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Disease Markers 23 (2007) 213–227 213
IOS Press
The epidemiology of human papillomavirus
infection and cervical cancer
F. Xavier Bosch and Silvia de Sanjos ´
e
Institut Catal`
a d’Oncologia, Epidemiology and Cancer Registration Unit, Av. Gran Via, s/n Km. 2,7, E-08907
L’Hospitalet de Llobregat, Barcelona, Spain
Tel.: +34 93 2607812; Fax: +34 93 2607787; E-mail: x.bosch@ico.scs.es
Abstract. Cervical cancer has been recognized as a rare outcome of a common Sexually Transmitted Infection (STI). The
etiologic association is restricted to a limited number of viral types of the family of the Human Papillomaviruses (HPVs). The
association is causal in nature and under optimal testing systems, HPV DNA can be identified in all specimens of invasive
cervical cancer. As a consequence, it has been claimed that HPV infection is a necessary cause of cervical cancer. The evidence
is consistent worldwide and implies both the Squamous Cell Carcinomas (SCC), the adenocarcinomas and the vast majority
(i.e. >95%) of the immediate precursors, namely High Grade Squamous Intraepithelial Lesions (HSIL)/Cervical Intraepithelial
Neoplasia 3 (CIN3)/Carcinoma in situ. Co-factors that modify the risk among HPV DNA positive women include the use of oral
contraceptives (OC) for five or more years, smoking, high parity (five or more full term pregnancies) and previous exposure to
other sexually transmitted diseases such as Chlamydia Trachomatis (CT) and Herpes Simplex Virus type 2 (HSV-2). Women
exposed to the Human Immunodeficiency Virus (HIV) are at high risk for HPV infection, HPVDNA persistency and progression
of HPV lesions to cervical cancer.
Keywords: Cervical cancer, human papillomavirus, HPV, epidemiology
1. Epidemiology of human papillomavirus
infections and cervical cancer
HPV infections of the cervix and the epidemiology
of cervical cancer in relation to HPV are being investi-
gated using as markers of exposure the presenceof viral
DNA in cellular scrapes or in biopsy tissue. Early DNA
detection methods lead to the hypothesisthat there was
an association between cervical cancer and HPV expo-
sure, however the development of Polymerase Chain
Reaction (PCR) and other amplification techniques al-
lowed an accurate assessment of the presence of viral
DNA in cervical specimens as well as a quantification
of the strength of the association down to the level of
HPV type and of variants of the main types. Serolog-
ical tests to detect antibodies to HPV antigens follow-
ing natural infections are still in evaluation phase for
large epidemiological studies. Natural HPV infections
only trigger a measurable antibody response under spe-
cial situations, resulting in significant under-detection.
In contrast antibody response to current HPV vaccines
based on pseudo viral like particles (VLPs) from the L1
genomic region of type specific HPVs is universal and
antibody titers are several fold (up to 40-fold) higher
that antibody titers following natural infection. There-
fore, most of the epidemiology of HPV and cervical
cancer is largely based on DNA detection techniques of
which most of the studies included in this review have
used either the clinically validated Hybrid Capture 2
method (HC2) or some of the internationally validated
PCR-based systems [1].
1.1. Prevalence of human papillomavirus DNA. The
international perspective
The prevalence of HPV DNA in cervical specimens
from the general population and from samples of wom-
en with normal cytology has been reported. The vari-
ability of results is considerable and relates to the se-
lection of women included in the surveys (i.e. proba-
ISSN 0278-0240/07/$17.00 2007 – IOS Press and the authors. All rights reserved
214 F.X. Bosch and S. de Sanjos´
e / The epidemiology of human papillomavirus infection and cervical cancer
bilistic samples of the population, women in screen-
ing programs and opportunistic series from clinical set-
tings) and to the testing systems employed. Two recent
sources have provided estimates that may reflect the
global prevalence, the age-specific prevalence and the
type-specific prevalenceas well as an approximation to
describing the international variability. In a multicen-
tric and centrally coordinated international study, the
International Agency for Research on Cancer (IARC)
provided data from 15 areas in four continents among
women 15–74 year old. The point age standardized
prevalencewas10.5 (95%CI 9.9–11.0)andranged from
a low end (less than 5%) in Mediterranean countries
and in some countries in South East Asia to a high
end (greater than 15%) in several countries in Latin
America and in a few populations in Africa) [2].
The second source is a comprehensive review of the
literature that used standardized criteria for study inclu-
sion and statistical analyses that adjusted the estimates
for the variables were influential in the comparability
of studies. In this review, the estimates of the popu-
lation prevalence worldwide (all ages) among women
with normal cytology was of 10.41% with a 95%CI
10.2–10.7. The age specific prevalence showed higher
proportions among the young age groups, a decline in
the young adults and a variable pattern afterwards. In
most countries, notably in the Americas, the prevalence
increased again in the post-menopausal age groups. In
Europe, the same pattern in the 40+age group is main-
tained in most surveys whereas in other high prevalence
countries in Asia the HPV DNA prevalence remained
fairly constant across all age groups [de Sanjose et al. in
press]. Figure 1 shows the summary of the age-specific
HPV DNA prevalencein women with normal cytology
in a model that compiled data from close to 140,000
women reported in 67 studies from Africa (7 studies),
America (17 studies), Europe (27 studies) and Asia (16
studies). The reason for the second increase in the HPV
detection rate in the old age groups is unclear. The
consistency of the finding in many individual studies
in countries with substantial variability in sexual be-
haviour would indicate that the observation translates
biological changes related to menopause-hormonal and
immunological status that would facilitate HPV DNA
detection from exposures earlier in life that remained
silent/undetectable for a number of years. However,
individual cohort studies and sexual behaviour surveys
also indicate that additional number of new sexual part-
ners habits in middle age and above might partially ex-
plainthe second peakof genuineincident infections [3].
The HPV type-specific prevalence of the five most
common HPV types in women with normal cytologyis
show in Fig. 2. HPV 16 is identified in 2.25% of wom-
en (25.5% of positives) followed by HPV 18 (0.8%),
31 (0.8%), 58 (0.7%) and 52 (0.6%). This distribution
reflects the biological advantage of HPVs 16 and 18
for persistency. The 33% relative proportion afforded
by HPVs 16 and 18 combined in women with normal
cytology is in contrast with the 70% relative frequency
of these two viral types observed in invasive cervical
cancer and translates the biological advantage for pro-
gression of HPV 16 and 18 also observed in several
natural history studies [4].
1.2. Behavioural determinants of human
papillomavirus infection
Several groups of studies have clearly shown that
HPV is predominantly and largely transmitted through
sexual intercourse. Other forms of transmission have
been occasionally described, but its implication in cer-
vical cancer is likely to be marginal, if any.
Epidemiological studies investigatingrisk factors for
HPV infection clearly and consistently have shown that
the key determinants among women are the number
of sexual partners, the age at which sexual intercourse
was initiated and the likelihood that at least one of her
sexual partners was an HPV carrier as measured by his
sexual behaviour traits [5]. The role of males as possi-
ble vectors of HPV was measured in the early epidemi-
ological studies by questionnaires that addressed the
sexual behaviour of the husbands or sexual partners of
cervical cancer cases and controls. More recent studies
had, in addition, the ability to measure HPV DNA in
exfoliated cells from the penile shaft, the coronal sulcus
and from the distal urethra [6].
Case-control studies have established that the risk of
cervical cancer for a given woman is predictable by the
sexual behaviour of her husband as much as for her
own sexual behaviour. In populations where female
monogamy is dominant, the population of female sex
workers plays an important role in the maintenance
and transmission of HPV infections. Moreover, the
probability that a woman is an HPV carrier and her
risk of developing cervical cancer have been shown to
be related to the presence of HPV DNA in the penis
or the urethra of her husband or sexual partner. These
observations confirmed in terms of HPV infections a
scientific hypothesis formulated almost 30 years ago
that male sexual behaviour is a central determinant of
the incidence of cervical cancer [7].
Studies on virgins offer a unique opportunity to
demonstrate the predominantly sexual nature of HPV
F.X. Bosch and S. de Sanjos´
e / The epidemiology of human papillomavirus infection and cervical cancer 215
HPV Prevalence
Age
24,9
17,7
16,3
13,2 11,7 10,2 8,9 8,8 8,8 7,5
10,2
0
5
10
15
20
25
30
<20 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65+
(De Sanjose et al in preparation)
Fig. 1. World-wide age-specific HPV-DNA prevalence among women from the general population.
Source: Meta-analysis of 38 studies
0.56
0.73
0.81
0.76
2.25
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
PREVALENCE
RELATIVE PROPORTION AMONG HPV POSITIVE (%)
Others (50.8)
HPV 52 (4.5)
HPV 58 (5.6)
HPV 31 (6. 1)
HPV 18 (7.5)
HPV 16
(25.5)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
HPV 16 HPV 18 HPV 31 HPV 58 HPV 52
HPV: Human Papillomavirus
(%)
Fig. 2. Overall HPV type specific prevalence & relative proportion of the 5 most common types among HPV positive women with normal
cytology.
transmission. Prevalence estimates of high risk HPV
DNA infection from early studies in virgins range from
0% to 31%. The wide range of these estimates indi-
cates the influence of methodological issues including
the sampling method used (scrapes vs. lavage), the sub-
site from which the samples were collected (cervical,
vaginal or vulvar) and the HPV DNA detection method
used. Variables of significant interest include the sen-
sitivity of the test, the number of HPV types used in the
testing system and the protocols followed to classify
the HPV negative specimens and the HPV of unknown
nature usually classed as HPV X. As HPV testing vari-
ability was better understood, several studies in which
identical sampling methods were taken from all women
216 F.X. Bosch and S. de Sanjos´
e / The epidemiology of human papillomavirus infection and cervical cancer
in a closed cohort and in which HPV DNA was reli-
ably measured, concluded that HPV DNA in cervical
specimens is only detected in the sexually experienced
women [5,8].
A longitudinal study of virgins who started sexual
activity during the study period in a Danish population-
based cohort study of 100 virgins and 105 monoga-
mous women showed that all women who stayed vir-
ginal throughout follow-up were consistently negative
for both HPV DNA and HPV 16 serum antibodies at
enrolment and at each follow-up visit. Only a fraction
of those virgins who initiated sexual activity became
positive for HPV DNA or HPV 16 serum antibodies.
The most important determinant of HPV DNA acquisi-
tion in this study was the number of sexual partners the
woman had had between enrolment and the follow-up
visit, both among initially virginal women and among
initially monogamous women [5]. In this study, detec-
tion of HPV 16 serum antibodies and development of
cervical lesions occurred only after HPV transmission,
suggesting that sexual intercourse is a necessary step in
the acquisition of genital HPVs and in the development
of the early stages of cervical neoplasia. A prospec-
tive study including 105 HPV-negative women carried
out in the San Francisco bay area found that sexual
behaviour, specifically exposure to new partners, rep-
resented the strongest risk factor for incident HPV in-
fection. The association between sexual behaviour and
incident HPV was quite notable, as the risk increased
nearly 10-fold for each new partner per month reported.
Many epidemiological studies have consistently
shown that sexual behaviour-related characteristics of
the individual and his or her partners are the most im-
portant risk factors for the acquisition of genital HPV
types. The relationship between number of partners
and age at first intercourse with the corresponding de-
tection of cervical and penile HPV DNA in adult wom-
en and men was examined among the controls (2,225
women and 1,140 men) of a series of 12 case-control
studies of cervical cancer carried out by the IARC in 10
countries: Algeria , Brazil, Colombia, India, Morocco,
Paraguay, Peru, Spain, Thailand and the Philippines.
The study showed that, in both sexes, genital HPV
DNA detection increased significantly with increasing
lifetime number of sexual partners and with decreasing
age at first sexual intercourse [7,8].
HPV data on social groups known to have or have
had a high risk sexual behaviour, such as female sex
workers and of attendees of STDs clinics have provided
further evidence that HPVs are predominantly sexually
transmitted. Two studies conducted in Spain and Den-
mark compared HPV DNA prevalence among women
from the general population and women belonging to
high-risk groups In all age groups, HPV prevalence was
highest among female sex workers, followed by women
attending STDs clinics or incarcerated. Women from
the general population had much lower age-specific
HPV prevalence rates [9,10].
1.3. The role of male in the transmission of human
papillomavirus and the risk of cervical cancer
Afterthe identification ofHPVs asthe sexually trans-
mitted agents etiologically linked to cervical cancer,
firm evidence for a roleof men as carriers and vectors of
oncogenic HPVs resulted from studies that introduced
HPV DNA detection in penile samples. However, stud-
ies in males are limited because of lack of standard-
ization of the methods to obtain cells from the male
external genitalia. The largest study to date explor-
ing the male role in cervical carcinogenesis using PCR
technology for the detection of penile HPV is the mul-
ticentric case-control study coordinated by the IARC.
This large study involved over 1,900couples that were
enrolled in one of seven case-control studies of cervi-
cal carcinoma in situ and cervical cancer carried out
in Brazil, Colombia, The Philippines, Spain and Thai-
land [7,8,11]. Participating men answered a detailed
risk-factor questionnaire and provided a specimen of
exfoliated cells from the distal urethra, the glans and
the coronal sulcus for HPV DNA detection.
Figure 3 shows the correlation between penile HPV
DNA and the sexual behaviour of the couple for sub-
jects enrolled in the studies conducted in Colombia [8]
and Spain [7]. Penile HPV prevalence clearly increased
with increasing numbers of sexual partners the men re-
ported had had. The increase was observed in male
partners of both monogamous and non-monogamous
women and penile HPV prevalence was systematically
higher in husbands of non-monogamous women than
in husbands of monogamous women [6].
Findings from the IARC studies conducted in low- to
intermediate-risk countries suchas Spain, Thailand and
the Philippines, indicate that the men’s lifetime number
of sexual partners and reporting sex workers as sexual
partners are key determinants of cervical cancer risk in
their wives. In Spain, the presence of HPV DNA in
the husband’s penis conveyed a 5-fold increased risk
of cervical cancer to their wives. The odds of cervi-
cal cancer among monogamous women increased up
to 9 to 10 fold in relation to the presence of high-risk
HPV types in the penis of their husbands. The ex-
F.X. Bosch and S. de Sanjos´
e / The epidemiology of human papillomavirus infection and cervical cancer 217
Source of data: Adapted from reference: IARC, 2005 [18]. Includes 595 men that were husbands or stable coital partners ofwomen
with and without cervical cancer.
0
5
10
15
20
25
30
1-5 6-20 >20 1-5 6-20 >20
27.7%
10.7%
24.5%
18.6%
15.7%
2.1%
HUSBAND S OF
NON-MONOGAMOUS WIVES HUSBAND S OF
MONOGAMO US WIVES
Husbands number of sexual partners
Penile HPV-DNA
Prevalence (%)
Fig. 3. Penile Human Papillomavirus DNA prevalence by number of sexual partners of husbands of monogamous and non-monogamous women
in Spain and Colombia.
Number of partners
0
1
2
3
4
5
6
-5 -20 20+
SPAIN
-5 -20 20+
COLOMBIA
Source of data: Adapted from reference: Muñoz N, et al., 1996 [8]
Fig. 4. Husband’s lifetime number of partners and risk of cervical cancer among wives in a low risk (Spain) and a high risk country (Colombia).
cess risk associated with HPV type 16 was 6 to 9 fold.
Furthermore, the prevalence of penile HPV showed a
positive trend with increasing number of sexual part-
ners and with the number of sexual partners who were
sex workers [7]. In contrast, in high-risk countries
such as Colombia and Brazil, no associations with cer-
vical cancer risk were found with penile HPV DNA
or with any other indicators of male sexual behaviour
(Fig. 4) [8]. The lack of association between most male
sexual behaviour-related variables and cervical cancer
risk found in high-risk countries could be explained
by the hypothesis that, in these populations, HPV is
a widespread infection that it reduces the ability of
case-control studies to discriminate subjects at a higher
risk. Cross-sectional HPV DNA detection in the penis
of adult men, even if high, is still a poor reflection of
lifetime exposure to HPV. Other biological markers of
lifetime sexual promiscuity in men such as seroposi-
tivity to Chlamydia Trachomatis(CT) are more consis-
tent in discriminating women at a high-risk of cervical
218 F.X. Bosch and S. de Sanjos´
e / The epidemiology of human papillomavirus infection and cervical cancer
cancer in relation to the behaviourof their male sexual
partners [12].
The clinical implications of recognizing the role of
men as occasional carries of HPV DNA and of sub-
clinical lesions that are source and routes of HPV trans-
mission are still under evaluation. In some instances,
careful examination of the male external genitalia of
sexual partners of women with HPV DNA or CIN le-
sions unveils minute lesions amenable to treatment.
These examinations, usually called penoscopy or geni-
toscopy, include observations under a colposcopic lens
of the external genitalia including the scrotum and peri-
anal regions, with or without acetic acid preparation. It
is generally accepted that HPV visible lesions in men
should be treated, howeverthe lack of specific antiviral
treatment detracts from recommendations of systemat-
ic examinations and additional diagnostic procedures
and eventual treatments of male partners. Some litera-
ture is available indicating that the systematic and reg-
ular use of condoms accelerates regression of male and
female lesions as well as of HPV DNA clearance [13].
Studies that have addressed concordance of genital
HPVs in heterosexual couples found a relatively poor
correlation of HPV positivity and HPV type in cervical
and penile samples [6]. This is particularly important
in the interpretation of case-control studies in which
women harbours cervical neoplasia, thus a long-term
consistent carrier of type-specific HPV-DNA whereas
the husband is, or has been, a transient HPV DNA carri-
er. Moreover, in some couples, the current partner may
not be the relevant one in determining the woman’s risk
of HPV persistence and progression to cervical neopla-
sia. Agreement in HPV findings, however, was also
modest in couples where both – wife and husband –
reported only one lifetime sexual partner [14]. Among
women with cervical neoplasia, the relevant infection
may have occurred years earlier, and the relatively low
prevalence of penile HPV infection in their husbands
suggests that viral shedding of advanced cervical le-
sions is limited. Also cross-sectional detection of pe-
nile HPV may measure relatively recent exposures to
HPVs that may be unrelated to the initiation of cervical
neoplasia in the partner. Finally, the low agreement
may be partly due to technical reasons, since a small-
er amount of penile exfoliated cells may be obtained
in men relative to the cellular yield obtained from the
cervix.
The IARC multicentric study on male circumcision
and its association with cervical cancer compared pe-
nile HPV DNA prevalence in circumcised and uncir-
cumcised men and estimated the woman’s risk of cer-
vical cancer according to the husband’s circumcision
status. The study found that circumcised men were
about 3 times less likely to harbour HPV in their pe-
nis than uncircumcised men. Male circumcision also
reduced the risk of both genital HPV DNA prevalence
and cervical cancer in the female partner, particularly
and most strongly, in women whose male consorts had
had a promiscuous sexual history [11]. Further, the
protection afforded bymale circumcision also refers to
the seroprevalence of CT [15]. These findings, along
with the literature on HIV transmission, also indicating
a strong protection of circumcised men against HIV
carriage and transmission, underline the relevance of
circumcision for the prevention of STIs including HPV.
Transmission of genital warts, largely due to HPV 6
and 11 occurs during sexual intercourse with and in-
fected partner. The infection is highly prevalent, with
estimates of point prevalence around 1% the sexually
active population with cumulative exposure of 17% in
the age range 20 of 29% [16]. Risk factors have been
clearly linked to the number of sexual partners and in-
fectivity is high with transmission rates estimates of
60% 65% [17]. Genital warts do not convey high-risk
of cervical cancer but HPV 6 and 11 have occasionally
been related to rare forms of vulvar verrucous carcino-
mas of the Buschke-Lowestein type.
1.4. Other routes of transmission of human
papillomavirus. Recurrent respiratory
papillomatosis
Despite the overwhelming evidence that genital
HPVs are predominantly sexually transmitted, some
clinical and epidemiological observations have docu-
mentedthat genital HPVscan alsobe transmittedin oth-
er ways, especially from mother to child. This is con-
sistent with other microbial and viral infections which
are predominantly or exclusively sexually transmitted
in adults (e.g., HIV, Hepatitis B Virus (HBV), HSV-2,
CT, Treponema Pallidum (TP) and Neisseria Gonor-
rhoea (NG)) and that may be transmitted to newborns
if present in the genital tract of a woman during preg-
nancy or at the time of delivery. The evidence for the
non-sexual transmission of HPVs has been reviewed
by several authors concludingthat: 1) Genital HPV in-
fections, including genital warts, may occur in sexually
na¨
ıve populations such as virgins,infants, and children;
2) There is some evidence of horizontal transmission of
low-risk HPVs; 3) Vertical and perinatal transmission
of HPVs from mother to child, does exist, although
rates are small and vary widely; 4) High-risk genital
F.X. Bosch and S. de Sanjos´
e / The epidemiology of human papillomavirus infection and cervical cancer 219
HPVs have been detected in non-genital mucosa, such
as that in the mouth, oropharynx and conjunctiva, and
they have been associated with a fraction of cancers of
the oral cavity and oropharynx and with conjunctival
SCC.
HPV transmission from the genital tract to the upper
respiratory was first suggested in1956, in a case report
of a male child who was born to a mother with condylo-
ma that developed symptomsof laryngeal papillomato-
sis and penile warts at 3 and 6 months after birth. Re-
current laryngeal papillomatosis is a rare, potentially
life-threatening condition, associated with HPV types
6 and 11, the HPV types most commonly detected in
genital warts. The disease can disseminate through the
tracheobronchial tree and progress to pulmonarypapil-
lomatosis and subsequent fatal chest infection. Since
the disease has a bimodal age distribution with the first
peak occurring in infancy, it has been postulated that
juvenile papillomatosis may be related to HPV infec-
tion acquired from a mother with genital warts or a sub-
clinical HPV infection. A study showed that the risk of
the juvenile form of laryngeal papillomatosis appeared
to be highest in first-born infants delivered vaginally
to an adolescent mother. In contrast, the risk factors
identified for the adult onset of the disease included
lifetime number of sex partners and high frequency of
oral sex, suggesting orogenital transmission [18].
A number of other case report series have indicat-
ed the possible non-sexual horizontal transmission of
HPVs, particularly of the low-risk HPV types. HPV
DNA was detected in finger brush samples of 3 out
of 8 women (one with the same types) with cervical
HPV, and in 9 out of 13 men (5 with the same types)
with penile HPV. In total, 27% of patients had the same
HPV types detected in both genital and hand samples.
These findings raise the possibility that patients with
genital warts may transfer not only genital HPVs to
their sexual partners by finger-genital contact but al-
so horizontally to their children. Finger-conjunctiva
HPV transmission has been suggested by studies re-
porting presence of HPV DNA, predominantly type 16,
in human ocular surface squamous neoplasias, includ-
ing conjunctival carcinomas. Indirect transmission via
HPV-contaminated fomites (clothing, sheets, towels,
objects, and instruments) has also been suggested by
some studies, but its impact in passing and inducing
active infections is most likely small if any [18]. Al-
though HPV DNA has been occasionally isolated from
medical instruments or in the event of medical exami-
nations or treatments (i.e. at the time of laser ablation
of CIN lesions in the vaporization fumes), there is at
present no evidence that the isolated viral DNA is able
to initiate an infection of the patient, her partner or the
care taker.
2. Human papillomavirus and cervical neoplastic
lesions
The evidence relating HPV infections to cervical
cancer includes a large and consistent body of stud-
ies indicating a strong and specific role of the viral in-
fection in all settings where investigations have taken
place. The association has been recognized as causal
in nature by a number of international review parties
since the early 90’s [19,20].
2.1. Human papillomavirus DNA prevalence in
cervical cancer specimens
State-of-the art amplification techniques used in
case-controlstudies, case-seriesand prevalencesurveys
have unequivocally shown that, in adequate specimens
of cervical cancer, HPV DNA can be detected in 90
to 100% of the cases. Figure 5 shows the prevalence
of HPV DNA in specimens of invasive cervical can-
cer identified in six regions of the world and investi-
gated using PCR technology in a common centralized
research laboratory. Allowing for the sampling and
testing variability, these results are consistent with a
universal presence of these viral markers in established
cancerous lesions. The prevalence applies equally to
the most common SCC and to the rarer adenocarcino-
ma, although the HPV type distribution in these two
histological forms varies slightly. Further, detailed in-
vestigations of the few cervical cancer specimens that
appear as HPV DNA negatives in most series has been
occasionally conducted and the results strongly sug-
gest that these are largely false negatives. As a conse-
quence, the claim has been made that this is the first
necessary cause of a human cancer ever identified, pro-
viding a strong rationale for the use of HPV tests in
screening programs and for the development of HPV
vaccines [21,22].
2.2. Human papillomavirus types involved in cervical
cancer and pre-cancerous lesions
Of the more than 35 HPV types found in the gen-
ital tract, HPV 16 accounts for some 50% to 60% of
the cervical cancer cases in most countries, followed
by HPV 18: 10–20%, HPV 45: 4–8% and HPV 31:
220 F.X. Bosch and S. de Sanjos´
e / The epidemiology of human papillomavirus infection and cervical cancer
0 102030405060708090100
AFRICA
Sub-Saharan
Northern
C-S. AMERICA
S. ASIA
EUROPE / N. AMERICA
TOTAL
Carcinoma
squamous-cell
(N=2281)
adenocarcinoma/
mixed
(N=196)
0 102030405060708090100
AFRICA
Sub-Saharan
Northern
C-S. AMERICA
S. ASIA
EUROPE / N. AMERICA
TOTAL
Carcinoma
squamous-cell
(N=2281)
adenocarcinoma/
mixed
(N=196)
Sources: Muñoz N, et al., 2003 [27]
Castellsagué X, et al., 2006 [23]
HPV prevalence (%)
Fig. 5. HVP DNA prevalence in cervical cancer by study region and histology.
020406080
100
16
18
45
31
33
52
58
35
59
56
51
39
68
73
82
Other
53.5%
70.7%
77.4%
80.3%
82.9%
85.2%
87.4%
88.8%
90.1%
91.3%
92.3%
93.0%
93.6%
94.1%
94.4%
100%
Cumulative proportion
Source of data: Adapted from reference: Muñoz, N et al., 2004 [26]
Fig. 6. Relative contribution of HPV types to cervical cancer: All world regions combined.
1–5%. Figure 6 [23] shows the cumulative distribution
of 15 HPV types in a series of close to 3,000 cervical
cancer cases. Of these, the 5 most common (HPVs 16,
18, 45, 31 and 33) account for 80% of the distribution
in squamous cell cancers and of 94% in adenocarcino-
mas. In most studies, HPV 18 predominates in adeno-
carcinomas in absolute or relative terms. The reasons
for such specificity are unknown.
The positive selection of HPV 16 in cervical can-
cer cases across the cervical neoplastic spectrum trans-
lates the biological advantage of this type in fully ex-
pressing its oncogenic capacity. A study among wom-
en with different degrees of HIV induced immunosup-
pression pointed at the likely increased ability of HPV
16 to escape immunesurveillance as compared to other
HPV types as one possible mechanism of such advan-
tage [24].
Table 1 compares the HPV type distribution in cer-
vical cancer in the pre-neoplastic precursor lesions
HSIL/CIN 2/3 and in women with normal cytology in
the published meta-analyses of the literature. The ta-
ble shows that HPVs 16, 18 and 45 are the only viral
types that are more frequently found in the invasive
form of neoplasia than in the precursor lesions. These
F.X. Bosch and S. de Sanjos´
e / The epidemiology of human papillomavirus infection and cervical cancer 221
Table 1
Comparison of overall and type-specific HPV prevalence between Squamous Cell
Carcinoma (SCC), High Squamous Intraepithelial Lesion (HSIL) cases and women
with normal cytology
A summary of literature reviews
HPV SCC (1) HSIL (1) NORMAL CYTOLOGY (2)
TYPE n HPV (%) n HPV (%) n women tested HPV+%
ALL 8550 87.6 4338 84.2 5.764 10.41
16 8594 54.3 4338 45.0 4.385 2.25
18 8502 12.6 4338 7.1 4.286 0.76
33 8449 4.3 4302 7.2 4.136 0.52
45 5174 4.2 2214 2.3 3.554 0.42
31 7204 4.2 4036 8.8 4.157 0.81
58 5646 3.0 2175 6.9 4.155 0.73
52 5304 2.5 2153 5.2 3.927 0.56
HPV: Human Papillomavirus.
SCC: Squamous Cell Carcinoma.
HSIL: High Squamous Intraepithelial Lesion.
Sources of data: Adapted from reference: (1) G.M. Clifford et al. [25]; (2) S. de
Sanjose et al. (in press).
findings are interpreted as if the ability to progress was
increased in HSIL lesions due to these three HPV types
than the corresponding lesions attributed to other HPV
types [25]. These results are consistent with some ob-
servations from cohort studies indicating that the prob-
ability or progression givenpersistence is significantly
higher in women exposed to HPVs 16 or 18 that to any
other viral types [4].
The distribution of HPV types in cervical cancer in
five different regions in the world is described in Ta-
ble 2 [26]. It is clear that HPVs 16 and 18 are consis-
tently the first two types involved in all regions explored
so far. HPV 45 seems to be a natural candidate for
the third ranking place and some additional variability
exists thereafter for the relatively rarer HPV types.
2.3. Risk estimates from case control studies
Observations on pre-invasive disease and cohort
studies on the HPV natural history have intrinsic limita-
tions for making inferences on cervical cancer causal-
ity. This is because in controlled settings, biologi-
cal progression is not allowed to continue beyond the
stage of high-grade squamous intraepithelial lesions
(HSIL/CIN 3) or carcinoma in situ. It is thus of impor-
tance to notice that the information applicable to cer-
vical cancer would primarily come from case control
studies in which the target disease is directly investi-
gated.
In an effort to simplifythe vast literature of case con-
trol studies, the results of the IARC multicenter case
control study on invasive cervical cancer will be used
as example. In brief, this project included nine case-
control studies in different parts ofthe world, mostly in
high-risk countries. A common protocol and question-
naire were used, and HPV DNA testing was done in two
central research laboratories using the MYO9/11 and
the General Primer (GP) GP5+/6+PCR testing sys-
tems. Figure 7 shows the summary results on the HPV
DNA prevalence in case and control specimens, the risk
estimates and their confidence intervals for SCC. The
figure shows very high Odds Ratios (ORs) with esti-
mates in the range of 50 to 150 with several estimates
in the several hundred range. These risk estimates lead
to calculations of attributable fractions in the range of
90 to 95% [27].
The results are strikingly consistent in the literature
for pre-invasive lesions, for SCC and adenocarcinomas
and for studies that tested for HPV DNA as a group or
studies that restricted the analyses to HR HPV types.
Studies that have compared risk factors for CIN 3 and
invasive cancer have not reported any significant dif-
ferences in their associations with HPV or with their
epidemiological profile (reviewed in [19]).
The pool of IARC studies was large enough to pro-
vide type-specific risk estimates for 18 types. Restrict-
ing the analyses to the studies that used the GP5+/6+
HPV detection system and to SCCs, the adjusted OR
for HPV DNA detection (the factor by which the refer-
ence risk of cervical cancer is multiplied if HPV DNA
is detected) was OR =158.2 (95% Confidence Interval
(CI) =113.2–220.6). The risk estimates for adenocar-
cinomas was OR =81.3 (95% CI =42.0–157.1) [23].
Type specific risk estimates for squamous cell cancer
are shown in Fig. 8 and were as follows: HPV 16:
OR =435; HPV 18: OR =248; HPV 45: OR =198;
222 F.X. Bosch and S. de Sanjos´
e / The epidemiology of human papillomavirus infection and cervical cancer
Table 2
Prevalence of the most common HPV types in cervical cancer by region
Sub-Saharan Northern Central-South South Asia Europe &
Africa Africa America North America
HPV type % HPV type % HPV type % HPV type % HPV type %
HPV 16 47.7 HPV 16 67.6 HPV 16 57.0 HPV 16 52.5 HPV 16 69.7
HPV 18 19.1 HPV 18 17.0 HPV 18 12.6 HPV 18 25.7 HPV 18 14.6
HPV 45 15.0 HPV 45 5.6 HPV 31 7.4 HPV 45 7.9 HPV 45 9.0
HPV 33 3.2 HPV 33 4.0 HPV 45 6.8 HPV 52 3.1 HPV 31 4.5
HPV 58 3.2 HPV 31 3.4 HPV 33 4.3 HPV 58 3.0 HPV 56 2.2
HPV: Human Papillomavirus.
Source of data: [Adapted from reference: N. Mu˜
noz et al. [26].
0.1 1 10 100 1200
OR (log)
PHILIPPINES
Squamous
Cell carcinoma controls
0 102030405060708090
100
BRAZIL
MALI
MOROCCO
PARAGUAY
THAILAND
PERU
SPAIN
COLOMBIA
*OVERALL
* OR adjusted by country and age-group
91.4
Source: Adapted from reference Muñoz N, et al., 2003 [27]
HPV DNA Prevalence (%)
Fig. 7. HPV-DNA prevalence and odds ratios for squamous carcinoma of cervix by country.
HPV 31: OR =124; HPV 52: OR =200; HPV 33:
OR =374; HPV 58: OR =115; HPV 35: OR =74;
HPV 59: OR =419; HPV 51: OR =67; HPV 56:
OR =45; HPV 39: infinity; HPV 68: OR =54. The
risk for any given high-risk type was not statistically
different from the risk reported for HPV 16. Likewise,
the proportion of multiple types in a given specimen
varies across studies and particularly in relation to the
HPV detection method used. However, in all studies
of invasive carcinoma the risk linked to multiple HPV
types does not vary significantly from the risk linkedto
single HPV types.
These studies and a recent International review done
at IARC concluded that the evidence is now sufficient
to consider as high-risk carcinogenic types HPVs 16,
18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73 and
82 [IARC, in press]. A second group of HPV types are
rarely found in cases and have been classified as Low-
risk types and these include HPVs 6, 11, 40, 42, 43,
44, 54, 61, 70, 72, 81 and CP6108. From IARC’s and
other studies, a small group of HPV types remains in
the category of uncertain risk currently including HPVs
26, 53, 66 and perhaps others.
2.4. Cohort studies
Repeated sampling of women being followed for vi-
ral persistence and cervical abnormalities has shown
that the median duration of the infections is around 8
months for high risk HPV types as compared to 4.8
months for the low-risk HPV types. In unrelated stud-
ies, the time estimates were fairly consistent. In one
study in a high-risk population in Brazil, the mean du-
ration of HPV detection was 13.5 months for high-risk
HPV types and 8.2 months for the non-oncogenic types.
HPV 16 tended to persist longer than the average for
high-risk types other than HPV 16. The results were
remarkably similar in a student population in the Unit-
F.X. Bosch and S. de Sanjos´
e / The epidemiology of human papillomavirus infection and cervical cancer 223
Source of data: Adapted from reference: Muñoz N, et al., 2003 [27]
500010005001005010510.50.1
Other double
16-18
X
11
6
18
16
68
73
56
59
35
58
33
31
45
52
51
OR for cervical cancer
Fig. 8. HPV type-specific risk estimate for cervical cancer.
ed States and in the United Kingdom. However, the
currently observed time intervals may still suffer from
imprecision in the estimates of time at first exposure,
from the variability in the end-pointdefinition and from
censoring due to treatment of the early lesions.
Follow-up studies of women with and without cer-
vical abnormalities have indicated that the continuous
presence of high risk HPV is necessary for the devel-
opment, maintenance and progression to CIN 3 and
above. A substantial fraction (i.e. 15–30%) of women
with high risk HPV DNA who are cytomorphological-
ly normal at recruitment will develop CIN 2/3 with-
in the subsequent 4-year interval. Conversely, among
women found to be high risk HPV DNA negative and
cytologically identified as atypical squamous cells of
undetermined significance (ASCUS), or borderline or
mild dysplasia, CIN 2/3 is unlikely to develop during
a follow-up of two years and their cytology is likely
to return to normal. Women found positive for-low
risk HPVs rarely become persistent carriers and their
probability of progression to CIN 2/3 is extremely low
(reviewed in [19]).
As on going cohorts expand their follow up time,
more precise estimates are being provided on the pre-
dictive value of viral persistence as defined by repeat-
ed measurements of viral types and variants. One of
such cohorts in Sao Paulo has shown that the inci-
dence of cervical lesions in women who were twice
HPV-negative was 0.73 per 1,000 women-months. The
corresponding incidence among women with repeated
HPV-16 or HPV-18 positive results was 8.68, a 12-
fold increased incidence. The OR for HPV persistence
among women who were twice HPV positive for the
same oncogenic types was OR =41.2 (95% CI =10.7–
158.3).
The follow up studies in Costa Rica are beginning
to assess the potential for progression-to-neoplasic le-
sionsof some ofthe mostfrequent high-risk HPVtypes.
The study confirms that the risk of progression (giv-
en persistence) is significantly higher for HPV 16 and
18 HPV carriers over the risk related to any of the re-
maining high-risk types included in the cocktail test
HC2 [4].
Finally, persistence of HPV DNA detection after
treatment for CIN 2/3 is an accurate predictor of re-
lapse, significantly more sensitive thanrepeated vaginal
cytology within the 24 months following surgery [28].
These results are useful in defining the clinical role of
HPV testing. In screening, in the management of AS-
CUS and the follow up of women following treatment
for HSIL.
3. Other environmental risk factors for cervical
cancer
Most of the sexual behaviour parameters that were
linked to cervical cancer in the past are being re-
224 F.X. Bosch and S. de Sanjos´
e / The epidemiology of human papillomavirus infection and cervical cancer
evaluated in studies that considered the strong influ-
ence of the presence of HPV. Soon after the introduc-
tion of HPV testing in research protocols, it became
clear that the key risk factors that reflected sexual be-
haviour, such as the number of sexual partners, merely
reflected the probability of HPV exposure. Because of
the growing evidencethat HPV is a necessary factor in
cervical cancer, it soon became a standard procedure in
the reports of case control studies to include analyses
restricted to HPV positive cases and controls to prop-
erly assess the contribution of additional factors to the
risk of cervical cancer. In relation to invasive cervi-
cal cancer, the IARC’s pooled HPV positive restricted
analyses included HPV positive 1,768 cases and 262
HPV positive controls and the key findings concerning
environmental risk factors are discussed briefly.
3.1. Long term use of oral contraceptives
Ever use of OC was associated with a significant
increase in risk of cervical cancer (OR =1.47 (95% CI
=1.02–2.12) with a clear dose response relationship
with duration. The use of OCs for less than 5 years was
not related to the risk of cervical cancer (OR =0.77
(95% CI =0.46–1.29)) but it increased significantly
for 5–9 years of use (OR =2.72 (95% CI =1.36–
5.46)) and for 10+years of use (OR =4.48 (95% CI
=2.24–9.36)).
The evidence for an association of cervical cancer
with the use of oral or other hormonal contraceptivesis
not entirely consistent. A number of studies that inves-
tigated HPV positive women found no associations or
only weak associations with HSIL/CIN 3 in subgroup
analyses. These apparently conflicting results may re-
flect the increased cytological surveillance of women
that are taking OCs in developed countries and the use
of different case definition (ASCUS up to HSIL/CIN3
as opposed to cervical cancer) in cohort studies.
Because of the potential public health importance
of an interaction between long-term use of OCs and
HPV infections in the development of cervical cancer,
efforts are now being devoted to verify the results in
different populations. A meta-analyses on the asso-
ciation between hormonal contraceptives and cervical
cancer concludes that there is a linear dose response
relationship and that the effect tends to return to av-
erage within a time interval of 5 to 10 years after OC
cessation. The relevant units at the World Health Or-
ganization examined the evidence with an international
working group that recognized the significance of the
association. However, the group also concluded that,
in balance, the benefits currently achieved by the use
of OCs in developing countries (i.e. unwanted preg-
nancy avoidance) outbalance the increase in risk and
should not require a major change in the current family
planning strategies.
3.2. High parity
Inthe IARC casecontrol studies,HPV positivewom-
en who reported seven or more full term pregnancies
had a four-foldincreased risk of cervical cancer as com-
pared to similar HPV positive women that were nul-
liparous (OR =3.8 (95% CI =2.7–5.5)). There was
still a two-fold increased risk when women reporting 7
or more pregnancies were compared to HPV positive
women who reported 1–2 full term pregnancies [29].
Similar results were obtained in Costa Rica and Thai-
land as well as among women with pre-invasive dis-
ease in the Portland Cohort Study. In Denmark and
in the Manchester cohort study, two populations with
low parity, the effects are less visible for pre-neoplastic
lesions (reviewed in [30]).
It has been speculated that the general reduction in
the average number of births in developed countries
over the last decades may have contributed to the re-
duction in cervical cancer incidence but formal proof
of the hypothesis has not yet been produced.
The combined effect in the risk of cervical cancer
of parity and exposure to OCs has been examined and
shown that at eachlevel ofOCs use there is an increased
risk with a significant trend with the number of lifetime
pregnancies. The trend is more remarkable as women
refer use of OCs for extended periods of time. As com-
pared to nulliparous women not having used OCs, use
for longer that five years and having had more than five
full term pregnancies increases the risk by a significant
11-fold [29]. In many of the studies reported, it was
difficult to further analysethe association by type of OC
use or by estrogens/progesterone dose levels. It is now
recognized that current formulations have significantly
reduced the product composition and the observed re-
sults might apply differently to current users of OCs.
However, these observations underlinethe need to con-
tinue conducting studies on the interaction of steroids
with the biology of HPV.
3.3. Cigarette smoking
The pooled results of the IARC’s studies found that
“ever smoking” was associated with a two-fold, statisti-
cally significant, increased risk of cervical cancer with
F.X. Bosch and S. de Sanjos´
e / The epidemiology of human papillomavirus infection and cervical cancer 225
a significant dose response. These findings are consis-
tent with those found for “current vs. never smoking”
among HPV positive women for pre-neoplastic cervi-
cal lesions in virtually all cohort studies in Costa Ri-
ca (OR =2.3), the US Portland (OR =2.7 for CIN
2–3), in Copenhagen (OR =1.9) and a large cohort
study in Manchester (OR =2.2) [30]. These studies
are providing growing evidence on the carcinogenic
effect of cigarette smoking in women with persistent
HPV infection. The monograph program at IARC re-
viewed the evidence in 2002 and concluded that smok-
ing was an independent risk factor for cervical can-
cer [31]. However the mechanisms by which cigarette
smoking may affect cervical cancer (i.e. a direct effect
of the tobacco metabolites, an indirect effect related
to tobacco-induced immunosupression or to reduced
dietary antioxidants) remain elusive.
3.4. Co-infection with the Human Immunodeficiency
Virus
The evidence of a putative interaction between HPV
and Human Immunodeficiency Virus (HIV) in the ori-
gin of cervical cancer was formally recognized when
cervical cancer was included as one of the criteria of
acquired immune deficiency syndrome (AIDS) among
HIV positive women. The subsequent literature large-
ly confirmed the evidence although some major con-
founders of the epidemiological association tend to ob-
scure the results notably the powerful impact of screen-
ing in some populations, the medical surveillance of
HIV carriers in developed countries and the short sur-
vival time of HIV/AIDS patients in many populations at
high risk of cervical cancer in relation to the time inter-
vals between HPV infection and cervical cancer [32].
3.5. Co-infection with other sexually transmitted
infections
Markers of exposure to two other Sexually Trans-
mitted Infections (STIs) have been repeatedly although
inconsistentcy found associated to cervical cancer. Re-
sults from the IARC’s multicenter study found a 2-fold
increased risk in cervical cancer for the presence of
antibodies to CT (OR =2.1 (95% CI =1.1–4.0)) and
of antibodies to HSV 2 (OR =2.19 (95%CI =1.41–
3.40)[33,34]. Non-specific inflammatorychanges have
also been related to modest increases in risk for pre-
neoplastic cervical lesions among HPV positive wom-
en. The difficulties with the evaluations of such factors
lie in the strong co-linearity observed among all STIs
and the limitations of some of the biomarkers currently
used to assess ever exposure or persistent exposure. to
assess ever exposure or persistent exposure.
4. Conclusion
In the last two decades, the aetiology of cervical
cancer has become a coherent description that includes
the identification of a limited group of HPV types as
the necessary, etiologic agents with a few additional
co factors intervening as such in the presence of the
viral DNA. The association is universal and the HPV
type variability is geographically limited. The clinical
implications of these findings have resulted in novel
screening and vaccination strategies for the prevention
of cervical cancer. Current vaccines may prompt a
change in the paradigm of cervical cancer prevention.
Acknowledgments
We acknowledge Meritxell Nomen and Cristina Ra-
jo who were responsible for the secretarial workload.
Partial support has been received from the Fondo de
Investigaciones Sanitarias, Spain (FIS PI030240 and
FIS 01/1237), from the European Commission (QLG4-
CT-2000-01238 & QLG4-CT-2001-30142), from the
Ag`
encia de Gesti´
o d’Ajuts Universitaris I de Recerca
(2005SGR00695) and from the Institutode Salud Car-
los III (Red de C ´
ANCER RCESP C03/09 & Red de
Salut P´
ublica RTICCC C03/10).
Partial support has been received from the Marato de
TV3 Foundation (051530).
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