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Condyloma acuminata: Diagnosis and Treatment of Genital Warts

References: (CDC Guidelines, 2021) (Höpfl et al., 2001 ) (Micali et al., 2004).

Definition

Condylomata acuminata (anogenital warts) are papillomatous proliferations of the squamous epithelium of the anogenital area caused by human papillomavirus (HPV).

Epidemiology of Genital Warts

Genital warts are a common disease, but the exact prevalence is unknown. The viral prevalence is 40–60% in the sexually active population, most of them without genital warts (Dunne et al., 2006). The manifestation of condyloma acuminata is seldom before sexual activity, but the occurrence of genital warts in children is not an evidence of child abuse.

Risk factors for genital warts are similar to other sexually transmitted diseases: sexually active young people with multiple partners, lack of circumcision, lack of condom use, and MSM.

Etiology of Condyloma Acuminata

Human papillomavirus (HPV):

HPV is a group of DNA viruses from the virus family Papillomaviridae. More than 100 types of papillomavirus are known so far. Sexual transmission causes the typical papillomatous lesions, especially HPV type 6, 11, 42–44. HPV is very resilient and can be transmitted using fingers or inanimate vectors.

Morphology:

HPV is of icosahedral shape, 60 nm in size. HPV contains double-stranded DNA; the genome has 8000 base pairs.

Immunology:

The persistence of viral DNA in adjacent epithelial cells is responsible for the high recurrence rate. The cellular immune system is responsible for the eradication of the infection; diseases affecting the cellular immune system (HIV or tumors) lead to insufficient eradication, relapse, and disease progression.

Oncogenic risk:

HPV induces penile cancer, cervical cancer, and cancer of the oropharynx. DNA of HPV is detectable in nearly 100% of precancerous lesions and in 50% of invasive penile carcinomas. The typical clinical lesions with high-risk papillomaviruses are flat warts (Condyloma plana), mainly caused by HPV 16, 18, 31, and 33. The transmission of HPV between women and men and vice versa also leads to the transmission of cancer risks.

Molecular mechanisms of tumor induction:

The first step of tumor induction by HPV infection is the expression of viral oncogenes (E6 and E7), which leads to the rapid degradation of p53 or pRB tumor suppressor gene proteins and immortalized cells. The second step of carcinogenesis (e.g., a spontaneous mutation) transforms the immortalized cell into a cancer cell.

Pathology of Condyloma Acuminata

Gross pathology:

Soft, reddish brown papillomatous tumors of the genital skin.

Microscopic Pathology:

Hyperkeratosis (thickening of the stratum corneum), acanthosis (diffuse epidermal hyperplasia), and koilocytosis (cells with halo nuclei).

Signs and Symptoms

Genital Warts

Soft, reddish brown papillomatous or flat tumors of the genital skin. They typically grow in clusters [fig. condyloma acuminata of the penis].

Location:

Typical manifestations are the external genitals (penis, coronary sulcus, penile shaft and scrotum), inguinal region, perineal region, urethra, mouth, anus and rectum.

Complications:

HPV infection can result in giant condyloma acuminata of the penis with aggressive growth (Buschke-Löwenstein tumor, verrucous penile cancer).

There is an increased risk of premalignant lesions or cancer: CIN (cervical), VIN (vulvar), PIN (penile), PAIN (perianal), VAIN (vaginal), Bowen disease or Erythroplasia de Queyrat, penile cancer, vulvar or cervical cancer.

Diagnosis of Condyloma Acuminata

Inspection:

Carefully inspect the external genitalia, the inguinal region, and the perianal region. The incubation with 5% acetic acid improves the identification of subclinical lesions (whitish-gray discoloration).

Cystoscopy:

Necessary with involvement of the meatus. Cystoscopy should be performed only after the therapy of visible condylomatat acuminata of the external genitalia.

Rectoscopy:

Necessary with lesions of the anus.

Skin biopsy:

A skin biopsy should be done when there are doubts about the clinical diagnosis or before operative treatment.

Molecular typing:

Molecular typing is possible with PCR, but it does not influence management and is not recommended in routine diagnosis.

Treatment of Condyloma Acuminata

Eradication of the virus is often impossible do to the presence of virus in adjacent epithelial cells. Therapy aims to eliminate exophytic lesions and prevent their further spread. Recurrence rates of 20–40% are reported after complete surgical excision.

Local Therapy

Podophyllotoxin:

One cycle of therapy is seven days long; initial treatment should be four cycles. 0.3–0.5% podophyllotoxin solution 2× daily for three days, then four days off therapy.

Imiquimod:

5% cream 3× per week for 16 weeks. The immunomodulatory effect causes the release of interferon and tumor necrosis factor. This leads to a cure of 35–50%, as shown in several randomized trials.

Sinecatechins:

Sinecatechins are derived from green tea and are available as 10% ointment, which is applied three times daily. Treatment results are comparable to imiquimod.

Trichloroacetic acid:

80% trichloroacetic acid 1–2× per week for six weeks, suitable for smaller lesions.

Circumcision

If the lesions involve the prepuce, a circumcision is necessary.

Laser Therapy

Before laser treatment, the diagnosis is confirmed by biopsy. The laser therapy leads to a heat necrosis of the lesions.

Urethral Manifestation:

Endoscopic laser coagulation of urethral lesions or therapy with 5% 5-fluorouracil ointment.

Prophylaxis

• Use of condoms has limited efficiency
• Abstaining from sexual activity or avoidance of the above-mentioned risk factors
• Polyvalent HPV vaccination before reaching sexual maturity.

Prognosis of Condyloma Acuminata

Most HPV infections go unnoticed; the virus infection either heals spontaneously or persists. The virus persistence in epithelial cells around the lesion is responsible for the high relapse rate. At present, curative therapy does not exist.

References

Center for Disease Control and Prevention: “Sexually Transmitted Infections (STI) Treatment Guidelines,” 2021. [Online]. Available: https://www.cdc.gov/std/treatment-guidelines/STI-Guidelines-2021.pdf

CDC Guideline on Anogenital warts: https://www.cdc.gov/std/treatment-guidelines/anogenital-warts.htm

E. F. Dunne, C. M. Nielson, K. M. Stone, L. E. Markowitz, and A. R. Giuliano, “Prevalence of HPV infection among men: A systematic review of the literature.,” J Infect Dis., vol. 194, no. 8, pp. 1044–1057, 2006.

IUSTI, “European guideline for the management of anogenital warts,” 2019. [Online]. Available: https://iusti.org/wp-content/uploads/2020/08/IUSTIHPVGuidelines2020.pdf

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