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Science to
Community Anal Cancer: In Gay and Bisexual Men
Clinical #3
Introduction Common Terms
These abnormalities are lesions or growths that
Anal cancer is a serious and pervasive health
occur in the surface layer of the skin (the
problem among and gay and bisexual men.
epithelial layer) in the anus chamber (the
Before the onset of the AIDS epidemic, the
squamous) and are described in two stages: low-
incidence of anal cancer among men with a
Research Team grade squamous intraepithelial lesions (LSIL)
history of receptive anal intercourse has been
Joel Palefsky, MD and high-grade squamous intraepithelial lesions
estimated at about 35 per 100,000. This is about
Elizabeth Holly, PhD (HSIL). They are differentiated by size, shape,
Naomi Jay, RN, NP the same incidence as that for cervical cancer
color, texture, and risk of further progression to
Michael Berry, MD prior to the implementation of broad screening
Ross Cranston, MD cancer. Together they are referred to as anal
Joe Thatcher, RN
programs promoting early detection and treat-
squamous intraepithelial lesions (ASIL). Other
Tere Darragh, MD ment among at-risk women.
Mary Ralston, PhD terms sometimes used include “dysplasia” or
Ruth Greenblatt, MD “intraepithelial neoplasms.” (See Figure 1)
Mark Welton, MD As with many cancers, the exact causes of anal
University of California cancer are not clearly understood. However,
Figure 1
San Francisco there is general scientific consensus that human
and Sue Goldie, MD
Anal Cancer: From Normal Cells to Cancer
papillomavirus (HPV) is at least partly to blame.
at Harvard
HPV is a sexually transmitted infection, found in
Normal LSIL HSIL Cancer
many different types in different parts of the
body. ASIL
Infection with HPV is common, with one large
study at UCSF detecting HPV in 61% of HIV- Risk of Progression
negative and 93% of HIV-positive of gay and Several UCSF studies have looked at the
bisexual men. Typically, infection is with not one incidence and natural history of HPV-related
but several different types of HPV. In this same anal lesions. They have been able to identify
study, 23% of HIV-negative and 61% of HIV- factors that appear to increase risk for HPV-
positive men were infected with multiple HPV related ASIL. These include HPV infection, a
types. Several studies have suggested that having history of receptive anal intercourse, and a lower
multiple types of HPV increases risk of progres- CD4 cell count (typically the result of HIV-
sion to cancer. related immune system damage).
The evidence for an association between HPV Scientists have also been able to observe the
and anal cancer is strong. Similar to cervical rates at which individuals develop LSIL or HSIL
cancer, the DNA for HPV is often detected in and progress (and regress) from one stage to
anal cancer tissues. The types of HPV detected another. Because HIV infection appears to
are also those known to cause cancer. Con- dramatically affect the risks for progression,
versely, anal cancer is rarely found without research results are usually distinguished for
finding some type of HPV also present. those who are living with HIV from those that
are not.
Anal Squamous One study, concluded in 1997, looked at
Intraepithelial Lesions incidence and progression of ASIL over a two-
year period among a group of gay and bisexual
Infection with HPV does not automatically result
men. The study found that the prevalence of
in the development of cancer; it may in fact
ASIL at baseline (at the start of the two-year
result in no disease at all. Some people develop
period) was 36% among men living with HIV
tissue abnormalities in the anus and not cancer.
and 7% among those who were HIV-negative.
Several of these tissue abnormalities are not
Of those that were normal at baseline, half of
known to be harmful, but several are believed to
those living with HIV developed ASIL during
be precursors to cancer.
the two-year period as compared with only 17%
of HIV-negative men. Of those who had some
abnormalities at baseline (these are sometimes Infection with Multiple Types
referred to as atypical squamous cells of undeter- of HPV
mined significance, or ASCUS), 30% of those
who were HIV-negative progressed to LSIL There are dozens of different types of HPV,
compared to 70% progression rate for those many of which have been found in anal lesions.
living with HIV. (See Table 1) The 1998 UCSF study on incidence and progres-
sion, used sophisticated genetic testing to
The same research team was also able to assess identify the different types of HPV found in
the relative risk of a number of factors for their those who were infected. The researchers also
positive or tried to determine whether specific types of HPV
negative impact were more closely associated with disease
Table 1 on the progres- progression.
Baseline Prevalence and Incidence of Progression/ sion of disease.
Regression Over 2 Years to HPV-Related Anal Lesions The role of individual HPV types could not be
among a Group of Gay and Bisexual Men The researchers’
data indicate determined because most subjects were infected
HIV-negative HIV-positive that the same with multiple types. The researchers were able to
ASIL at baseline 7% 36% factors most determine that infection with multiple HPV types
Normal baseline, developed ASIL over 2 years 17% 52% strongly was associated with an increased incidence and
Normal baseline, developed HSIL over 2 years 8% 20%
associated with progression of disease. Using statistical analysis,
Progression from ASCUS at baseline to LSIL 31% 70% they identified the following risk factors for
Progression from LSIL at baseline to HSIL 36% 62%
detection of an
anal lesion are developing HSIL:
Regression from ASCUS at baseline to normal 62% 30%
also associated • Lower CD4 cell levels (for those who were
Regression from LSIL at baseline to normal 50% 5%
with disease living with HIV)
progression • Persistent HPV infection
(HPV infection, HIV infection, history of • Anal infection with multiple HPV types
receptive anal intercourse). • Infection with HPV types known to be
carcinogenic.
A larger UCSF follow-up study completed in
1998 found equally alarming rates of anal HSIL
among a group of gay and bisexual men, with a The researchers noted that, for a small number of
disproportionate impact on those living with individuals who developed ASIL during the
HIV. Of the HIV-positive study participants, 38% course of the study, no HPV was detected. They
developed HSIL during the study as compared suggest a possible explanation is the presence of
with 17% for HIV-negative men. For those with types of HPV not detectable using current testing
LSIL, 52% of the HIV-positive men progressed methodology. Researchers also noted that the
to HSIL as did 41% of the HIV- increased risk for developing HSIL with multiple
negative men. HPV types suggests the possibility of coopera-
Table 2 tion between specific HPV types in disease
Prevalence of Abnormal Anal Pap Smears The researchers for both studies pathogenesis.
in a Group of Male and Female, HIV- caution that their data are drawn
Positive and HIV-Negative Adolescents* from dense urban areas with
highly sexually active popula- Methods of Detecting ASIL
Male Female
HIV-positive 53% 21% tions of gay men and therefore Infection with HPV is certainly an important
HIV-negative 17% 6% cannot fully reflect other areas. factor in risk for possible disease. Yet the high
Yet the high prevalence of anal prevalence of infection in groups known to be at
* Data from the Reaching for Excellence in Adolescent HPV infection demonstrated in
Care and Health (REACH) study, conducted at 15 risk for anal cancer makes screening for infection
sites in 13 U.S. cities (Moscicki, 2000). HIV-negative and HIV-positive alone an unproductive exercise. Instead, scien-
gay men appears to be true as tists have been working to identify reliable
well of individuals who have more recently methods of identifying those with ASIL.
initiated sexual activity. At a recent cancer
conference, researchers reported a high preva- Several UCSF studies have established that
lence of anal HPV infection in a cohort of HIV- cytological screening is reliable and effective. In
negative and HIV-positive adolescent men and much the same way a Pap smear is used for
women. (See Table 2) identifying those at increased risk for cervical
cancer, clinicians can use a swab to gather cells
from the area of the anus where cancer typically
develops. This is the transitional area where the
epithelial lining of the anus meets the epithelial Treatment
lining of the rectum. The swab contents are then
Standard treatment of anal cancer is a protocol of
“smeared” on a slide, observed under micro-
combined chemotherapy and radiotherapy.
scope, and analyzed for the presence of abnor-
Typically, a diagnosis of LSIL results only in
mal cells.
more frequent monitoring in case it progresses to
HSIL. When HSIL is diagnosed, treatment may
If abnormalities are detected, direct observation
be called for to reduce the likelihood of progres-
can be done using colposcopy, in which a small
sion to cancer. This may include surgical
camera and light source, enclosed within a tube,
removal of the lesions.
are inserted. A trained colposcopist, again using
many of the same observational methodologies
Data on the efficacy of treatment are scarce.
developed for cervical cancer, can usually
However, treatment of cervical lesions has been
identify HPV-related lesions and cancer. Biop-
shown to be effective in substantially reducing
sies of visible lesions are also used to confirm
the risk of progression to cancer.
their source and classify them as LSIL, HSIL, or
cancerous.
Conclusion
Cost Effectiveness of Infection with HPV is highly prevalent among
Screening gay and bisexual men. This population also
has a high incidence of HPV-associated anal
Much of the success in reducing the incidence of lesions and cancer. Gay and bisexual men
cervical cancer has come from expanded living with HIV have an even higher inci-
screening programs. Similarly, the prevention of dence and progression of disease.
anal cancer depends on the early identification This is similar to the story for cervical
and treatment of HSIL. For those living with cancer. However, with strong advocacy and a
HIV, anal cancer may be one of the few malig- concerted effort by researchers, clinicians, and
nancies that can actually be prevented. public health leaders, dramatic reductions in
the incidence of cervical cancer have been
To assess the implications of screening those at achieved.
the highest risk—gay and bisexual men living
A similar effort may well be in order
with HIV—a Harvard-UCSF research team set targeting the gay and bisexual men who are
up a complex mathematical model to forecast the most at risk, particularly those who are living
cost of screening and subsequent related with HIV. Further research is needed to
treatments with the savings in suffering and lost determine the prevalence and incidence of
productivity. They were able to use the work of ASIL in the general population of gay and
the UCSF and other researchers who had studied bisexual men outside of major urban centers.
the incidence of ASIL and anal cancer, as well as
Programs are needed to train colposcopists
cost figures from the screening for and treatment in the skills of identifying and biopsying
of cervical cancer. ASIL; training of colorectal surgeons is
needed to optimize identification and treat-
The researchers concluded that screening every ment of ASIL. Further research is also needed
two years for those early in HIV disease (CD4 on newer, medical therapies for ASIL so that
counts greater than 500/mm3) was cost-effective costly and painful surgery can be avoided.
over a wide range of assumptions. For those with
Finally, research is needed to identify other
more advanced HIV disease (CD4 counts less groups that may benefit from anal screening,
than 500/mm3), screening every year was most including women, and to document the
cost effective. Screening every six months efficacy of anal screening programs in
provided little additional benefit over annual lowering the incidence of anal cancer among
screening in nearly all sensitivity analyses. those at risk. Widespread screenings of high
risk groups may be a cost effective opportu-
Regardless of when screening was initiated, the nity to prevent anal cancer and may well
cost-effectiveness of either a yearly or biannual result in lower rates of this disease. Public
screening schedule was comparable with other health leaders should give serious consider-
accepted preventative measures in clinical ation to encouraging bi-annual screening for
medicine, including cervical cancer screening all gay and bisexual men, and annual screen-
using Pap smears. ing for those gay and bisexual men who are
living with HIV.
Clinical #3 • June 2000
References Acknowledgements
Darragh T, Jay N, Tupkelewicz B, Hogeboom C, We would like to acknowledge our incredible study subjects,
Holly E, Palefsky J. Comparison of Conven- study volunteers, lab technicians, the National Cancer
tional Cytologic Smears and ThinPrep Institute and the National Center for Research Resources
(NIH grants CA54053, CA63933, and 5 M01-RR-00079),
Preparations from the Anal Canal. Acta Cytol. and the UCSF/Moffitt General Clinical Research Center.
1997; 41,4:1167-1170.
Goldie S, Kuntz K, Weinstein M, Freedberg K, Editorial assistance from Progressive Health Partners
Welton M, Palefsky J. The Clinical Effective- www.phpartners.com.
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Anal Squamous Intraepithelial Lesions in
Homosexual and Bisexual HIV-Positive Men.
JAMA. 1999;281:1822-1829.
Jay N, Berry JM, Hogeboom C, Holly E,
Materials
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JM, Darragh T. High incidence of anal high-
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