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Management of condyloma acuminatum
Therapv Management of condyloma acuminatum Paul D. Silva, M.D.,* John Paul Micha, M.D.,* and Douglas G. Silva, M.D., D.D.S.** Orange and Los Angeles, CA This article describes an approach to the evaluation and treatment of condyloma acuminatum (anogenital warts) that is based on the results of new Clinical research on the biology of the human papillomavirus. A more extensive diagnostic protocol, including routine cervicovaginal examination and Papanicolaou smear, is proposed for female patients because of the close association of genital human papillomavirus infections with cervical carcinoma. Two highly effective therapies, cryosurgery and carbon dioxide laser photocoagulation, are described and compared with older regimens. Recent developments in immunotherapy for resistant condyloma acuminatum are also discussed. (J AM ACAD DERMATOL 13:457-463, 1985.)
Young adults with anogenital human papillomavirus infections are being seen with increasing frequency in dermatologic practice. Data from the Centers for Disease ControP show that (1) there was a 500% increase in the incidence of condyloma acuminatum from 1966 to 1981, (2) dermatologists see the largest percentage of male patients with the disease and are second only to gynecologists in consultations from female patients, and (3) of the 946,000 consultations in 1981, 65 % were from patients between the ages of 15 and 29 years. Condyloma acuminatum is a sexually transmitted disease. 2-4 Up to two thirds of the sexual contacts of affected patients develop lesions. 3,4 The incubation period ranges from 3 weeks to 8 months, with an average of3 months. 4 Condyloma acumimitum is caused by specific human paplllomavirus types (Table I). Although condyloma acuminatum may spontaneously regress, 4 patients with this disease should always be evaluated and From the Department of Ohstetrics and Gynecology, UniverSity of California, Irvine, Medical Center, *and The Schools of Medicine and Dentistry, University of California, Los Angeles, Center for the Health Sciences. ** Reprint requests to: Dr. John Paul Micha, Hoag Memorial Hospital Presbyterian Cancer Center, 30 I Newport Blvd., Newport Beach, CA 92663.
treated, especially in the light of recent research findings linking the human papillomavirus to genital squamous cell carcinoma in women. 5,6
PRETREATMENT EVALUATION FOR FEMALE PATIENTS External genitalia, urethra, and anorectal region Evaluation should begin with a careful inspection of the external genitalia and perianal region. The frequencies with which different sites are volved have been reported as follows: posterior introitus, 73%; labia minora and clitoris, 32%; labia majora, 31%; perineum, 23%; anus, 18%; and urethra, 8%.4 A magnifying lens or laupe can be useful in detecting smaller lesions. Benign diseases sometimes confused with condyloma acuminatum are molluscum contagiosum, syphHis (condyloma latum), the hypertrophic vulvar dystrophies, and angiofibroma. TypicalcondylQmata, distinguishable by their moist, filiform appearance, do not require biopsy; however, flat, pig.. mented, giant, and ulcerated lesions, as well as lesions resistant to therapy, should be ~ampled. These are the features often associated with neoplasia. Without histologic examination of suspicious lesions, dysplasia or carcinoma cannot be ruled out. Vulvar condylomata have been reported
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Table I. Currently recognized human papillomavirus types and lesions from which they have been isolated* HPV type
Lesions
HPV l HPV2 HPV3 HPV4 HPV 5 HPV6 HPV7 HPV 8 HPV9 HPVlO
Myrmecia type of deep plantar warts, common warts, genital warts, focal epithelial hyperplasia Common warts, filiform warts, plantar warts, palatal warts, genital warts Flat warts, BV, squamous cell skin cancer Palmar and plantar warts of small hyperkeratotic type, common warts BY, squamous cell skin cancer, Bowen's lesions Genital warts, flat lesions of the uterine cervix, Buschke-Lowenstein tumors Common warts BV, squamous cell skin cancer, Bowen's lesions BV BV, flat warts, genital warts, squamous cell carcinomas of the uterine cervix, vulval carcinomas, bowenoid lesions of vulva Laryngeal papillomas, flat lesions of the uterine cervix, genital warts, squamous cell carcinomas of the uterine cervix, Buschke-Lowenstein tumors BV Focal epithelial hyperplasia BY, squamous cell skin cancer BY Squamous cell carcinomas of the uterine cervix, bowenoid papulosis, Bowen's lesions, flat lesions of uterine cervix, genital warts, vulval carcinoma, penile carcinoma BV Squamous cell carcinomas of the uterine cervix, penile carcinoma BY BV BV
HPV 11 HPV HPV HPV HPV HPV
12 13 14 15 16
HPV 17 HPV 18 HPV 19 HPV20 HPV21 HPV22 HPV 23 HPV24 HPV 25,
BY BY BY BY
EV: Epidermodysplasia verruciformis; HPV: human papillomavirus, *Compiled from the following reviews: (1) Syrjaneri J: Current concepts of human papillomavirus infections inthe genital tract and their relationship to intraepithelial neoplasia and squamous cell carcinoma (Obstet Gynecol Surv 39:252-265, 1984); (2) Pfister H: Biology and biochemistry of papHiomaviruses (Rev Physiol Biochem Phannacol 99: 111-181, 1984); and (3) Gissmann L, Boshart M, Durst M, et al: Presence of human papillomavirus in genital tumors (J Invest Dermatol 83:265-285, 1984). Data also from Lutzner MA, Blanchet-Bardon C, Orth G: Clinical observations, virologic studi,es, and treatment trials in patients with epidermodysplasia verruciformis, a disease induced by specific human papillomaviruses. J Invest Dennarol 83:185-255, 1984.
in 6% to 48% of patients with vulvar intraepithelial neopla~ia, *.7-9 and there are numerous case reports of squamous cell carcinomas in association with vulvar condyloinata. lO If indicated, a 4-mm circular punch biopsy instrument can be used to remove a core of epidermis and dermis from the involved area. Infiltration of a local anesthetic agent, such as 1% xylocaine solution, is required for external lesions. If nec*Roy, M: How to treat patients with condyloma. Contemp Obstet Gynecol 20:185-189, 1982.
essary, hemostasis can be obtained with silver nitrate applicators, ferric subsulfate solution, or a single suture. Condyloma acuminatum of the external uretnral meatus should be treated before cystourethroscopy, since marked proximal urethral spread of the lesions has been reported to occur shortly after endoscopy. II Bladder condylomata are rare, with less than ten cases reported. 12 ,13 Such patients should be referred to a urologist. The perianal region is commonly involved with multiple condylomata. In such cases, rectal ex-
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amination and anoscopy should be employed, since condyloma acuminatum occasionally involves the anal canal and the distal rectum. 14 ,IS
Vagina and cervix Following external genital examination, a thorough cervical and vaginal examination should be performed. Of patients with external condyloma acuminatum, up to 20% will have gross vaginal lesions 3 and up to 6% will have recognizable cervical lesions. 4 The rationale for treating cervical and vaginal lesions includes four considerations. First, the cervix and vagina probably act as a reservoir for reinfection of the external genitalia. Second, human papillomavirus is a sexually transmitted organism, and before its spread to sexual contacts can be arrested, complete elimination of the virus from contagious areas must be achieved. Third, cervical and vaginal condylomata may act as a source of congenital infection in the newborn, causing laryngeal papillomatosisl 6,17 or anogenital wartS. IS -20 Fourth, as will be discussed further, cervical infection with certain human papillomavirus types is closely linked to squamous cell carcinoma of the cervix. 21 A Papanicolaou smear of the exocervix and endocervix should be obtained, since most cervical human papillomavirus infections are not visible to the unaided eye,22,23 Cytologic or colposcopic evidence of human papillomavirus cervical infection has been reported in 50% of women with vulval condyloma acuminatum. 23 A biopsy should be performed on all visible cervical lesions, since the correlation with dysplastic and malignant epithelial changes is greatest in this organ. Biopsy of the cervix can be done with a Kevorkian biopsy forceps, which removes about 3 mm3 of tissue. Bleeding is usually easily controlled with simple pressure, ferric subsulfate solution, or silver nitrate applicators, No local anesthesia is necessary, although mild discomfort is not uncommon. If evidence of cervical human papillomavirus infection is found through biopsy or cytologic study, colposcopy and endocervical biopsy should be performed by a specialist to determine the exact
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location and extent of disease, as well as to rule out neoplasia. Two clinical research findings explain the rationale for this approach, First, cervical condylomatous changes are associated with cervical intraepithelial neoplasia in up to 84% of cases 24; high-grade cervical intraepithelial neoplasia (carcinoma in situ) progresses to invasive cervical carcinoma in 30% to 70% of cases. 25 ,26 Second, patients with cervical intraepithelial neoplasia or invasive cervical carcinoma have evidence of human papillomavirus infection in 91 % of cases. 27 If confinnation of the results of a study showing that 36% of patients with vulvar condylomata have cervical intraepithelial neoplasia is obtained,23 colposcopy and endocervical biopsy will be recommended in all patients with external condyloma acuminatum. Recent studies using deoxyribonucleic acid hybridization technics have shown that human papillomavirus types 6,10, 11, 16, and 18 are mainly involved in genital infections (Table I), Although human papillomavirus types 6, 10, 11, and 16 have been isolated from invasive and noninvasive genitallesions ,28-33 human papillomavirus type 18 has been found only in invasive genital carcinomas, 34 Studies have shown that the deoxyribonucleic acid of human papiIlomavirus can be found in 90% of cervical carcinoma biopsies ,21 giving strong circumstantial evidence for a direct role of the human papillomavirus in cervical carcinogenesis. Thus, until further information is obtained, screening for cervical dysplasia and long-term follow-up, with regular pelvic examinations and Papanicolaou smears, are essential for all patients with human papillomavirus genital infections. PRETREATMENT EVALUATION FOR MALE PATIENTS
Evaluation of the male external genitalia is similar to that for female patients, consisting of careful inspection, as well as biopsy of suspicious lesions. The frequencies with which different sites are involved have been reported as follows: frenulum, corona, and glans, 52%; prepuce, 33%; urinary meatus, 23%; shaft of penis, 18%; anus, 8%; and scrotum, 2%.4 There is a high incidence of anal
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involvement in male homosexuals. 15 Anoscopy and rectal examination should be performed if perianal lesions are present. Urethral involvement should be suspected if condylomata are present in the region of the external urethral meatus or if there are unexplained symptoms of dysuria, frequency, urgency, bleeding, discharge, or change in the urinary stream. Most lesions occur in the distal 4 ern of the urethra, and the proximal urethra is not involved without concurrent disease in the distal urethra. 35 After treatment of proximal lesions , cystourethroscopy or urethrography can be used to determine the extent of proximal urethral involvement. Patients with bladder, proximal urethral, or extensive urethral lesions are rare and should be referred to a urologist, since major surgery, including cystectomy, may be necessary.35,36 TREATMENT
External genital and perianal condyloma acuminatum
Podophyllin is an effective first-line therapy for these lesions. It is applied as a 10% to 25% solution in tincture of benzoin and washed off by the patient, preferably in a bath or shower, I to 4 hours after application. Application with a glass rod, orange stick, or pointed wooden stick allows for complete coating of the complex surfaces of the lesions and several millimeters of surrounding normal-appearing skin. Care should be taken to avoid painting large areas of normal skin, since severe local irritation and systemic absorption can occur. When lesions covered by the prepuce are treated, the applied solution must be allowed to dry for several minutes before the prepuce is returned to its usual position. If necessary, surrounding skin can be protected with either petrolatum before application of podophyllin or talcum powder afterward. Clinical trials of podophyllin have shown cure rates ranging from 22% to 98%.2.37-40 Our experience has shown that patients who have small condylomata limited to the external genitalia can be cured with one to three weekly podophyllin applications in the majority of cases. Localized recurrences can usually be effectively treated with podophyllin also. Podophyllin should not be used during pregnancy, in infants, or on the vagina or cervix,
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since severe systemic toxicity has been reported. Podophyllin has cytodestructive and antimitotic actions. 40 Toxicity has included bone marrow suppression, severe sensorimotor neuropathy requiring ventilatory support, stillbirth, and death. 41,42 For this reason, we do not allow patients to apply podophyllin to themselves. When podophyllin is contraindicated, or when three weekly applications have failed, one to three weekly applications of 50% trichloroacetic acid can be tried. The use of trichloroacetic acid in combination with podophyllin does not improve cure rates. 39 The method of application for the two substances is similar. If trichloroacetic acid is accidentally applied to unaffected areas or comes into contact with the physician's skin, it can be neutralized with sodium bicarbonate solution. Trichloroacetic acid does not need to be washed off the lesions at a later time. Cryosurgery, with cure rates of 90%,43,44 is more effective than topical chemotherapy. Although cure rates are similar to those of electrocautery, cryosurgery is preferable because it requires no local anesthesia. 45 We use a cryosurgical probe cooled by nitrous oxide. After the lesion is moistened with saline solution, the probe will adhere to the lesion, allowing it to be pulled away from surrounding skin. Freezing should be continued until the entire lesion and 1 to 2 mm of surrounding normal-appearing skin is incorporated into the ice ball. Cryosurgery produces a local burning sensation, which, along with local necrosis and ulceration, often persists for 1 week. Complete healing takes 2 to 3 weeks. Treatments can be repeated at intervals of 1 to 2 weeks. Cures are usually obtained after one to three treatments. The carbon dioxide laser has been used to treat condyloma acuminatum, with reported cure rates of greater than 90%.46-49 External genital and vaginal condylomata are superficial lesions; thus photocoagulation to a depth of 1 to 2 mm is usually adequate. Several centimeters of grossly uninvolved surrounding epithelium should be photocoagulated also. Small areas can be treated in the office after infiltration of a local anesthetic agent; however, larger areas require general or regional anesthesia. Healing usually occurs within 3 to 4 weeks. Pain can be controlled with oral analgesics or topical anesthetic agents. Secondary bacterial
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infection can be prevented by antiseptic cleansing solutions, sitz baths, and blow drying of the ex~ ternal genitalia. Cosmesis is excellent, since the laser causes minimal scarring. Cures usually occur after a single treatment. Major disadvantages of this treatment modality include cost of instrumen~ tation and necessity for regional or general anes~ thesia when extensive lesions are treated. We use this method as the treatment of choice for large, confluent lesions or multiple, widespread smaller lesions.
Vagina Vaginal condylomata, if localized, can be treated by biopsy excision, electrocautery, or cryosurgery. We treat multiple diffuse lesions by carbon dioxide photocoagulation under colposcopic guidance. This procedure requires general or regional anesthesia. An alternative treatment regimen consists of daily intravaginal applications of 5% 5-fluorouracil cream for 5 days. 50 The vulva and urethra should be protected with zinc oxide ointment or petrolatum to try to prevent local irritation. Nevertheless, severe erosive vulvitis and urethritis may develop.
Cervix Patients with microscopic or gross cervical human papillomavirus infection should be treated with cryosurgery or laser photocoagulation of the entire cervical transformation zone. Colposcopy is essential prior to treatment of the cervix to rule out neoplasia and to delineate the extent of the lesion. Treatment to a depth of about 7 rnm is required in order to destroy the epithelium of endocervical glands underlying the squamocolumnar junction. 51 Cryosurgery can be done in the office with a flat, circular probe that covers the cervix. Laser photocoagulation, if extensive, requires general or regional anesthesia. Cryosurgery produces a profuse vaginal discharge that can last 3 weeks, whereas photocoagulation of the cervix produces discharge for only 1 to 2 weeks. The laser is the treatment of choice for large cervical condylomata.
Anorectal region Skin surrounding the external anal opening can be treated sparingly with podophyllin. The patient
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would be warned that a marked local burning sensation can occur, but it resolves when the solution is washed off, 1 to 4 hours after application. Lesions of the anal canal have been treated successfully, in the majority of cases, with weekly applications of bichloracetic acid under anoscopic guidance. 15 With this technic the lesions are dabbed once lightly with a cotton-tipped applicator. Cryosurgery, with anoscopic guidance if necessary, is an effective outpatient technic. Surgical resection, electrocautery, and carbon dioxide photocoagulation should usually be reserved for treatment failures or extensive lesions.
Urethra Most lesions are limited to the external urethral meatus and respond well to topical chemotherapy or office cryosurgery. Podophyllin should be used only on meatal lesions , since its use in the urethral canal may cause significant systemic absorption. Distal urethral lesions can be treated with 5% 5-fluorouracil cream ll; however, applications four times a day for up to 14 days may be necessary, and recurrences are common. 52 Recently the carbon dioxide laser has been used with 100% success for photocoagulation of distal urethral lesions. 53.54 Extensive urethral lesions and bladder condylomata usually require a combination of several treatment modalities. They should be referred to a urologist for combinations of electrocautery, surgical resection, and topical chemotherapy. 11-13,35.36,55
Oral warts Oral warts are sometimes seen in patients with condyloma acuminatum and often have a similar appearance. 56 ,57 A shave biopsy should be done to verify the diagnosis. We have successfully treated these lesions with electrocautery under local anesthesia. Florid oral papillomatosis is rare and difficult to treat. It may develop into squamous cell carcinoma. 58 ,59 Patients with extensive oral warts should be referred to an oral surgeon or otorhino~ laryngologist for treatment. IMMUNOTHERAPY
Autogenous vaccine has been used to successfully treat resistant cases of condyloma acuminatum60-62 ; however, concern about the oncogen-
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icity of human papillomavirus precludes recommending use of the vaccine until further studies are perfonned. Initial results with levamisole,63 an immunopotentiator, were promising, but subsequent studies have not found it to be as usefup2 Patients with resistant condyloma acuminatum have been shown to have depressed immunoglobulin levels; recently interferon has been used to successfully treat a small number of such patients.'" The University of California, Irvine, Medical Center is currently involved in a large trial of interferon for resistant condyloma. Preliminary results are promising. Interferon has also been used successfully to treat patients with previously untreated condylomata. 64 We currently do not recommend the use of interferon outside of a research setting. An inadequate number of patients have been studied to reveal possible adverse effects, and there has been one case report of bowenoid dysplasia's developing during therapy. 65 As yet, data are not sufficient to individualize treatment of human papillomavirus infections on the basis of their specific viral type. Therefore it is recommended that all condylomata be treated as though they are premalignant in female patients. In addition to eliminating the premalignant potential in a given patient, this approach should impact the incidence of this transmissible disease. It is essential that all sexual partners of patients with condyloma acuminatum be examined. Patients who have recurrent or resistant disease should undergo cystourethroscopic and proctoscopic examination, and there should be careful reevaluation of their sexual partner to reveal any foci for reinfection. Studies in the basic science of human papillomavirus and clinical research are rapidly evolving. The clinician will require frequent updates to learn new ways of evaluating and treating this common but challenging disease. *Gall SA, Hughes CE: Interferon for the treatment of resistant condyloma acuminatum. Presented at the Fifteenth Annual Meeting of the Society of Gynecologic Oncologists, Miami, FL, February, 1984.
REFERENCES 1. Condyloma acuminatum- United States, 1966-1981 : Current trends. MMWR 32:306-308, 1983.
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2. Barrett TJ, Silbar JD: Genital warts: A venereal disease. JAMA 154:333-334, 1954. 3. Teokharov BA: Non-gonococcal infections of the female genitalia. Br J Vener Dis 45:334-340, 1969. 4. Oriel 10: Natural history of genital warts. Br J Vener Dis 47:1-13, 1971. 5. Syrjanen J: Current concepts of human papillomavirus infections in the genital tract and their relationship to intraepithelial neoplasia and squamous cell carcinoma. Obstet Gynecol Surv 39:252-265, 1984. 6. Pfister H: Biology and biochemistry of papillomaviruses. Rev Physiol Biochem Pharmacol 99:111-181, 1984. 7. Buscema J, Woodruff 10, Parmley TH, et al: Carcinoma in situ of the vulva. Obstet Oynecol 55:225-230, 1980. 8. Friedrich EO, Wilkinson EF, Fu YS: Carcinoma in situ of the vulva: A continuing challenge. Am J Obstet Oynecol 136:830-838, 1980. 9. Crum CP, Braun LA, Shah KV, et al: Vulvar intraepithelial neoplasia. Cancer 49:468-471, 1982. 10. Rhatigan RM, Saffos RO: Condyloma acuminatum and squamous carcinoma of the vulva. South Med J 70:591594, 1977. 11. Dretler SP, Klein LA: The eradication of intraurethral condyloma acuminatum with 5 per cent 5-fluorouracil cream. J Urol1l3:195-l98, 1975. 12. Debenedictis TJ, Marmar JL, Praiss DE: Intraurethral condyloma acuminatum: Management and review of the literature. 1 Ural 118:767-769, 1977. 13. Hotchkiss RS, Rouse AJ: Papillomatosis of the bladder and ureters, preceded by condyloma acuminatum of the vulva: A case report. J Uroll00:723-725, 1968. 14. Shah IC, Hertz RE: Giant condyloma acuminatum of the anorectum. Dis Colon Rectum 15:207-210, 1972. 15. Swerdlow DB, Salvati EP: Condyloma acuminatum. Dis Colon Rectum 14:226-231, 1971. 16. Cook TA, Cohn AM, Brunschwig JP, et al: Wart viruses and laryngeal papillomas. Lancet 1:782, 1973. 17. Cook TA, Cohn AM, Brunschwig JP, et al: Laryngeal papilloma: Etiologic and therapeutic considerations. Ann Otol Rhinol Laryngol 82:649-655, 1973. 18. Eftaiha MS, Amshel AL, Shonberg IL: Condyloma acuminatum in an infant and mother. Dis Colon Rectum 21:369-371, 1978. 19. Tang C, Shermeta DW, Wood C: Congenital condyloma acuminatum. Am J Obstet OynecolI31:912-913, 1978. 20. Patel R, Groff DB: Condyloma acuminatum in childhood. Pediatrics 50:153-154, 1972. 21. Gissmann L, Boshart M, Durst M, et al: Presence of human papillomavirus in genital tumors. J Invest Dermatol 83:265-285, 1984. 22. Roy M, Meisels A, Fortier M, et al: Vaginal condylomata: A human papillomavirus infection. Clin Obstet Oynecol 24:461-483, 1981. 23. Walker PO, Colley NV, Grubb C, et al: Abnormalities of the uterine cervix in women with vulval warts. Br J Vener Dis 59:120-123, 1983. 24. Grunebaum AN, Sedlis A, Sillman F, et al: Association of human papillomavirus infection with cervical intraepithelial neoplasia. Obstet Oynecol 62:448-455, 1983. 25. Gad C: The management and natural history of severe dysplasia and carcinoma in situ of the uterine cervix. Br J Obstet Oynaecol 83:554-559, 1976.
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26. Nelson JH, Averette HE, Richart RM: Dysplasia, carcinoma in situ, and early invasive cervical carcinoma. CA 34:306-327, 1984. 27. Reid R, Stanhope CR, Herschman BR, et al: Genital warts and cervical cancer. Cancer 50:377-387, 1982. 28. Crum CP, Ikenberg H, Richart RM, et al: Human papillomavirus type 16 and early cervical neoplasia. N Engl J Med 310:880-883, 1984. 29. Gissmann L, de Villiers E, zur Jausen H: Analysis of human genital warts and other genital tumors for human papillomavirus type 6 DNA. lnt J Cancer 29:143-146, 1982. 30. Gissmann L, Wolnik L, Ikenberg H, et al: Human papillomavirus types 6 and 11 DNA sequences in genital and laryngeal papillomas and in some cervical cancers. Proc Nat! Acad Sci USA 80:560-563, 1983. 31. McCance DJ, Walker PG, Dyson JL, et al: Presence of human papillomavirus DNA sequences in cervical intraepithelial neoplasia. Br Med J 287:784-788, 1983. 32. Ikenberg H, Gissmann L, Gross G, et al: Human papiIlomavirus type-16-related DNA in genital Bowen's disease and in bowenoid papulosis. lnt J Cancer 32:563565, 1983. 33. Durst M, Gissman L, lkenberg J, et al: A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Nat! Acad Sci USA 80:3812-3815, 1983. 34. Boshart M, Gissmann L, Ikenberg H, et al: A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer. EMBO J 3:1151-1157, 1984. 35. Kleiman H, Lancaster Y: Condyloma acuminatum of the bladder. J Urol 88:52-55, 1962. 36. Bissada NK, Cole AT, Fried FA: Extensive condylomata acuminata of the entire male urethra and the bladder. J UroI112:201-203, 1974. 37. Culp OS, Magid MA, Kaplan IW: Podophyllin treatment of condyloma acuminatum. J Urol 51:655-659, 1944. 38. Simmons PO: Podophyllin 10% and 25% in the treatment of ano-genital warts. Br J Vener Dis 57:208-209, 1981. 39. Gabriel G, Thin RNT: Treatment of anogenital warts. Br J Vener Dis 59:124-126, 1983. 40. Von Krogh G: Podophyllotoxin for condyloma acuminatum eradication. Acta Derm Venereol [Suppl] (Stockh) 98: 1-48, 1981. 41. Chamberlain MJ, Reynolds AL, Yeoman WB: Toxic effect of podophyllum application in pregnancy. Br Med J 3:391-392, 1972. 42. Slater GE, Rumack BH, Peterson RG: Podophyllin poisoning. Obstet GynecoI 52:94-96, 1978. 43. Ghosh AK: Cryosurgery of genital warts in cases in which podophyllin treatment failed or was contraindicated. Br J Vener Dis 53:49-53, 1977. 44. Balsdon MJ: Cryosurgery of genital warts. Br J Vener Dis 54:352-353, 1978. 45. Simmons PO, Langlet F, Thin RNT: Cryotherapy versus electrocautery in the treatment of genital warts. Br J Vener Dis 57:273-274, 1981. 46. Baggish MS: Treating viral venereal infections with the CO2 Laser. J Reprod Med 27:737-742, 1982.
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47. Baggish MS: Carbon dioxide laser treatment for condylomata acuminata venereal infections. Obstet Gynecol 55:711-715, 1980. 48. Calkins JW, Masterson BJ, Magrina JF: Management of condylomata acuminata with the carbon dioxide la&er. Obstet GynecoI59:105-108, 1982. 49. Bellina JH: The use of the carbon dioxide laser in the management of condyloma acuminatum with eight-year follow-up. Am J Obstet Gyneco1l47:375-378, 1983. 50. Ferenczy A: Comparison of 5-fluorouracil and CO 2 laser for treatment of vaginal condylomata. Obstet Gynecol 64:773-778, 1984. 51. Anderson MC, Hartley RB: Cervical crypt involvement by intraepithelial neoplasia. Obstet Gynecol 55:546-550, 1980. 52. Robertson DHH, McMillan A, Young H: Clinical practice in sexually transmissible diseases. Kent, United Kingdom, 1980, Pitman Medical, p. 347. 53. Rosenberg SK, Fuller T, Jacobs H: Continuous-wave carbon dioxide laser treatment of giant condylomata acuminata of the distal urethra and perineum: Technique. J UroI126:827-829, 1981. 54. Fuselier HA, McBurney EI, Brannan W, et al: Treatment of condylomata acuminata with carbon dioxide laser. Urology 15:265-266, 1980. 55. Gartman E: Intraurethral verruca acuminata in men. J Urol 75:717-718, 1956. 56. Doyle JL, Grodjesk IE, Manhold JH: Condyloma acuminatum occurring in the oral cavity. Oral Surg 26:434440, 1968. 57. Knapp MJ, Uohara 01: Oral condyloma acuminatum. Oral Surg 23:538-545, 1967. 58. Kanee B: Oral florid papillomatosis complicated by verrucous squamous carcinoma. Arch Dennatol 99: 196202, 1969. 59. Samitz MH, Ackennan AB, Lantis LR: Squamous cell carcinoma arising at the site of oral florid papillomatosis. Arch Dermatol96:286-289, 1967. 60. Powell LC, Pollard M, Jinkins JL: Treatment of condyloma acuminatum by autogenous vaccine. South Med J 63:202-205, 1970. 61. Nel WS, Fourie ED: Immunotherapy and 5% topical 5fluorouracil ointment in the treatment of condyloma acuminatum. S Afr Med j 47:45-49, 1973. 62. Abcarian J, Smith D, Sharon N: The immunotherapy of anal condyloma acuminatum. Dis Colon Rectum 19:237244, 1976. 63. Krupp 1M, cited by Roy M, Meisels A, Fortier M, et al: Vaginal condylomata: A human papillomavirus infection. Clin Obstet Gynecol 24:461-483, 1981. 64. Schonfeld A, Schattner A, Crespi M, et al: Intramuscular human interferon-B injections in treatment of condyloma acuminatum. Lancet 1:1038-104i, 1984. 65. Gross G, lkenberg H, Gissmann L: Bowenoid dysplasia in human papillomavirus-16 DNA-positive flat condylomas during interferon-B treatment. Lancet 1:1467~ 1468, 1984.
Young adults with anogenital human papillomavirus infections are being seen with increasing frequency in dermatologic practice. Data from the Centers for Disease ControP show that (1) there was a 500% increase in the incidence of condyloma acuminatum from 1966 to 1981, (2) dermatologists see the largest percentage of male patients with the disease and are second only to gynecologists in consultations from female patients, and (3) of the 946,000 consultations in 1981, 65 % were from patients between the ages of 15 and 29 years. Condyloma acuminatum is a sexually transmitted disease. 2-4 Up to two thirds of the sexual contacts of affected patients develop lesions. 3,4 The incubation period ranges from 3 weeks to 8 months, with an average of3 months. 4 Condyloma acumimitum is caused by specific human paplllomavirus types (Table I). Although condyloma acuminatum may spontaneously regress, 4 patients with this disease should always be evaluated and From the Department of Ohstetrics and Gynecology, UniverSity of California, Irvine, Medical Center, *and The Schools of Medicine and Dentistry, University of California, Los Angeles, Center for the Health Sciences. ** Reprint requests to: Dr. John Paul Micha, Hoag Memorial Hospital Presbyterian Cancer Center, 30 I Newport Blvd., Newport Beach, CA 92663.
treated, especially in the light of recent research findings linking the human papillomavirus to genital squamous cell carcinoma in women. 5,6
PRETREATMENT EVALUATION FOR FEMALE PATIENTS External genitalia, urethra, and anorectal region Evaluation should begin with a careful inspection of the external genitalia and perianal region. The frequencies with which different sites are volved have been reported as follows: posterior introitus, 73%; labia minora and clitoris, 32%; labia majora, 31%; perineum, 23%; anus, 18%; and urethra, 8%.4 A magnifying lens or laupe can be useful in detecting smaller lesions. Benign diseases sometimes confused with condyloma acuminatum are molluscum contagiosum, syphHis (condyloma latum), the hypertrophic vulvar dystrophies, and angiofibroma. TypicalcondylQmata, distinguishable by their moist, filiform appearance, do not require biopsy; however, flat, pig.. mented, giant, and ulcerated lesions, as well as lesions resistant to therapy, should be ~ampled. These are the features often associated with neoplasia. Without histologic examination of suspicious lesions, dysplasia or carcinoma cannot be ruled out. Vulvar condylomata have been reported
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Table I. Currently recognized human papillomavirus types and lesions from which they have been isolated* HPV type
Lesions
HPV l HPV2 HPV3 HPV4 HPV 5 HPV6 HPV7 HPV 8 HPV9 HPVlO
Myrmecia type of deep plantar warts, common warts, genital warts, focal epithelial hyperplasia Common warts, filiform warts, plantar warts, palatal warts, genital warts Flat warts, BV, squamous cell skin cancer Palmar and plantar warts of small hyperkeratotic type, common warts BY, squamous cell skin cancer, Bowen's lesions Genital warts, flat lesions of the uterine cervix, Buschke-Lowenstein tumors Common warts BV, squamous cell skin cancer, Bowen's lesions BV BV, flat warts, genital warts, squamous cell carcinomas of the uterine cervix, vulval carcinomas, bowenoid lesions of vulva Laryngeal papillomas, flat lesions of the uterine cervix, genital warts, squamous cell carcinomas of the uterine cervix, Buschke-Lowenstein tumors BV Focal epithelial hyperplasia BY, squamous cell skin cancer BY Squamous cell carcinomas of the uterine cervix, bowenoid papulosis, Bowen's lesions, flat lesions of uterine cervix, genital warts, vulval carcinoma, penile carcinoma BV Squamous cell carcinomas of the uterine cervix, penile carcinoma BY BV BV
HPV 11 HPV HPV HPV HPV HPV
12 13 14 15 16
HPV 17 HPV 18 HPV 19 HPV20 HPV21 HPV22 HPV 23 HPV24 HPV 25,
BY BY BY BY
EV: Epidermodysplasia verruciformis; HPV: human papillomavirus, *Compiled from the following reviews: (1) Syrjaneri J: Current concepts of human papillomavirus infections inthe genital tract and their relationship to intraepithelial neoplasia and squamous cell carcinoma (Obstet Gynecol Surv 39:252-265, 1984); (2) Pfister H: Biology and biochemistry of papHiomaviruses (Rev Physiol Biochem Phannacol 99: 111-181, 1984); and (3) Gissmann L, Boshart M, Durst M, et al: Presence of human papillomavirus in genital tumors (J Invest Dermatol 83:265-285, 1984). Data also from Lutzner MA, Blanchet-Bardon C, Orth G: Clinical observations, virologic studi,es, and treatment trials in patients with epidermodysplasia verruciformis, a disease induced by specific human papillomaviruses. J Invest Dennarol 83:185-255, 1984.
in 6% to 48% of patients with vulvar intraepithelial neopla~ia, *.7-9 and there are numerous case reports of squamous cell carcinomas in association with vulvar condyloinata. lO If indicated, a 4-mm circular punch biopsy instrument can be used to remove a core of epidermis and dermis from the involved area. Infiltration of a local anesthetic agent, such as 1% xylocaine solution, is required for external lesions. If nec*Roy, M: How to treat patients with condyloma. Contemp Obstet Gynecol 20:185-189, 1982.
essary, hemostasis can be obtained with silver nitrate applicators, ferric subsulfate solution, or a single suture. Condyloma acuminatum of the external uretnral meatus should be treated before cystourethroscopy, since marked proximal urethral spread of the lesions has been reported to occur shortly after endoscopy. II Bladder condylomata are rare, with less than ten cases reported. 12 ,13 Such patients should be referred to a urologist. The perianal region is commonly involved with multiple condylomata. In such cases, rectal ex-
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amination and anoscopy should be employed, since condyloma acuminatum occasionally involves the anal canal and the distal rectum. 14 ,IS
Vagina and cervix Following external genital examination, a thorough cervical and vaginal examination should be performed. Of patients with external condyloma acuminatum, up to 20% will have gross vaginal lesions 3 and up to 6% will have recognizable cervical lesions. 4 The rationale for treating cervical and vaginal lesions includes four considerations. First, the cervix and vagina probably act as a reservoir for reinfection of the external genitalia. Second, human papillomavirus is a sexually transmitted organism, and before its spread to sexual contacts can be arrested, complete elimination of the virus from contagious areas must be achieved. Third, cervical and vaginal condylomata may act as a source of congenital infection in the newborn, causing laryngeal papillomatosisl 6,17 or anogenital wartS. IS -20 Fourth, as will be discussed further, cervical infection with certain human papillomavirus types is closely linked to squamous cell carcinoma of the cervix. 21 A Papanicolaou smear of the exocervix and endocervix should be obtained, since most cervical human papillomavirus infections are not visible to the unaided eye,22,23 Cytologic or colposcopic evidence of human papillomavirus cervical infection has been reported in 50% of women with vulval condyloma acuminatum. 23 A biopsy should be performed on all visible cervical lesions, since the correlation with dysplastic and malignant epithelial changes is greatest in this organ. Biopsy of the cervix can be done with a Kevorkian biopsy forceps, which removes about 3 mm3 of tissue. Bleeding is usually easily controlled with simple pressure, ferric subsulfate solution, or silver nitrate applicators, No local anesthesia is necessary, although mild discomfort is not uncommon. If evidence of cervical human papillomavirus infection is found through biopsy or cytologic study, colposcopy and endocervical biopsy should be performed by a specialist to determine the exact
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location and extent of disease, as well as to rule out neoplasia. Two clinical research findings explain the rationale for this approach, First, cervical condylomatous changes are associated with cervical intraepithelial neoplasia in up to 84% of cases 24; high-grade cervical intraepithelial neoplasia (carcinoma in situ) progresses to invasive cervical carcinoma in 30% to 70% of cases. 25 ,26 Second, patients with cervical intraepithelial neoplasia or invasive cervical carcinoma have evidence of human papillomavirus infection in 91 % of cases. 27 If confinnation of the results of a study showing that 36% of patients with vulvar condylomata have cervical intraepithelial neoplasia is obtained,23 colposcopy and endocervical biopsy will be recommended in all patients with external condyloma acuminatum. Recent studies using deoxyribonucleic acid hybridization technics have shown that human papillomavirus types 6,10, 11, 16, and 18 are mainly involved in genital infections (Table I), Although human papillomavirus types 6, 10, 11, and 16 have been isolated from invasive and noninvasive genitallesions ,28-33 human papillomavirus type 18 has been found only in invasive genital carcinomas, 34 Studies have shown that the deoxyribonucleic acid of human papiIlomavirus can be found in 90% of cervical carcinoma biopsies ,21 giving strong circumstantial evidence for a direct role of the human papillomavirus in cervical carcinogenesis. Thus, until further information is obtained, screening for cervical dysplasia and long-term follow-up, with regular pelvic examinations and Papanicolaou smears, are essential for all patients with human papillomavirus genital infections. PRETREATMENT EVALUATION FOR MALE PATIENTS
Evaluation of the male external genitalia is similar to that for female patients, consisting of careful inspection, as well as biopsy of suspicious lesions. The frequencies with which different sites are involved have been reported as follows: frenulum, corona, and glans, 52%; prepuce, 33%; urinary meatus, 23%; shaft of penis, 18%; anus, 8%; and scrotum, 2%.4 There is a high incidence of anal
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involvement in male homosexuals. 15 Anoscopy and rectal examination should be performed if perianal lesions are present. Urethral involvement should be suspected if condylomata are present in the region of the external urethral meatus or if there are unexplained symptoms of dysuria, frequency, urgency, bleeding, discharge, or change in the urinary stream. Most lesions occur in the distal 4 ern of the urethra, and the proximal urethra is not involved without concurrent disease in the distal urethra. 35 After treatment of proximal lesions , cystourethroscopy or urethrography can be used to determine the extent of proximal urethral involvement. Patients with bladder, proximal urethral, or extensive urethral lesions are rare and should be referred to a urologist, since major surgery, including cystectomy, may be necessary.35,36 TREATMENT
External genital and perianal condyloma acuminatum
Podophyllin is an effective first-line therapy for these lesions. It is applied as a 10% to 25% solution in tincture of benzoin and washed off by the patient, preferably in a bath or shower, I to 4 hours after application. Application with a glass rod, orange stick, or pointed wooden stick allows for complete coating of the complex surfaces of the lesions and several millimeters of surrounding normal-appearing skin. Care should be taken to avoid painting large areas of normal skin, since severe local irritation and systemic absorption can occur. When lesions covered by the prepuce are treated, the applied solution must be allowed to dry for several minutes before the prepuce is returned to its usual position. If necessary, surrounding skin can be protected with either petrolatum before application of podophyllin or talcum powder afterward. Clinical trials of podophyllin have shown cure rates ranging from 22% to 98%.2.37-40 Our experience has shown that patients who have small condylomata limited to the external genitalia can be cured with one to three weekly podophyllin applications in the majority of cases. Localized recurrences can usually be effectively treated with podophyllin also. Podophyllin should not be used during pregnancy, in infants, or on the vagina or cervix,
Journal of the American Academy of Dermatology
since severe systemic toxicity has been reported. Podophyllin has cytodestructive and antimitotic actions. 40 Toxicity has included bone marrow suppression, severe sensorimotor neuropathy requiring ventilatory support, stillbirth, and death. 41,42 For this reason, we do not allow patients to apply podophyllin to themselves. When podophyllin is contraindicated, or when three weekly applications have failed, one to three weekly applications of 50% trichloroacetic acid can be tried. The use of trichloroacetic acid in combination with podophyllin does not improve cure rates. 39 The method of application for the two substances is similar. If trichloroacetic acid is accidentally applied to unaffected areas or comes into contact with the physician's skin, it can be neutralized with sodium bicarbonate solution. Trichloroacetic acid does not need to be washed off the lesions at a later time. Cryosurgery, with cure rates of 90%,43,44 is more effective than topical chemotherapy. Although cure rates are similar to those of electrocautery, cryosurgery is preferable because it requires no local anesthesia. 45 We use a cryosurgical probe cooled by nitrous oxide. After the lesion is moistened with saline solution, the probe will adhere to the lesion, allowing it to be pulled away from surrounding skin. Freezing should be continued until the entire lesion and 1 to 2 mm of surrounding normal-appearing skin is incorporated into the ice ball. Cryosurgery produces a local burning sensation, which, along with local necrosis and ulceration, often persists for 1 week. Complete healing takes 2 to 3 weeks. Treatments can be repeated at intervals of 1 to 2 weeks. Cures are usually obtained after one to three treatments. The carbon dioxide laser has been used to treat condyloma acuminatum, with reported cure rates of greater than 90%.46-49 External genital and vaginal condylomata are superficial lesions; thus photocoagulation to a depth of 1 to 2 mm is usually adequate. Several centimeters of grossly uninvolved surrounding epithelium should be photocoagulated also. Small areas can be treated in the office after infiltration of a local anesthetic agent; however, larger areas require general or regional anesthesia. Healing usually occurs within 3 to 4 weeks. Pain can be controlled with oral analgesics or topical anesthetic agents. Secondary bacterial
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infection can be prevented by antiseptic cleansing solutions, sitz baths, and blow drying of the ex~ ternal genitalia. Cosmesis is excellent, since the laser causes minimal scarring. Cures usually occur after a single treatment. Major disadvantages of this treatment modality include cost of instrumen~ tation and necessity for regional or general anes~ thesia when extensive lesions are treated. We use this method as the treatment of choice for large, confluent lesions or multiple, widespread smaller lesions.
Vagina Vaginal condylomata, if localized, can be treated by biopsy excision, electrocautery, or cryosurgery. We treat multiple diffuse lesions by carbon dioxide photocoagulation under colposcopic guidance. This procedure requires general or regional anesthesia. An alternative treatment regimen consists of daily intravaginal applications of 5% 5-fluorouracil cream for 5 days. 50 The vulva and urethra should be protected with zinc oxide ointment or petrolatum to try to prevent local irritation. Nevertheless, severe erosive vulvitis and urethritis may develop.
Cervix Patients with microscopic or gross cervical human papillomavirus infection should be treated with cryosurgery or laser photocoagulation of the entire cervical transformation zone. Colposcopy is essential prior to treatment of the cervix to rule out neoplasia and to delineate the extent of the lesion. Treatment to a depth of about 7 rnm is required in order to destroy the epithelium of endocervical glands underlying the squamocolumnar junction. 51 Cryosurgery can be done in the office with a flat, circular probe that covers the cervix. Laser photocoagulation, if extensive, requires general or regional anesthesia. Cryosurgery produces a profuse vaginal discharge that can last 3 weeks, whereas photocoagulation of the cervix produces discharge for only 1 to 2 weeks. The laser is the treatment of choice for large cervical condylomata.
Anorectal region Skin surrounding the external anal opening can be treated sparingly with podophyllin. The patient
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would be warned that a marked local burning sensation can occur, but it resolves when the solution is washed off, 1 to 4 hours after application. Lesions of the anal canal have been treated successfully, in the majority of cases, with weekly applications of bichloracetic acid under anoscopic guidance. 15 With this technic the lesions are dabbed once lightly with a cotton-tipped applicator. Cryosurgery, with anoscopic guidance if necessary, is an effective outpatient technic. Surgical resection, electrocautery, and carbon dioxide photocoagulation should usually be reserved for treatment failures or extensive lesions.
Urethra Most lesions are limited to the external urethral meatus and respond well to topical chemotherapy or office cryosurgery. Podophyllin should be used only on meatal lesions , since its use in the urethral canal may cause significant systemic absorption. Distal urethral lesions can be treated with 5% 5-fluorouracil cream ll; however, applications four times a day for up to 14 days may be necessary, and recurrences are common. 52 Recently the carbon dioxide laser has been used with 100% success for photocoagulation of distal urethral lesions. 53.54 Extensive urethral lesions and bladder condylomata usually require a combination of several treatment modalities. They should be referred to a urologist for combinations of electrocautery, surgical resection, and topical chemotherapy. 11-13,35.36,55
Oral warts Oral warts are sometimes seen in patients with condyloma acuminatum and often have a similar appearance. 56 ,57 A shave biopsy should be done to verify the diagnosis. We have successfully treated these lesions with electrocautery under local anesthesia. Florid oral papillomatosis is rare and difficult to treat. It may develop into squamous cell carcinoma. 58 ,59 Patients with extensive oral warts should be referred to an oral surgeon or otorhino~ laryngologist for treatment. IMMUNOTHERAPY
Autogenous vaccine has been used to successfully treat resistant cases of condyloma acuminatum60-62 ; however, concern about the oncogen-
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icity of human papillomavirus precludes recommending use of the vaccine until further studies are perfonned. Initial results with levamisole,63 an immunopotentiator, were promising, but subsequent studies have not found it to be as usefup2 Patients with resistant condyloma acuminatum have been shown to have depressed immunoglobulin levels; recently interferon has been used to successfully treat a small number of such patients.'" The University of California, Irvine, Medical Center is currently involved in a large trial of interferon for resistant condyloma. Preliminary results are promising. Interferon has also been used successfully to treat patients with previously untreated condylomata. 64 We currently do not recommend the use of interferon outside of a research setting. An inadequate number of patients have been studied to reveal possible adverse effects, and there has been one case report of bowenoid dysplasia's developing during therapy. 65 As yet, data are not sufficient to individualize treatment of human papillomavirus infections on the basis of their specific viral type. Therefore it is recommended that all condylomata be treated as though they are premalignant in female patients. In addition to eliminating the premalignant potential in a given patient, this approach should impact the incidence of this transmissible disease. It is essential that all sexual partners of patients with condyloma acuminatum be examined. Patients who have recurrent or resistant disease should undergo cystourethroscopic and proctoscopic examination, and there should be careful reevaluation of their sexual partner to reveal any foci for reinfection. Studies in the basic science of human papillomavirus and clinical research are rapidly evolving. The clinician will require frequent updates to learn new ways of evaluating and treating this common but challenging disease. *Gall SA, Hughes CE: Interferon for the treatment of resistant condyloma acuminatum. Presented at the Fifteenth Annual Meeting of the Society of Gynecologic Oncologists, Miami, FL, February, 1984.
REFERENCES 1. Condyloma acuminatum- United States, 1966-1981 : Current trends. MMWR 32:306-308, 1983.
Journal of the American Academy of Dermatology
2. Barrett TJ, Silbar JD: Genital warts: A venereal disease. JAMA 154:333-334, 1954. 3. Teokharov BA: Non-gonococcal infections of the female genitalia. Br J Vener Dis 45:334-340, 1969. 4. Oriel 10: Natural history of genital warts. Br J Vener Dis 47:1-13, 1971. 5. Syrjanen J: Current concepts of human papillomavirus infections in the genital tract and their relationship to intraepithelial neoplasia and squamous cell carcinoma. Obstet Gynecol Surv 39:252-265, 1984. 6. Pfister H: Biology and biochemistry of papillomaviruses. Rev Physiol Biochem Pharmacol 99:111-181, 1984. 7. Buscema J, Woodruff 10, Parmley TH, et al: Carcinoma in situ of the vulva. Obstet Oynecol 55:225-230, 1980. 8. Friedrich EO, Wilkinson EF, Fu YS: Carcinoma in situ of the vulva: A continuing challenge. Am J Obstet Oynecol 136:830-838, 1980. 9. Crum CP, Braun LA, Shah KV, et al: Vulvar intraepithelial neoplasia. Cancer 49:468-471, 1982. 10. Rhatigan RM, Saffos RO: Condyloma acuminatum and squamous carcinoma of the vulva. South Med J 70:591594, 1977. 11. Dretler SP, Klein LA: The eradication of intraurethral condyloma acuminatum with 5 per cent 5-fluorouracil cream. J Urol1l3:195-l98, 1975. 12. Debenedictis TJ, Marmar JL, Praiss DE: Intraurethral condyloma acuminatum: Management and review of the literature. 1 Ural 118:767-769, 1977. 13. Hotchkiss RS, Rouse AJ: Papillomatosis of the bladder and ureters, preceded by condyloma acuminatum of the vulva: A case report. J Uroll00:723-725, 1968. 14. Shah IC, Hertz RE: Giant condyloma acuminatum of the anorectum. Dis Colon Rectum 15:207-210, 1972. 15. Swerdlow DB, Salvati EP: Condyloma acuminatum. Dis Colon Rectum 14:226-231, 1971. 16. Cook TA, Cohn AM, Brunschwig JP, et al: Wart viruses and laryngeal papillomas. Lancet 1:782, 1973. 17. Cook TA, Cohn AM, Brunschwig JP, et al: Laryngeal papilloma: Etiologic and therapeutic considerations. Ann Otol Rhinol Laryngol 82:649-655, 1973. 18. Eftaiha MS, Amshel AL, Shonberg IL: Condyloma acuminatum in an infant and mother. Dis Colon Rectum 21:369-371, 1978. 19. Tang C, Shermeta DW, Wood C: Congenital condyloma acuminatum. Am J Obstet OynecolI31:912-913, 1978. 20. Patel R, Groff DB: Condyloma acuminatum in childhood. Pediatrics 50:153-154, 1972. 21. Gissmann L, Boshart M, Durst M, et al: Presence of human papillomavirus in genital tumors. J Invest Dermatol 83:265-285, 1984. 22. Roy M, Meisels A, Fortier M, et al: Vaginal condylomata: A human papillomavirus infection. Clin Obstet Oynecol 24:461-483, 1981. 23. Walker PO, Colley NV, Grubb C, et al: Abnormalities of the uterine cervix in women with vulval warts. Br J Vener Dis 59:120-123, 1983. 24. Grunebaum AN, Sedlis A, Sillman F, et al: Association of human papillomavirus infection with cervical intraepithelial neoplasia. Obstet Oynecol 62:448-455, 1983. 25. Gad C: The management and natural history of severe dysplasia and carcinoma in situ of the uterine cervix. Br J Obstet Oynaecol 83:554-559, 1976.
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26. Nelson JH, Averette HE, Richart RM: Dysplasia, carcinoma in situ, and early invasive cervical carcinoma. CA 34:306-327, 1984. 27. Reid R, Stanhope CR, Herschman BR, et al: Genital warts and cervical cancer. Cancer 50:377-387, 1982. 28. Crum CP, Ikenberg H, Richart RM, et al: Human papillomavirus type 16 and early cervical neoplasia. N Engl J Med 310:880-883, 1984. 29. Gissmann L, de Villiers E, zur Jausen H: Analysis of human genital warts and other genital tumors for human papillomavirus type 6 DNA. lnt J Cancer 29:143-146, 1982. 30. Gissmann L, Wolnik L, Ikenberg H, et al: Human papillomavirus types 6 and 11 DNA sequences in genital and laryngeal papillomas and in some cervical cancers. Proc Nat! Acad Sci USA 80:560-563, 1983. 31. McCance DJ, Walker PG, Dyson JL, et al: Presence of human papillomavirus DNA sequences in cervical intraepithelial neoplasia. Br Med J 287:784-788, 1983. 32. Ikenberg H, Gissmann L, Gross G, et al: Human papiIlomavirus type-16-related DNA in genital Bowen's disease and in bowenoid papulosis. lnt J Cancer 32:563565, 1983. 33. Durst M, Gissman L, lkenberg J, et al: A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Nat! Acad Sci USA 80:3812-3815, 1983. 34. Boshart M, Gissmann L, Ikenberg H, et al: A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer. EMBO J 3:1151-1157, 1984. 35. Kleiman H, Lancaster Y: Condyloma acuminatum of the bladder. J Urol 88:52-55, 1962. 36. Bissada NK, Cole AT, Fried FA: Extensive condylomata acuminata of the entire male urethra and the bladder. J UroI112:201-203, 1974. 37. Culp OS, Magid MA, Kaplan IW: Podophyllin treatment of condyloma acuminatum. J Urol 51:655-659, 1944. 38. Simmons PO: Podophyllin 10% and 25% in the treatment of ano-genital warts. Br J Vener Dis 57:208-209, 1981. 39. Gabriel G, Thin RNT: Treatment of anogenital warts. Br J Vener Dis 59:124-126, 1983. 40. Von Krogh G: Podophyllotoxin for condyloma acuminatum eradication. Acta Derm Venereol [Suppl] (Stockh) 98: 1-48, 1981. 41. Chamberlain MJ, Reynolds AL, Yeoman WB: Toxic effect of podophyllum application in pregnancy. Br Med J 3:391-392, 1972. 42. Slater GE, Rumack BH, Peterson RG: Podophyllin poisoning. Obstet GynecoI 52:94-96, 1978. 43. Ghosh AK: Cryosurgery of genital warts in cases in which podophyllin treatment failed or was contraindicated. Br J Vener Dis 53:49-53, 1977. 44. Balsdon MJ: Cryosurgery of genital warts. Br J Vener Dis 54:352-353, 1978. 45. Simmons PO, Langlet F, Thin RNT: Cryotherapy versus electrocautery in the treatment of genital warts. Br J Vener Dis 57:273-274, 1981. 46. Baggish MS: Treating viral venereal infections with the CO2 Laser. J Reprod Med 27:737-742, 1982.
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47. Baggish MS: Carbon dioxide laser treatment for condylomata acuminata venereal infections. Obstet Gynecol 55:711-715, 1980. 48. Calkins JW, Masterson BJ, Magrina JF: Management of condylomata acuminata with the carbon dioxide la&er. Obstet GynecoI59:105-108, 1982. 49. Bellina JH: The use of the carbon dioxide laser in the management of condyloma acuminatum with eight-year follow-up. Am J Obstet Gyneco1l47:375-378, 1983. 50. Ferenczy A: Comparison of 5-fluorouracil and CO 2 laser for treatment of vaginal condylomata. Obstet Gynecol 64:773-778, 1984. 51. Anderson MC, Hartley RB: Cervical crypt involvement by intraepithelial neoplasia. Obstet Gynecol 55:546-550, 1980. 52. Robertson DHH, McMillan A, Young H: Clinical practice in sexually transmissible diseases. Kent, United Kingdom, 1980, Pitman Medical, p. 347. 53. Rosenberg SK, Fuller T, Jacobs H: Continuous-wave carbon dioxide laser treatment of giant condylomata acuminata of the distal urethra and perineum: Technique. J UroI126:827-829, 1981. 54. Fuselier HA, McBurney EI, Brannan W, et al: Treatment of condylomata acuminata with carbon dioxide laser. Urology 15:265-266, 1980. 55. Gartman E: Intraurethral verruca acuminata in men. J Urol 75:717-718, 1956. 56. Doyle JL, Grodjesk IE, Manhold JH: Condyloma acuminatum occurring in the oral cavity. Oral Surg 26:434440, 1968. 57. Knapp MJ, Uohara 01: Oral condyloma acuminatum. Oral Surg 23:538-545, 1967. 58. Kanee B: Oral florid papillomatosis complicated by verrucous squamous carcinoma. Arch Dennatol 99: 196202, 1969. 59. Samitz MH, Ackennan AB, Lantis LR: Squamous cell carcinoma arising at the site of oral florid papillomatosis. Arch Dermatol96:286-289, 1967. 60. Powell LC, Pollard M, Jinkins JL: Treatment of condyloma acuminatum by autogenous vaccine. South Med J 63:202-205, 1970. 61. Nel WS, Fourie ED: Immunotherapy and 5% topical 5fluorouracil ointment in the treatment of condyloma acuminatum. S Afr Med j 47:45-49, 1973. 62. Abcarian J, Smith D, Sharon N: The immunotherapy of anal condyloma acuminatum. Dis Colon Rectum 19:237244, 1976. 63. Krupp 1M, cited by Roy M, Meisels A, Fortier M, et al: Vaginal condylomata: A human papillomavirus infection. Clin Obstet Gynecol 24:461-483, 1981. 64. Schonfeld A, Schattner A, Crespi M, et al: Intramuscular human interferon-B injections in treatment of condyloma acuminatum. Lancet 1:1038-104i, 1984. 65. Gross G, lkenberg H, Gissmann L: Bowenoid dysplasia in human papillomavirus-16 DNA-positive flat condylomas during interferon-B treatment. Lancet 1:1467~ 1468, 1984.