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Natural History and Clinical Management of Anal Human Papillomavirus Disease in Men and Women Infected with Human Immunodeficiency Virus

  1. Peter V. Chin-Hong1 and
  2. Joel M. Palefsky2
  1. 1Division of Infectious Diseases, Department of Medicine, University of California, San Francisco
  2. 2Departments of Laboratory Medicine and Medicine, University of California, San Francisco
  1. Reprints or correspondence: Dr. Peter V. Chin-Hong, Box 0512, 521 Parnassus Ave., Rm. C-233, University of California, San Francisco, San Francisco, CA 94143-0512 (pvch{at}itsa.ucsf.edu).
 
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Abstract

Before the introduction of highly active antiretroviral therapy (HAART), several studies demonstrated a high prevalence of human papillomavirus (HPV) infection and associated anal intraepithelial neoplasia (AIN) in men who have sex with men, particularly in human immunodeficiency virus (HIV)–infected men with low CD4+ cell counts. Similarly high levels of anal HPV infection and AIN have been found in HIV-positive women. HIV-positive men and women are at an increased risk of developing anal cancer compared with the general population. Data suggest that there has been no reduction in the incidence of AIN after the introduction of HAART. Screening efforts have the potential to decrease the incidence of invasive anal cancer, and cost-effectiveness analyses have demonstrated the utility of anal cancer screening in select populations. Treatment for AIN remains challenging, but AIN is easier to treat when the lesions are small, and it is likely that a screening program would identify affected individuals at an earlier stage of disease.

HIV-infected patients have a high prevalence of human papillomavirus (HPV)–associated anal disease. HPV is one of the most common sexually transmitted agents. The oncogenic role of HPV in anogenital cancer is clear, with extensive evidence that HPV is necessary but insufficient for the development of cervical cancer [1]. The role of HPV in anal cancer and its precursor, anal intraepithelial neoplasia (AIN), is becoming equally compelling. Biologically, cervical cancer resembles anal cancer in several ways. They both arise in the transformation zone, the juncture between the columnar epithelium of the endocervix (or the rectum) and the squamous epithelium of the exocervix (or the anus). Cervical and anal cancer are strongly linked to HPV and are believed to be preceded by AIN II or III [2].

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Epidemiology of Anal Hpv Infection, Ain, and Anal Cancer in Hiv-Positive Men and Women

The impact of anal cancer among the HIV-infected population can best be appreciated by a comparison with cervical cancer epidemiology. The incidence of cervical cancer was estimated to be 40–50 cases per 100,000 individuals before cervical cancer cytology screening was routinely performed. After the adoption of Papanicolaou tests to identify and treat cervical intraepithelial neoplasia (CIN), the incidence of cervical cancer decreased to ∼8–10 cases per 100,000 individuals [3]. Before the HIV infection epidemic, the incidence of anal cancer was estimated to be as high as 37 cases per 100,000 men who have sex with men (MSM), which is comparable to the incidence of cervical cancer before cervical cytology screening was introduced.

Several studies suggest that the incidence of anal cancer is even higher among HIV-positive men and women. There is evidence that the incidence of anal cancer among HIV-positive MSM is twice that for HIV-negative MSM [4]. Data from the US AIDS Cancer Registry Match Study [5] showed that the relative risk of invasive anal cancer was 37 in HIV-positive men and 6.8 in HIV-positive women compared with the general population. In San Francisco County, California, the incidence of anal cancer among all white and Hispanic men aged 40–64 years quadrupled, from 3 cases per 100,000 individuals during 1973–1979, before the HIV infection epidemic, to >14 cases per 100,000 individuals during 1996–1999 [6]. There were 94 cases of anal cancer in men and 27 cases in women in San Francisco County during 1995–1999 in all age groups. Only a small proportion of all white and Hispanic men aged 40–64 are HIV-positive MSM, so it is likely that the incidence of anal cancer among HIV-positive MSM is substantially higher than 14 cases per 100,000 individuals and possibly in the range of 70–100 cases per 100,000 individuals. Anal cancer, like cervical cancer, is potentially preventable. Screening for and treating precursor lesions such as AIN may lead to a reduction in the incidence of anal cancer.

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Anal Hpv Infection

Like cervical HPV infection and CIN in cervical cancer, anal HPV infection is an important risk factor for AIN and anal cancer. In one study, the prevalence of anal HPV infection was 60% among HIV-negative MSM and 93% among HIV-positive MSM [7]. Multiple HPV types were found in 73% of HIV-positive and 23% of HIV-negative participants, and infection with multiple HPV types was associated both with prevalent AIN and progression to a higher grade of AIN over time. In women, data from the Women's Interagency HIV Study showed that 76% of 223 HIV-positive women were found to have anal HPV infection, as did 42% of high-risk HIV-negative women (i.e., commercial sex workers and injection drug users). Furthermore, anal HPV infection was more common than cervical HPV infection among both HIV-positive and high-risk HIV-negative women [8].

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Prevalence of Ain in Hiv-Positive Men and Women

As in the cervix, the anus displays changes ranging from AIN I to AIN III. AIN I is not thought to progress directly to cancer, whereas AIN II and III are likely to be true precursors to anal cancer. In the cervix, atypical squamous cells of indeterminate significance (ASCUS) is a screening cytologic diagnosis that is relatively nonspecific, but in the anus, it is often associated with detection of AIN on high-resolution anoscopy (HRA) and via biopsy. One cross-sectional study of MSM showed that the prevalence of AIN was high in HIV-positive men (36%) compared with HIV-negative men (7%) [9]. In women, a cross-sectional study [10] reported that 26% of 251 HIV-positive women had AIN diagnosed, compared with 8% of the 68 HIV-negative women.

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Natural History of Ain in Hiv-Positive Men and Women

In a study from San Francisco, 32% of HIV-positive men who had no anal disease at the time of entry into the study had AIN I diagnosed within 2 years, compared with 9% of HIV-negative men [9]. In the same study, 30% of those with AIN I at baseline had no disease at 2 years of follow-up, but all were HIV negative [9]. Conversely, AIN I often progresses to AIN II or AIN III; >50% of the HIV-positive men who had AIN I at baseline developed AIN II or AIN III within 2 years [9].

In a study from Seattle, Washington, of MSM who were free of AIN at baseline, AIN II or AIN III developed in 15% of HIV-positive and 8% of HIV-negative men in an average of 21 months [11]. In San Francisco, the 4-year incidence of AIN II or AIN III among HIV-positive MSM was 38%. Among those with an indeterminate diagnosis, ASCUS, or AIN I at baseline, the 4-year incidence of AIN II or AIN III was 57% [12]. Overall, the 4-year incidence of AIN II or III was 49% among HIV-positive MSM (figure 1).

Figure 1
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Figure 1

Four-year incidence of anal intraepithelial neoplasia (AIN) II and III in HIV-positive men who have sex with men (MSM), by CD4+ cell count (cells/μL), and in HIV-negative MSM.

Once AIN II or AIN III is found in the anal epithelium, it rarely regresses, even in HIV-negative individuals [12]. There have been no studies that have established the rate of progression from AIN II or AIN III to invasive cancer, but this likely requires years to decades in most cases. However, progression from AIN II or III to invasive cancer has clearly been observed (J. Palefsky, unpublished data). There has been extensive experience with Bowen disease (perianal AIN II or III), of which ∼5% of lesions undergo malignant change [13, 14].

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Role of Haart in The Natural History of Ain

The use of HAART has had a dramatic effect on the morbidity and mortality of HIV-infected individuals [15], including a reduction in most opportunistic infections and HIV-related malignancies [16]. Studies of the impact of HAART on AIN are limited, but the data thus far suggest that use of HAART does not lead to decreased incidence of AIN. In one recent study, 75% of men treated with HAART experienced no regression of AIN II or III [17], and HAART had little impact on the natural history of AIN.

The failure of HAART to decrease the incidence of AIN or progression of existing AIN, if confirmed in ongoing studies, has important implications for the future incidence of anal cancer. Before the epidemic of HIV infection, individuals usually died of other HIV-related complications, and there was insufficient time for anal cancer to develop. If HAART leads to improved survival but does not alter the incidence or progression of AIN, then individuals who receive HAART may have sufficient time to develop anal cancer. Consistent with this, data from 1996–1999 in San Francisco County (after HAART use became widespread) show a continued increase in the incidence of anal cancer among all white and Hispanic men aged 40–64 years [6].

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Model of Pathogenesis of Ain in Hiv-Positive Men and Women

Figure 2 illustrates the pathogenesis of HPV-related AIN, with a potential increase in the incidence of AIN and invasive anal cancer in the HAART era. HPV infection is acquired early with the initiation of sexual activity. HIV infection follows. More sexual activity may result in infection with different types of HPV, which is represented by different lines. Early in the course of HIV disease, the immune response is relatively intact, with low levels of HPV and relatively little AIN. With advancing HIV disease, as measured by low CD4+ cell counts, there is an attenuation of HPV-specific immunity with corresponding increased levels of HPV, development of AIN I, and progression to AIN II or III. Although immunosuppression may be linked to the development of AIN, the role of immunosuppression in progression from AIN to invasive cancer is not clear. Several studies show that, unlike other HIV-related malignancies, the incidence of anal and cervical cancer remains level after a diagnosis of AIDS or with a CD4+ cell count of <50 cells/μL [4, 18]. Progression to cancer may therefore reflect other factors, such as host genomic mutations. Recent data by Haga et al. [19] have characterized some of the genetic changes seen in AIN. By use of comparative genomic hybridization, the investigators showed that the proportion of AIN tissue samples with genetic changes increased with the increasing grade of AIN.

Figure 2
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Figure 2

Pathogenesis of human papillomavirus (HPV)–related anal intraepithelial neoplasia (AIN) and anal cancer, before and after the introduction of HAART.

Overall, in our model, HPV infection plays an important role in the initial development of AIN, and the attenuated immune response plays a role by not eliminating epithelial cells that express HPV proteins. The consequence is sustained high-level expression of HPV proteins, such as E6 and E7, which may lead to genomic instability [20]. Once genetic changes have occurred, these may be the driving force toward progression from AIN II or III to cancer rather than immunosuppression. If this is correct, it would be expected that reconstitution of HPV-specific immunity through HAART use would have little impact on the natural history of AIN II or III—as, indeed, seems to be the case from current data.

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Screening for Ain

Because AIN II and III are the likely precursors to anal cancer, a screening program to prevent anal cancer should focus on the detection and subsequent removal of these lesions. Given the similarity between cervical and anal cancer, and on the basis of the success of CIN screening in reducing mortality, a protocol for AIN screening was proposed by Palefsky et al. [21] and others. Like CIN screening, anal cytologic examination is the first step, followed by confirmation of the disease stage by HRA and biopsy.

Operationally, a sample of cells is blindly obtained by rotating a water-moistened Dacron swab (Baxter Healthcare) in the anal canal. Dacron is used instead of cotton because cells cling to cotton, and this may decrease the cellular yield. The goal is to obtain samples of the lower rectum, the squamocolumnar junction, and the anal canal. To increase the cellular exfoliative yield, patients are instructed to refrain from anal sex and to avoid douching or having enemas before testing.

Like cervical cytologic examination, the findings of anal cytologic examination are classified as “normal” or “abnormal.” The “abnormal” category comprises ASCUS, low-grade squamous intraepithelial lesions, or high-grade squamous intraepithelial lesions. All individuals with abnormal anal cytology should be referred to a specialist for the next step: HRA and biopsy of visible lesions. Patients with ASCUS are referred to specialists because ASCUS found during anal cytologic examination has a high predictive value for AIN on HRA and biopsy [9, 21]. Determination of AIN severity can only be performed after histopathologic assessment via biopsy, because the stage of AIN cannot be determined by cytologic examination alone. Data from Palefsky et al. [21] show that high-grade squamous intraepithelial lesions revealed by anal cytologic examination have a high predictive value for detection of biopsy-proven AIN II or III, but ASCUS or low-grade squamous intraepithelial lesions revealed by anal cytologic examination are not reliable for the determination of the true grade of the anal lesion.

HRA, which is similar to cervical colposcopy and which uses identical equipment (a powerful light source and binocular lenses), permits the identification and biopsy of lesions that have contributed to abnormal cytologic findings. As in cervical colposcopy, acetic acid can allow the visualization of abnormal tissue by a change known as “acetowhitening.” With acetic acid (3%), HPV-related lesions turn white, compared with surrounding normal tissue. Although this procedure improves the diagnostic sensitivity of HRA, acetowhitening is nonspecific. Other signs can improve the specificity; these include abnormal vascular patterns, similar to those see in CIN [22], and changes induced by the administration of Lugol solution (iodine), in which abnormal cells remain unstained or appear light yellow, in contrast to the mahogany color of the surrounding stained normal tissue.

Palefsky et al. [21] have proposed screening guidelines for specific populations including all MSM, regardless of HIV infection status. Other groups who should be considered for screening include the following: women with cervical cancer, high-grade vulvar disease, or cancer; all HIV-positive men and women, regardless of sexual orientation; individuals with perianal condyloma acuminata; and transplant recipients [23]. Analyses by Goldie et al. [24, 25] have suggested that screening of MSM may be cost-effective for the prevention of anal cancer. The optimal screening intervals for HIV-positive men were every year to every 2 years. Cost-effectiveness data for HIV-infected women and other groups are not yet available. A summary of our screening recommendations is presented in figure 3.

Figure 3
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Figure 3

Protocol for screening anal intraepithelial neoplasia (AIN). ASCUS, atypical squamous cells of indeterminate significance; HSIL, high-grade squamous intraepithelial lesions; LSIL, low-grade squamous intraepithelial lesions.

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Treatment of Ain

There are several goals in treating AIN. First, the treatment of AIN prevents anal cancer by removing AIN II or III. Second, treatment of AIN results in symptomatic relief. AIN is generally asymptomatic, but it can be associated with itching or bleeding.

We treat AIN II and AIN III to prevent cancer. We treat AIN I to reduce the risk of further spread or enlargement to the point at which topical therapy is no longer possible, to reduce the risk of progression to AIN II or III, to reduce AIN I–associated symptoms, and to reduce patient anxiety. For all grades of AIN, the decision to treat and the form of treatment depend on the size of the lesion, the location of the lesion, and the goals of treatment. Algorithms for the treatment of AIN I and AIN II or III are presented in figures 4 and 5, respectively. Few studies have been performed on the efficacy of treatment for AIN, either for long-term removal of AIN or for the ultimate goal, the reduction of the risk of developing anal cancer. The following discussion is based on our experience, not on the results of clinical trials.

Figure 4
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Figure 4

Treatment of anal intraepithelial neoplasia (AIN) I

Figure 5
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Figure 5

Treatment of anal intraepithelial neoplasia (AIN) II and III. Imiquimod and podophyllotoxin have not been approved by the US Food and Drug Administration for this indication.

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General Principles of Therapy for Ain

Size of the Lesion

In general, smaller lesions are easier to treat than larger ones. Lesions that are <1 cm2 at the base and relatively flat can usually be treated successfully with local topical therapy. Because of the ease of treating small lesions, we use this approach to treat lesions of any grade. At the other end of the spectrum are diffuse lesions. Lesions that are circumferential are very difficult to treat successfully in these patients. Surgery is the usual approach to treatment, and multiple staged procedures may be needed [26]. Surgery is associated with substantial morbidity, primarily in the form of postoperative pain, and treatment of circumferential disease may lead to anal stenosis or incontinence. The outcome is poor; disease commonly persists or recurs because of the difficulty in removing the entire lesion. Consequently, we typically do not treat a patient with circumferential AIN with surgery unless the goal is to rule out invasive cancer with mapping of the lesion while the patient is anesthetized, or to remove any foci of disease that are causing symptoms.

After explaining the issues to our patients, we usually observe them closely, with follow-up examinations every 4–6 months. This approach should allow for the early detection of anal cancer if it is going to occur, and treatment of early anal cancer is usually successful. We explain to the persons that most individuals with circumferential anal AIN II or III will not develop anal cancer, but that they should notify their clinician immediately if they develop symptoms between follow-up visits that could indicate progression. Symptoms include new bleeding, development of pain, rapid new growth of an anal lesion, or swelling in the inguinal region that could indicate metastatic adenopathy. We also emphasize that we still do not know the long-term rates or the time course of progression to cancer.

Patients who have lesions that fall into the middle category—that is, lesions that are too large for topical therapy but smaller than those associated with circumferential disease—may benefit from surgical removal. If the patient has AIN II or III, we treat the patient whenever possible. If the patient has AIN I, we will treat for symptomatic relief, but if the patient is asymptomatic, then the benefits of therapy may not outweigh the risks. In this case, we will usually continue to observe the patient and will not administer treatment unless the condition progresses to AIN II or III. Individuals with AIN I who are not treated should be examined every 6 months because of the high rate of progression to AIN II or III.

Location of the Lesion

Perianal lesions. Small lesions (<1 cm2 at the base) that are on the perianal surface may be treated with provider-applied or patient-applied therapies. The latter are best used when the lesions are readily apparent to the patient, because the patient will not be able to successfully apply these treatments to small lesions whose locations are not obvious. Patient-applied therapies for perianal AIN I, usually condyloma, include purified podophyllotoxin, a gel applied in cycles of 3 days on and 4 days off and imiquimod, a cream that is applied 3 times per week. These treatments have both been approved by the US Food and Drug Administration (FDA) for this purpose, and both are often successful. If neither is successful, or if the lesions are too small for patient-applied therapy, then the clinician may proceed directly to provider-applied therapies. These include administration of liquid nitrogen, administration of 80% trichloroacetic acid (TCA), surgical excision, electrocautery, laser ablation, infrared coagulation, loop electrosurgical excision procedure, and administration of intralesional interferon. Liquid nitrogen or 80% TCA are usually tried first and require several applications at intervals of 1–2 weeks.

We use a similar approach for the treatment for small perianal AIN II or III. These are usually treated with one of the provider-applied therapies. Patient-applied therapies may be tried as well, but they have not been approved by the FDA for this purpose.

If a perianal lesion is circumferential, then treatment decisions are based in part on the grade of the lesion. We treat circumferential AIN II or III more aggressively than AIN I because of the higher risk of progression. Local surgical therapy is sometimes successful, and pockets of remaining lesion may be treated with local administration of TCA or liquid nitrogen after surgery. Sometimes, we refer a patient with perianal circumferential AIN I for surgery for symptomatic relief, but because of the low success rate, we more often attempt to control the disease with topical therapy. After we make multiple attempts at therapy, we observe the patient closely without attempting further therapy.

Patients whose lesions fall into the middle-size category may be treated successfully, but usually treatment of these lesions requires more than topical therapy. As noted above, we are usually more aggressive with treatment of AIN II or III than for AIN I unless the patient is symptomatic.

Intra-anal lesions. Treatment of intra-anal lesions is even more difficult than treatment of perianal lesions because of the variable topography of the anal canal, presence of hemorrhoids, and anal crypts. The principles of treatment of intra-anal disease are similar to those of perianal disease, but given the difficulties of treating inside the anal canal, our threshold for treatment is higher. Before any treatment is offered for AIN, invasive cancer must be thoroughly excluded. Successful treatment of AIN is based on adequate visualization via HRA—even in the operating room.

Small lesions (<1 cm2) are usually treated regardless of their pathologic characteristics because of the ease of treatment. Inside the anal canal, topical therapies, including TCA, liquid nitrogen, and infrared coagulation, may be used, but we do not use patient-applied therapies, such as podophyllotoxin or imiquimod. Circumferential intra-anal disease is generally not treated. Middle-sized lesions are usually treated surgically if AIN II or III is present. If AIN I is present, we treat the lesions surgically if relief of symptoms is required, but, in many cases, we observe the patient closely without surgery, unless the patient develops symptoms or the condition progresses to AIN II or III.

Surgery is performed by an anal surgeon and is an outpatient procedure. Sedation followed by a field block is often used. HRA is performed in the operating room, and the lesion is identified. Biopsy with fulguration of the surrounding area is performed. A laser may also be used. Patients generally have significant postoperative pain for up to 2 weeks after surgery. Postoperative bleeding is common, but infection, stenosis, or incontinence are uncommon complications.

Recurrence and Persistence of Disease

Treatment of HIV-positive patients with AIN is particularly challenging. The lesions in HIV-positive patients are often larger than those in HIV-negative patients, and the lesions recur at a higher rate or are never eliminated at all. In a recent prospective study [26], 29 HIV-positive patients and 8 HIV-negative patients were surgically treated and observed for ∼30 months. Although no HIV-negative patient developed recurrence of disease, 23 of 29 HIV-positive patients had persistent or recurrent AIN II or III.

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Follow-Up of Patients With Ain

Patients with extensive untreated disease should be monitored closely for the development of invasive anal cancer. As described above, we usually observe patients who have untreated AIN II or III every 4–6 months with repeat HRA to determine whether there are any signs of progression. Pain is not normally a symptom of AIN, and if it is present, a thorough examination must be performed to exclude invasive cancer. Patients with untreated AIN I are usually assessed every 6 months.

After surgery, we usually examine patients with HRA as soon as they are able to tolerate insertion of an anoscope, usually within 2 months of the procedure. The goal of this examination is to determine whether there are remaining pockets of disease, because these pockets are sometimes small enough to be treated topically. In addition, the anal surgeon should examine the patient postoperatively to exclude postsurgical complications.

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Conclusions

The prevalence of HPV-associated AIN in HIV-infected men and women is striking, and the incidence of anal cancer is increasing. In the era of HAART, the incidence of anal cancer may increase even further. An AIN screening program for HIV-positive individuals may reduce the incidence of anal cancer. Development of an infrastructure to train clinicians to identify and treat AIN is needed. Studies are needed to determine the safety and efficacy of different forms of therapy, both to treat AIN and to reduce the incidence of anal cancer. Finally, newer approaches to therapy are needed, including treatments that are noninvasive, specific to HPV infection, and effective for the treatment of large areas of the epithelium.

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Acknowledgments

We thank Michael Berry, for his thoughtful review, and Terry O'Donnell, for administrative support.

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Footnotes

  • Financial support: Grants R01CA54053, R01 CA/AI 88739, and a grant from the General Clinical Research Center, University of California, San Francisco, with funds provided by the Division of Research Resources 5 M01-RR-00079, US Public Health Service (Washington, D.C.).

  • Received January 24, 2002.
  • Revision received June 20, 2002.
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References

  1. ↵
    1. Bosch FX,
    2. Manos M,
    3. Munoz N,
    4. et al
    . Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. J Natl Cancer Inst 1995;87:796-802.
    Abstract/FREE Full Text
  2. ↵
    1. Goedert JJ
    1. Palefsky JM
    . Anogenital squamous cell cancer and its precursors. In: Goedert JJ, editor. Infectious causes of cancer: targets for intervention. Totawa, NJ: Humana Press; 2000. p. 263-87.
  3. ↵
    1. Qualters JR,
    2. Lee NC,
    3. Smith RA,
    4. et al
    . Breast and cervical cancer surveillance, United States, 1973–1987. MMWR Morb Mortal Wkly Rep 1992;41:1-7.
    Medline
  4. ↵
    1. Goedert JJ,
    2. Cote TR,
    3. Virgo P,
    4. et al
    . Spectrum of AIDS-associated malignant disorders. Lancet 1998;351:1833-9.
    CrossRefMedlineWeb of Science
  5. ↵
    1. Frisch M,
    2. Biggar RJ,
    3. Goedert JJ
    . Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst 2000;92:1500-10.
    Abstract/FREE Full Text
  6. ↵
    1. Cress R,
    2. Holly E
    . Incidence of anal cancer in California, 1988–1999. Am J Public Health. (in press).
  7. ↵
    1. Palefsky JM,
    2. Holly E,
    3. Ralston MR,
    4. 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;177:361-7.
    Abstract/FREE Full Text
  8. ↵
    1. Palefsky JM
    . Perspectives: anal cancer in HIV infection. Topics HIV Med 2000;8:14-7.
  9. ↵
    1. Palefsky JM,
    2. Holly E,
    3. Hogeboom CJ,
    4. et al
    . Virologic, immunologic, and clinical parameters in the incidence and progression of anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual men. J Acquir Immune Defic Syndr Hum Retrovirol 1998;17:314-9.
    MedlineWeb of Science
  10. ↵
    1. Holly E,
    2. Ralston MR,
    3. Darragh TM,
    4. et al
    . Prevalence and risk factors for anal squamous intraepithelial lesions in women. J Natl Cancer Inst 2001;93:843-9.
    Abstract/FREE Full Text
  11. ↵
    1. Critchlow CW,
    2. Surawicz CM,
    3. Holmes KK,
    4. et al
    . Prospective study of high grade anal squamous intraepithelial neoplasia in a cohort of homosexual men: influence of HIV infection, immunosuppression and human papillomavirus infection. AIDS 1995;9:1255-62.
    MedlineWeb of Science
  12. ↵
    1. Palefsky JM,
    2. Holly E,
    3. Ralston MR,
    4. et al
    . High incidence of anal high-grade squamous intra-epithelial lesions among HIV-positive and HIV-negative homosexual and bisexual men. AIDS 1998;12:495-503.
    CrossRefMedlineWeb of Science
  13. ↵
    1. Marfing TE,
    2. Abel M,
    3. DM G
    . Perianal Bowen's disease and associated malignancies. Dis Colon Rectum 1987;30:782-5.
    CrossRefMedlineWeb of Science
  14. ↵
    1. Cleary R,
    2. Schaldenbrand J,
    3. Fowler J,
    4. et al
    . Perianal Bowen's disease and anal intraepithelial neoplasia: review of the literature. Dis Colon Rectum 1999;42:945-51.
    CrossRefMedlineWeb of Science
  15. ↵
    1. Murphy E,
    2. Collier A,
    3. Kalish LA,
    4. et al
    . Highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced HIV disease. Ann Intern Med 2001;135:17-26.
    Abstract/FREE Full Text
  16. ↵
    1. International Collaboration on HIV and Cancer
    . Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst 2000;92:1823-30.
    Abstract/FREE Full Text
  17. ↵
    1. Palefsky JM
    . Anal squamous intraepithelial lesions: relation to HIV and human papillomavirus infection. J Acquir Immune Defic Syndr 1999;21(Suppl):S42-8.
    MedlineWeb of Science
  18. ↵
    1. Frisch M,
    2. Biggar RJ,
    3. Engels E,
    4. et al
    . Association of cancer with AIDS-related immunosuppression in adults. AIDS-Cancer Match Registry Study Group. JAMA 2001;285:1736-45.
    Abstract/FREE Full Text
  19. ↵
    1. Haga T,
    2. Kim S H,
    3. Jensen R,
    4. et al
    . Detection of genetic changes in anal intraepithelial neoplasia (AIN) of HIV-positive and HIV-negative men. J Acquir Immune Defic Syndr 2001;26:256-62.
    CrossRefMedlineWeb of Science
  20. ↵
    1. Palefsky J,
    2. Holly E
    . Molecular virology and epidemiology of human papillomavirus and cervical cancer. Cancer Epidemiol Biomarkers Prev 1995;4:415-28.
    MedlineWeb of Science
  21. ↵
    1. Palefsky JM,
    2. Holly E,
    3. Hogeboom CJ,
    4. et al
    . Anal cytology as a screening tool for anal squamous intraepithelial lesions. J Acquir Immune Defic Syndr Hum Retrovirol 1997;14:415-22.
    MedlineWeb of Science
  22. ↵
    1. Jay N,
    2. Berry M,
    3. Hogeboom CJ,
    4. et al
    . Colposcopic appearance of anal squamous intraepithelial lesions—relationship to histopathology. Dis Colon Rectum 1997;40:919-28.
    CrossRefMedlineWeb of Science
  23. ↵
    1. Sillman FH,
    2. Sentovich S,
    3. Shaffer D
    . Ano-genital neoplasia in renal transplant patients. Ann Transplant 1997;2:59-66.
    Medline
  24. ↵
    1. Goldie SJ,
    2. Kuntz KM,
    3. Weinstein MC,
    4. et al
    . The clinical effectiveness and cost-effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV-positive men. JAMA 1999;281:1822-9.
    Abstract/FREE Full Text
  25. ↵
    1. Goldie SJ,
    2. Kuntz KM,
    3. Weinstein MC,
    4. et al
    . Cost-effectiveness of screening for anal squamous intraepithelial lesions and anal cancer in human immunodeficiency virus-negative homosexual and bisexual men. Am J Med 2000;108:634-41.
    CrossRefMedlineWeb of Science
  26. ↵
    1. Chang G,
    2. Berry J,
    3. Jay N,
    4. Palefsky JM,
    5. Welton ML
    . Surgical treatment of high-grade anal squamous intraepithelial lesions: a prospective study. Dis Colon Rectum 2002;45:453-8.
    CrossRefMedlineWeb of Science
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  1. Clin Infect Dis. (2002) 35 (9): 1127-1134. doi: 10.1086/344057
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