Department of General, Vascular and Oncologic Surgery, Czerniakowski Hospital in Warsaw
Head of Department: Professor Mariusz Frączek, MD, PhD
Similarly to venereologists, dermatologists and gynaecologists, a coloproctologist surgeon is also a specialist dealing with patients affected by sexually transmitted diseases. The responsible pathogens include bacteria, viruses, protozoa, fungi and parasites. This heterogeneous group of diseases can damage many organs and systems. The human papillomavirus (HPV) is transmitted through direct skin-to-skin or mucosa-to-mucosa contact, most often during sexual intercourse, to later persist in keratinocytes. The most important risk factors include non-use of condoms and a large number of sexual partners. Proctological symptoms may occur in patients of both sexes, who are involved in different sexual practices, including anal sex. A patient presenting with genital warts may suffer from several coexisting venereal diseases, which are not always symptomatic; therefore serological testing for HIV, HBV/HCV and syphilis is advisable. Advice on the prevention of sexually transmitted infections, the need for diagnosis and treatment of sexual partners is also a good practice. It should be reported in medical documentation that this information has been provided.
HPV infection is the most common sexually transmitted disease. Up to 86% of sexually active people may be infected by the virus (1). Warts develop in only 10% of these people. The pathogen not only easily spreads, but it shows cancerogenic potential. Up to 80% of anal cancers are caused by HPV infection (2). Of the more than 100 serotypes of the virus, HPV16 is most cancerogenic for patients with perianal lesions (3). Higher rates of anal cancer are reported for homosexual men with HIV infection (46/100,000) compared to seronegative individuals (5/100,000) (4).
The disease is usually diagnosed based on clinical evaluation. Macroscopic lesions are often accompanied by pruritus, burning sensation, less commonly by pain, wet feeling in the anus or blood staining. Physical examination should begin with abdominal and inguinal evaluation. Visual inspection of the genitals and the anus should be supplemented with anal palpation and anoscopy. Single or multiple papular, papillous lesions with a tendency to merge into one another, which may exfoliate and are located in the genital or anal area, are a typical symptom of HPV infection. Although biopsy and histopathological examination are not required to confirm the diagnosis, they become necessary in the case of atypical lesions, ulcerations, bleeding and tissue discolouration, as well as in immunocompromised patients. Histopathological verification should be also contemplated at further stages, in the absence of improvement or clinical picture deterioration despite treatment. Gynaecological consultation and cytology should be recommended in each woman with viral anal warts.
The onset of symptoms may occur many months after exposure. In about 1/3 of patients, symptoms may resolve spontaneously within 4 months, whereas in other cases the disease remains stable or multiple new lesions develop (5). Since it is impossible to estimate which patients are classified into the first group, treatment should be offered to all patients (6). Absence of evident symptoms does not indicate the lack of infectiousness. It is estimated that the risk of infecting a sexual partner persists for 6 months after symptom resolution. The patient should be also warned that the symptoms may recur, particularly during periods of reduced immunity (due to infection, increased physical exercise or sunlight exposure).
The treatment of viral warts involves chemical and surgical destruction as well as immune therapy. The choice of method depends on, among other things, the size and extent of lesions, comorbidities, patient’s preferences and consent to the proposed therapy. In this regard, both the possibility and regularity of local application of medications as well as patience in waiting for the disappearance of warts and knowledge of the potential complications of method used are also important. Extensive, merging lesions located in the perianal region or in the anal canal are an indication for surgical treatment. Further part of the paper describes different methods for the treatment of HPV infection, starting from first-line therapies.
Imiquimod is a substance whose efficacy is mainly due to modulatory effects on the immune response by stimulating macrophages and monocytes to produce interferon α and cytokines, mainly IL-12 and TNF-α. It is usually used as 5% (Aldara) or 3.75% cream (Zyclara). The 5% imiquimod cream is applied 3 times a week prior to normal sleeping hours. The cream should be left on for 6 to 10 hours and then removed by washing with water. The therapy should be continued for 16 weeks or until warts disappear. The lower concentration formulation is to be used daily for 8 weeks. The efficacy of 5% imiquimod cream is 35-75%, with recurrence rates of 6-26% (7, 8). Although studies indicate lower efficacy of the 3.75% cream, shorter treatment duration is its advantage (9). The medication causes a number of local adverse effects, such as reddening, irritation, erosions and ulceration. These symptoms usually resolve after treatment discontinuation, allowing the patient to resume the therapy. Local symptoms may be accompanied by flu-like manifestations. The cream may reduce the efficacy or local contraceptives during the application period.
Podophyllotoxin in the form of 0.5% solution (Condyline) and 0.15% cream (Wartec) has antimitotic activity. The preparation is applied twice daily for 3 consecutive days. The remnants of the drug should be washed off after 4 hours. The 3-day treatment cycle should be repeated after a 4-day interval, which may be repeated four times. The skin around the lesions should be protected against active substance, e.g. by applying a protective layer of vaseline. Sexual contacts should be discontinued during therapy. According to a systematic literature review, the efficacy of podophyllotoxin in the form of solution and cream is 45-83% and 43-70%, respectively (7). Local irritation is more common and may be more severe compared to imiquimod. Symptoms are most severe in the first treatment period. Podophyllotoxin often causes headache.
Sinecatechin used in the form of 10 or 15% ointment (Veregen) is an antiviral substance derived from green tea extract. It most probably acts by influencing apoptosis and genes whose products modulate antiviral responses. The ointment is applied on the affected anoderm three times daily, without the need to remove the remaining formulation before another application. The efficacy of the ointment (10 and 15%) shown in randomised trials in the treatment of external genital and perianal warts is up to 58% throughout the treatment group (surprisingly higher among women – 65%), with only minor local adverse effects (10, 11). The need for long-term treatment is a disadvantage of this drug (12).
1. Stier EA, Sebring MC, Mendez AE et al.: Prevalence of anal human papillomavirus infection and anal HPV-related disorders in women: a systematic review. Am J Obstet Gynecol 2015; 213(3): 278-309.
2. De Vuyst H, Clifford GM, Nascimento MC et al.: Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis. Int J Cancer 2009; 124: 1626-1636.
3. Ln C, Franceschi S, Clifford GM: Human papillomavirus types from infection to cancer in the anus, according to sex and HIV status: a systematic review and meta-analysis. GM Lancet Infect Dis 2017 Nov 17. pii: S1473-3099(17)30653-9. DOI: 10.1016/S1473-3099(17)30653-9.
4. Tian T, Mijiti P, Bingxue H et al.: Prevalence and risk factors of anal human papillomavirus infection among HIV-negative men who have sex with men in Urumqi city of Xinjiang Uyghur Autonomous Region, China. PLoS One 2017; 12(11): e0187928. DOI: 10.1371/journal.pone.0187928. eCollection 2017.
5. Yanofsky VR, Patel RV, Goldenberg G: Genital warts: a comprehensive review. J Clin Aesthet Dermatol 2012; 5: 25-36.
6. Vender R, Bourcier M, Bhatia N, Lynde C: Therapeutic options for external genital warts. J Cutan Med Surg 2013; 17 (suppl. 2): 61-67.
7. Lacey CJ, Woodhall SC, Wikstrom A, Ross J: 2012 European guideline for the management of anogenital warts. J Eur Acad Dermatol Venereol 2013; 27: 263-270.
8. 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.
9. Rosen T, Nelson A, Ault K: Imiquimod cream 2.5% and 3.75% applied once daily to treat external genital warts in men. Cutis 2015; 96: 277.
10. Stockfleth E, Beti H, Orasan R et al.: Topical Polyphenon E in the treatment of external genital and perianal warts: a randomized controlled trial. Br J Dermatol 2008; 158: 1329-1338.
11. Tatti S, Swinehart JM, Thielert C et al.: Sinecatechins, a defined green tea extract, in the treatment of external anogenital warts: a randomized, controlled trial. Obstet Gynecol 2008; 111: 1371-1379.
12. Meltzer SM, Monk BJ, Tewari KS: Green tea catechins for treatment of external genital warts. Am J Obstet Gynecol 2009; 200(3): 233.e1-7.
13. Godley MJ, Bradbeer DS, Gellan M, Thin RNT: Cryotherapy compared with trichloroacetic acid in treating genital warts. Genitourin Med 1987; 63: 390-392.
14. Damstra RJ, van Vloten WA: Cryotherapy in the treatment of condylomata acuminata: a controlled study of 64 patients. J Dermatol Surg Oncol 1991; 17: 273.
15. Sonnex C, Lacey CJ: The treatment of human papillomavirus lesions of the lower genital tract. Best Pract Res Clin Obstet Gynaecol 2001; 15: 801-816.
16. Ammori BJ, Ausobsky JR: Electrocoagulation of perianal warts: a word of caution. Dig Surg 2000; 17: 296-297.
17. Workowski KA, Bolan GA, Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015; 64: 1-137.
18. De Toma G, Cavallaro G, Bitonti A et al.: Surgical management of perianal giant condyloma acuminatum (Buschke-Lowenstein tumor). Report of three cases. Eur Surg Res 2006; 38: 418-422.
19. Trombetta LJ, Place RJ: Giant condyloma acuminatum of the anorectum: trends in epidemiology and management: report of a case and review of the literature. Dis Colon Rectum 2001; 44: 1878-1886.
20. Oh C, Albanese C: S-plasty for various anal lesions. Am J Surg 1992; 163: 606-608.
21. Wroński K, Bocian R: Surgical excision of extensive anal condylomata is a safe operation without risk of anal stenosis. Postepy Hig Med Dosw (Online) 2012; 66: 153-157.
22. Klaristenfeld D, Israelit S, Beart RW et al.: Surgical excision of extensive anal condylomata not associated with risk of anal stenosis. Int J Colorectal Dis 2008; 23(9): 853-856.
23. Jensen SL: Comparison of podophyllin application with simple surgical excision in clearance and recurrence of perianal condylomata acuminata. Lancet 1985; 2: 1146-1148.
24. Carrozza PM, Merlani GM, Burg G, Hafner J: CO2 laser surgery for extensive, cauliflower-like anogenital condylomata acuminata: retrospective long-term study on 19 HIV-positive and 45 HIV-negative men. Dermatology 2002; 205: 255-259.
25. Hsu VM, Aldahan AS, Tsatalis JP et al.: Efficacy of Nd:YAG laser therapy for the treatment of verrucae: a literature review. Lasers Med Sci 2017; 32(5): 1207-1211.
26. Blokker RS, Lock TM, de Boorder T: Comparing thulium laser and Nd:YAG laser in the treatment of genital and urethral condylomata acuminata in male patients. Lasers Surg Med 2013; 45: 582-588.
27. Komericki P, Akkilic M, Kopera D: Pulsed dye laser treatment of genital warts. Lasers Surg Med 2006; 38: 273-276.
28. Volz LR, Carpiniello VL, Malloy TR: Laser treatment of urethral condyloma: a five-year experience. Urology 1994; 43: 81-83.
29. Huang J, Zeng Q, Zuo C et al.: The combination of CO2 laser vaporation and photodynamic therapy in treatment of condylomata acuminata. Photodiagnosis Photodyn Ther 2014; 11: 130-133.
30. Chen K, Chang BZ, Ju M et al.: Comparative study of photodynamic therapy vs CO2 laser vaporization in treatment of condylomata acuminata: a randomized clinical trial. Br J Dermatol 2007; 156(3): 516-520.
31. Kofoed K, Norrbom C, Forslund O et al.: Low prevalence of oral and nasal human papillomavirus in employees performing CO2-laser evaporation of genital warts or loop electrode excision procedure of cervical dysplasia. Acta Derm Venereol 2015; 95(2): 173-176.
32. Ferenczy A, Bergeron C, Richart RM: Human papillomavirus DNA in CO2 laser-generated plume of smoke and its consequences to the surgeon. Obstet Gynecol 1990; 75: 114-118.
33. Ilmarinen T, Auvinen E, Hiltunen-Back E et al.: Transmission of human papillomavirus DNA from patient to surgical masks, gloves and oral mucosa of medical personnel during treatment of laryngeal papillomas and genital warts. Eur Arch Otorhinolaryngol 2012; 269: 2367-2371.
34. Lacey CJ, Goodall RL, Tennvall GR et al.: Randomised controlled trial and economic evaluation of podophyllotoxin solution, podophyllotoxin cream, and podophyllin in the treatment of genital warts. Sex Transm Infect 2003; 79: 270-275.
35. Batista CS, Atallah AN, Saconato H, da Silva EM: 5-FU for genital warts in non-immunocompromised individuals. Cochrane Database Syst Rev 2010; 14;(4):CD006562.
36. Snoeck R, Bossens M, Parent D et al.: Phase II double-blind, placebo-controlled study of the safety and efficacy of cidofovir topical gel for the treatment of patients with human papillomavirus infection. Clin Infect Dis 2001; 33: 597-602.
37. Matteelli A, Beltrame A, Graifemberghi S et al.: Efficacy and tolerability of topical 1% cidofovir cream for the treatment of external anogenital warts in HIV-infected persons. Sex Transm Dis 2001; 28: 343-346.
38. Yang J, Pu YG, Zeng ZM et al.: Interferon for the treatment of genital warts: a systematic review. BMC Infect Dis 2009; 9: 156.
39. Reichman RC, Oakes D, Bonnez W et al.: Treatment of condyloma acuminatum with three different interferon-alpha preparations administered parenterally: a double-blind, placebo-controlled trial. J Infect 1990; 162(6): 1270-1276.
40. Pasmatzi E, Kapranos N, Monastirli A et al.: Large benign condyloma acuminatum: successful treatment with isotretinoin and interferon alpha. Acta Derm Venereol 2012; 92: 249-250.
41. Yew YW, Pan JY: Complete remission of recalcitrant genital warts with a combination approach of surgical debulking and oral isotretinoin in a patient with systemic lupus erythematosus. Dermatol Ther 2014; 27: 79-82.
42. Zhao J, Zeng W, Cao Y et al.: Immunotherapy of HPV infection-caused genital warts using low dose cyclophosphamide. Expert Rev Clin Immunol 2014; 10: 791-799.
43. Zhang Y, Duan Y, Zhao J et al.: Low-dose oral cyclophosphamide therapy is effective for condylomata acuminata. Chin Med J 2013; 126: 3198-3199.
44. Ying Z, Li X, Dang H: 5-aminolevulinic acid-based photodynamic therapy for the treatment of condylomata acuminata in Chinese patients: a meta-analysis. Photodermatol Photoimmunol Photomed 2013; 29: 149-159.
45. Liang J, Lu XN, Tang H et al.: Evaluation of photodynamic therapy using topical aminolevulinic acid hydrochloride in the treatment of condylomata acuminata: a comparative, randomized clinical trial. Photodermatol Photoimmunol Photomed 2009; 25: 293-297.
46. Eassa BI, Abou-Bakr AA, El-Khalawany MA: Intradermal injection of PPD as a novel approach of immunotherapy in anogenital warts in pregnant women. Dermatol Ther 2011; 24: 137-143.
47. Jardine D, Lu J, Pang J et al.: A randomized trial of immunotherapy for persistent genital warts. Hum Vaccin Immunother 2012; 8: 623-629.
48. Işik S, Koca R, Sarici G, Altinyazar HC: A comparison of a 5% potassium hydroxide solution with a 5-fluorouracil and salicylic acid combination in the treatment of patients with anogenital warts: a randomized, open-label clinical trial. Int J Dermatol 2014; 53(9): 1145-1150.
49. Dhadda AS, Anand A, Boynton C, Chan S: External beam radiotherapy for extensive genital condyloma acuminate: a role in selected patients? Clin Oncol (R Coll Radiol) 2008; 20: 91-92.
50. Ormerod AD, van Voorst Vader PC, Majewski S et al.: Evaluation of the Efficacy, Safety, and Tolerability of 3 Dose Regimens of Topical Sodium Nitrite With Citric Acid in Patients With Anogenital Warts: A Randomized Clinical Trial. JAMA Dermatol 2015; 151: 854-861.
51. Werner RN, Westfechtel L, Dressler C, Nast A: Anogenital warts and other HPV-associated anogenital lesions in the HIV-positive patient: a systematic review and meta-analysis of the efficacy and safety of interventions assessed in controlled clinical trials. Sex Transm Infect 2017; 93: 543-550.