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). The anal canal and cervical canal share a common embryologic origin: both have a squamocolumnar transition zone and are prone to infection with HPV, a sexually transmitted virus. HPV infection, in combination with cofactors, may stimulate dysplastic changes in the cervix or anus that may develop through precursor stages into squamous cell cancer. In the United States, the current incidence of anal cancer in the general population is approximately 1:100,000 per year. In HIV-infected men and women, the incidence of anal cancer and the prevalence of its precursors are significantly higher than in the general population.

Rates of anal cancer also are higher among men who have sex with men (MSM), whether HIV infected or uninfected, compared with the general population. Before the HIV epidemic, the anal cancer incidence among MSM was estimated to be as high as 37:100,000. This incidence is comparable to the incidence of cervical cancer in women before the introduction of screening using Papanicolaou (Pap) tests. Current rates in an HIV-infected MSM population are estimated to be as high as 70-144 per 100,000.

Although most studies have examined anal dysplasia and cancer among MSM, the prevalence of anal intraepithelial neoplasia (AIN), a precursor to anal cancer, also is high among HIV-infected women. A recent study found a significantly increased rate of AIN (16%) in a group of HIV-infected women when compared with a control group having similar risk factors. In some studies of HIV-infected women, anal dysplasia has been seen more frequently than cervical dysplasia, and it has not been exclusive to those with behavioral risk factors (e.g., history of anal intercourse).

Some studies have shown that, among 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. It is posited that HPV can spread throughout the anogenital region in the absence of sexual contact. In a study of HIV-infected 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.

Screening strategies for anal dysplasia and cancer and the optimal management of abnormal test results are controversial areas in which questions remain unanswered. The rationale for screening for anal cancer and its precursors is based on the success of cervical Pap screening in reducing cervical cancer incidence and mortality. Because of the similarities between cervical and anal dysplasia, many experts postulate that many of the paradigms of managing cervical cytologic abnormalities may be translated to management of anal dysplasia. However, there are no randomized clinical trials that document the value of screening for anal precancers.

Currently, there are no national recommendations that call for routine screening for anal cancer, but many experts recommend screening all HIV-infected individuals for anal dysplasia, if adequate diagnostic and treatment resources and referral networks exist. The New York State Department of Health AIDS Institute recommends that an anal Pap test be done at baseline and annually thereafter for MSM, patients with a history of anogenital warts, and women with abnormal cervical or vulvar histology, and many HIV clinics elsewhere do routine screening. Further investigations are ongoing to define appropriate screening intervals, diagnostic approaches, indications for therapy, and modalities of treatment.

ART and subsequent immune reconstitution does not appear to alter the prevalence or distribution of anal cancers and anorectal disease nor does it appear to reduce the progression of AIN and other cancer precursors.

For information on prevention of HPV infection, see "Prevention," below.

S: Subjective

Patients with anal dysplasia usually are 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 (note, however, that oncogenic HPV types also may be present). Anal cancer may cause nonspecific symptoms such as pain (with defecation or after intercourse), itching, bleeding, or sensation of a rectal mass.

Risk factors for anal dysplasia and cancers include the following:

• HIV infection
• CD4 count of <200 cells/µL
• RAI
• HPV infection
• Genital warts (or history of genital warts)
• Immunosuppression
• High-grade cervical or vulvar dysplasia
• Cigarette smoking
• Multiple sex partners

Ask patients about these risk factors, about previous history of anal dysplasia or cancer, and about previous screening.

O: Objective

Examine the genital and perianal region, and perform a digital anorectal examination. Look and feel for masses, condylomata, and other abnormalities such as hypo- or hyperpigmented plaques or lesions, and lesions that bleed. Note that simple visual examination may not reveal abnormalities. In women, also examine the vulva, vagina, and cervix. Examine the inguinal lymph nodes.

If the digital examination is performed in conjunction with an anal Pap test, the Pap specimen should be obtained before the introduction of lubrication.

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 for a description of how high-resolution anoscopy [HRA] is performed).

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 using a Pap test can be considered if follow-up evaluation of an abnormal cytologic result (ASCUS or higher, see Bethesda 2001 grading system, below) by high-resolution anoscopy is available either on-site or by referral.

P: Plan

Screening

As mentioned above, there are no national guidelines for anal cancer screening in people with HIV infection. However, some experts recommend that anal Pap tests and digital anal examination be part of the initial evaluation of both male and female HIV-infected patients. The intervals for screening have not been established, but (based on recommendations for cervical cancer screening) if the first test result is normal, the anal Pap usually is repeated in approximately 6 months. If both results are normal, then anal Pap tests can be performed annually. Some clinicians would consider more frequent screening in patients with genital warts, cervical dysplasia, or a history of treatment for anal dysplasia. Any patients with positive results should be referred for further evaluation; see below.

An anal Pap test is done using a standard Pap kit. The swab or cytobrush should be inserted into the anal canal, past the anorectal junction, and withdrawn while rotating it against the anal walls to collect cells. The sample should then be handled according to the kit manufacturer's instructions. (See "References," below, for information about a video on how to conduct an anal Pap screen that is available from the Johns Hopkins University Local Performance Site of the Pennsylvania/MidAtlantic AIDS Education and Training Center.)

As with 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 — cannot exclude HSIL (ASC-H)
• Low-grade squamous intraepithelial lesion (LSIL)
• High-grade squamous intraepithelial lesion (HSIL)
• Squamous cell carcinoma (SCC)

Other abnormalities, such as atypical glandular cells (AGC), may be noted.

All individuals with abnormal anal cytology, defined as ASCUS or higher, should be referred for HRA and biopsy to grade the lesion. HRA typically is performed at specialty anal cancer practices or clinics, colorectal surgery and gastrointestinal specialty facilities, and some academic medical centers.

Evaluation of Cytologic Abnormalities

HRA of the anal canal should be performed using a colposcope for magnification (16x) and the application of 3% acetic acid with or without Lugol iodine solution to aid in visualization of dysplastic lesions. Abnormal areas should be examined by biopsy. 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 HSIL to prevent anal cancer is biologically plausible, following the model of cervical dysplasia treatment. However, the indications for treatment of anal dysplasia, the efficacy of treatment, and the most effective treatments have not been optimally defined.

The focus of treatment is on high-grade, premalignant dysplasia. For patients with HSIL, refer to an anal dysplasia specialty clinic, if possible. The optimal treatment for high-grade dysplasia is not known, and it should be individualized in consultation with a specialist. Specific treatment may vary depending on the size, location, extent of the lesions, and histological grade. Therapies include topical 5-fluorouracil, cryotherapy, infrared coagulation, laser therapy, and surgical excision. Infrared coagulation, an in-office procedure, has been shown to be effective in treating HIV-infected patients with high-grade dysplasia. With some therapies, treatment-associated pain and other complications may occur, and recurrence of dysplastic lesions is common.

LSIL is not considered premalignant, but it 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.

Prevention

Prevention of HPV infection can be challenging. Latex or plastic barriers may block transmission of HPV in areas covered by these barriers, but infection may occur through bodily contact outside the area covered by the barriers. Nonetheless, their use is recommended to prevent transmission or acquisition of HPV.

A quadrivalent HPV vaccine against certain oncogenic (types 16 and 18) and wart-causing (types 6 and 11) types of HPV is FDA approved for prevention of anal dysplasia and anal cancer caused by the covered types in males and females 9-26 years of age, and for prevention of genital warts (it also is approved for prevention of cervical cancer and cervical, vaginal, and vulvar dysplasia). A second vaccine against HPV types 16 and 18 has been approved for females (see chapter Cervical Dysplasia).

The HPV vaccines have not been thoroughly studied in HIV-infected persons and thus are not specifically recommended for them; studies to evaluate efficacy, safety, immunogenicity, and tolerability are under way. The vaccines are not contraindicated for use by HIV-infected persons, and many clinicians do provide them.

Patient Education

• All HIV-infected men and women should be encouraged to use condoms during vaginal, anal, and oral sex to prevent the spread of HPV. However, condoms do not offer complete protection from HPV.
• All patients should be counseled on how to reduce or avoid unprotected anal receptive intercourse.
• Both women and men who are HIV infected 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 for early detection of precancerous lesions, further grading of abnormalities by HRA, 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 provider if these symptoms develop.
• If an anal Pap test is being performed, advise patients to avoid having anal sex, douching, or using enemas before the test.

References

• Centers for Disease Control and Prevention. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.
• Chiao EY, Giordano TP, Palefsky JM, et al.Screening HIV-infected individuals for anal cancer precursor lesions: a systematic review. Clin Infect Dis. 2006 Jul 15;43(2):223-33.
• 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.
• Diamond C, Taylor TH, Aboumrad T, et al. Increased incidence of squamous cell anal cancer among men with AIDS in the era of highly active antiretroviral therapy. Sex Transm Dis. 2005 May;32(5):314-20.
• Hessol NA, Holly EA, Efird JT, et al. Anal Intraepithelial neoplasia in a multisite study of HIV-infected and high-risk HIV-uninfected women. AIDS. 2009 Jan 2;23(1):59-70.
• Palefsky JM, Cranston RD. Anal Intraepithelial Neoplasia: Diagnosis, Screening, and Treatment [online resource]. Waltham, MA: Up to Date; May 2009. [Fee required.]
• Palefsky JM, Holly EA, Efirdc JT, et al.Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men. AIDS. 2005 Sep 2;19(13):1407-14
• 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.
• 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.
• A video titled Anal Pap Smear: A Simple, Fast and Easy Procedure is available on CD-ROM at-cost to health care professionals ($12.00 for 1-4 copies) by calling the Johns Hopkins University Local Performance Site of the Pennsylvania Mid/Atlantic AIDS Education and Training Center to order: 888-333-2855 (toll free) or by downloading the order form on the AETC NRC website.