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Review: Anal human papillomavirus and anal squamous cell cancer
Anal human papillomavirus and anal squamous
cell cancer in people living with HIV/AIDS:
implications for southern Africa
S Chirkut
Subash Chirkut, FCS(SA), Consultant General Surgeon
King Edward VIII Hospital, Durban; Department of Surgery, University of KwaZulu-Natal, Durban
E-mail: [email protected]
Keywords: anal human papillomavirus, squamous cell cancer, HIV, HPV, southern Africa
Southern Africa has the largest burden of human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) in
the world. Highly active antiretroviral therapy (HAART) is increasingly being made available in the region. The disease has shifted
from being a death sentence to that of a chronic disorder with the availability of HAART. The morbidity and mortality in people
living with HIV/AIDS (PLWHA) in the developed world seems to be shifting from that of opportunistic infection to malignancy,
particularly non-AIDS-defining cancer. A similar trend may be imminent in the developing world owing to the availability of
HAART. Squamous cell cancer of the anus is a cancer with a seemingly increasing incidence in PLWHA. This review explores the
possible impact that a rise in the incidence of squamous cell cancer of the anus would have on the region, and strategies that
may be employed to identify and counteract this escalation.
South Afr J Infect Dis 2014;29(1):12-18
Peer reviewed. (Submitted: 2013-06-13. Accepted: 2013-11-15.) © FIDSSA
(For 2014 DHET applications: South Afr J Epidemiol Infect 2014;29(1):12-18)(ISSN 1015-8782)
Introduction
This narrative review will discuss squamous cell cancer of
the anus and will focus on the epidemiology, risk factors and
potential for screening and vaccine prevention in HIV-infected
persons living in southern Africa.
Globally, 34-million people were estimated to be living with
human immunodeficiency virus (HIV) at the end of 2011. SubSaharan Africa remains the most severely affected. Nearly one
in 20 adults (4.9%) live with HIV and this accounts for 69% of
people living with HIV/acquired immune deficiency syndrome
(AIDS) (PLWHA) worldwide.1 In 2010, 70% of all new HIV
infections worldwide occurred in sub-Saharan Africa.2
Epidemiology
In the USA, between 1973 and 2000, the incidence of anal
cancer in the Surveillance, Epidemiology and End Results
Program registries increased, particularly in men. Ageadjusted, gender-specific annual incidence rates increased
from 1.06 per 100 000 in 1973-1979 to 2.04 per 100 000
in 1994-2000 in men, and from 1.39 per 100 000 in 19731979 to 2.06 per 100 000 in 1994-2000 in women.11 Other
more current cancer registries reported a similar temporal
increase.8
The roll-out of highly active antiretroviral therapy (HAART) in
the public sector in southern African countries over the last
decade has led to tremendous gains in survival for PLWHA.3,4
Although anal cancer is rare, accounting for approximately
1.5-2% of anorectal cancer worldwide,5 the incidence of
this cancer is on the rise, especially in PLWHA in the era of
HAART.6,7 Anal cancer is the fourth most common cancer in
the USA,8 and the third most common cancer in Australia in
PLWHA.9 The risk of anal cancer, compared with that of the
general population is elevated 24-fold in women who are
HIV-infected, 32-fold in heterosexual men or men who have
sex with women (MSW) who are HIV-infected, and 52-fold
in homosexual men or men who have sex with men (MSM)
who are HIV-infected.8 The vast majority of anal cancer is
squamous cell cancer of the anus.10
In 2004, 60 new cases of anal cancer were diagnosed in men
(0.4 per 100 000 person-years) and 53 cases were diagnosed
in women (0.29 per 100 000 person-years) in South Africa.
Anal cancer accounted for 0.23% of all cancer in the country.12
It must be highlighted that the South African National Cancer
Registry is a pathology-based registry, which results in the
under-reporting of many malignancies, and that the true
incidence of anal cancer in the country is unknown.13
Compared to the general population, the age of diagnosis of
squamous cell cancer of the anus in PLWHA is a younger age
(62 years old vs. 42 years old, p-value < 0.0019).14
If similar trends are observed in southern Africa, squamous
cell cancer of the anus is likely to become a major clinical
issue with important public health implications for the region.
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Review: Anal human papillomavirus and anal squamous cell cancer
Risk factors
as 8.6 months.28 Other reports have shown AIN progressing to
squamous cell cancer of the anus over 3-5 years.6
Historically, squamous cell cancer of the anus was believed
to develop as a result of chronic irritation from benign
conditions.15 However, studies have shown that this is not
the case.16 The major risk factor for squamous cell cancer of
the anus is infection with oncogenic human papillomavirus
(HPV). Other risk factors include multiple sexual partners,
being HIV-seropositive, cigarette smoking, anal receptive
intercourse (ARI), and immunosuppression following a solid
organ transplant.17-20
Human papillomavirus in men who have sex with
men
Squamous cell cancer of the anus may be thought to occur as
a result of a sexually transmitted infection with HPV.21 In this
regard, squamous cell cancer of the anus appears to be more
similar aetiologically to genital malignancies than to those of
the gastrointestinal tract.11 Barrier contraceptives appear to be
less effective in preventing HPV infection than other sexually
transmitted infections.22
One of the groups at highest risk of AIN and squamous
cell cancer of the anus are MSM and bisexual men.29,30 It
is important to note that squamous cell cancer of the anus
was on the rise in MSM before the AIDS epidemic, owing to
sexual transmission of HPV.31,32 MSM who are HIV-negative
have an estimated incidence rate of 35 per 100 000 personyears, which is similar to the incidence of cervical cancer in
women who are not HIV-infected prior to Papanicolau (Pap)
screening programmes.33 Squamous cell cancer of the anus
incidence rates in MSM who are HIV-positive are much higher;
approximately 70-100 per 100 000 person-years.28,34,35 These
rates exceed some of the highest reported incidence of
cervical cancer anywhere in the world.36
Human papillomavirus and squamous cell cancer
of the anus
Human papillomavirus in men who have sex with
women
Both anal and cervical cancer share an aetiological link to
high-risk types of HPV infection.23 Using polymerase chain
reaction, the presence of the HPV genome has been identified
in 80-85% of cases of squamous cell cancer of the anus.24
The transformation zone of the cervix is the target area
for HPV owing to the transition of two types of epithelium,
namely keratinised squamous epithelium in the endocervix
and columnar epithelium in the endocervical canal. Similarly,
the anorectal junction has a transition zone at the dentate
line, where the squamous epithelium of the anus meets the
columnar epithelium of the rectum. This area, as well as the
distal squamous epithelium, is susceptible to HPV infection,
and is the area of interest when performing anal cancer
screening.25
HPV infection may occur in the anal canal of PLWHA in the
absence of ARI.37 Piketty et al documented the incidence
of HPV infection in MSW who were HIV-positive to be 46%,
compared to 85% in MSM who were HIV-infected.38
Human papillomavirus in women
Data from the Women’s Interagency HIV Study showed that
76% of women who were HIV-positive were found to have
anal HPV infection, as did 42% of high-risk women who were
HIV-negative, i.e. commercial sex workers (CSWs) and drug
injection users. Furthermore, anal HPV infection was more
common than cervical HPV infection in women who were
HIV-positive (79% vs. 53%) and high-risk women who were
HIV-negative (43% vs. 24%).34,39 High-grade AIN was reported
in 26% of women who were HIV-positive compared with 8%
of women who were HIV-negative.40 In Bronx County, USA,
3% of the USA HIV population live. Routine anal pap smear
screening is available for PLWHA. Seventy-five per cent of
the 715 women who are HIV-infected and who live there had
abnormal anal cytology. 10.5% had high-grade AIN.41 Apart
from the incidence of high-grade disease, the findings are
comparable to the previous study. HPV DNA is 2-3 times as
frequent in cervicovaginal lavage specimens, and 15 times
more common in anal-swab specimens from women who are
HIV-infected than from women who are not infected with HIV.42
HPV replicates exclusively in the nuclei of squamous cells. The
virus infects keratinocytes in the basal layer of the stratified
squamous epithelium. Viral gene expression leads to the
expression of six nonstructural viral regulatory proteins; E1,
E2, E4, E5, E6 and E7. E6 and E7 are viral oncoproteins that
inactivate p53 and pRb (retinoblastoma), respectively, cellular
tumour-suppressor proteins.20,26
The histopathological classification of anal intraepithelial
neoplasia (AIN) 1, 2 and 3 corresponds to cervical intraepithelial
neoplasia (CIN) 1, 2 and 3. Similar to cervical cancer, a newly
revised Bethesda System of cervical cytological classification
also applies to AIN.27 AIN 1 is thought to be a low-grade
squamous intraepithelial lesion, whereas AIN 2 and 3 are
high-grade squamous intraepithelial lesions (HSILs). Similar
to cervical cancer, treatment is recommended for HSIL anal
lesions.6
One of the greatest risks for anal HPV infection is a history of
ARI,43 a practice that has an estimated lifetime prevalence of
6-40% in heterosexual men and women,44 and is increasingly
being reported in present times.45 The risk of HIV transmission
is greater during unprotected ARI, than that of unprotected
vaginal receptive intercourse (VRI) because of the fact that
the rectal mucosa lacks a protective humoral immune
barrier that is present in cervicovaginal secretions, and is
Kreuter et al demonstrated that if left untreated, high-grade AIN
could progress to squamous cell cancer of the anus in as little
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more susceptible to traumatic abrasions that may facilitate
transmission. There is an approximately an 18-fold increased
risk of HIV transmission in women from unprotected ARI than
unprotected VRI.46
cytokines, e.g. interleukin-6, may modulate HPV gene
expression, and that the HIV Tat protein may potentiate the
expression of HPV E6 and E7 gene products, considered to be
crucial in inducing chromosomal instability.54
Although it is established that HPV infection can be transmitted
to women through ARI, alternative routes of transmission may
be possible.47 Moscicki et al demonstrated an association
between cervical disease and abnormal anal cytology, and
postulated that HPV may be a multisite infection.43 Sexual
practices other than sexual intercourse that involve the cervix
and anus may also be implicated.39 Another possibility is that
anal HPV infection may behave as a sexually transmitted
infection and an opportunistic infection in a person who is
HIV-infected.38
Sexual practices
Reliable data are lacking on the effect of the HIV epidemic
on the incidence of squamous cell cancer of the anus in
southern Africa. Public health authorities have long believed
that almost all cases of AIDS in African adults are attributed
to “heterosexual transmission”, a rubric tacitly understood
to refer to penile-vaginal intercourse.55 It has been assumed
that the impact of squamous cell cancer of the anus in Africa
would not be great because of the predominantly heterosexual
spread of HIV.56
Human papillomavirus and human immunodeficiency virus
However, this assumption is questionable. Firstly, sexual
orientation and sexual practices are issues that are not often
discussed openly in Africa. This may partly be because 40 of
Africa’s 53 countries have deemed homosexuality to be illegal
in various capacities,57 and equal protection under the law
remains a legal reality in only one African state, South Africa.58
Even in South Africa, there seems to be a disconnection
between the legally mandated protection in the constitution
and the daily life of MSM and lesbian women or women who
have sex with women.59,60
A USA study analysed the incidence of various cancer types
in 54 780 individuals who were HIV-positive in two large
prospective cohorts. The highest incidence rates of all nonAIDS-defining malignancies in this study were observed for
anal cancer, continuously increasing from 1992-2003. The
rate of anal cancer increased from 19 per 100 000 personyears to 78.2 per 100 000 person-years in recent times in the
HIV-positive population.48 More recent epidemiological studies
have confirmed similar findings.49
42.8% of female CSWs at truck stops between Durban and
Johannesburg admitted to having had ARI with their clients.61
The same researchers noted that 42% of South African truck
drivers reported a lifetime of anal intercourse.62 A recent study
from Kenya confirmed the high rate of ARI in female CSWs
(40.8%).63 Kalicham et al reported that 15% of heterosexual
men and 11% of heterosexual women who frequent alcoholserving venues (shebeens) in Cape Town had had anal
intercourse in the previous month.64 Studies have documented
a 98.7% incidence of ARI in street boys in Tanzania, even
though they do not regard themselves as MSM.65 A crosssectional study that was conducted on high school youth in
Addis Ababa, Ethiopia, illustrated that one in 20 youth were
involved in oral and anal sex practices.66 Similar results have
been reported in South Africa.67 The Soweto Men’s Study
indicated that 50% of South African MSM also had sex with
women.68 This finding has been validated in African MSM from
Malawi, Namibia and Botswana.69
A USA primary care HIV clinic that caters to a predominantly
heterosexual population found that 27% of persons who
were HIV-infected had high-grade AIN.50 These researchers
concluded that patients who are HIV-infected are at high risk
of high-grade AIN and squamous cell cancer of the anus,
irrespective of their sexual practices.50 AIN and squamous cell
cancer of the anus have recently been included as an indicator
condition to guide HIV testing in some studies.51
HPV is a common viral sexually transmitted disease that is
rapidly cleared. Only one per cent of patients develop genital
warts. Approximately 75% of sexually active adults acquire
one or more HPV types at some point in their lifetime. However,
most do not show clinical manifestations of the infection.25
Squamous cell cancer of the anus in PLWHA is thought to be
associated with persistent HPV infection.16
HIV may facilitate and increase HPV virulence, decreasing
the number of Langerhans cells in the anal mucosa.52
Intraepithelial Langerhans cells acts as antigen-presenting
cells for intraepithelial lymphocytes in the human anal
mucosa. The number of Langerhans cells in the anal mucosa
may increase during mucosal infection, in particular in HPVinfected tissue. HIV is associated with the dramatic failure of
Langerhans cells to increase in response to HPV, resulting in
the virus evading the immune system. This may explain why
PLWHA have more persistent HPV.53
These and other studies have prompted some authorities
to hypothesise that both homosexual and heterosexual anal
intercourse may be more prevalent in Africa than has been
traditionally assumed,55 and that the role they play in shaping
heterosexual HIV epidemics should not be underestimated.70
To this end, behavioural interventions aimed at heterosexual
populations should include anal intercourse as a target
behaviour for HIV transmission risk reduction.71
Also, the pattern of human sexual behaviour has been
changing, with changes in participant anatomy, risk behaviour,
Other hypotheses are that the HIV-induced expression of
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external devices, agents to enhance sexual performance and
the number of partners involved. Sexual partners are also
affected by one another’s sexual history. Therefore, men who
do not identify themselves as MSM and women may be at risk
of AIN and squamous cell cancer of the anus, especially if they
are infected with HIV.37
Given the recognised progression of HPV to cancer, despite
HAART, it is imperative that healthcare providers include a
closer examination of the perianal area on a regular basis.
It is believed that increased awareness of squamous cell
cancer of the anus in the setting of HIV/AIDS will lead to earlier
recognition and treatment, as well as improved outcome and
long-term survival.87
Human papillomavirus types
Opportunities for prevention
Over 20 oncogenic types of HPV have been identified. The most
common oncogenic HPV types are 16 and 18.22 HPV subtype 16
appears to be the most frequently associated with squamous
cell cancer of the anus, and is detected in approximately 70%
of cases in population-based studies from the developed
world.72 However, when comparing tissue specimens from
around the world, a statistically significant lower prevalence
of HPV type 16 is associated with squamous cell cancer of the
anus in South Africa. Only 10% of squamous cell cancer of the
anus specimens from the region demonstrated HPV 16 DNA.73
These findings have been confirmed by similar findings with
regard to HPV types involved in cervical cancer in southern
Africa.74 There may be other HPV types or variants of HPV 16
that are more prevalent in southern Africa.75
Screening
As PLWHA continue to live longer because of HAART and
prophylactic therapy, a rise in the incidence of squamous cell
cancer of the anus is expected. Therefore, better surveillance
and screening for AIN and squamous cell cancer of the anus
is required.31
The feasibility of screening for squamous cell cancer of the anus
using an anal Pap test has been researched extensively over the
past decade.6 At present, no direct evidence exists to support
the effectiveness of an anal Pap test screening programme in
reducing squamous cell cancer of the anus-associated mortality
or morbidity.88 However, based on expert opinion, some authors
have proposed anal Pap testing for at-risk groups.23,89,90 The
incidence and mortality of cervical cancer has decreased to 33%
of pre-Pap screening levels in countries where cervical screening
with Pap testing is routinely performed.91 Annual cervical Pap
smear screening in women who are HIV-infected in the USA
results in a 2.1-month gain in quality-adjusted life expectancy
for an incremental cost of $12 800 per quality-adjusted lifeyears (QALY) saved. Annual Pap screening after two negative
smears obtained six months apart provides an additional 0.04
QALYs at a cost of $14 800 per QALY saved.92
It is important to note that individuals who are HIV-infected are
more likely to harbour multiple HPV types.33,76
Highly active antiretroviral therapy and human
papillomavirus
In contrast to several virus-associated diseases, such
as human herpesvirus 8-associated Kaposi’s sarcoma,
Epstein Barr virus-associated non-Hodgkin’s lymphoma and
cytomegalovirus-associated retinitis, HAART seems to have
no beneficial effects on non-AIDS-defining cancers, such
as squamous cell cancer of the anus.6 Despite HAART, the
prevalence and incidence of AIN and squamous cell cancer of
the anus in individuals who are HIV-infected have increased.36
There is ongoing debate as to whether or not patients who are
at risk should be screened for AIN and squamous cell cancer
of the anus. Concerns are greatest for patients who are HIVpositive.41,93-95 If the natural history of anal disease does not
differ dramatically from that of the cervix, then protocols
developed for the treatment and follow-up of cervical disease
may be applied to the anal canal in high-risk individuals.
This would include using anal cytology to screen high-risk
individuals and performing colposcopic examinations of
patients with abnormal cytology.96
There was a significant increase in HPV-induced lesions,
including squamous cell cancer of the anus, in an analysis that
compared anal pathologies in patients who were HIV-infected
in the pre-HAART period and the HAART period. The authors
remarked that HPV-induced lesions did not seem to respond
to HAART, when compared to other malignancies.77 Many other
studies from around the world have also shown an increase in
the incidence of AIN and squamous cell cancer of the anus in the
HAART era.35,78-82 Current statistics also suggest that HAART has
not significantly altered the rate of HIV-related cervical cancer,83
and that anal and cervical cancer are not associated with lower
CD4+ levels.84 The contemporary consensus is that HAART
will probably not be associated with a reversal of high-grade
dysplasia since these lesions have already acquired irreversible
chromosomal alterations.85 Some reviewers propose that
the HAART is associated with prolonged survival, resulting in
an increased risk of non-AIDS-defining cancer.20,86 AIN and
squamous cell cancer of the anus could become a major public
health issue for this population in the future.28
South Afr J Infect Dis
In the USA, it has been established that screening MSM who
are HIV-positive every two years with anal cytology would offer
quality-adjusted life expectancy benefits at a cost per QALY
saved of $13 000, which is comparable to that for cervical
screening.97
The cost-effectiveness of screening women who are HIVinfected is not yet available.34 Sixty per cent of women who
were HIV-infected with high-grade AIN in a USA cohort did
not practise ARI. These investigators suggest that PLWHA,
regardless of sexual practices, should be screened for AIN and
squamous cell cancer of the anus.27,50
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while Cervarix® (GlaxoSmithKline, Rixensart, Belgium) protects
against HPV 16 and 18. Theoretically, if the HPV vaccine is
effective in preventing cervical HPV infection, it may also
prevent anal HPV infection.84
There are no South African or international AIN and squamous
cell cancer of the anus screening guidelines,98 and the benefits
of screening have not been established.99 However, authorities
in the field have proposed screening guidelines for specific
populations.50 The New York State Department of Health AIDS
Institute has adopted screening for individuals at high risk of
HPV infection, included MSM who are HIV-infected, females
with abnormal vaginal Pap smears and individuals with a
history of anogenital HPV infection.100
Given the challenges associated with treating HPV-associated
neoplasia and the increased risk of HPV-associated cancer
in PLWHA, HPV vaccination may be an important new
approach to reduce the risk of HPV-associated cancer in
this population.84,109,110 The major question is whether or not
preventative HPV vaccines will be safe and effective in PLWHA.84
One recent trial confirmed the safety and immunogenicity of
Gardasil® in persons who were HIV-infected.108
Anal Pap smear screening involves inserting a swab blindly
into the anal canal and rotating the swab on the anal mucosa
as the swab is removed. The obtained cells are either fixed
onto a slide, or in fluid for liquid cytological examination.
Abnormalities detected by anal Pap smears are further
evaluated by high-resolution anoscopy, which is similar to
cervical colposcopy.101 Anal cytology has a sensitivity and
specificity that is comparable with that of cervical cytology.93
The way forward
The incidence of AIN and squamous cell cancer of the anus in
southern Africa is presently unknown, and is a potential area
for future research.
Dysplasia may not be confined to the anal canal in PLWHA.
Therefore, evaluation should include examination of the perianal
area, perineum and genitalia, including the inguinal nodes.27
A routine examination of the anal canal in this population is
recommended.87,102 It seems that there is a need to educate
clinicians about screening for anal symptoms in PLWHA.98
While a review of two African cancer registries in the preHAART era111,112 did not identify an increased incidence of
squamous cell cancer of the anus, with the availability of
HAART, there is potential for an increase in the incidence
of squamous cell cancer of the anus. This is reflected by
various studies from the developed world. If HAART results
in an increase in the incidence of squamous cell cancer of
the anus in southern Africa, the added burden of diagnosing
and treating this condition will further strain the public health
system where the majority of PLWHA access their healthcare
services.
There is controversy surrounding the management of
squamous cell cancer of the anus and its precursor lesions in
PLWHA. This is beyond the scope of this review.
Cervical HPV DNA testing is increasingly being used in
screening protocols for cervical cancer because of its greater
sensitivity in detecting CIN.103 At present, HPV DNA testing has
not been incorporated into any proposed screening or clinical
management algorithms for anal cancer precursors. HPV
DNA testing is not recommended as a primary anal cancer
screening test, as an adjunct to anal cytology, or as a reflex
test for atypical squamous cells on anal cytology.104
The possibility of screening for this condition and its precursor
lesions, especially in PLWHA, needs to be evaluated, as this will
impact on present guidelines employed in the management of
PLWHA.
A routine perianal and digital rectal examination, together with
a history of ARI and anal symptoms, is advocated for PLWHA. If
abnormalities are identified, then PLWHA should be referred to
a surgeon or clinician who is familiar with perianal pathology
for further investigation and management.
Vaccination
The World Health Organization recognises the importance
of cervical cancer and other HPV-related diseases as global
public health problems, and recommends that routine HPV
vaccination should be included in national immunisation
programmes. This is provided that the prevention of cervical
cancer or other HPV-related diseases constitutes a public
health priority.105 In the USA, the Centers for Disease Control
and Prevention recommends HPV vaccination in girls aged 1326 years and in boys aged 13-21 years.106 In February 2014,
the South African Department of Health and the Department
of Basic Education plan to administer HPV vaccines to 9- and
10-year-old girls in underprivileged schools in South Africa as
part of a school health programme.107
The present cost of HPV vaccines is arguably high to
be realistically considered in southern Africa. If the
pharmaceutical industry can be petitioned to reduce the cost
of these vaccines, as was achieved with HAART, then their use
could be considered.113 However, it is believed that the present
vaccines will have a limited impact in southern Africa because
of the different oncogenic HPV types in the region.
Perhaps an operative long-term strategy for the prevention
of HPV-related diseases would be the development of a costeffective, oncologically relevant vaccine for the region.
Funding
Two HPV preventive vaccines are licensed for the prevention
of cervical cancer.108 Gardasil® (Merck and Co, Whitehouse
Station, USA) protects against HPV types 6, 11, 16 and 18,
South Afr J Infect Dis
The author personally funded this review article.
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2014;29(1)
Review: Anal human papillomavirus and anal squamous cell cancer
Conflict of interest
incidence of anal cancer. JAMA. 1982;247(14):1988-1990.
31. Barnardt P. Non-diagnostic Aids-associated malignant neoplasm. S Afr J HIV Med.
2007:11-4.
The author declares no conflict of interest.
32. Mbulaiteye SM, Parkin DM, Rabkin CS. Epidemiology of AIDS-related malignancies an
international perspective. Hematol Oncol Clin North Am. 2003;17(3):673-966.
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Please note that, for reference/citation purposes:
Southern African Journal of Epidemiology and Infection (South Afr J Epidemiol Infect) (ISSN 1015-8782) has now officially changed to:
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For 2014 DHET subsidy applications, please use the following reference:
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