Treating Anal Dysplasia

Clinical Case: Infrared Coagulation

In part 1 (Screening for Anal Cancer: Who, When, and How) of this 2-part case, we presented a 38-year-old man with HIV who was found to have anal intraepithelial neoplasia grade 3 (AIN3). He was referred for infrared coagulation (IRC) of the AIN3 lesions. After being counseled on the risks and potential benefits of the procedure and alternative therapies, the patient elected to undergo IRC.

The area of AIN3 was identified on anoscopy. The edges of the lesion were demarcated with Lugol's iodine (Figure 1a). The lesion was infiltrated with 1% lidocaine with epinephrine. The lesion was then treated with 1.5-second pulses of IRC. The entire lesion, including the edges, was treated. The coagulated surface layer of epithelium was then removed using a dry swab (Figure 1b). The base was sharply debrided until the submucosal vessels were exposed, and these were coagulated with additional pulses of IRC (Figure 1c). The procedure was repeated on the second lesion.

The patient was given acetaminophen/oxycodone for postprocedure pain and stool softeners to prevent pain and bleeding. He was advised to avoid receptive anal sex for at least 2 weeks. He was also advised to avoid strenuous lifting for 2 weeks.

Figure 1a: The area of high-grade AIN is demarcated with Lugol's iodine.

Figure 1b: The high-grade AIN lesion after 1 application of IRC.

Figure 1c: The lesion after sharp debridement and coagulation of submucosal vessels.

Progression of High-Grade AIN to Invasive Anal Cancer

The progression rate from high-grade AIN to invasive cancer is not well studied. Recent research revealed the following:

• Anal cancer developed in 5 of 32 (16%) HIV-infected patients with high-grade AIN at a mean of 6 years of follow-up. Patients received treatment of condyloma, but not of high-grade AIN lesions.^[1]

• Anal cancer developed in 5 of 36 (14%) HIV-infected patients with perianal high-grade AIN after a mean of 2.2 years of follow-up.^[2] Patients received some treatment with imiquimod and limited surgery.

• In a cohort of patients with extensive high-grade AIN, 2 of 184 (1%) developed anal cancer with a median follow-up of 41 months.^[3] Patients were treated with an aggressive combination of surgery and office-based treatments.

Ablative Treatment of High-Grade AIN With IRC

Infrared coagulator. The infrared coagulator is a medical device that delivers controlled pulses of visible and infrared light through an applicator that is applied directly to the skin. The light results in thermal coagulation to a controlled depth, which is determined by the length of the pulse. This device is approved by the US Food and Drug Administration for treatment of condyloma, hemorrhoids, and chronic rhinitis and tattoo removal. It is contraindicated for patients with cancer or severe photosensitivity reactions. The infrared coagulator has been successfully used by surgeons, internists, gynecologists, nurse practitioners, and physician assistants.

IRC for high-grade AIN lesions. Infrared coagulation is often used in the office setting to treat anal intraepithelial lesions. In my experience, the difficult aspect of this treatment strategy is performing a careful, detailed anoscopy to locate all high-grade AIN lesions. IRC itself is relatively straightforward to perform after identifying the lesions that require treatment.

Infrared coagulation of anal lesions can cause mild to moderate postprocedural pain and bleeding for up to 2 weeks. Complete healing usually occurs within 2-4 weeks. Rare complications (<1%) include infection of the treated area and severe bleeding, resulting in emergency department evaluation or hospital admission. Severe bleeding can occur 1-2 weeks after the procedure

Efficacy of IRC for high-grade AIN. No randomized clinical trial data are available to support the efficacy of IRC for treatment of high-grade AIN lesions. The existing data are from retrospective reviews and 1 prospective single-arm clinical trial. One retrospective review of 68 HIV-infected men who have sex with men (MSM) found that 72% of high-grade AIN lesions were successfully treated with a single IRC treatment.^[4] However, high-grade AIN lesions were commonly found on follow-up at other untreated sites, resulting in approximately 40% of patients being cleared of high-grade AIN after receiving a single IRC treatment. Recurrent lesions were relatively common and had a similar response to a second treatment. A second study found a per-lesion cure rate of 64%.^[5]

A prospective series of 18 HIV-infected patients with anal cancer found that 64% of high-grade AIN lesions treated at study entry were cured at 1 year.^[6] Ten of 18 patients had postprocedural pain, which was described by 4 as mild and by 6 as moderate, and 11 had postprocedural bleeding with 10 describing it as mild and 1 as moderate.

Alternatives to IRC. Some clinicians have moved to electrocautery or fulguration to treat anal lesions, noting that these procedures are quicker and more precise. Moreover, the equipment for these procedures is less expensive, but a smoke evacuator is necessary. In practice, many patients have diffuse lesions that cannot be managed with IRC alone. Often, these patients are followed with serial examinations and biopsies with the goal of identifying invasive cancer at an early stage should it develop, rather than attempting to clear all high-grade AIN lesions. This has prompted researchers to investigate alternative therapies that can be applied to the entire anal canal.

Topical Treatment of AIN

A safe, effective, patient-applied topical therapy would greatly simplify the management of high-grade AIN. Three topical therapies are under investigation:

• 5-fluorouracil;

• Imiquimod; and

• Cidofovir.

5-Fluorouracil. Topical 5-fluorouracil has been studied in 2 retrospective case series of HIV-infected patients with diffuse high-grade AIN. Jay and colleagues^[7] treated 41 patients with cycles of 1 application of 5-fluorouracil twice daily for 5 days, followed by 9 days off. Of the 23 patients who completed at least 3 cycles, 1 had no response, 19 had partial response, and 3 had complete response. A second prospective study enrolled 34 HIV-infected men with high-grade AIN who were treated with twice weekly, with 1-g applications of topical 5-fluorouracil for 16 weeks.^[8] At the end of therapy, high-grade AIN was detected in 20 patients (59%). Of the patients whose high-grade AIN cleared, 50% had no recurrence on anoscopy 6 months after completing therapy. Moderate to serious side effects, including erythema, burning, and mild to severe erosions, occurred in 41%.

Imiquimod. A recent study reported on the follow-up of a previous trial of 3 times weekly imiquimod applied anally for 16 weeks for the treatment of AIN.^[9] The study population of 19 HIV-infected MSM demonstrated 74% efficacy for resolution of AIN at the initial treated site after a mean follow-up of 30.3 months with a concomitant reduction in human papillomavirus (HPV) and high-risk HPV DNA load. However, 24.6% of participants had recurrence of high-grade AIN at the same site after a mean of 24.6 months, and 58% of participants developed new AIN lesions at different sites from those that were previously treated. The recurrence and evolution of new lesions suggest that maintenance imiquimod therapy may have a role after standard dose treatment in this population at high risk for anal cancer.

Cidofovir. A topical formulation of cidofovir, an antiviral agent used as an alternate therapy for cytomegalovirus infections, has been used successfully to treat anogenital condyloma.^[10] This drug is now under investigation as a treatment for perianal high-grade AIN.^[11] No data exist for intra-anal administration of topical cidofovir.

Options for Preventing High-Grade AIN

The options for prevention of high-grade AIN are limited to preventing new infections with additional strains of high-risk HPV. HPV vaccination is a promising prevention tool. In a large clinical trial of young HIV-uninfected men,^[12] the Merck quadrivalent HPV vaccine prevented HPV 6/11/16/18-related external genital lesions. This trial also included a substudy of young MSM. The vaccine was shown to prevent persistent anal infection related to the same HPV types.^[13] The AIDS Malignancy Consortium presented data on the safety and immunogenicity of the quadrivalent vaccine in HIV-infected men.^[14] They found that the vaccine was safe and highly immunogenic, with over 95% of men seroconverting for each of the 4 vaccine types. This single-arm study did not establish efficacy.

Another prevention option to be considered is consistent use of condoms. Although condoms are not 100% effective in preventing new HPV infections, they have been shown to be partially effective. A randomized clinical trial of monogamous heterosexual couples with HPV infection found that couples randomly assigned to condom use had faster clearance of HPV infection and HPV-related lesions.^[15,16] Another option is to reduce the number of receptive anal sex partners.

Future research. Much remains to be learned about preventing anal cancer. First, we need data to confirm that commonly used ablative treatments, such as IRC, are actually efficacious in clearing patients of high-grade AIN. It is also imperative that topical treatments, such as imiquimod and 5-fluorouracil, are evaluated to give additional options for managing high-grade AIN. Ideally, a therapeutic vaccine would help clear HPV infections and AIN. Once efficacious treatments of high-grade AIN have been established, a randomized clinical trial of screening vs no screening will be needed to define the utility of anal cancer screening.

Clinical Case Concluded

The patient was seen 6 months after IRC treatment for repeat high-resolution anoscopy and biopsies. An additional area of AIN2/3 was found and successfully retreated with IRC. Biopsies performed 6 months after the second IRC treatment showed either low-grade AIN or normal tissue. The patient was referred back to his primary care provider for repeat anal cytology after 1-2 years, with the recommendation for referral for high-resolution anoscopy if the anal cytology becomes abnormal.