Dandapani et al. HIV– positive anal cancer
HIV– positive anal cancer: an update for the clinician
Savita V Dandapani1, Michael Eaton1, Charles R Thomas Jr2, Paul G Pagnini1
1Department of Radiation Oncology, University of Southern California, Keck School of Medicine, Los Angeles, California, USA; 2Department of Radiation
Medicine, Oregon Health and Science University, Knight Cancer Institute, Portland, Oregon, USA
Anal cancer used to be a rare cancer traditionally associated with elderly women. There are approximately 5260 cases per year
in the U.S. (1). The onslaught of the Human Immunodeficiency Virus (HIV) virus has led to a change in anal cancer demo-
graphics. Anal cancer is on the rise in the U.S and the number of anal cases documented has quadrupled in the past 20 yrs
correlating with the rise of the HIV epidemic. The incidence of anal cancer is 40 to 80 fold higher in the HIV positive (HIV+)
population when compared to the general population (2). With the advent of highly active antiretroviral therapy (HAART),
HIV+ patients are living longer as less are progressing to AIDS. As a consequence non AIDS defining cancers such as anal can-
cer are on the rise. Factors implicated in the etiology of anal cancer in HIV+ patients include (Human papillomavirus) HPV
virus status, sexual habits, and a history of smoking. HPV 16 and receptive anal intercourse (RAI) increase the risk of anal
cancer by 33% over the general population. In the general population, the rate of anal cancer is approximately 0.9 cases per
100,000. In patients with a history of RAI, the rate approaches 35 cases per 100,000 which is equivalent to the prevalence of
cervical cancer (3). Smokers are eight times more likely to develop anal cancer. There has been much discussion about tailor-
ing treatment decisions in HIV+ patients with anal cancer. This review focuses on squamous cell carcinomas of the anal canal
which comprise 80 to 90% of all anal cancers diagnosed and highlight key issues in the management of HIV+ anal cancer pa-
tients including recent clinical trials.
Anal cancer, HIV, Anal canal
J Gastrointest Oncol 2010; 1: 34-44. DOI: 10.3978/j.issn.2078-6891.2010.005
No potential conflict of interest.
Corresponding author: Charles R. Thomas, Jr., MD, Professor and Chair,
Department of Radiation Medicine, Oregon Health and Science University,
Knight Cancer Institute, Mail Code KPV4, 3181 SW Sam Jackson Park Road,
Portland, OR 97239-3098. Fax: 503-346-0237. Ph:503-494-8756. Email: thom-
Submitted August 3, 2010. Accepted for publication August 19, 2010.
Available at www.thejgo.org
© 2010 Journal of Gastrointestinal Oncology. All rights reserved.
Anal cancer is on the rise in the US especially in the HIV
positive population. In the early 1990’s the incidence of anal
cancer was approximately one case per 100,000 person-
years (4). By 2004, the number of cases increased 30%
(4). In the HIV positive population the rate of anal cancer
increased from 19 to 78.2 per 100,000 person-years (4). 80%
of anal cancers involve the anal canal with the majority being
squamous cell carcinomas (5).
One major factor implicated in the increase in anal cancer
from the 1990’s to now is the HIV virus. It is known that
the incidence of anal cancer is 40 to 80 times higher in the
HIV+ population. HIV+ patients tend to get anal cancer at a
younger age, are more frequently men, and more frequently
homosexual men who practice RAI (6). Cancer has been
associated with HIV since the first reports of AIDS in the
1980s. Three different cancers are AIDS defining: Kaposi’s
sarcoma, Non-Hodgkin’s Lymphoma (B cell), and invasive
cervical cancer. Anal cancer is part of a group of non-AIDS
defining cancers which include Hodgkin’s lymphoma, lung
adenocarcinoma, hepatocellular carcinoma, oropharyngeal
carcinoma, kidney carcinoma, melanoma, and conjunctival
carcinoma (primarily sub-Saharan Africa) (4). These non
AIDS defining cancers have a two to three fold higher
incidence in the HIV+ population (7).
There are other factors implicated in the etiology of anal
cancer in addition to HIV. Anal cancer, similar to cervical
cancer, is known to be associated with the HPV virus, sexual
behavior, and tobacco use. HPV-16 is the most prevalent
subtype associated with anal cancer and precancerous lesions
followed by HPV-33 and HPV-39 (8). HPV is known to
play a definitive role in the development of anal and cervical
Journal of Gastrointestinal Oncology, Vol 1, No 1, September 2010
squamous cell cancer. HIV+ patients are more likely to be co-
infected with HPV, approximately 2 to 6 fold higher probably
secondary to similar risk factors such as sexual behavior. In
the HIV+ population, men have an increased relative risk of
developing anal cancer compared to women (37.9 versus 6.8)
(9). That risk increases depending on sexual practices. Men
who has sex with men (MSM) is associated with a higher
incidence of anal cancer. HIV+ MSM have doubled the rate of
anal cancer as compared to HIV- MSM (70-100 per 100,000
versus 35 per 100,000) (10).
HPV infection persists in HIV+ patients compared
to immunocompetent patients. HIV+ patients are seven
times more likely to have persistent HPV infection. There
is a suggestion that immunosuppression in HIV+ patients
prevents clearance of HPV and subsequent higher risk of
developing anal cancer.
The discovery and subsequent use of antiretroviral drugs
(HAART) in the late 1990’s has led to a significant decrease
in AIDS defining cancers. In the U.S, recommendations
set forth by the United States Department of Health and
Human Services for initiating HAART treatment include:
all HIV positive patients who present with AIDS defining
illness, and HIV positive patients with CD4<200 (cluster
of differentiation 4) (11). It is also recommended that
clinicians consider treatment for asymptomatic HIV
positive patients with CD4 counts between 201-350 (11).
However, HAART has not reduced the incidence of non-
AIDS defining cancers such as anal cancer. One theory is
that immunosuppression plays a role in the development of
anal cancer. It has been suggested that immunosuppression
not only leads to increased risk of non AIDS defining cancers
but also increases the aggressive nature of such cancers (7).
A French study examined the incidence of cancer in a cohort
of HIV+ patients and found that a CD4 count less than 200
cells per uL and HIV viral load >100,000 copies per mL were
associated with an increased risk of anal cancer. The majority
of patients (93%) diagnosed with anal cancer had been
treated with antiretroviral therapy for over 6 months (12).
Anal cancer and cervical cancer share many similar
characteristics. Both anal cancer and cervical cancer develop
from precursor lesions: anal intraepithelial neoplasia (AIN)
and cervical intraepithelial neoplasia (CIN) respectively.
The incidence and mortality from cervical cancer in the U.S.
has significantly diminished with the routine use of cytology
screening with the Papanicolau (Pap) smear test. Pap smears
identify precancerous lesions and early treatment of these
lesions has been shown to prevent the development of cervical
cancer. As a result the rate of cervical cancer dramatically
decreased in the U.S. In countries where screening for cervical
cancer is not routinely done the incidence and mortality of
cervical cancer is much greater.
Squamous cell carcinoma of the anus is thought to
arise from a precancerous lesion. The etiology of this
precancerous lesion is thought to involve integration of
HPV into the patient’s genome. Similar to cervical cancer,
a Bethesda staging criteria has been devised for precursor
anal lesions (13). AIN1 is thought to be low grade squamous
intraepithelial lesion (LSIL) whereas AIN 2, 3 are high
grade squamous intraepithelial lesion (HSIL). Similar to
cervical cancer, treatment is recommended for high grade
precancerous (HSIL) anal lesions.
Studies have identified additional risk factors in the
development of AIN. Wilkin et al (2004) studied the risk of
developing AIN in HIV+ men (14). Almost three-quarters of
men with abnormal anal cytology had co-infection with a high
risk HPV serotype (HPV 16>>52>18>45) (14). Multivariate
analysis indicated that abnormal cytology was more likely in
patients with a history of RAI and no HAART treatment. AIN
histology on biopsy was more likely in patients with history
of RAI, history of no HAART use, young age (<40) and low
CD4 count (<350). CD4 count was the most significant
prognostic factor. Patient who were on HAART and had
persistent low CD4 counts were also more likely to have AIN.
The relationship between AIN and HAART use, CD4 count,
and viral load is probably confounded as patients with lower
CD4 counts are more likely to have high viral loads and to be
started on HAART.
Recently physicians have begun to advocate anal cancer
screening in the high risk HIV+ population. Studies support
the high incidence of precancerous lesions in the HIV+
population. Wilkin et al. (2004) analyzed the prevalence
of anal precursor lesions in HIV+ men and reported that
almost ½ of patients had abnormal cytology on the anal Pap
smear and subsequently 40% of these patients were found
to have AIN histology by biopsy (14). Kreuter et al (2010)
prospectively examined a population of 400 HIV+ MSM over
a period of 5 yrs and determined that over 70% had some
degree of AIN (10). 35% had high grade AIN and 2.5% had
anal cell cancer detected on screening. More importantly
Kreuter et al (2010) demonstrated that untreated AIN can
progress to anal cancer in as little as 8 months (10). Previous
studies in the mid 1990’s had showed AIN progressing to anal
cancer over 3-5 years (14, 15). Also studies indicate that that
the incidence of AIN has increased with the widespread use
of HAART in the HIV+ population (15).
The feasibility of screening for anal cancer has been
research extensively over the past decade. New York State
has established screening guidelines for anal cancer in HIV+
patients (16). They recommend that all HIV+ patients
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