12.2.1 Location

Anatomic locations in which condylomata acuminata are found include the perianal region and anal canal, as well as other parts of the perineum, vulva, vagina, and penis. Treatment of perianal condylomata acuminata without treatment of concomitant anal canal condylomata acuminata is doomed to failure. More than three-fourths of the group of patients studied by Schlappner and Shaffer ²⁷ were found to have internal condylomata acuminata. Thus, failure of the examiner to study the anorectum with an anoscope could have resulted in the failure to diagnose intra-anal lesions in 94% of the patients. Carr and William ¹³ also found a high percentage of internal warts in men with external warts. In a group of immunocompromised patients, de la Fuente et al ²⁸ found that condylomata were limited to the anoderm in 27%, located in the anal canal in 20%, and located in both the anoderm and anal canal in 53%. In men, anal canal condylomata acuminata are frequently associated with penile condylomata; in women, associated condylomata may be found in the vagina, vulva, urethra, and cervix.

12.2.2 Pathology

Condylomata acuminata vary from pinhead-size lesions to projecting cauliflowerlike masses. Their surface is papilli-form, and they are pink or white in color (▶ Fig. 12.2a). Individual warts, which may be sessile or pedunculated, have a tendency to grow in radial rows that may become confluent and form almost an entire sheet, around the anal orifice (▶ Fig. 12.2b). They are almost invariably multiple and may be so numerous as to obscure the anal aperture. In addition, these warts frequently extend into the anal canal and even the rectum. Vulvar warts can grow so luxuriantly as to conceal the introitus. Because of the moisture and warmth in the anal region, the warts may become sodden and white. They may produce an irritating discharge with a disagreeable odor. Anal warts are often soft and friable and therefore may bleed.

Microscopically, anal warts show marked acanthosis of the epidermis with hyperplasia of prickle cells, parakeratosis, and an underlying chronic inflammatory cell infiltration. Vacuolation of the cells of the upper prickle layer is present (▶ Fig. 12.3). ²⁹

12.2.3 Symptoms

Patients with condyloma acuminatum present with relatively minor complaints. Almost all note visible perianal warts. Two-thirds of the patients experience pruritus ani, which may be caused by the irritation of the warts themselves or the patient’s inability to cleanse the anal area properly after defecation. Approximately one-half of the patients experience some bleeding with defecation because of the friability of some of these warts. Other patients complain of anal wetness. A majority of patients with condyloma acuminatum experience discomfort or pain. Female patients may present with a vaginal discharge.

12.4.1 Podophyllin

Podophyllin is a cytotoxic agent applied locally in a vehicle such as liquid paraffin or tincture of benzoin, the latter having the advantage that it adheres better to the warts. Concentrations from 5 to 50% have been used, but a 25% suspension is the one generally employed. The method of application is to paint the warts accurately, avoiding the adjacent skin because podophyllin is intensely irritating. Dusting powder is then applied to the surrounding skin. Patients are instructed to wash the treated area 6 to 8 hours after each application to prevent damage to the surrounding skin. This treatment is repeated at weekly intervals as required. Single applications are rarely effective. In some cases, treatment with podophyllin must be abandoned because of the soreness and irritation of the perianal skin.

Podophyllin has several disadvantages. ⁴⁷ It is not a pure compound, and therefore batches may vary in potency. It cannot be applied to perianal or anal warts by patients themselves, so repeated visits to the office may be necessary. Local reactions may be severe and penetration into keratinized warts is poor, so only recently acquired lesions may respond to treatment. In a review, Miller ⁴⁸ summarized the local side effects reported with the use of podophyllin; these included severe necrosis and scarring of the anogenital area, fistula-in-ano, and dermatitis. The application of large amounts of podophyllin may result in severe systemic toxic effects, which include the hematologic, hepatic, renal, gastrointestinal, respiratory, and central nervous systems. ^{49 , 50} Karol et al ⁵¹ have recommended the avoidance of treatment with podophyllin during pregnancy because of the possible teratogenic effect and even intrauterine death. ⁴⁹ Finally, prolonged courses of treatment with podophyllin are probably undesirable since it does produce dysplasia. Moreover, treatment with podophyllin may induce temporary cell changes that are difficult to differentiate histologically from carcinoma (▶ Fig. 12.4). The effects of local application of podophyllin on condylomata are typified by the presence of enlarged, swollen cells with pale, basophillic cytoplasm, dispersed chromatin material, and large perinuclear and paranuclear vacuolation. Other changes include eosinophilic cells with pyknotic nuclei and various types of nuclear alterations. These histologic abnormalities are temporary and will reverse completely within a few weeks after discontinuation of the drug. ¹⁰

Podophyllotoxin, one of the active compounds of podophyllin, has been found to be effective in wart clearance in 45 to 53% of cases, but wart recurrence has been observed to be as high as 91%. ⁵² The agent is relatively safe and can be self-administered, but the availability of other medications has hindered its use.

12.4.2 Bichloroacetic and Trichloroacetic Acid

Swerdlow and Salvati ¹² proposed the caustic agent bichloroacetic acid. The technique involves cleansing and drying the perianal region with cotton and witch hazel. The caustic agent is spread on with an applicator, with care taken not to apply the chemical to adjacent skin because a burn will result. If too much acid is applied, it should be wiped off, the area should be washed with water, and sodium bicarbonate should be applied as a local antidote if necessary. The lesions that are cauterized change from pink to a frosty white color. Lesions within the anal canal are treated similarly but dabbed gently with a cotton ball before the walls of the anal canal are allowed to fall back together.

Analgesic agents are prescribed routinely, but they are necessary only when massive involvement is present. Patients are instructed to keep the perianal area clean and dry. The caustic agent is applied at intervals of 7 to 10 days to achieve maximum benefit from the treatment. The patient’s sexual partners also should be treated.

Approximately 25% of the patients in Swerdlow and Salvati’s ¹² report had recurrences. These patients were treated with further short courses of therapy. The number of treatments needed varied according to the size and number of warts. It ranged from 1 to 13 treatments, with most patients receiving 4 or fewer.

Swerdlow and Salvati ¹² noted that when patients treated with bichloroacetic acid as an office procedure were compared to patients treated with other modes of therapy, the former were more comfortable, did not develop posttreatment scars and strictures, and had prompt resolution of warts without losing time from work. The limited availability of bichloroacetic acid has led to use of trichloroacetic acid, which is less caustic.

12.4.3 Imiquimod

Imiquimod (Aldara; Valeant Pharmaceuticals, Bridgewater, NJ) is an imidazoquinoline, a synthetic compound, which is an immune response stimulator, enhancing both innate and acquired immune pathways (particular T helper cell type 1–mediated immune responses) resulting in antiviral, antineoplastic, and immunoregulatory activities. ⁵³ The mechanism of action of imiquimod involves cytokine induction in the skin, which then triggers the host’s immune system to recognize the presence of a viral infection or malignancy, ultimately to eradicate the associated lesion. Imiquimod, a patient-applied topical 5% cream, is clinically efficacious and safe in the management of condylomata acuminata and other warty manifestations of HPV infections. In a randomized, vehicle-controlled, clinical trial conducted in the United States, 50% of patients treated three times per week for up to 16 weeks experienced complete clearance. ⁵⁴ The clinical outcome of imiquimod therapy in this condition is dependent on gender, with a superior efficacy in females compared to males. This is believed to be attributable to the higher degree of keratinization of the skin on the penis compared to the vulva, the most common locations for genital warts in male and female patients, respectively. In this study, 72% of females treated for up to 16 weeks with imiquimod cleared their warts compared to 33% of males, the majority of whom were circumcised. In a recent phase IIIB, international, open-label trial, Garland et al ⁵⁵ studied 943 patients from 114 clinic sites in 20 countries with the application of imiquimod 5% cream three times per week for up to 16 weeks. Complete clinical clearance was observed in 47.8% of patients during the initial treatment period, with clearance in an additional 5.5% of patients during the extended treatment period beyond 16 weeks. The overall clearance rate for the combined treatment period was 53.3%. In a treatment failure analysis, the overall clearance rate was 65.5% (females 75.5%, and males 56.9%). Low recurrence rates of 8.8 and 23% were observed at the end of the 3- and 6-month follow-up periods, respectively. The sustained clearance rates (patients who cleared during treatment and remained clear at the end of the follow-up period) after 3 and 6 months were 41.6 and 33.3%, respectively. Local erythema occurred in 67% of patients. The lower degree of keratinization and the semiocclusive effect of the foreskin in uncircumcised males are proposed as possible reasons for the higher clearance rates (62%) observed in a study of uncircumcised males who applied imiquimod three times a week for up to 16 weeks compared to efficacy (33%) in the predominantly circumcised male population in the U.S. trial. ⁵⁶

Another study reported a 50% clearance rate (72% females, 33% males). ⁵⁷ The low recurrence rate of 13% in the 3-month follow-up period after imiquimod treatment is favorable compared to the physician-administered therapies, i.e., cryotherapy, trichloroacetic acid, and podophyllin, and the patient-applied therapy podophyllotoxin. ^{54 , 58}

Recently, the FDA has approved a 3.75% cream (Zyclara; Valeant Pharmaceuticals, Bridgewater, NJ) for daily use. Safety and efficacy have not been evaluated in pregnant, breastfeeding, or immunosuppressed patients, or in patients with intravaginal, cervical, rectal, or intra-anal warts. FDA approval was based on two randomized, double-blinded, placebo-controlled trials involving 601 adult patients with external genital warts treated with vehicle or imiquimod 3.75% cream daily for up to 8 weeks. Sixteen weeks after the start of the study period, treated patients had a clearance rate of 27 to 29%, while patients receiving the vehicle had a clearance rate of 9 to 10%. ⁵⁹ Treatment-related adverse effects that occurred in > 1% of those treated with imiquimod 3.75% cream included application site pain, pruritus, irritation, erythema, bleeding, and discharge. ⁶⁰