Published in the Bulletin of Experimental Treatments for AIDS Winter 2001 issue, by the San Francisco AIDS Foundation.

Anal Cancer and Colon Cancer

Genital Warts

Winter 2001 Table of Contents

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Anal Neoplasia: A Growing Concern

Disease of the Anal and Cervical Regions

The term neoplasia (plural of neoplasm) refers to abnormal cell growth and tumor (abnormal tissue) formation in the body; neoplasia may be benign (noncancerous) or malignant (cancerous). The full spectrum of AIN (mild to severe) is also known as dysplasia, a condition that refers to abnormalities in the structure, size, and organization of cells. Severe dysplasia is essentially synonymous with carcinoma in situ (cancer confined to its site of origin); neither term should be confused with invasive cancer. In this article, anal cancer and anal carcinoma refer to invasive anal cancer.

Cervical intraepithelial neoplasia (CIN), a precursor to invasive cervical cancer in women, provides the most useful model for understanding AIN. Similar tissue structure and apparently similar natural history (normal progression) of disease states in the anal and cervical regions have led clinicians and researchers to develop a working analogy between the two zones. What little is known about anal neoplasia-especially in persons with HIV infection-has been largely based on studies done in the past ten years. In contrast, a substantial body of data has been collected over the past several decades relating to the etiology (cause) and pathogenesis (development) of cervical neoplasia. In the absence of large-scale natural history studies of AIN, experts have often deduced from what is known of CIN and applied cervical neoplasia data cautiously to the study and treatment of anal neoplasia.

AIN typically presents as lesions (localized tissue changes) in the transformation, or transition, zone of the anal canal, where the squamous epithelium of the anus meets the columnar epithelium of the rectum. These lesions are frequently referred to as anal squamous intraepithelial lesions, or ASIL. Similarly, most occurrences of CIN first appear in the transformation zone of the cervix, where the squamous epithelium of the exocervix (outer cervix) joins with the columnar epithelium of the endocervix (inner cervix). These cervical lesions are often referred to as cervical squamous intraepithelial lesions, or CSIL. (The epithelium is the thin layer of cells that covers internal and external body surfaces. Squamous cells are flat, scale-like cells such as those comprising the surface of the skin; columnar cells are prismatic [prism-shaped] in form and comprise the majority of cells in both large and small intestines.)

HPV

Both the anal and cervical regions are frequent sites of HPV infection. HPV is a blanket term for over 100 distinct papillomaviruses (a subset of neoplasm-inducing papovaviruses) that cause a variety of human warts, including common warts of the extremities, internal and external genital warts, and tissue changes associated with cancer of the anus and cervix. HPV infection of the anus or cervix may be latent, subclinical, or readily apparent. The latent, or clinically invisible, infection period can last from two weeks up to about eight months after the virus has been acquired via mucosal tissues (moist linings of body orifices, such as the anus); in some people, HPV infection may remain latent for years or decades. Subclinical, or not clinically obvious, manifestations of HPV infection can be detected only with a high-resolution anoscope or colposcope, small devices used for viewing the anal canal and cervix, respectively (see "Step II: Anoscopy"). Apparent HPV infection typically presents in the form of visible, usually benign genital warts known as condyloma acuminata, or as dysplasia.

Condylomas, or condylomata, and mild, low-grade dysplasia are frequently related to HPV types 6 and 11, two of the less-virulent viral types (i.e., types that are less likely to cause disease). In contrast, cancer of the anus and cervix have been linked particularly to HPV type 16, in addition to 18, 31, 33, 35, and other viral types that mainly present in subclinical forms. Some HPV types also appear to cause warts and cancer of the penis; cancer of the mouth (especially the tonsils), skin, and vulva; and recurrent respiratory papillomatosis (papillomas, or benign tumors, of the respiratory tract).

Persons with HIV and HPV tend to be infected simultaneously with several different HPV types. In a study done in the mid-1990s by Joel Palefsky, MD, and colleagues from the University of California, San Francisco (UCSF), 73% (196) of 269 HIV positive MSM with anal HPV infection were infected with multiple HPV types. (Type 16 was by far the most common viral type, occurring in 41% [109] of the 269 HPV positive subjects.) The appearance of a condition associated with a less-virulent HPV type, such as genital warts, therefore may not rule out the coexistence of an oncogenic, or cancer-causing, viral type. (See Anal Cancer and Colon Cancer for more information on genital warts.) Specific HPV types are detected by using polymerase chain reaction (PCR) assays, which amplify viral genetic material, or the Hybrid Capture test, which can distinguish between benign and oncogenic viral types.

HPV is commonly transmitted by anal and vaginal sexual intercourse; it may also be transmitted by finger-genital contact, according to a study published in the October 1999 issue of Sexually Transmitted Infections, and presumably by finger-anal contact. Although HPV is hardly a household term, it is widespread. By the beginning of 2000, according to the Centers for Disease Control and Prevention (CDC), genital HPV infection was the most common sexually transmitted disease (STD) in the U.S., affecting approximately 20 million people. Among MSM, HPV infection is almost universal in some areas of the country. In the study mentioned in the previous paragraph, Dr. Palefsky and colleagues found that 61% of 262 HIV negative MSM and 93% of 346 HIV positive MSM-all of whom lived in San Francisco-were infected in the anus with at least one HPV type. (Dr. Palefsky and colleagues have reported on this cohort in a number of different venues; unless otherwise indicated, this group of 346 HIV positive and 262 HIV negative MSM will subsequently be referred to as the San Francisco cohort.)

Grading and Types of Malignancies

HPV most readily infects and causes lesions in the transformation zones of the anal and cervical canals, which are thought to be susceptible due to the overlap and joining together of different tissue types. (For the purposes of this article, this section will focus on ASIL although similar pathological characteristics are seen with CSIL.) If HPV-infected cells in the anal transformation zone (or anywhere else in the anal or perianal region) start replicating abnormally, a spectrum of different neoplastic (abnormal tissue) irregularities may develop. Cellular changes are staged, or graded, according to the Bethesda System, which was developed by the National Cancer Institute (NCI) in 1988 for grading cell specimens from cervical/vaginal Papanicolaou ("Pap") smears. (A Pap smear is a microscopically analyzed slide of cells swabbed from mucosal tissue; see "Step I: Anal Cytology" for more information on this technique.) The grading stages below are from anal Pap smears.

AIN I, considered mild dysplasia, is also known as low-grade ASIL, or LSIL. Dysplastic cells have abnormal nuclei and abnormal ratios of nucleus to cytoplasm (the nucleus is the central part of a cell that contains its genetic material; the cytoplasm is the gel-like substance that composes cells and lies outside the cell nucleus). Visible anal warts, considered very mild to mild dysplasia, are also a form of LSIL.

AIN II, considered moderate dysplasia, and AIN III, severe dysplasia or anal carcinoma in situ, are also known as HSIL, or high-grade ASIL. HSIL is a progressive, potentially precancerous condition that requires attention whether the person is HIV positive or not; a small proportion of AIN III-type lesions that are not treated or removed may develop into invasive cancer, destroying adjacent tissues and/or organs and ultimately causing death. The prognosis (prediction of future disease course) with LSIL, a marker for HPV infection, is much less clearly defined at this time, but generally requires follow-up (future monitoring). As already mentioned, genital warts are usually harmless but may be accompanied by virulent (more aggressive, disease-causing) HPV types in persons with HIV. Other untreated low-grade lesions may spontaneously resolve (diminish or disappear). Conversely, LSIL may evolve into HSIL and thus act as a precursor to cancer. High-grade lesions in the anal canal resolve or regress in fewer than 25% of cases, even in persons taking HAART. As with high-grade CSIL and cervical cancer, HSIL may take several years to progress to anal cancer, indicating a potentially serious rise in new cases of anal carcinoma as HIV positive persons live longer. However, the natural history of anal neoplasia will be known only after large prospective studies are completed.

Different degrees of anal carcinoma may be staged according to the NCI's classification system based on tissue biopsy, or sampling. Stage 0 refers to early carcinoma in situ. Stage I cancer is localized, no larger than 2 cm in size, and not found on the external sphincter, the muscle that controls the opening of the anus. Stage II cancer is larger than 2 cm in size but does not affect adjacent organs or lymph nodes. If the cancer has spread either to organs located near the anal canal (e.g., the urethra [urinary canal], bladder, or vagina) or to nearby lymph nodes, it is classified as Stage IIIA. If it has spread to both adjacent lymph nodes and organs, it is classified as Stage IIIB. Cancer classified as Stage IV has spread to abdominal lymph nodes at some distance from the original carcinoma as well as to a part of the spine known as the sacrum and to other body organs. Recurrent cancer reappears after treatment, either to the site of the original lesion or to another area of the body.

HPV and ASIL: Risk Factors

While there is no single cause for ASIL, a number of different risk factors appear to make certain people more susceptible to anal lesions. Prior HPV infection is high on this list of facilitating factors. Not surprisingly, many of the risk factors that have been determined for HPV infection itself are the same as those for anal neoplasia (see next section). The higher the total number of one's sexual partners, the higher the relative risk of contracting HPV, even in heterosexual women without a history of anal intercourse. HIV negative persons with an STD, such as genital herpes, tend to have higher HPV infection rates compared with healthy persons, as do those who engage in receptive anal intercourse (whether MSM or women) and those who use recreational drugs rectally (e.g., methamphetamine ["speed"] or MDMA ["ecstasy"] injected with a syringe). The same is likely true for HIV positive MSM; a correlation between the degree of immunosuppression in the individual and the likelihood of HPV infection has been documented. Cigarette smoking is also a risk factor.

Likewise, MSM with suppressed immune systems-notably those with HIV infection and low CD4 cell counts (fewer than 200 cells/mm3)-are particularly vulnerable to ASIL. Nevertheless, even HIV positive MSM with higher CD4 cell levels are twice as likely to experience anal lesions as are HIV negative MSM. The anal cancer rate among HIV negative MSM is greater than 35 cases per 100,000 people, while the rate among the population as a whole is only about 0.9 per 100,000 people, indicating that increased awareness about anal carcinoma is necessary for MSM generally and for HIV positive MSM in particular.

Even though women are less likely to engage in receptive anal intercourse, especially when compared with MSM, recent data indicate that HIV positive women also have unusually high rates of anal HPV infection. In a report presented by Dr. Palefsky at the XIII International AIDS Conference held July 9-14, 2000, in Durban, South Africa, 76% (170) of subjects in a cohort of 223 HIV positive women showed evidence of anal HPV DNA (genetic material). Prevalence of HPV infection was inversely related to CD4 cell level (i.e., women with fewer CD4 cells/mm3 were more likely to have anal HPV). According to Ruth Greenblatt, MD, one of the study authors, anal neoplasia currently appears to be more common than cervical neoplasia in the HIV positive female population surveyed at the San Francisco site of WIHS, the Women's Interagency HIV Study. (For additional WIHS data on women with anal HPV infection, see "Lessons Learned from Natural History Studies in Women" in this issue of BETA.) Other researchers have reported a high risk for ASIL among HIV positive female and male adolescents aged 13-18 as well.

Keeping in mind the statistics mentioned above, it follows that men who engage in receptive anal intercourse, regardless of HIV status, are at increased risk for ASIL and anal cancer. Trauma to the anal region likely contributes to the elevated risk. Conversely, HIV positive women who may not participate in anal sex frequently or at all seem to have a predisposition to anal infection with HPV due to immune suppression or other risk factors. As Dr. Palefsky and colleagues reported in the February 1, 2001 issue of the Journal of Infectious Diseases, cervical HPV infection may act as a reservoir or source of anal HPV infection. Studies show that women who have high-grade lesions or cancer of the cervix or vulva are more likely to develop anal lesions, as are persons infected with HPV who have had genital warts. Other independent risk factors for ASIL include cigarette smoking and a history of injection drug use.

LSIL to HSIL: Risk Factors

HIV-related suppression of the immune system not only increases the likelihood of becoming infected with HPV and developing ASIL, but it also appears to increase the chances that existing low-grade lesions will evolve into HSIL and, presumably, anal cancer. Dr. Palefsky and colleagues from UCSF characterized the incidence and progression of LSIL and HSIL in the all-male San Francisco cohort over a two-year period. Participants were periodically evaluated using HPV tests, anal cytology (microscopic analysis of cells collected by treated swab), anoscopy (visual surveillance of the anal canal using an anoscope), and biopsies of visible lesions (i.e., removal of abnormal tissue for microscopic examination). Additional data were collected regarding HIV serostatus, CD4 cell count, lifestyle factors, sexual habits, and medical history.

Among 224 subjects whose anal tissues were normal at baseline, 20% (17 of 87) who were HIV positive and 8% (11 of 137) who were HIV negative developed HSIL within two years of follow-up. Among 69 subjects who had LSIL at baseline, 62% (34 of 55) who were HIV positive and 36% (5 of 14) who were HIV negative had lesions that progressed to HSIL within two years of follow-up. Men with HIV as a group fared worse than the HIV negative subjects in the study, and HIV positive men with fewer than 200 CD4 cells/mm3 displayed the greatest risk of developing anal disease. According to these researchers, the relative risk (RR) for progression of anal disease was 2.4 in HIV positive men generally; in those with weaker immune systems, the RR was 3.1. (Relative risk is a measure of comparative risk of developing a disease or condition. The measurement is calculated by dividing the proportion of people with the disease in question who are also exposed to the relevant risk factor by the proportion of people with the disease who have not been exposed to the risk factor.) Results from this study were published in the April 1, 1998 issue of the Journal of Acquired Immune Deficiency Syndromes.

Dr. Palefsky's team also identified persistent infection with multiple HPV types, including oncogenic types, as being yet another risk factor for ASIL disease progression. Again, the risk for HIV positive men was higher than for HIV negative men. Among HIV positive men, 62% (25 of 40) who were infected with a single HPV type and 77% (70 of 90) who were infected with multiple HPV types displayed ASIL progression. Among HIV negative men, anal lesions progressed in 42% (21 of 50) with a single HPV type and 57% (11 of 19) with multiple HPV types.

Although prospective research data are lacking, HIV positive women potentially have a similar risk of anal disease progression as their male counterparts. HIV-HPV coinfected women in the San Francisco WIHS cohort were more likely to have multiple HPV types than the HIV negative/HPV positive women surveyed. Furthermore, lower CD4 cell levels were associated with an increase in the mean (average) number of HPV types.

HIV-HPV Interactions

The higher risk for both anal HPV infection and ASIL seen in HIV positive persons is likely caused by several cofactors. In the laboratory, the expression of oncogenic HPV type 16 E6 and E7 proteins appears to be enhanced by the HIV-1 Tat protein. Cytokines (chemical messenger proteins) secreted by HIV-infected lymphocytes (a type of white blood cell) may contribute to the risk of neoplasia development. In addition, HIV-related immunosuppression may result in the loss of a cell-mediated immune response specifically against HPV. Other cofactors also may be involved.

Symptoms of Disease

Persons with anal dysplasia may not experience any overt symptoms or they may experience bleeding, irritation, pruritis (itching), or a burning sensation. Severe dysplasia is not believed to cause more symptoms than low-grade dysplasia. Persons with invasive cancer are likely to report anal abscesses, masses of tissue ("lumps"), ulcers, anal discharge, and tenesmus (a frequent urge to defecate accompanied by pain, cramping, and straining).

Therapeutic Interventions

Because no treatment guidelines have been approved thus far by the U.S. Public Health Service (USPHS), all forms of therapy for persons with ASIL are considered experimental. Furthermore, opinion remains divided within the medical community as to the relative effectiveness of various procedures. Currently, the most common treatment for invasive anal carcinoma consists of chemotherapy (anticancer drugs) combined with radiation therapy. The most common treatments for higher-grade lesions include surgery (cold-scalpel or electrofulguration), laser therapy, and the use of topical agents. Targeted treatment outcomes are the elimination of all neoplasms; the prevention of their recurrence, which is difficult to achieve; and increased survival and quality of life for people with the disease. Before the advent of chemotherapy/radiation treatment (see below), removal of the rectum and anus (a procedure known as abdominoperineal resection, or APR) used to be performed on those with more severe stages of anal carcinoma. However, this type of radical surgery should be considered only when the potential benefit clearly outweighs the potential risk, as when no other treatment option exists or if radiation treatment causes excessive pain or proctitis (inflammation of the rectum marked by soreness and bloody stools). Anyone considering treatment should consult with several health-care providers-including at least one cancer specialist (oncologist)-before undergoing any course of action.

In persons with low-grade lesions, regular monitoring done approximately every six months to detect any changes that may indicate a progression to HSIL should be sufficient (see "Screening Techniques" below). Low-grade lesions are often not treated directly unless the person with LSIL feels
it is necessary, e.g., due to physical discomfort.

Chemotherapy/Radiation Combination Treatment

This combination treatment is currently considered standard therapy for invasive anal carcinoma. The chemotherapeutic (medicinal) component of this approach, given by IV (intravenously), is as follows:

• 1,000 mg/m² of 5-fluorouracil per 24 hours for four days, given as a continuous 96-hour infusion on days
  1-4 and repeated on days 29-32
  plus
• 10 mg/m² of mitomycin C or 75 mg/m² of cisplatin on days 1 and 29.

Mild to life-threatening adverse effects are commonly reported in persons who use chemotherapeutic drugs.
5-fluorouracil may lower white blood cell counts, and both mitomycin C and cisplatin may cause bone marrow suppression, leading to low white blood cell and platelet counts. Suppression of the bone marrow and low blood cell levels are potentially life-threatening. Some adverse effects caused by chemotherapy may resolve on their own over time or persist; still others may not appear until months or years after the medication is used. Any noticeable side effects should be reported to a clinician.

Radiation therapy involves targeting the DNA, or genetic material, of malignant cells with high-energy rays or radioactive particles. This procedure, also known as radiotherapy, may shrink or eliminate tumors, destroy cancerous cells, or prevent malignant cells from growing and dividing. Radiation therapy is given daily (Monday through Friday) for approximately five weeks beginning on the same day that chemotherapy is started (day 1). The area treated includes the anus and the lymph node regions in the pelvis and groins (inguinal nodes). The dose of radiation therapy can vary from a low dose of 3,000 cGy (centigray) to a more commonly used dose of about 5,500 cGy, delivered in increments or fractions of approximately 200 cGy daily.

Radiation treatment may cause a host of side effects, most of which do not persist. However, a physician should be notified if symptoms such as nausea, vomiting, unexplained weight loss, pain, or bleeding should continue.

Surgery

Surgical removal of diseased tissue, also known as cold-scalpel resection, is often done when lesions grow larger than 1 cm2. Neoplastic tumors may also be surgically destroyed using an electric current; this process is called electrofulguration. Both of these procedures are likely to cause considerable pain and discomfort to the individual for several weeks following surgery. They may also lead to complications such as the inability to control defecation ("bowel movements") or anal stenosis (constriction of the anal canal). Anal stenosis may be avoided by removing malignant lesions in stages, particularly those that form around the circumference of the anal canal. Another drawback to surgery is the possibility of incomplete removal of diseased tissue, which may lead to a recurrence of HSIL and malignant lesions.

Laser Therapy

Anal lesions may also be destroyed using intense heat delivered by powerful, controlled, and extremely narrow light beams. Laser therapy, also known as laser ablation, holds certain advantages over the surgical procedures mentioned above. For example, lasers reduce the likelihood of infection at the affected site and are more precise than traditional scalpels. However, very little data on the effectiveness of using lasers for anal carcinoma have been collected, and it is not known if this relatively new method of treating this disease will prevent the side effects and complications associated with more traditional surgical methods. In addition, the high cost of laser equipment and limited number of specialists who are trained to perform this procedure make widespread use of lasers unlikely in the near future.

Topical Agents

Applying medicine directly to high-grade anal lesions may seem like a less risky or at least less painful alternative to surgery and radiation/chemotherapy. However, topical agents may cause bleeding, local infection, ulcerations, and scarring; they may also make the treated area more painful. To date, no topical agents are proven to be effective in anal disease, although new therapies are being evaluated in ongoing studies. In general, small anal lesions (smaller than 1 cm2) are more likely to respond well to localized topical treatment. TCA is most often used, both internally and externally. Some clinicians use other agents, such as podophyllin, for internal lesions; however, the safety and effectiveness of such treatments remain questionable. (See "Genital Warts" sidebar for more information on TCA and other topical therapies specifically for condylomas).

The HAART Factor

Antiretroviral therapies used to treat HIV have shown secondary benefit in treating other diseases or disorders seen in people with HIV infection, such as Mycobacterium avium complex (MAC) and other OIs. This appears to be due chiefly as a result of improved immune function seen in people who use HAART. Antiretroviral medications have also decreased rates of Kaposi's sarcoma (KS) and primary brain lymphoma in people with HIV, but not other lymphomas or anal neoplasia. In a cohort of 800 MSM currently being followed by Dr. Palefsky and other UCSF researchers (i.e., the San Francisco cohort with additional subjects included), the natural history of anal carcinoma to date does not seem to be altered by treatment with HAART. Preliminary data do suggest, however, that people who begin taking HAART with higher CD4 cell counts on average show the slowest rates of disease progression. These unpublished data were reported during a plenary lecture given at the 4th International AIDS Malignancy Conference, held May 16-18, 2000, in Bethesda, MD.

Further studies may yet show that improved immune function gained by the use of HAART can lower the risk of anal cancer by controlling HPV infection and causing LSIL to stabilize or resolve rather than progress to HSIL. From what is known already, it seems more likely that as HIV positive people live longer while taking HAART, their chances of developing progressive diseases such as anal cancer will increase over time. Conversely, some evidence indicates that HAART may stabilize or reverse CSIL in women with HIV.

HPV Vaccines

An effective HPV vaccine would likely have a profound impact on the incidence not only of condylomas but on anal (and cervical) cancer as well. However, developing a prophylactic, or preventive, vaccine to inhibit HPV infection from taking place presents researchers with significant challenges, many of which are similar for other sexually transmitted viral infections. HPV is difficult to culture (grow) in the laboratory and is found only in humans, making animal studies difficult to perform. Potentially useful animal models include canine oral papillomavirus (COPV) in dogs and papillomavirus infections in rabbits. People are generally exposed to viral STDs on a chronic and repetitive basis (i.e., through sex); the level of immunity offered by any HPV vaccine candidate would have to account for this phenomenon. This is theoretically possible, as with the effective and widely available vaccine for HBV (there are far fewer HBV types than HPV types, however).

Persons with prior HPV infection would benefit from an effective therapeutic (treatment) vaccine, which hopefully would eradicate the virus altogether, or at least control the infection by preventing any abnormal effects such as warts and cellular changes. To date, no such vaccine has been developed.

Prevention and treatment of active HPV infection in people with HIV seems to have taken on a new urgency: a team of researchers recently reported that HPV infection may speed the progression of HIV disease, much as HIV infection appears to accelerate the progression of anal neoplasia. Otoniel Martinez-Maza, PhD, and other researchers from the University of California, Los Angeles (UCLA), discovered that growth factors and proteins produced by HPV-infected cells stimulated latent (inactive) HIV-infected cells and prompted them to generate new copies of HIV in vitro (in the test tube). Whether a similar phenomenon takes place in vivo (in the body) remains to be confirmed. This report appeared in the December 2000 issue of Obstetrics and Gynecology.

In addition, Deborah Greenspan, BDS, DSc, and colleagues from UCSF have reported dramatic increases in the prevalence of HPV-related oral warts in HIV positive persons taking HAART, particularly protease inhibitor (PI) drugs.

Screening Techniques

In the absence of an effective HPV vaccine, and because not every case of anal carcinoma is accompanied by HPV infection, preventing anal cancer from developing in high-risk groups may be accomplished by educating such populations about the disease and about practicing safer sex (e.g., using condoms). Disease prevention may also be achieved through the screening process. (Although HPV infection is a high-risk factor for anal neoplasia, testing for it is primarily used for research. Nevertheless, HPV infection should be considered a marker for high-risk groups, such as HIV positive MSM or women, who should be screened on a regular basis.)

Screening for anal cancer is a three-step process.

Step I: Anal Cytology

The first step involves anal cytology, or the examination of anal cells for structural abnormalities. This screening process, which can be easily performed during a routine visit to the doctor, is similar to cervical/vaginal Pap smears done in women. The procedure is simple, inexpensive, and causes mild discomfort at most. Dacron swabs are inserted into the anal opening and swirled along the tissues lining the anal canal, including the transformation zone and the lower rectum. The cell-coated swabs are rubbed or smeared onto a glass slide, sprayed with a fixative, and later microscopically examined at a laboratory. (Dacron swabs, available from Baxter Healthcare Corporation, are recommended over plain cotton swabs, as anal cells tend to cling to cotton.) A more accurate and uniform interpretation of cytology may be achieved with the Cytyc ThinPrep system, approved by the Food and Drug Administration (FDA), in which cell samples are transferred to a preservative solution instead being smeared onto a slide. At the laboratory, a processor separates and filters debris and other noncellular material (e.g., blood and mucus) from the solution; the "rinsed" anal cells are then fixed onto slides of potentially greater clarity than those created using the traditional Pap smear procedure.

Step II: Anoscopy

A visual examination of the anal tissues will likely be warranted if abnormal anal cytology is discovered during the initial screening process. Abnormal cytology includes evidence of ASIL and some cases of atypical squamous cells of undetermined significance (ASCUS). Visual diagnostic evaluation cannot be done with the naked eye, even with an intense light source; it must be performed with a high-resolution anoscope. This small instrument, equipped with a light and magnifying lens, is inserted shallowly into the anal canal and allows the physician to examine any lesions that may exist, particularly in the transformation zone. So-called microinvasive cancers that often develop at the base of benign warts also may be detected during anoscopy. A solution of 3% acetic acid, swabbed directly onto anal tissues before examination with the anoscope, causes lesions and areas of abnormal cell cytology to appear white. The acid application is an essential component of this procedure. For instance, flat condylomas, which may signal infection with an oncogenic HPV type, are often invisible without the aid of acetic acid.

Step III: Anal Biopsy

Biopsy refers to the surgical removal of a small amount of tissue that is then analyzed by microscope to establish a diagnosis (a determination as to the existence of a disease or condition). This procedure can also be done during a regular out-patient visit to the doctor. A biopsy of lesions and abnormal tissues discovered during an anoscopic examination allows the physician to grade any neoplastic tissue and propose a course of treatment, neither of which should be done on the basis of cytology alone.

The Cervical Cancer Model

The screening protocol, or formula, for the anal canal outlined above is not officially sanctioned by any medical or government body. Rather, it is based on the screening method used for women at high risk for developing cervical cancer. The similarities seen between anal and cervical lesions and carcinoma, including etiology strongly related to certain HPV types, appear to warrant employing a similar method of detection.

Cervical cytology, i.e., the introduction of the Pap smear, has been credited for much of the decline seen in cases of cervical cancer over the past few decades in developed countries. The incidence of cervical carcinoma was approximately 35 cases per 100,000 persons in the U.S. before the use of Pap smears-statistically equal to the current incidence of anal carcinoma in HIV negative MSM. The cervical cancer rate has dropped to about 8 cases per 100,000 since cervical cytology became widespread. It is hoped that anal screening will lead to a similar decline in anal cancer rates among MSM. Anal Pap smears-especially ThinPrep slides-appear to be as sensitive as cervical smears (an approximate sensitivity rate of 73%). And the high-grade lesions detected by anoscopy correspond in significant ways to similar high-grade lesions detected in cervical colposcopy (a colposcope is much like an anoscope, and is used to visually examine the cervix and vagina. For more information on CIN and cervical cancer, see "Cervical Intraepithelial Neoplasia" in the June 1996 issue of BETA.)

Barriers to Screening

One might suppose that the diagnostic usefulness of anal screening, and its apparent necessity in a time of potential increases in an already high rate of incidence among specific populations, would lead to widespread use of this tool. Nonetheless, anal screening is currently being done by only a very small number of clinicians, and mostly in a research setting. Aside from the lack of officially recognized diagnostic and therapeutic strategies, other factors contribute to the general indifference toward anal neoplasia. Some physicians, especially those who do not have many patients among high-risk groups, may not feel that special vigilance or training are essential for this relatively uncommon condition. Likewise, many people-even among those who are most prone to developing the disease-may not know that they are at risk for anal cancer.

Another barrier has traditionally been the lack of a cost/benefit analysis that compares the costs of anal screening, treatment, and follow-up with those of a similar disease, such as cervical cancer. Two such analyses have recently been conducted, however, and the results suggest that a benefit would be achieved with periodic screening of both HIV positive and HIV negative MSM.

Cost/Benefit Analysis for HIV Positive MSM

In a report that appeared in the May 19, 1999 issue of the Journal of the American Medical Association, Sue J. Goldie, MD, MPH, of the Harvard School of Public Health and colleagues estimated the cost-effectiveness of anal cytology screening in a hypothetical cohort of HIV positive MSM. By calculating the effect of different screening strategies (including no screening) on lifetime costs, life expectancy, and quality-adjusted life expectancy for this population, Dr. Goldie's team arrived at an encouraging result: screening for ASIL raised quality-adjusted life expectancy regardless of HIV disease stage.

Specifically, these researchers found that screening done every two years, beginning during acute (early) HIV infection, led to a quantified benefit (a 2.7-month gain in quality-adjusted life expectancy) at an incremental cost of $13,000 per QALY saved, compared with no screening. (QALY, or quality-adjusted life year, refers to a year of life graded between 0.0 and 1.0 according to the type of ill health experienced during the year.) Annual screening augmented this benefit at an incremental cost of $16,600 per QALY saved; screening done every six months provided no significant added benefit. For those undergoing screening during later HIV disease (i.e., with lower CD4 cell levels), a projected cost-effectiveness ratio of less than $25,000 per QALY saved could be gained with annual screening. As the researchers pointed out, these results compare favorably with other preventive measures in HIV disease, such as the use of TMP-SMX (Bactrim, Septra) for Pneumocystis carinii pneumonia (PCP) prophylaxis ($13,000 per year of life saved). In addition, anal screening in this population appears to be much less expensive than cervical cancer screening done every three years in HIV negative women ($180,000 per year of life saved).

Cost/Benefit Analysis for HIV Negative MSM

Dr. Goldie and colleagues then applied a similar mathematical model in a cost/benefit analysis of anal cytology screening for HIV negative MSM. Annual screening provided less than 0.5 quality-adjusted months of additional life expectancy at an incremental cost of $34,800 per QALY gained. Screening every two years cost $15,100 per QALY gained compared with screening every three years, which was associated with a 1.8-month increase in the quality-adjusted life expectancy at a cost of $7,000 per QALY gained. In this case, the figures for screenings done every two or three years compare well with other, standard preventive health interventions. The results of this second analysis were published in the June 1, 2000 issue of the American Journal of Medicine.

Real-World Implications

The data derived from these two studies indicate that annual screening of HIV positive MSM and biennial or triennial screening of HIV negative MSM may confer an appreciable life-saving benefit at a reasonable cost. Additional analyses are needed to determine the cost-effectiveness of screening in HIV positive women and adolescents; similar screening intervals for these groups may also prove beneficial and economically sound.

Awaiting Standard of Care

There is clearly a need to define a standard of care for anal neoplasia. Current treatments, which are still evolving and problematic, have shown some success in eliminating premalignant and malignant lesions, or at least preventing them from spreading to other parts of the body. More importantly, anal screening appears to be a successful, cost-effective method for detecting anal cancer and its precursor conditions and thereby extending the lives of individuals at high risk.

From the data currently available, it seems prudent to screen all persons who are prone to anal cancer. If the majority of women in developed nations are able to receive regular cervical screenings, there is no medical reason why HIV negative MSM as well as HIV positive MSM, women, and adolescents should not expect a similar anal examination. With evidence that anal cancer may already be preventable, clinicians should make an effort to learn more about the disease. This is especially true for clinicians with patients in high-risk groups.

Some proposals and guidelines regarding genital HPV infection are already beginning to appear on a national scale. The CDC has drawn up an outline of recommendations aimed at setting basic, preliminary standards for preventing and evaluating genital HPV infection. These proposals were based on a meeting of experts convened by the CDC on April 13-14, 1999, in Atlanta, and include language specifically addressing anal cancer. The document is available at www.cdc.gov/nchstp/dstd/Reports_ Publications/HPVSupplement%20.pdf. In December 2000, Congress approved an HPV education and prevention program, drafted by Rep. Tom Coburn (R-OK), as a provision to the FY (fiscal year) 2001 Health and Human Services (HHS) bill. Though the provision focuses on HPV education for health-care professionals and the public in the context of cervical cancer, it may open the way
for continued discussions of and recommendations regarding HPV and genital neoplasia as part of the national health-care agenda.

It is incumbent upon persons in high-risk groups to strongly request that they be evaluated and to encourage their health-care providers to attend training sessions to become proficient in screening and treatment modalities. (For information about training programs in San Francisco, interested clinicians should contact Dr. Joel Palefsky by e-mail at joelp@medicine.ucsf.edu.) When there is sufficient demand, a medical procedure like anal screening can become more commonplace. Those people most at risk for anal cancer must ensure that it becomes routine. Until then, safer sexual practices will help to prevent HPV transmission and the transmission of additional oncogenic viral types to those already infected.

Special thanks to Dr. Joel Palefsky for his assistance in preparing this article.

Nicholas Cheonis is Associate Editor of BETA.

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