Condyloma acuminatum

Authors

Vishal Gupta (Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India)

Neetu Bhari (Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India)

Somesh Gupta (Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India)

Executive summary

The present guidelines aim to provide comprehensive information on genital condyloma acuminata, including the epidemiology, clinical features, diagnosis and management. The guidelines provide evidence-based recommendations on the diagnosis, prevention and treatment of genital condyloma acuminata in adults in Asia, including patients with HIV co-infection.

Methodology

A PubMed search was performed, using the keywords “condyloma acuminata”, “anal wart”, “anogenital wart”, “genital wart” and “genital HPV”. A total 3291 results were found in publications during last five years. A careful review of the titles and abstracts was done to find all the studies pertaining to epidemiology, clinical features, diagnosis, treatment and prevention of conduloma acuminata. After review, 190 studies were selected for detailed analysis.

Diagnosis

Various diagnostic procedures described are

1. PCR (LE: 2b)

2. Serology (LE: 2b)

3. Immunohistochemistry (LE: 3)

Prevention

1. Vaccination (LE: 1a)

2. Male circumcision (LE: 1a)

3. Condoms (LE: 3)

Vaccination

According to AdvisoryCommittee on Immunization Practices (ACIP) recommendations, 2011, following protocol should be followed:

1. Females: Either routine vaccination with 3-dose series at age 11-12 years or through age 13-26 years if not vaccinated previously

2. Males: Routine vaccination with 3-dose series at age 11-12 years or if previously unvacci-nated through age 13-21 years

3. Vaccination is recommended through age 26 years for immuno-compromised men (including those with HIV infection) and men who have sex with men.

HIV and Condylomaacuminata

In HIV-affected individuals, the course of HPV is more aggressive, with a greater risk of treatment resistance, increased chances of intraepithelial neoplasia as well as cancers.

Treatment

Physician administered

1. Photodynamic therapy (LE: 1a)

2. Immunotherapy (LE: 1a) 3. Cryotherapy (LE: 1b)

4. Podophyllin (LE: 1b)

5. Laser (LE: 2)

6. Surgery (LE: 3)

Provider administered

1. Polyphenon 10% (LE: 1a)

2. 5- Fluorouracil (LE: 1a)

3. Interferon (LE: 1a)

4. Imiquimod 5%(LE: 1b)

5. Podophyllotoxin (LE: 1b)

6. Sinecatechins (LE: 3)

7. Cidofovir (LE: 3)

Introduction

Human papilloma virus (HPV) is the most common sexually transmitted disease in the world.

Almost 80% of the world's population is exposed by the age of 50 years. HPV causes not only anogenital warts (AGW), but also oropharyngeal, genital and anal cancers.^[1]

HPV infections most commonly affect young adults, females being more commonly affected than males. Over a 100 HPV types have been identified, with HPV types 6 and 11 being re-sponsible for approximately 90% of genital warts, and HPV types 16 and 18 for 70% of inva-sive cervical cancers. An important complication of genital warts is substantial psychosocial and economic burden. Apart from the inconvenience and discomfort of treatment, the fear of recurrence, transmission, and the possible threat of cancer, patients are also burdened by the shame and embarrassment related to the diagnosis of genital warts. Costs relate to routine screening for cervical cancer, treatment of genital warts, and the management and follow-up of malignancies.^[2]

External genital warts or condylomata acuminata are extremely common, with between 500,000 to one million new cases diagnosed each year in the United States alone.^[3] Not enough data is available for Asia.

Anal wart is another common manifestation. In a study from Spain, a prevalence of 25% was reported in 640 HIV-infected men (473 MSM and 167 heterosexuals), with most common HPV types involved were type 1 and 6.^[4]

Epidemiology

In a review study, the annual incidence of AGW (including new and recurrent) ranged from 160 to 289 per 100,000 of the adult population, with a median of 194.5. New AGW incidence rates among males ranged from 103 to 168 per 100,000, with a median of 137 and among females from 76 to 191 per 100,000, with a median of 120.5 per annum. Incidence was not iced to peak before 24 years of age in females and between 25-29 years among males.^[5] In a survey of 167,767 patients in a Urology clinic in Korea, the prevalence of condylomaa-cuminata was 0.37%.^[6] In a study from NewDelhi, India, HPV DNA was detected in 84 (94.4%) of 89 patients of AGW by the Linear Array HPV Genotyping Test. HPV-6 and -11 were the commonest HPV types, presentin 55.05% and 41.57% of cases respectively. HPV high-risk types were present in 25.84% of cases, mostly in combination with low-risk types.^[7]

In a study from Korea, HPV genotyping was done in 150 patients of genital warts, showed highrisk HPV types in 31 cases (23.5%), and of these, 27 cases (20.5%) contained both high-risk and low-risk HPV types. In the multivariate analysis, location of the lesions (base of the penis or the pubic area), morphology of the warts (papular or mixed genital warts), and lack of circumcision significantly increased the association with high-risk HPV infection in male genital warts.^[8]

Risk factors

Risk factors for persistent HPV infection include multiple sex partners, sex at an early age, history of sexually transmitted infections and smoking. Condom use is only partially protective against HPV infection.^[9] In a meta-analysis, in Spain, 21 studies with 8046 circumcised and 6336 uncircumcised men were included and male circumcision was associated with a sta-tistically significant reduced genital HPV prevalence.^[10]

Transmission

Transmission occurs by way of skin-to-skin contact through sexual intercourse, oral sex, anal sex, or other contact involving the genital area. The virus may remain latent for months to years until a trigger causes replication of viral DNA, leading to the clinical manifestation of AGWs.

Clinical features

Human papilloma virus is the most common sexually transmitted infection in the world. Genital HPV infection can be divided into low-risk infections (causing AGWs) and high-risk infections (causing cervical intraepithelial neoplastic (CIN), and cervical and other cancers). External genital warts occur at multiple sites in nearly 50% of patients and typically appear in anogenital areas, such as the vulva, penis, groin, perineum, perianal skin, or mucosal surfaces.

Four main morphological types are condylomatous, keratotic, papular, and flat. Papular warts are skin-colored, dome-shaped papules of 1- to 4-mm size, that occur only on the fully keratinized skin. Flat warts can occur on the fully keratinized skin or moist skin and are macules or barely elevated papules. Keratotic warts have thick horny layer and are seen only on the fully keratinized skin. Condyloma acuminata are a cauliflower shaped lesion, seen only on the moist surfaces. 10 Physical symptoms may also accompany warts, such as pruritus, burning, pain, and obstruction.^[11]

Patients with anal condyloma acuminata may be asymptomatic or present with painless papules, itching, and discharge or bleeding per rectum. It is not uncommon to have involvement of more than one area; multiple lesions may also be present and extend into the anal canal or rectum.^[12] Various studies support the importance of an exhaustive proctological examination in patients suffering from condylomatosis of the genital area, as it was found that out of 362 patients with both endoanal and perianal condyloma, only half of them were detectable by perianal clinical examination.^[13]

HPV-associated intermediate malignancy or premalignant conditions include giant condyloma acuminata (also called Buschke-Loewenstein tumor), anal, penile and vaginal or vulvar intraepithelial neoplasia while frankly malignant diseases include invasive anal, penile, or vulvar carcinoma. In HIV-infected individuals, the course of HPV is more aggressive, more risk of treatment-resistant with increase chances of intraepithelial neoplasia as well as can-cers.^[14]

Diagnosis

Most condylomata are diagnosed clinically on the basis of their characteristic morphology and location. Investigations for diagnosis and management are needed only in a small proportion of cases.

Histopathology

A Biopsy is indicated in the case of atypical lesions, lesions with doubtful diagnosis, larger lesions, lesions that are not responsive to therapy and in immuno-compromised patients. In immuno-histochemistry, P16 staining is found to be useful in differentiating condyloma acuminate from bowenoid papulosis. In a study, 36 skin biopsy specimens (24 samples of condyloma and 12 of bowenoid papulosis) were stained with an antibody to p16 protein and all cases of bowenoid papulosis showed diffuse while 75% of condyloma lesions showed sporadic and focal positive staining for p16 protein. (LE: 3)^[15]

In situ hybridisation

Rarely, in some cases, additional confirmation of HPV infection or typing maybe desired, where in-situ hybridization (ISH) test maybe useful. It can detect a very low copy number of HPV DNA sequences in paraffin-embedded tissue sections. In a study, 210 cervical tissue specimens were evaluated to detect HPV DNA using ISH and PCR, and a concordance rate of 78.2% was found between these two modalities.(LE: 3)^[16]

Polymerase chain reaction

HPV L1 sequencing and type-specific HPV-6, 11, 16, and 18 real-time polymerase chain reaction for identification and typing of HPV can be done, however this test is useful only for research settings and has not much diagnostic or prognostic value. (LE: 2b)^[17]

Serology

Serology is used occasionally. When measured in cases of suspected HPV infection, 36% (18/50) of sera were positive for type-specific neutralizing antibodies. It is not used routinely, and use is limited to research setting. (LE: 2b)^[18]

Preventive Vaccine

The current generation of HPV vaccines, Cervarix and Gardasil have demonstrated a high degree of efficacy in clinical trials against HPV serotypes.^[19] Cervarix and Gardasil are two prophylactic HPV vaccines designed primarily for cervical cancer prevention. Cervarixis effective against HPV16, -18, the two most common cancer-causing types. Gardasilis also effective against HPV-16, 18, in addition, itisalso effective against HPV-6 and -11, most common causes of genital warts and respiratory papillomatosis. According to ACIP, 2011 recommendation, for females, either routine vaccination with 3-dose series at age 11 or 12 years can be done or it can be done through age 26 years if not vaccinated previously. The most important determinant of vaccine impact to reduce cervical cancer isits duration of efficacy. As per current evidence, Cervarix's efficacy has been proven for 6.4 years and Gardasil's for 5 years.^[20] In Australia national HPV vaccination programme, the percentage of genital-warts declined from 11.5% and 11.3% in women under 21 years and 21-30 year-old respectively to 0.85% and 3.1%, respectively. Similarlythe percentage of men under 21 yearsand 21-30 yearage group reducedfrom 12.1% and 18,2% respectively in 2007 to 2.2% and 18.2% respectively in 2011. No significant difference was seen in age group more than 30 years. (LE: 1a)^[21]

The results show high efficacy against detection of new anogenital lesions in males 29 months after receiving the quadri valent HPV vaccine.^[22][23][24] The ACIP recommended routine use of quadrivalent HPV vaccine in males aged 11 or 12 years. The ACIP also recommended vaccination with HPV for males aged 13 through 21 years who have not been vaccinated pre-viously or who have not completed the 3-dose series. (LE: 1a) males aged 22 through 26 years may also be vaccinated.^[25]

In a randomized controlled trial in the per protocol susceptible population, vaccine efficacy against condyloma was 99% (96% to 100%).(LE: 1b)^[26] There is a definite risk of viral transmission to the asymptomatic partners in HPV infection, as HPV DNA wasdetected in 34.5% of asymptomatic male partners of infected women. Thus, partner protection should be recommended to minimize the viral transmission.^[27] (LE: 2b). The genital HPV infections are multifocal and they can be clinically evident at one site and mayremain dormant at other.^[28]

Though it has been proved now that HPV infection is a transient infection with a median duration of 8 months, and after 24 months, only 9% of the infection persist.^[29] This emphasizes that extensive investigations to detect asymptomatic infection may not be required.

Treatment

Provider administered

Photodynamic therapy

A 5-amino levulinic acid-mediated photodynamic therapy (ALA-PDT) is an effective technique in the treatment of condylomata acuminata. ALA-PDT is proposed to act by selective destruction of subclinical virus-shedding area and activation of specific immune cells in the lesional skin. (LE: 1a)^[30] It has also been used in combinationwith CO₂ laser, withdecreasedrecurrence rate and increased clearance rate. (LE: 1a)^[31] Safety and efficacy have been documented for condylomataacuminata on the distal urethra. (LE: 1b)^[32] In a randomized con-trolled trial, the group receiving PDT showed 95.3% clearance of AGW with only 9.38% pa-tients showed recurrence. (LE: 1b)^[33] The cervical condylomatous lesions have also shown good improvement with a low recurrence rate. (LE: 3)^[34]

Laser

The CO₂, Pulsed-dye, Argon, Holmium, and Nd:YAG lasers have been described as treatment options for AGW. Single-period CO₂ laser therapy was found eneficial for vulvar condylomata acuminata. (LE: 3)^[35] The combination treatment using CO₂ laser and photodynamic therapy shown good results for HIV seropositive men with intra-anal warts (LE: 3)^[36] The Nd:YAG and Thulium lasers have been used for external and urethral condylomas in 115 patients with complete clearance, however, 34% patients developed recurrences. (LE: 2)^[37] Recurrent BuschkeLöwenstein tumours found to be treatable with CO₂ laser vaporization with complete remission (LE: 3)^[38]

Surgery

Surgical excision is considered as the treatment of choice in large pedunculated lesions. (LE: 3)^[39]

Cryotherapy

Cryotherapy act by crystallizing the cytosol of the cells, resulting in cell necrosis and activation of immune system. It has a reported efficacy of 79-88% for wart clearance with recurrence in 25-39% of cases. Weekly sessions are done usually up to 12 weeks for external genital warts. (LE: 1b)^[40] It is an inexpensive, easy method with no serious side effects and is also a safe therapy in pregnant women. Mild side effects as blistering, local necrosis, scarring and hypo pigmentation can occur.

Immunotherapy

Intralesional antigen immunotherapy has been used for the treatment of warts. Induced delayed type hypersensitivity is the proposed mechanism of action. L1-virus like particles (VLP) immunotherapy was found to be associated with a significantly reduced rate of recurrence of genital warts when used in combination with conventional destructive therapy. (LE: 1b)^[41] In a randomized control trial of 89 patients, intralesional Mycobacterium w (Mw) vaccine showed similar efficacy and safety as of imiquimod 5% cream, with a complete clearance in 66.7% of patients and a mean reduction in size of 83.23%. (LE: 1b)

Podophyllin

Topical solution of 20%, is applied by physician , once a week for up to eight weeks. It is an antimitotic and antiproliferative agent. Local side effects in form of edema, inflammation and erosions can be seen. (LE: 1b)^[42]

Patient administered therapy

Imiquimod 5%

Imiquimod 5% cream is a topical immune response modifier, which has antiviral and antitumorous properties by inducing the production of cytokines(interleukins,interferon, TNF-alpha). Imiquimod is recommended therapy for AGW as topical application 3 times every week till complete clearance of wart or maximum 16 weeks. (LE: 1b)^[43]

Imiquimod 3.75% cream is also available in many countries and appears to be as effective as 5% when applied daily for 8 weeks and is said to increase tolerability, decrease treatment du-ration and side effects. (LE: 3)^[44]

Podophyllotoxin

Podophyllotoxin inhibits the proliferation of human skin keratinocytes and cures genital warts by inhibiting proliferation of HPV-infected cells. Podophyllotoxin is used 2 times on 3 consecutive days every week until warts completely cleared, or for a maximum period of 4 weeks. Local side effects in the form of erythema, edema and inflammation can occur. (LE: 1b)^[45] In a randomized controlled trial to compare the effectiveness of self applied podophyllotoxin 0.5% solution and podophyllotoxin 0.15% cream, compared to clinic applied 25% podophyllin in the treatment AGW, complete clearance was seen in 75%, 64.5% and 53.1% of patients respectively. (LE: 1b)^[46]

Sinecatechins and Polyphenon E 10% ointment

15% Sinecatachins ointment is used for the treatment of external genital warts. Three times daily application is recommended till complete wart clearance or maximum 16 weeks. Anti-viral, immune stimulation and anti carcinogenic activity are proposed mechanism of actions. Mild local side effects can be noted as redness, burning, pain, itching and swelling. (LE: 3)^[47] Polyphenon E is a botanical agent consisting predominately of catechins extracted from Camellia sinensis. The exact mechanism of action of polyphenon E is unknown but proposed mechanism are keratinocytes growth inhibition potential and its antioxidative activity. Recommended frequency of application is three times daily until complete clearance of all warts, but for no longer than 16 weeks. Polyphenon E 10% ointment is generally well tolerated in adults with external genital and perianal warts, local skin reactions as erythema, irritation, pain, and pruritus can occur rarely. Clearance rate of 50-70% was noted in a meta-analysis with approximately 10% recurrence rate. (LE: 1a)^[48]

Cidofovir

Cidofoviris a nucleotide analog of deoxycytidine monophosphate. It selectively competitively inhibits viral DNA polymerase. Topical cidofovir has been successfully used in the management of condyloma acuminatum and other HPV-mediated diseases. (LE: 3)^[49]

5-Fluorouracil (5-FU)

5-Fluorouracil is a pyrimidine anti-metabolite that functions as an anti-neoplastic agent by blocking DNA synthesis. Daily application of 5% 5-FU cream has been found effective in external genital and perianal wart. (LE: 1a)^[50]

Interferon

It acts in HPV infections by virtue of its antiviral, anti-proliferative mechanisms and, in addition, it also stimulates the immune system of the body.It can be used either intralesional route or by systemic routes (subcutaneous or intramuscular), former is more effective. (LE: 1a)^[51] Biphasic vesicles for topical delivery of interferon alpha are also available.^[52]

Other treatment modalities (single or combination)

• Low-dose oral cyclophosphamide therapy: (LE: 3)^[53]

• Systemic interleukin 2 and topical cidofovir: (LE: 3)^[54]

• Local hyperthermia 44°c: (LE: 3)^[55]

• Oral retinoid and intramuscular interferon-γ therapy: (LE: 3)^[56]

• Combination of radiofrequency surgical dissection and oral acitretin: (LE: 3)^[57]

• A 32P application device for the treatment of condyloma acuminatum in the rectum: (LE: 3)^[58]

• Oral pidotimod plus vitamin C after laser vaporization: (LE: 3)^[59]

• Chemoradiotherapy used for large Buschke-Lowenstein tumor: (LE: 3)^[60]

Treatment summary

• Few smaller lesions: topical patient administered therapy as imiquimod, 5-FU cream, polyphenon ointment

• Few larger lesion: Surgery, cryotherapy, podophyllin

• Multiple lesions: Immunotherapy, Interferon, PDT, laser, combination therapies

Table 1. Efficacy of various treatments for genital condyloma acuminata

Abbreviations

HPV: Human papilloma virus, AGW: anogenital warts, ISH: in-situ hybridization, 5-FU: 5-Fluorouracil

References

4. Matsukura T, Mitsuishi T, Sugase M, Kawashima M Human papillomavirus type 7-associated condyloma.Dermatology. 2010;221:5-8.

1. Hathaway JK. HPV: diagnosis, prevention, and treatment.ClinObstet Gynecol. 2012 ;55:671-80.

2. Bhatia N, Lynde C, Vender R, BourcierM. Understanding genital warts: epidemiology, pathogenesis, and burden of disease of human papillomavirus. J Cutan Med Surg.2013;17Suppl 2:S47-54.

3. Yanofsky VR, Patel RV, Goldenberg G. Genital warts: a comprehensive review. J ClinAesthetDermatol. 2012;5:25-36.

4. Darwich L, Cañadas MP, Videla S, Coll J, Piñol M, Cobarsi P, Molina-López RA, Vela S, García-Cuyás F, Llatjos M, Sirera G, Clotet B; HIV-HPV Can Ruti Team. Condylomata, cytological abnormalities and human papillomavirus infection in the anal canal in HIVinfected men. HIV Med. 2012 ;13:549-57.

5. Patel H, Wagner M, Singhal P, Kothari S. Systematic review of the incidence and pre-valence of genital warts. BMC Infect Dis. 2013;13:39.

6. Lee CB, Choe HS, Hwang SJ, Lee SJ, Cho YH. Epidemiological characteristics of ge-nital herpes and condyloma acuminata in patients presenting to urologic and gyneco-logic clinics in Korea. J Infect Chemother. 2011;17:351-7.

7. Kumar P, Dar L, Saldiwal S, Varma S, DattUpadhyay A, Talwar D, Sharma VK, Verma KK, Dwivedi SN, Raj R, Gupta S. Intralesional Injection of Mycobacterium w Vaccine vs Imiquimod, 5%, Cream in Patients With Anogenital Warts: A Randomized Clinical Trial. JAMA Dermatol. 2014 Aug.

8. Park SJ, Seo J, Ha SH, Jung GW. Prevalence and determinants of high-risk human papilloma virus infection in male genital warts. Korean J Urol. 2014;55:207-12.

9. Juckett G, Hartman-Adams H. Human papillomavirus: clinical manifestations and prevention. Am Fam Physician. 2010;82:1209-13.

10. Albero G, Castellsaguams H. Human papillomavirus: cliniircumcision and genital human papillomavirus: a systematic review and meta-analysis. Sex Transm Dis. 2012 ;39:104-13.

11. Lynde C, Vender R, Bourcier M, Bhatia N. Clinical features of external genital warts. J Cutan Med Surg. 2013;17Suppl 2:S55-60.

12. McCutcheon T. Anal condyloma acuminatum. GastroenterolNurs. 2009;32:342-9.

13. Delbello A, Colli C, Martínez Tdel R, Trevisan G. Anal canal and rectal condylomato-sis:exhaustive proctological examination and STD patients. Acta Dermatovenerol Alp Panonica Adriat. 2010;19:13-6.

14. Wieland U, Kreuter A, Pfister H. Human papilloma virus and immunosuppres-sion. CurrProblDermatol. 2014;45:154-65.

15. Kazlouskaya V, Shustef E, Allam SH, Lal K, Elston D. Expression of p16 protein in lesional and perilesionalcondylomaacuminata and bowenoidpapulosis: clinical signi-ficance and diagnostic implications. J Am AcadDermatol. 2013;69:444-9

16. Kelesidis T, Aish L, Steller MA, Aish IS, Shen J, Foukas P, Panayiotides J, Petrikkos G, Karakitsos P, Tsiodras S. Human papillomavirus (HPV) detection using in situ hybridization in histologic samples: correlations with cytologic changes and polymerase chain reaction HPV detection. Am J ClinPathol. 2011;136:119-27.

17. Mills A, Balasubramaniam R, Longacre TA, Kong CS, Pinsky BA. Developed L1 sequencing and type-specific, real-time polymerase chain reaction for the detection and typing of human papillomaviruses in formalin-fixed, paraffin-embedded tis-sues. ArchPathol Lab Med. 2013;137:50-4.

18. Wu XL, Zhang CT, Zhu XK, Wang YC. Detection of HPV types and neutralizing antibodies in women with genital warts in Tianjin City, China. Virol Sin. 2010;25:8-17.

19. Blomberg M, Dehlendorff C, Munk C, Kjaer SK. Strongly decreased risk of genital warts after vaccination against human papillomavirus: nationwide follow-up of vaccinated and unvaccinated girls in Denmark. Clin Infect Dis. 2013;57:929-34.

20. Harper DM. Currently approved prophylactic HPV vaccines. Expert Rev Vaccines. 2009;8:1663-79.

21. Ali H, Donovan B, Wand H, Read TR, Regan DG, Grulich AE, Fairley CK, Guy RJ. Genital warts in young Australians five years into national human papillomavirus vaccination programme:national surveillance data. BMJ. 2013;346:f2032.

22. Yancey AM, Pitlick JM, Forinash AB. The prophylactic role for the human papillo-mavirus quadrivalent vaccine in males. Ann Pharmacother. 2010;44:1314-8.

23. Giuliano AR, Palefsky JM, Goldstone S, Moreira ED Jr, Penny ME, Aranda C, Vardas E, Moi H, Jessen H, Hillman R, Chang YH, Ferris D, Rouleau D, Bryan J, Marshall JB, Vuocolo S, Barr E, Radley D, Haupt RM, Guris D. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. N Engl J Med. 2011 Feb 3;364:401-11.

24. Palefsky JM, Giuliano AR, Goldstone S, Moreira ED Jr, Aranda C, Jessen H, Hillman R, Ferris D, Coutlee F, Stoler MH, Marshall JB, Radley D, Vuocolo S, Haupt RM, Guris D, Garner EI. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. NEngl J Med. 2011 Oct 27;365:1576-85.

25. Centers for Disease Control and Prevention (CDC). Recommendations on the use of quadrivalent human papillomavirus vaccine in males--Advisory Committee on Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep. 2011 23;60:1705-8.

26. FUTURE I/II Study Group, Dillner J, Kjaer SK, Wheeler CM, Sigurdsson K, Iversen OE, Hernandez-Avila M, Perez G, Brown DR, Koutsky LA, Tay EH, Garctee on Im-munization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep. 2011 23;60:1705-8. AcM, Steben M, Bosch FX, Joura EA, Majewski S, Muñoz N, Myers ER, Villa LL, Taddeo FJ, Roberts C, Tadesse A, Bryan JT, Maansson R, Lu S, Vuoco-lo S, Hesley TM, Barr E, Haupt R. Four year efficacy of prophylactic human papillo-mavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepi-thelial neoplasia and anogenital warts: randomised controlled trial. BMJ. 2010 Jul 20;341:c3493.

27. Lauro C, Ammaturo FP, Quirino L, Rotondi M, Soriano A, Panariello S.[Evaluation of partners of women with HPV infection]. Minerva Ginecol. 2000;52:503-7.

28. Rymark P, Forslund O, Hansson BG, Lindholm K. Genital HPV infection not a local but a regional infection: experience from a female teenage group. Genitourin Med. 1993 Feb;69:18-22.

29. Strand A, Rylander E. Human papillomavirus. Subclinical and atypical manifestations. DermatolClin. 1998 Oct;16:817-22.

30. Ying Z, Li X, Dang H. 5-aminolevulinic acid-based photodynamic therapy for the treatment of condylomata acuminata in Chinese patients: a meta-analysis. PhotodermatolPhotoimmunolPhotomed. 2013;29:149-59.

31. Zhu X, Chen H, Cai L, Yu Z, Cai L. Decrease recurrence rate of condylomataacumi-nata by photodynamic therapy combined with CO2 laser in mainland China: a meta-analysis. Dermatology. 2012;225:364-70.

32. Li J, Yi Y, Zhu W. [Three stages of 5-aminolevulinic acid-photodynamic therapy forcondylomaacuminatum of external urethral meatus]. Zhong Nan Da XueXueBao Yi Xue Ban. 2011;36:1115-9.

33. Liang J, Lu XN, Tang H, Zhang Z, Fan J, Xu JH. Evaluation of photodynamic therapy using topical aminolevulinic acid hydrochloride in the treatment of condylomata acuminata: a comparative, randomized clinical trial. PhotodermatolPhotoimmunolPho-tomed. 2009;25:293-7.

34. Chen MK, Luo DQ, Zhou H, Huang ZW, Zhang QF, Han JD. 5-aminolevulinic acid-mediated photodynamic therapy on cervical condylomataacuminata. Photomed Laser Surg. 2011;29:339-43.

35. Li XC, Zhu L, Gu Y, Jin HM, Wang CY, Xu T, Lang JH. [Outcome prediction of sin-gle-period CO(2) laser therapy for vulvar condylomata acuminate]. Zhonghua Yi Xu-eZaZhi. 2012;92:1759-62.

36. Xu J, Xiang L, Chen J, He Q, Li Q, Li J, Wang J. The combination treatment using CO₂ laser and photodynamic therapy for HIV seropositive men with intraanal warts. Photodiagnos is PhotodynTher. 2013;10:186-93.

37. Blokker RS, Lock TM, de Boorder T. Comparing thulium laser and Nd:YAG laser in the treatment of genital and urethral condylomataacuminata in male patients. Lasers Surg Med. 2013 ;45:582-8.

38. Perniola G, d'Itri F, Di Donato V, Achilli C, Lo Prete E, Panici PB. Recurrent BuschkeLöwenstein tumor treated using CO(2) laser vaporization. J Minim Invasive Gynecol. 2010;17:662-4.

39. Qian G, Yu H. Giant condylomaacuminata of Buschke-Lowenstein: successful treatment mainly by an innovative surgical method. DermatolTher. 2013;26:411-4.

40. Gilson RJ, Ross J, Maw R, Rowen D, Sonnex C, Lacey CJ. A multicentre, rando-mised, double-blind, placebo controlled study of cryotherapy versus cryotherapy and podophyllotoxin cream as treatment for external anogenital warts. Sex Transm Infect. 2009;85:514-9.

41. Jardine D, Lu J, Pang J, Palmer C, Tu Q, Chuah J, Frazer IH. A randomized trial of immunotherapy for persistent genital warts. Hum Vaccin Immunother. 2012;8:623-9.

42. Akhavan S, Mohammadi SR, ModarresGillani M, Mousavi AS, ShiraziM. Efficacy of combination therapy of oral zinc sulfate with imiquimod, podophyllin or cryotherapy in the treatment of vulvar warts. J ObstetGynaecol Res.

43. Komericki P, Akkilic-Materna M, Strimitzer T, Aberer W. Efficacy and safety of imiquimod versus podophyllotoxin in the treatment of anogenital warts. Sex Transm Dis. 2011;38:216-8.

44. Berman B, Wolf J. The role of imiquimod 3.75% cream in the treatment of external genital warts. Skin Therapy Lett. 2012;17:5-7.

45. Komericki P, Akkilic-Materna M, Strimitzer T, Aberer W. Efficacy and safety of imi-quimod versus podophyllotoxin in the treatment of anogenital warts. Sex Transm Dis. 2011;38:216-8.

46. C Lacey, R Goodall, T Ragnarson, R Maw, G Kinghorn, P Fisk, S Barton, and I Byrne. Randomised controlled trial and economic evaluation of podophyllotoxin solution, podophyllotoxin cream, and podophyllin in the treatment of genital warts. Sex Transm Infect. Aug 2003; 79: 270–275.

47. Fantasia HC. Sinecatechins ointment 15% for the treatment of external genital warts. NursWomens Health. 2012;16:418-22.

48. Tzellos TG, Sardeli C, Lallas A, Papazisis G, Chourdakis M, Kouvelas D. Efficacy, safety and tolerability of green tea catechins in the treatment of external anogenital warts: a systematic review and meta-analysis. J EurAcadDermatolVenereol. 2011;25:345-53.

49. Nambudiri VE, Mutyambizi K, Walls AC, Fisher DC, Bleday R, Saavedra AP. Successful treatment of perianal giant condyloma acuminatum in an immunocom-promised host with systemic interleukin 2 and topical cidofovir. JAMA Dermatol. 2013;149:1068-70.

50. Batista CS, Atallah AN, Saconato H, da Silva EM. 5-FU for genital warts in nonimmunocompromised individuals. Cochrane Database Syst Rev. 2010;:CD006562.

51. Yang J, Pu YG, Zeng ZM, Yu ZJ, Huang N, Deng QW. Interferon for the treatment of genital warts: a systematic review. BMC Infect Dis. 2009;9:156.

52. Foldvari M, Badea I, Kumar P, Wettig S, Batta R, King MJ, He Z, Yeboah E, Gaspar K, Hull P, Shear NH. Biphasic vesicles for topical delivery of interferon alpha in hu-man volunteers and treatment of patients with human papillomavirus infections. Curr Drug Deliv. 2011;8:307-19.

53. Zhang Y, Duan Y, Zhao J, Huang B, Cao YC. Low-dose oral cyclophosphamide therapy is effective for condylomataacuminata. Chin Med J (Engl). 2013;126:3198-9.

54. Nambudiri VE, Mutyambizi K, Walls AC, Fisher DC, Bleday R, Saavedra AP. Successful treatment of perianal giant condylomaacuminatum in an immunocom-promised host with systemic interleukin 2 and topical cidofovir. JAMA Dermatol. 2013;149:1068-70.

55. Huo W, Li GH, Qi RQ, Zhang L, Yan XX, Chen HD, Gao XH. Clinical and immuno-logic results of local hyperthermia at 44 °C for extensive genital warts in patients with diabetes mellitus. Int J Hyperthermia. 2013;29:17-20.

56. Tian YP, Yao L, Malla P, Song Y, Li SS. Successful treatment of giant condylomaa-cuminatum with combination retinoid and interferon-with underlying superficS. 2012 ;23:445-7.

57. Mavrogianni P, Fallidas E, Nicolaidou E, Villias K, Stefanaki I, Katsambas A, Lira T, Apostolopoulos P, Androne I, Rouvas G, Tsibouris P, Alexandrakis G. Therapeutic combination of radiofrequency surgical dissection and oral acitretin in the management of perianal Buschke-Lowenstein tumour: a case report. Int J STD AIDS. 2012;23:362-4.

58. Ma YB, Liu YW, Gu AC, Xu F, Liu PA, Yuan SF, Zhai CT. [A 32P application de-vice for the treatment of condylomaacuminatum in the rectum]. Zhonghua Nan KeX-ue. 2011;17:47-51.

59. Zervoudis S, Iatrakis G, Peitsidis P, Peitsidou A, Papandonopolos L, Nikolopoulou MK, Papadopoulos L, Vladareanu R Complementary treatment with oral pidotimod plus vitamin C after laser vaporization for female genital warts: a prospective study. J Med Life. 2010;3:286-8.

60. Armstrong N, Foley G, Wilson J, Finan P, Sebag-Montefiore D. Successful treatment of a large Buschke-Lowenstein tumour with chemo-radiotherapy. Int J STD AIDS. 2009;20:732-4.