected with different types of HPV at the same time. In adults, genital HPV infection is transmitted primarily through sexual contact and, less commonly, through oral sex, skin-to-skin, and fomites. In children, HPV infection can occur as a result of sexual abuse, vertical transmission, self-infection, infection through close household contact, and through fomites. HPV penetrates the cells of the basal layer of the epidermis through microtraumas on the skin or mucous membrane.
The incubation period of infection ranges from 3 weeks to 8 months, with an average of 2 - 4 months. The disease is more common in individuals with the following predisposing factors: immunodeficiency, unprotected sexual intercourse, multiple sexual partners, a sexual partner with multiple sexual partners, a history of sexually transmitted infections, early sexual activity, a shorter period of time between meeting a new partner and engaging in sexual intercourseliving with him, not being circumcised and smoking. Other predisposing factors are moisture, maceration, trauma and epithelial defects in the penile region.
Histopathology
Histological examination reveals papillomatosis, focal parakeratosis, severe acanthosis, multiple vacuolated koilocytes, vascular distension and large keratohyalin granules.
Clinical manifestations
Penile warts are usually asymptomatic and may occasionally cause itching or pain. Genital warts are usually located on the frenulum, glans penis, inner surface of the foreskin and coronal sulcus. At the onset of the disease, penile warts typically appear as small, discrete, soft, smooth, pearly, dome-shaped papules.
Lesions may occur individually or in clusters (grouped). They can be pedunculated or broad-based (sessile). Over time, papules can coalesce into plaques. Warts may be filiform, exophytic, papillomatous, verrucous, hyperkeratotic, cerebriform, fungiform, or cauliflower-shaped. The color may be flesh-colored, pink, erythematous, brown, violet, or hyperpigmented.
Diagnosis
The diagnosis is made clinically, usually based on history and examination. Dermoscopy and in vivo confocal microscopy help improve diagnostic accuracy. Morphologically, warts can vary from finger-shaped and pineal to mosaic. Among the features of vascularization one can find glomerular, hairpin and punctate vessels. Papillomatosis is an integral feature of warts. Some authors suggest using the acetic acid test (whitening of the surface of warts when acetic acid is applied) to facilitate the diagnosis of penile warts.
The sensitivity of this test is high for hyperplastic penile warts, but for other types of penile warts and subclinical infected areas the sensitivity is considered low. Skin biopsy is rarely warranted but should be considered in the presence of atypical features (eg, atypical pigmentation, induration, attachment to underlying structures, hard consistency, ulceration, or bleeding), when the diagnosis is uncertain, or for warts that are refractory to various treatments. Although some authors propose PCR diagnostics to, among other things, determine the HPV type that determines the risk of malignancy, HPV typing is not recommended in routine practice.
Differential diagnosis
Differential diagnosis includes pearlescent penile papules, Fordyce granules, acrochordons, condylomas lata in syphilis, molluscum contagiosum, granuloma annulare, lichen planus, lichen planus, seborrheic keratosis, epidermal nevus, capillary varicose lymphangioma, lymphogranuloma venereum, scabies, syringoma, post-traumatic neuroma, schwannoma, bowenoid papulosis and squamous cell carcinoma.
Pearly penile papulesPresent as asymptomatic, small, smooth, soft, yellowish, pearly white or flesh-colored, conical or dome-shaped papules with a diameter of 1 - 4 mm. The lesions are usually uniform in size and shape and symmetrically distributed. Typically, papules are located in single, double or multiple rows in a circle around the crown and groove of the glans penis. Papules tend to be more noticeable on the dorsum of the crown and less noticeable towards the frenulum.
Fordyce granules- these are enlarged sebaceous glands. On the glans and shaft of the penis, Fordyce granules appear as asymptomatic, isolated or grouped, discrete, creamy yellow, smooth papules with a diameter of 1 - 2 mm. These papules are more noticeable on the shaft of the penis during erection or when the foreskin is pulled. Sometimes a dense chalky or cheese-like material can be squeezed out of these granules.
Acrochordons, also known as skintags ("skin tags"), are soft, flesh-colored to dark brown, pedunculated or broad-based skin growths with a smooth outline. Sometimes they may be hyperkeratotic or have a warty appearance. Most acrochordons measure between 2 and 5 mm in diameter, although they can sometimes be larger, especially in the groin. Acrochordons can appear on almost any part of the body, but are most often seen on the neck and intertriginous areas. When they appear in the penile area, they can mimic penile warts.
Condylomas lata- These are skin lesions in secondary syphilis caused by the spirochete, Treponema pallidum. Clinically, condylomas lata appear as moist, grey-white, velvety, flat or cauliflower-like, wide papules or plaques. They tend to develop in warm, moist areas of the genitals and perineum. Secondary syphilis is characterized by a non-pruritic, diffuse, symmetrical maculopapular rash on the trunk, palms and soles. Systemic manifestations include headache, fatigue, pharyngitis, myalgia, and arthralgia. Erythematous or whitish rashes on the oral mucosa may occur, as well as alopecia and generalized lymphadenopathy.
Granuloma annulareis a benign, self-limiting inflammatory disease of the dermis and subcutaneous tissue. The pathology is characterized by asymptomatic, firm, brownish-purple, erythematous or flesh-colored papules, usually arranged in a ring. As the condition progresses, central involution may be noted. A ring of papules often grows together to form a ring-shaped plaque. Granuloma is usually located on the extensor surfaces of the distal extremities, but can also be detected on the shaft and glans penis.
Lichen planus of the skinis a chronic inflammatory dermatosis manifesting as flat, polygonal, purple, itchy papules and plaques. Most often, the rash appears on the flexor surfaces of the hands, back, torso, legs, ankles and glans penis. Approximately 25% of lesions occur on the genitals.
Epidermal nevusis a hamartoma arising from embryonic ectoderm that differentiates into keratinocytes, apocrine glands, eccrine glands, hair follicles and sebaceous glands. The classic lesion is a solitary, asymptomatic, well-circumscribed plaque that follows Blaschko's lines. The onset of the disease usually occurs in the first year of life. Color varies from flesh to yellow and brown. Over time, the lesion may thicken and become warty.
Capillary varicose lymphangioma is a benign saccular dilation of cutaneous and subcutaneous lymph nodes. The condition is characterized by clusters of blisters resembling frog spawn. The color depends on the content: whitish, yellow or light brown color is due to the color of the lymph fluid, and reddish or bluish color is due to the presence of red blood cells in the lymph fluid as a result of hemorrhage. The blisters may undergo changes and take on a warty appearance. Most often found on the extremities, less often in the genital area.
Lymphogranuloma venereumis a sexually transmitted disease caused by Chlamydia trachomatis. The disease is characterized by a transient painless genital papule and, less commonly, an erosion, ulcer or pustule followed by inguinal and/or femoral lymphadenopathy known as buboes.
Usually,syringomasare asymptomatic, small, soft or dense, flesh-colored or brown papules measuring 1 - 3 mm in diameter. They are usually found in the periorbital areas and on the cheeks. However, syringomas can appear on the penis and buttocks. When located on the penis, syringomas can be mistaken for penile warts.
Schwannomas- These are neoplasms originating from Schwann cells. Schwannoma of the penis usually presents as a single, asymptomatic, slowly growing nodule on the dorsal aspect of the penile shaft.
Bowenoid papulosisis a precancerous focal intraepidermal dysplasia that usually appears as multiple red-brown papules or plaques in the anogenital area, particularly the penis. The pathology is consistent with squamous cell carcinoma in situ. Progression to invasive squamous cell carcinoma occurs in 2 to 3% of cases.
Usually,squamous cell carcinomapenis manifests itself in the form of a nodule, ulcer or erythematous lesion. The rash may appear warty, leukoplakia, or sclerosis. The most favored site is the glans penis, followed by the foreskin and the shaft of the penis.
Complications
Penile warts can be a cause of significant concern or distress for the patient and their sexual partner due to their cosmetic appearance and contagiousness, stigmatization, concerns about future fertility and cancer risk, and their association with other sexually transmitted diseases. It is estimated that 20 - 34% of affected patients have underlying sexually transmitted diseases. Patients often experience feelings of guilt, shame, low self-esteem and fear. People with penile warts have higher rates of sexual dysfunction, depression and anxiety compared to the healthy population. This condition can have a negative psychosocial impact on the patient and negatively affect their quality of life. Large exophytic lesions may bleed, cause urethral obstruction, and interfere with sexual intercourse. Malignant transformation is rare except in immunocompromised individuals. Patients with penile warts are at increased risk of developing anogenital cancer, head cancer, and neck cancer as a result of coinfection with high-risk HPV.
Forecast
If no treatment is given, genital warts may resolve on their own, remain unchanged, or increase in size and number. Approximately one third of penile warts regress without treatment, and the average time until they disappear is approximately 9 months. With proper treatment, 35 to 100% of warts disappear within 3 to 16 weeks. Although the warts resolve, the HPV infection may remain, leading to recurrence. Relapse rates range from 25 to 67% within 6 months of treatment. Among patients with subclinical infection, recurrent infection (reinfection) after sexual intercourse and in the presence of immunodeficiencies, a higher percentage of relapses occurs.
Treatment
Active treatment of penile warts is preferable to follow-up because it leads to faster resolution of the lesions, reduces fears of infecting a partner, relieves emotional stress, improves cosmetic appearance, reduces social stigma associated with penile lesions, and relieves symptoms (eg, itching, soreness or bleeding). Penile warts that persist for more than 2 years are much less likely to resolve on their own, so active treatment should be offered first. Counseling of sexual partners is mandatory. Screening for sexually transmitted diseases is also recommended.
Active treatments can be divided into mechanical, chemical, immunomodulatory and antiviral. There are very few detailed comparisons of different treatment methods with each other. Effectiveness varies depending on the treatment method. To date, no one treatment has been proven to be consistently superior to other treatments. The choice of treatment should depend on the physician's skill level, patient preference and tolerance to treatment, as well as the number of warts and the severity of the disease. The comparative effectiveness, ease of administration, side effects, cost and availability of the treatment should also be taken into account. In general, self-administered treatment is considered less effective than self-administered treatment.
The patient carries out treatment at home (as prescribed by the doctor)
Treatment methods used in the clinic
Methods used in the clinic include podophyllin, liquid nitrogen cryotherapy, bichloroacetic acid or trichloroacetic acid, oral cimetidine, surgical excision, electrocautery, and carbon dioxide laser therapy.
Liquid podophyllin 25%, derived from podophyllotoxin, works by stopping mitosis and causing tissue necrosis. The drug is applied directly to the wart of the penis once a week for 6 weeks (maximum 0. 5 ml per treatment). Podophyllin should be washed off 1 to 4 hours after treatment and should not be applied to areas with high skin moisture. The effectiveness of wart removal reaches 62%. Due to reports of toxicity, including death, associated with the use of podophyllin, podofilox, which has a much better safety profile, is considered preferred.
Liquid nitrogen, the treatment of choice for penile warts, can be applied using a spray bottle or cotton-tipped applicator directly to and 2 mm around the wart. Liquid nitrogen causes tissue damage and cell death by rapidly freezing to form ice crystals. The minimum temperature required to destroy warts is -50°C, although some authors believe that -20°C is also effective.
The effectiveness of wart removal reaches 75%. Side effects include pain during treatment, erythema, desquamation, blistering, erosion, ulceration and dyspigmentation at the application site. A recent phase II parallel randomized trial in 16 Iranian men with genital warts showed that cryotherapy using Wartner's formulation containing a mixture of 75% dimethyl ether and 25% propane was also effective. Further research is needed to confirm or refute this conclusion. It must be said that cryotherapy using Wartner’s composition is less effective than cryotherapy using liquid nitrogen.
Bichloroacetic acid and trichloroacetic acid can be used to treat small penile warts because their ability to penetrate the skin is limited. Each of these acids works by coagulating protein followed by cell destruction and consequently removing the penile wart. A burning sensation may occur at the application site. Relapses after using bichloroacetic or trichloroacetic acid occur as often as with other methods. The drugs can be used up to three times a week. The effectiveness of wart removal ranges from 64 to 88%.
Electrocoagulation, laser therapy, carbon dioxide laser or surgical excision work by mechanically destroying the wart and can be used in cases where there is a fairly large wart or a cluster of warts that is difficult to remove with conservative treatment methods. Mechanical treatment methods have the highest percentage of effectiveness, but their use has a higher risk of scars on the skin. Local anesthesia applied to non-occluded lesions 20 minutes before the procedure or a mixture of local anesthetics applied to occluded lesions one hour before the procedure should be considered as measures that reduce discomfort and pain during the procedure. General anesthesia may be used to surgically remove large lesions.
Alternative Treatments
Patients who do not respond to first-line treatments may respond to other treatments or a combination of treatments. Second-line therapy includes topical, intralesional, or intravenous cidofovir, topical 5-fluorouracil, and topical ingenol mebutate.
Antiviral therapy with cidofovir may be considered for immunocompromised patients with treatment-refractory warts. Cidofovir is an acyclic nucleoside phosphonate that competitively inhibits viral DNA polymerase, thereby preventing viral replication.
Side effects of topical (intralesional) cidofovir include irritation, erosion, post-inflammatory pigmentary changes, and superficial scarring at the application site. The main side effect of intravenous cidofovir is nephrotoxicity, which can be prevented with saline hydration and probenecid.
Prevention
Genital warts can be prevented to a certain extent by delaying sexual activity and limiting the number of sexual partners. Latex condoms, when used consistently and correctly, reduce HPV transmission. Sexual partners with anogenital warts should be treated.
HPV vaccines are effective before sexual activity in primary prevention of infection. This is because vaccines do not provide protection against diseases caused by vaccine types of HPV that an individual acquired through previous sexual activity. The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention, the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, the American Academy of Family Practice, and the International Human Papillomavirus Society recommend routine vaccination of girls and boys with the HPV vaccine.
The target age for vaccination is 11 - 12 years for girls and boys. The vaccine can be administered as early as 9 years of age. Three doses of the HPV vaccine should be given at month 0, months 1 to 2 (usually 2), and months 6. Catch-up vaccination is indicated for men under 21 years of age and women under 26 years of age if they have not been vaccinated at the target age. Vaccination is also recommended for men who are gay or immunocompetent under the age of 26, if they have not been vaccinated previously. Vaccination reduces the likelihood of becoming infected with HPV and subsequently developing penile warts and penile cancer. Vaccinating both men and women is more beneficial in reducing the risk of genital warts of the penis than vaccinating only men, since men can acquire HPV infection from their sexual partners. The prevalence of anogenital warts decreased significantly from 2008 to 2014 due to the introduction of the HPV vaccine.
Conclusion
Penile warts are a sexually transmitted disease caused by HPV. This pathology can have a negative psychosocial impact on the patient and negatively affect his quality of life. Although approximately one third of penile warts resolve without treatment, active treatment is preferred to speed up the resolution of warts, reduce fears of infection, reduce emotional distress, improve cosmetic appearance, reduce social stigma associated with penile lesions, and relieve symptoms.
Active treatment methods can be mechanical, chemical, immunomodulatory and antiviral, and often combined. So far, no one treatment has been proven to be superior to others. The choice of treatment method should depend on the physician's level of proficiency in this method, the patient's preference and tolerability of treatment, as well as the number of warts and the severity of the disease. The comparative effectiveness, ease of use, side effects, cost and availability of the treatment should also be taken into account. HPV vaccines before sexual activity are effective in primary prevention of infection. The target age for vaccination is 11 - 12 years for both girls and boys.