Clinical Manual for Management of the HIV-Infected Adult
2006 Edition

Section 6: Disease-Specific Treatment

Anal Dysplasia

Background

Anal cancer is a squamous cell cancer associated with human papillomavirus (HPV), the same virus that is associated with cervical cancer (see chapter Cervical Dysplasia). In the United States, the current incidence of anal cancer in the general population is approximately 1:100,000 per year, and rising. The incidence of anal cancer is significantly higher in HIV-infected women and men than in the general population. Rates are also higher in men who have sex with men (MSM), whether HIV infected or uninfected. Before the HIV epidemic, the anal cancer incidence in an MSM population was 35:100,000. Current rates in an HIV-infected MSM population are as high as 70-80:100,000. Thus, the incidence of anal cancer in this population is greater than the incidence of cervical cancer in women before the introduction of cervical cytology screening.

The cervical canal and anal canal share a common embryologic origin: Both have a squamocolumnar transition zone and are prone to infection with genitotropic HPV, a sexually transmitted virus. HPV infection, in combination with other cofactors, may stimulate dysplastic changes in the cervix or anus that may develop through precursor stages (squamous intraepithelial lesions [SIL]) into squamous cell cancer.

A small but growing body of literature suggests a high prevalence of anal HPV infection and dysplasia in HIV-infected individuals. Some studies have shown that, in HIV-infected individuals, anal HPV infection is present in 93% of MSM and 76% of women, and anal dysplasia (any grade) is present in 56% of MSM and 26% of women. Receptive anal intercourse (RAI) may increase the likelihood of anal HPV infection, but is not a prerequisite for anal HPV or dysplasia. In a study of HIV-positive heterosexual men with no history of RAI, anal HPV infection was found in 46% and anal dysplasia in 32%. Patients with lower CD4 cell counts appear to be at higher risk of developing anal dysplasia. It is not clear whether effective antiretroviral therapy (ART) and immune reconstitution offer protection against dysplasia.

Prevention of HPV infection is difficult. Latex or plastic barrier may be partially effective through bodily contact outside the area covered by the barriers. Vaccines against certain strains of HPV may be available soon, though their efficacy in preventing anal dysplasia (as opposed to cervical dysplasia), and their efficacy in HIV-infected individuals, is unknown.

The field of anal dysplasia and anal cancer is a relatively new area of scientific investigation, and many questions about the disorder and its medical management remain unanswered. Because of the similarities between cervical and anal dysplasia, researchers postulate that many of the paradigms of managing cervical cytologic abnormalities may be translated to the anal canal. No national or international guidelines have been developed for anal cancer screening or the management of anal dysplasia. Further, many centers lack the resources for anal dysplasia screening and treatment. In areas with adequate diagnostic and treatment resources, some specialists recommend screening all HIV-infected individuals for anal dysplasia and, if indicated, intervening to prevent the development of anal cancer. Further investigation is needed to define appropriate screening intervals, diagnostic approaches, indications for therapy, and modalities of treatment.

S: Subjective

Patients with anal dysplasia are usually asymptomatic and the condition cannot be identified without screening tests. Exophytic anal condylomata may cause itching, discomfort, or bleeding, but are usually associated with low-risk phenotypes of HPV and low-grade dysplasia. Anal cancer may cause nonspecific symptoms such as pain, bleeding, and the development of a mass lesion.

Risk factors for anal dysplasia are not well understood, but include the following:

• Receptive anal intercourse (RAI)
• HPV infection
• Genital warts (or history of genital warts)
• HIV infection
• CD4 count <200 cells/µL
• Iatrogenic immunosuppression
• High-grade cervical or vulvar dysplasia
• Cigarette smoking

O: Objective

Examine the perianal and anal region, and perform digital anorectal examination. Look for lesions, masses, condylomata, and other abnormalities. In women, also examine the vulva, vagina, and cervix. Simple anoscopic examination with the naked eye may not reveal any abnormality because dysplastic tissue tends to be flat and difficult to differentiate from normal anal tissue; application of 3% acetic acid is required (see below).

A: Assessment

HIV-infected individuals with anal dysplasia have an increased risk of progression to anal cancer. If the history or physical examination reveals abnormalities suggestive of anal dysplasia or anal cancer, an appropriate evaluation should be undertaken. Because most patients with anal dysplasia have no symptoms, anal cancer screening should be considered if follow-up evaluation of abnormal cytologic results is available.

P: Plan

Screening

No national or international guidelines for anal cytology screening in people with HIV infection. However, some experts recommend annual or biannual screening regardless of sex or sexual practices. Anal cytologic screening is performed using Papanicolaou (Pap) smears (for technique, see the study by Berry and Palefsky referenced below). Papanicolaou smear testing is sensitive for the detection of dysplastic anal cells, but does not reliably distinguish the grade of abnormality. Like cervical cytology, anal cytology is graded using the Bethesda 2001 system, which categorizes disease in increasing order of severity as follows:

• Negative for intraepithelial lesion or malignancy
• Atypical squamous cells of undetermined significance (ASCUS)
• Atypical squamous cells suggestive of high-grade (ASC-H)
• Low-grade squamous intraepithelial lesion (LSIL)
• High-grade squamous intraepithelial lesion (HSIL)
• Squamous cell carcinoma (SCC)

All individuals with abnormal anal cytology should be referred for high-resolution anoscopy (HRA) and biopsy to grade the lesion. If available, refer to an anal dysplasia specialty center.

Evaluation of Cytologic Abnormalities

HRA of the anal canal should be performed using a colposcope for magnification (x16) and the application of 3% acetic acid with or without Lugol's Iodine solution to aid in visualization of dysplastic lesions. Abnormal areas should be biopsied. Anoscopic features of high-grade disease are similar to those seen in the cervix; these include coarse punctation, mosaicism, and the presence of ring glands.

Treatment

The goal of treatment is to prevent progression to anal cancer. Treatment of high-grade anal dysplasia to prevent anal cancer is biologically plausible, following the model of cervical dysplasia treatment. However, the indications for treatment for anal dysplasia, the efficacy of treatment, and the optimal treatments have not been defined clearly.

The focus of treatment is high-grade, premalignant dysplasia. For patients with HSIL, refer to an anal dysplasia specialty clinic, if possible. If treatment is not available, or is not pursued, patients diagnosed with high-grade anal disease should be informed about the initial symptoms of anal cancer and asked to follow up promptly should these symptoms develop.

The optimal treatment for high-grade dysplasia is not known. Specific treatment may vary depending on the size, location, and extent of the lesions and the available treatment modalities. In some cases, treatment of small intra-anal lesions with 80% trichloroacetic acid or liquid nitrogen has been successful. More promising, infrared coagulation has shown 70% efficacy at 3 months in clinical cohorts. This office procedure involves identifying the lesion by HRA and applying an infrared energy source to destroy the lesion.

For perianal lesions, topical therapy with podophyllotoxin or imiquimod may be considered. For large or extensive lesions, surgical treatments such as cold-scalpel excision and electrofulguration are typically required. Unfortunately, postoperative pain and other complications may occur, and recurrence of dysplastic lesions is common. Low-grade dysplasia is not considered premalignant, but frequently progresses to high-grade dysplasia. Some specialists do not treat LSIL but monitor regularly instead with HRA, whereas others choose to treat LSIL to prevent progression.

Patient Education

• Women and men with HIV infection have an increased risk of developing anal dysplasia and cancer. MSM are at higher risk than other men of developing anal dysplasia.
• Emphasize the importance of keeping follow-up appointments to allow early detection of precancerous lesions and appropriate monitoring and treatment of abnormalities.
• Patients who have anal dysplasia should be informed about anal cancer symptoms, such as new-onset anal pain, bleeding, or the development of a mass. Patients should call their health care providers if these symptoms develop.

References

• Berry JM, Palefsky JM. Anogenital Neoplasia and HIV. In: Peiperl L, Coffey S, Volberding PA, eds. HIV InSite Knowledge Base [textbook online]; San Francisco: UCSF Center for HIV Information; November 1998. Accessed February 7, 2006.
• Chin-Hong PV, Palefsky JM. Natural history and clinical management of anal human papillomavirus disease in men and women infected with human immunodeficiency virus. Clin Infect Dis. 2002 Nov 1;35(9):1127-34.
• Palefsky JM, Holly EA, Ralston ML, et al. Prevalence and risk factors for human papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)-positive and HIV-negative homosexual men. J Infect Dis. 1998 Feb;177(2):361-7.
• Piketty C, Darragh TM, Da Costa M, et al. High prevalence of anal human papillomavirus infection and anal cancer precursors among HIV-infected persons in the absence of anal intercourse. Ann Intern Med. 2003 Mar 18;138(6):453-9.
• Williams AB, Darragh TM, Vranizan K, et al. Anal and cervical human papillomavirus infection and risk of anal and cervical epithelial abnormalities in human immunodeficiency virus-infected women. Obstet Gynecol. 1994 Feb;83(2):205-11.
• Wright TC Jr, Cox JT, Massad LS, et al. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002 Apr 24;287(16):2120-9.