Vaccine 24S3 (2006) S3/11S3/25

Chapter 2: The burden of HPV-related cancers

D. Maxwell Parkin a, , Freddie Bray b,1
a

Clinical Trial Service Unit & Epidemiological Studies Unit, Richard Doll Building, University of Oxford,
Old Road Campus, OXFORD OX3 7LF, UK
b Cancer Registry of Norway, Institute of Population-Based Research, Montebello, Oslo, Norway
Received 3 March 2006; accepted 15 May 2006

Abstract
On the basis of current evidence regarding human papillomavirus (HPV) and cancer, this chapter provides estimates of the global burden
of HPV-related cancers, and the proportion that are actually caused by infection with HPV types, and therefore potentially preventable. We
also present trends in incidence and mortality of these cancers in the past, and consider their likely future evolution.
2006 Elsevier Ltd. All rights reserved.

1. Burden of HPV-related cancer

1.1. Cancer of the cervix
Cancer of the cervix uteri is the second most common
cancer among women worldwide, with an estimated 493,000
new cases and 274,000 deaths in 2002 [2]. Some 83% of the
cases occur in developing countries, where cervical cancer
accounts for 15% of female cancers, with a risk before age
65 of 1.5%, while in developed countries it accounts for only
3.6% of new cancers, with a cumulative risk (ages 064)
of 0.8% [2]. The highest incidence rates are observed in subSaharan Africa, Melanesia, Latin America and the Caribbean,
South-Central Asia, and South East Asia (Fig. 1).
Fig. 2 shows incidence rates recorded in cancer registries
around 1995 [3]. There is a range in incidence of at least 20fold. In general, the lowest rates (less than 15 per 100,000)
are found in Europe (except some Eastern European countries), North America and Japan. The incidence is generally
higher in the developing countries of Latin America (agestandardized incidence rates (ASR) 33.5 per 100,000) and the
Caribbean (ASR 33.5), sub-Saharan Africa (ASR 31.0), and

Corresponding author. Tel.: +44 1865 743743; fax: +44 1865 743985.
E-mail addresses: max.parkin@ctsu.ox.ac.uk (D.Maxwell Parkin),
freddie.bray@kreftregisteret.no (F. Bray).
1 Tel.: 47 2245 1334.
0264-410X/$ see front matter 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.vaccine.2006.05.111

South-Central (ASR 26.5) and Southeast Asia (ASR 18.3).

Very low rates are observed in China, and in Western Asia
(Fig. 1); the lowest recorded rate is 0.4 per 100,000 in Ardabil,
northwest Iran [4].
The majority of cases of cervical cancer are squamous cell
carcinomas (SCCs); adenocarcinomas are less common. In
general, the proportion of adenocarcinoma cases is higher in
areas with a low incidence of cervical cancer, and this histology may account for up to 25% of cervical cancer cases
in many Western countries [3] (Fig. 2). The relatively high
proportion of adenocarcinomas is a consequence of cytological screening, which historically, probably had little effect in
reducing the risk of adenocarcinoma of the cervix, because
these cancers, and their precursors, occur within the cervical canal (from the glandular epithelium), and were not
readily sampled by scraping the epithelium of the ectocervix
[5].
Mortality rates are substantially lower than incidence.
Worldwide, the ratio of mortality to incidence is 55%. Survival rates vary between regions with quite good prognosis in
low-risk regions (73% at 5 years in US registries [6] and 63%
in Europe [7]), but even in developing countries, where many
cases present at relatively advanced stages, survival rates are
fair (for example, 30.5% in the African population of Harare,
Zimbabwe [8]).
Because cervical cancer affects relatively young women,
it is an important cause of lost years of life in the developing

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Fig. 1. Age-standardised (World) incidence rates of cervical cancer 2002 [2].

1.2. Cancers of the external genitalia

been confirmed by case-control studies which suggest that the

risk is reduced about threefold [10,11]. Circumcision protects
against sexually transmitted infections, like HIV [12], by preventing accumulation of infected vaginal secretions, or more
likely by simply reducing the surface area of non-keratinized
epithelium. The geographical correlation between the incidence of penile and cervical cancers (Fig. 4c), has suggested
a common aetiology, as has concordance of these two cancers
in married couples [13]. HPV-DNA is detectable in about
4050% of all penile cancers, and serological studies have
confirmed the role of HPV-16 and -18 [1].

1.2.1. Cancer of the penis

On a global basis, cancer of the penis is a rare cancer,
accounting for less than 0.5% of cancers in men. In Western countries, the ASR is less than 1 per 100,000. Incidence
rates greater than this are observed in cancer registries in
India, Southeast Asia (Thailand and Viet Nam), Latin America (Paraguay, Puerto Rico, Peru, Brazil) and in Eastern and
Southern Africa (Fig. 3). Incidence in Jewish populations is
particularly low (0.04 per 100,000 in the Jewish population
of Israel in 19931997) [3].
The importance of circumcision in determining the risk of
penile cancer has been evident for many years, and this has

1.2.2. Cancers of the vulva

Fig. 5 shows some incidence rates of cancers of the vulva
worldwide. ASRs mostly lie between 0.5 and 1.5 per 100,000.
The geographical pattern is not immediately obvious, and is
not similar to that of cervical cancer, since high rates are
observed in several European populations (Scotland, Denmark, Spain, Italy), and low rates in several populations
in sub-Saharan Africa, Southeast Asia, and Latin America. Bosch and Cardis [14], using cancer incidence data
from 1978 to 1982, found that the incidence of cervical
cancer was strongly correlated with penile cancer, and of
other cancers of the female genitalia; however, this is not

world. Yang et al. [9] found that it was responsible for

2.7 million (age-weighted) years of life lost (YLL) worldwide
in 2000 and it is the biggest single cause of YLL from cancer
in the developing world. In Latin America, the Caribbean and
Eastern Europe, cervical cancer makes a greater contribution
to YLL than diseases such as tuberculosis, maternal conditions or AIDS. It also makes the largest contribution to YLL
from cancer in the populous regions of sub-Saharan Africa
and South-Central Asia.

D. Maxwell Parkin, F. Bray / Vaccine 24S3 (2006) S3/11S3/25

Fig. 2. Age-standardised (World) incidence rates of cervical cancer by histological subtype in selected cancer registries circa 19931997 [3].

Fig. 3. Age-standardised (World) incidence rates of penile cancer in selected cancer registries circa 19931997 [3].

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cological malignancy leads to an increased risk, especially if

associated with pelvic irradiation [15].
The number of new cases of cancer of the penis and female
genitalia worldwide can be estimated from the number of
cervical cancer cases, and the ratio of incidence rates at each
of these sites to those of cervical cancer, by world area and
age group [3]. The estimated numbers in 2002 were 40,000
cases of cancer of the female genitalia and 26,300 cases of
cancer of the penis worldwide.
1.3. Cancers of the anus
Cancers of the anus are those arising in the anal
canaltumours of the external skin (anal margin) are classified along with skin cancers. The canal is lined in its upper
part by colorectal-type of mucosa, and in its lower third
by squamous epithelium, with specialized transitional zone
epithelium in between. Therefore, cancers are predominantly
SCCs, adenocarcinomas, or basaloid and cloacogenic carcinomas. In most populations SCC is twice as common in
females as in males (Fig. 6). Incidence is particularly high
amongst homosexual males, so the incidence rates among
males in some populations (e.g. San Francisco) are correspondingly elevated (Fig. 6), and the risk is increased further
by infection with HIV. Risk is increased by cigarette smoking,
anal intercourse, and the number of lifetime sexual partners
[17].
1.4. Cancers of the mouth and oro-pharynx

Fig. 4. Correlation between incidence rates of cancer of the cervix, and

cancer of the vulva (a), vagina (b) and penis (c). Rates are age-standardised
(World) based on data circa 19931997 from all cancer registries accepted
in volume VIII of Cancer Incidence in Five Continents. Weights for size of
points are person-years of observation in each registry [3].

obvious when rates for the period 19931997 are compared

(Fig. 4a).
Although the majority of tumours are SCCs, distinct subtypes are recognised, particularly the warty and basaloid
types, which are associated with HPV infection and the precursor lesions of vulvar intraepithelial neoplasia (VIN), and
the verrucous type, which is not [15].
1.2.3. Cancers of the vagina
Cancers of the vagina are less frequent than vulvar cancers: the ASR is 0.30.7 per 100,000 in most countries. There
is no clear association with incidence of cancers of the vulva
or cervix (Figs. 4b and 5). Many SCCs are preceded by vaginal intraepithelial neoplasia (VAIN). Clear-cell carcinoma
of the vagina is a well-known complication of exposure to
diethylstilboestrol in utero [16]; simultaneous or prior gynae-

Cancer of the mucosa of the oral cavity and of the pharynx are frequently considered as a group, as there are many
similarities in their epidemiology, treatment and prognosis. Cancers of the nasopharynx and salivary glands differ histologically and aetiologically. The incidence rates of
oro-pharyngeal cancers vary widely and are highest in the
geographical regions where tobacco use and alcohol consumption are popular. A high incidence of these cancers
is observed in the Indian subcontinent, Oceania (Australia,
Papua-New Guinea), Switzerland, The Netherlands, France,
Latin America (Brazil) and Southern Africa (Fig. 7). In 2002,
an estimated 405,000 cases occurred worldwide, two-thirds
of them in developing countries, and there were 211,000
deaths [2]. The highest incidences among males are reported
in Northern and Eastern France, while the highest incidences
in females are in India and Pakistan [3]. The male:female
ratio of occurrence varies from 2 to 15:1, depending on the
anatomical sub-site, with the extreme ratios characteristic of
tongue, mouth and pharyngeal cancers. Cancers of the mouth
and of the tongue generally predominate in developing countries, whereas pharyngeal cancers are common in developed
countries, including Central and Eastern Europe.
Although HPV is accepted as an aetiological factor for oral
and pharyngeal cancers, the major risk factors are tobacco
and alcohol, with the effects of these two agents being multiplicative [18]. Tobacco exposure occurs through smoking

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Fig. 5. Age-standardised (World) incidence rates of vulvar and vaginal cancer in selected cancer registries circa 19931997 [3].

in the high-risk populations of Europe, Australia and Latin

America, and has been estimated to be responsible for about
41% of these cancers in men, and 11% in women worldwide
[19]. Chewing tobacco is the major exposure in the Indian
subcontinent, Papua New Guinea, and to a lesser extent, in

Southeast Asia [18]. Chewing has traditionally been in the

form of betela large quid made up of varying proportions of tobacco, lime and condiments wrapped in the leaf
of the piper betel. Recently, sales of commercially prepared
and marketed powdered tobacco have become increasingly

Fig. 6. Age-standardised (World) incidence rates of anal cancer by histological subtype and sex in selected cancer registries circa 19931997 [3].

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Fig. 7. Age-standardised (World) incidence rates of cancer of the mouth and pharynx * 2002 [3].

popular, and there are indications that these may be even more
harmful. Oral snuff (dipping) is used in some countries in
Europe (Sweden) and in the US amongst the young [18].
Alcohol increases the risk of these cancers, and this risk
relates to the quantity of alcohol consumed, rather than the
type of beverage [20].
Epidemiological studies worldwide have linked a generally impoverished diet, particularly one lacking in vegetables
and fruits, with an excess risk for these cancers. Cancer of the
lip is associated with sunlight exposure and outdoor occupations in white populations.

2. Quantication of the role of HPV in human cancer

Oncogenic HPV can be detected by PCR in virtually all
cases of cervical cancer, and it is generally accepted that the
virus is necessary for the development of cancer, so that all
cases of cancer can be attributed to infection [1].
With respect to SCCs of the vulva and vagina, penile cancer, and anal cancer, the relative risk associated with HPV
infection is difficult to quantify, because of the small size of
most studies, and the absence of comparable measurements
of prevalence of infection in normal subjects. The fraction of
these cancers attributed to HPV infection is therefore generally equated with the proportion of cancer cases infected with

HPV in various series. In studies using PCR methodology,

the prevalence of HPV in vaginal cancer is about 6065%
and 2050% in vulvar cancers [1] (75100% in the basaloid and warty type associated with VIN and only 223% of
the keratinizing carcinomas [21]). HPV-related vulvar cancer occurs in younger women than the typical keratinizing
squamous histology related to chronic inflammatory precursors. For anal cancer, Frisch et al. [22] observed in a series
of 386 cases from Denmark and Sweden, 95% and 83% of
cancers involving the anal canal in women and men, respectively, were positive for oncogenic HPV. Prevalence in a US
case-control study (of about 300 subjects) was approximately
90% of cancers, and HPV-16 was the most frequent HPV type
detected (73%), followed by HPV-18 (6.9%) [17]. For penile
cancer, Bezerra et al. [23] found HPV DNA in 30% of 71 cases
of penile cancer from Brazil, and Rubin et al. [24] found HPV
DNA in 42% of 148 cases from the US and Paraguay.
Several studies have investigated the prevalence of HPV
in cancers of the mouth and pharynx. In a review of 60 studies, Kreimer et al. [25] calculated the average to be 23.5%
for cancers of the oral cavity and 35.6% for oro-pharyngeal
cancers. HPV-16 was the predominant type (87% and 68%
of HPV-infected oro-pharyngeal cancers and oral cavity,
respectively).
The population attributable fraction (PAF) of a disease is
defined as the proportion of the new cases of disease observed

3.71
402,900
5.17
561,100
Percentages in different world areas, reported by Munoz et al. [28], weighted by the corresponding number of cases in each [2].

5,801,800

33,900

28,100

5,060,700

527,200

374,700

10,862,500
a

All sites

70 [28]a
63 [24]
80 [29,30,21]
92 [17,22]
95 [25]
89 [25]

0
26,300
0
14,500
175,900
42,500

0
10,500
0
13,000
5200
5100

0
6600
0
12,000
5000
4500

492,800
0
40,000
15,900
98,400
9600

492,800
0
16,000
14,300
2900
1100

344,900
0
12,800
13,100
2800
1000

492,800
26,300
40,000
30,400
274,300
52,100

492,800
10,500
16,000
27,300
8200
6200

4.54
0.10
0.15
0.25
0.08
0.06

344,900
6600
12,800
25,100
7800
5500

3.18
0.06
0.12
0.23
0.07
0.05

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Cervix
100
Penis
40
Vulva, vagina 40
Anus
90
Mouth
3
Oro-pharynx
12

% all
cancer
Attributable
to HPV
Attributable to Total
HPV 16/18
cancers
Total
cancers

Attributable
to HPV

Attributable to Total
HPV 16/18
cancers

Attributable
to HPV

Both sexes
Females
Males

Of which, HPV
16 and/or 18
(%) [Refs]
Attributable
to HPV (%)

Time trend studies make use of published rates of mortality

and incidence. Comparative studies of mortality, in particular, must take into account the deaths certified as Uterus,
part unspecified. The proportion of uterine deaths ascribed
to this category varies widely, both between countries, and
over time, and it can be very high, for example, over 50%

Site

3. Time trends of cervical cancer

Table 1
HPV infection-attributable cancer in 2002: by sex and HPV type

in a population that are attributable to exposure to a risk factor. The PAF therefore provides an upper limit to the numbers
of cases that could be prevented, for example, if vaccination
was 100% effective. The estimated numbers of cases of cancer attributable to infection with all HPV types worldwide
have been published [26]. All cases of cervical cancer were
assumed to be related to HPV, while for the ano-genital cancers, the estimated attributable fraction was based upon the
proportion of tumours in which the virus can be detected; the
fractions assumed were 40% of cancers of the external genitalia (vulva, vagina, penis) and 90% of cancers of the anus.
This method, however, overestimates attributable fractions,
by including some cancer cases in which the presence of the
virus was coincidental without, for example, expressing viral
oncoproteins. The estimate of HPV-attributable cancers of
the oral cavity and pharynx, on the other hand, makes use
of data from the International Agency for Research on Cancer (IARC) multi-national study [27] in which prevalence
of HPV16 E6 or E7 antibody in controls (1.6%) as well as
cases (6.4% mouth cancers, 15.3% oro-pharyngeal cancers)
was available. An allowance was also made for the fact that
assessment of HPV-DNA presence by PCR assay may lead
to an overestimation of cases in which the virus is aetiologically involved, as suggested by the lower proportion of cases
with E6/E7 expression (4.6% of oral cancers and 12% of oropharyngeal cancers). The resulting attributable fractions (3%
for oral cancer, 12% for oro-pharynx) are, therefore rather
lower than the percentage of tumours with detectable HPVDNA (4% and 18%, respectively). The results are shown in
Tables 1 and 2.
Although the study of HPV prevalence in oral and pharyngeal cancers by Herrero et al. [27] has the advantage of being
the largest available (1670 cases), and allows attributable
fractions to be corrected for the presence of HPV in normal control subjects, the prevalence of HPV in tumour tissue
in this study (4% of oral cancers, 18% of oro-pharyngeal
tumours) was considerably lower that the averages calculated by Kreimer et al. [25], based on 3611 cases from 60
studies (32.5% and 35.6%, respectively), so it is possible that
the HPV-attributable cases at these sites in Tables 1 and 2
may be considerably underestimated. Table 1 also provides
an estimate of the numbers of cancer cases attributable to
HPV 16 and/or 18, based on the percentage of HPV-positive
cancers at each site that contained HPV-16 or -18. Of the
561,000 cancers estimated to be caused by HPV, 71.8% were
caused by HPV-16 and -18.

Attributable to % all
HPV 16/18
cancer

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Table 2
HPV infection-attributable cancer in 2002: developed & developing countries (source: [26])
Site

Cervix
Penis
Vulva, vagina
Anus
Mouth
Oro-pharynx
All sites

Attributable to
HPV (%)
100
40
40
90
3
12

Developed countries
Total cancers

Developing countries

Attributable to HPV

% all cancer

83,400
5200
18,300
14,500
91,200
24,400

83,400
2100
7300
13,100
2700
2900

1.7
0.0
0.1
0.3
0.1
0.1

5,016,100

111,500

2.2

in France and Italy for women aged over 30 in 1995. Some

form of reallocation of these deaths to more specific categories is generally necessary before rates are calculated.
Loos et al. [31] have described appropriate methods, and have
provided corrected mortality figures for 35 European countries. A further problem arises when incidence and mortality
rates are calculated using the entire female population as the
population-at-risk; women who have had a total hysterectomy for reasons other than the presence of cervical neoplasia
are not at risk of cervical cancer, and should be excluded from
the population-at-risk. However, this is difficult since the
prevalence of hysterectomy is generally unknown, although
it can be substantial in some age groups and countries, and
may vary by time as well as place and age. Correction of the
population-at-risk may have a substantial impact on the estimated rates of incidence and mortality, especially in older
age groups, although the impact on the observed trends in
Ontario and England and Wales was not significant [5].
Cytological screening programmes have been shown to
reduce incidence or mortality of cervical cancer in populations where they have been intensive or systematically
applied. Often, these reductions have taken place against a
background increase in incidence that affects successive generations (birth cohorts). These changes in risk are most likely
to result from changing sexual behaviour with increased
transmission of oncogenic HPV types. The study of time
trends of cervical cancer has therefore been important in
assessing both changes in exposure among women born in
different generations, as well as the effectiveness of organised
screening programmes.
The following section reviews the historic and current patterns of cervical cancer worldwide, and provides scenarios
with regards to future rates at the global level. Trends in cervical cancer are also compared with other HPV-related cancers
to assess the extent to which HPV-related cancers share the
same high-risk (HR) HPV as risk factors.

Total cancers

Attributable to HPV

% all cancer

409,400
21,100
21,700
15,900
183,100
27,700

409,400
8400
8700
14,300
5500
3300

7.0
0.1
0.1
0.2
0.1
0.1

5,827,500

449,600

7.7

of its manifestation as invasive cancer by effective screening. The geographic pattern described earlier is relatively
recent. Before the introduction of screening programmes in
the 1960s and 1970s, the incidence in most of Europe, North
America, and Australia/New Zealand was much as we see
in developing countries today [5] (Fig. 8). Rates of cervical cancer incidence and mortality have declined in the last
40 years in many western countries (Fig. 9). The declines in
mortality predated the introduction of screening in some populations (e.g. the US), and was ascribed to factors correlated
with improving socioeconomic levels [5], as well as a steady
improvement in stage at diagnosis, and more effective treatment and improved survival certainly played a major role [5].
More recently, the beneficial effects of screening programmes
have been recognised. Since the efficacy of cervical screening was never tested in randomised controlled trials, much
of the evidence of its effectiveness is based on the reduction in incidence and mortality from invasive cervical cancer
following the introduction of organised programmes in the
1950s and 1960s. The trends in incidence and mortality in
the Nordic countries are the best known examples. Declines
in incidence parallel the extent and coverage of the organ-

3.1. Trends before and after introduction of screening

3.1.1. Developed countries
Current patterns of incidence worldwide reflect the net
effect of two influences: the underlying risk of disease (presumably related to transmission of HPV) and prevention

Fig. 8. Time trends in age-standardised (World) incidence rates of cervical

cancer incidence in four Nordic countries [48].

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Fig. 9. (a) Time trends in age-standardised (World) incidence rates of cervical cancer incidence based on data from selected cancer registries accepted in
successive Volumes of Cancer Incidence in Five Continents [48]. (b) Time trends in age-truncated (World, ages 2034) incidence rates of cervical cancer
incidence based on data from selected cancer registries accepted in successive volumes of Cancer Incidence in Five Continents [48].

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ised programmes, and were most marked in the age groups

targeted by these programmes [5]. Similar observations were
made in Canada and the US [5].
In spite of the overall declines in crude or age-adjusted
incidence and mortality in Western countries, increases have
been reported among young women, presumably reflecting
changing sexual habits and increased transmission of HPV
in younger generations. This phenomenon was first described
in England and Wales [32], where successive generations of
women born since the mid-1930s have been at increasingly
high-risk. Similar observations have been made elsewhere
in Europe [5]. In some countries of Eastern Europe, where
there has been little or no screening, mortality rates have been
rising rapidly (e.g. Bulgaria, Romania, and Russia), particularly amongst recently born generations. In more affluent
countries, however, there is evidence of recent declines (e.g.
the Czech Republic, Hungary and Poland).
3.1.2. Developing countries
Less information is available regarding trends in developing countries. In general, incidence and mortality rates have
been relatively stable in many countries, or shown modest
declines [5]. The absence of an overall decline as observed
in high resource populations probably reflects the lack of
screening implementation, or where programmes have been
introduced, their low population coverage and poor quality
cytology. In Fig. 9, declines in incidence are relatively slight
in Bombay, India, in contrast to the dramatic declines in
cervical cancer in Shanghai. The declines in Chinese populations have been attributed to screening, treatment and
improved female genital hygiene, although increasing rates
are seen among younger women and this has been linked to
changing economic circumstances and sexual behaviour [5].
Despite the steady decline in cervical cancer, incidence in
Cali, Colombia (Fig. 9) rates in the 1990s were one-third
of those observed three decades earlier the population continues to have one of the highest rates in the world [3].
3.2. Trends in cervical cancer incidence by age and
histology
Temporal studies have often failed to separate adenocarcinomas from SCCs, even though there may be some
heterogeneity in their aetiology, and in their susceptibility
to detection by cytology screening. Screening using the Pap
test has been shown to effectively detect SCC in early stages,
while it has been considered much less effective at detecting
adenocarcinoma [5].
In addition to the problems of Uterus unspecified cancers, and the changes in prevalence of hysterectomy, alluded
to above, the study of trends by histological subtype must take
into account changes over time in the proportions of cases of
cervical cancer coded as unspecified or of ill-defined histology.
The impact of screening on the incidence of cervical cancer is difficult to separate from the effects of other factors in

determining the rate of diagnosis. Screening has been in use

for several decades in many parts of the world, so that it is
difficult to estimate what the risk of cervical cancer would
have been in the absence of screening. There is also lack of
information on the extent and quality of screening, particularly when a large proportion of tests are outside organised
programmes.
One informal way to evaluate changing risk patterns
alongside the impact of screening, is the joint assessment
of the effects of age at diagnosis, period of diagnosis, and
birth cohort using age-period-cohort (APC) modelling [33].
For cervical cancer, changing rates among successive generations point to modifications in the population prevalence
of persistent infection with oncogenic HPV types, while
period effects act as surrogate measures of events that quickly
change incidence or mortality with the same order of magnitude regardless of the age group under study. They can be
viewed as representing the effects of cytological screening
as the intervention should deflect trends downwards across
targeted age groups over the same period of time.
3.2.1. Trends in SCC of the cervix
Since most cervical cancers are SCC, studies of all types
largely reflect trends in rates of this histology. Fig. 10 shows
the cervical SCC trends in Sweden and Slovakia as part of a
recent APC analysis of trends in 13 European countries [34].
In this analysis, the non-identifiability problem inherent in
APC models (the indexes of age, period and cohort are not
independent, but are exactly linearly dependent on each other)
was addressed assuming a constant pattern of age-specific
risk over time. There were large declines in risk by calendar period in Northern Europe, but a pattern of escalating
risk in successive generations born after 1930 in many European countries. The decreased incidence of SCC in Sweden
is accompanied by a decline in the period slope, implying that
it is the consequence of screening. A recent study reported
little or no increase in risk in young women in Sweden (due to
effective screening), and a levelling off of risk in cohorts born
since the mid-1940s [35]. A bleaker picture emerges from
several Southern and Eastern European countries (e.g. Slovenia and Slovakia (Fig. 10) where trends by period remained
stable, but marked increases in risk among consecutive births
cohort have been observed, related to an absence of screening
among a population where sexual behaviour has changed.
An earlier birth cohort analysis of cervical SCC trends in
25 countries [36] reported declining rates of SCC in successive generations in the US (except US Hispanic), Australia,
non-Maori women of New Zealand, and a number of Northern and Western European countries, in both younger (age<50
years) and older women (age 5074 years). In contrast, in Finland, the UK, Slovakia, Slovenia and Israel, SCC rates have
increased in recent birth cohorts of young women.
3.2.2. Trends in adenocarcinoma of the cervix
Studies in the last twenty years in Europe and
North America have reported increasing rates of cervical

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Fig. 10. Effects of age, birth cohort and calendar period in the time trends of cervical squamous cell carcinoma and adenocarcinoma incidence in Sweden and
Slovakia. Estimates were obtained from an age-period-cohort model that fixed the underlying age curve [34,37].

adenocarcinoma. Most have noted increasing rates among

younger women (age<40 years) [5]. The European study
[37] reported increases in age-adjusted adenocarcinoma rates
in the majority of 13 countries as a result of a generational
increase in risk that first affected women born in the early1930s through to the mid-1940s. As noted earlier, differences
in geographic and temporal profiles of the two main subtypes of invasive cervical cancer is in keeping with the relative inability of cytological screening to reduce the rates
of invasive adenocarcinoma. In Fig. 10, there are periodspecific increases in risk in both Sweden and Slovakia, which
may partly be the result of increasing accuracy in the specificity of the diagnosis of adenocarcinoma with calendar time.
Interestingly, the trends in cohort-specific risk in both countries coincide more with the corresponding cervical SCC
trends. Interpretation is, however, complex as cohort-specific
increases among recent generations of women may be the
result of an increasing prevalence of oncogenic HPV types.
If cohort trends are stable however, it may be that increasing
risk has been diminished by screening programmes (e.g. for
squamous cell but not adeno tumours in Northern Europe).
However, other reasons related to sexual behaviour and attitudes to screening cannot be discounted.

Recent work suggests that the efficacy of cytological

examinations has improved during the 1990s, and may have
been responsible for some reductions in adenocarcinoma in
this period [38]. A European study [37] reported declines
in period-specific risk of adenocarcinoma among younger
women in the U.K., Denmark and Sweden during the 1990s,
indicating that the Pap test may have had a recent impact in
reducing incidence in Europe.

4. Quantifying the contributions of changes in HPV

infection and screening on incidence of cancer
Although observed trends are the net result of changes in
risk, as determined by infection and persistence of oncogenic
HPV, and prevention of invasive disease via screening, quantifying their relative contributions is difficult. There is little
information on changes in incidence or prevalence of HPV
infection. Increases in HPV-16 have been reported in Finland in women aged in their twenties [39], while in Sweden,
rises in HPV-16 during the 1970s and early-1980s in women
aged under 35 have been reported [40]. It would be useful to
relate the prevalence and distribution of HR-HPVs to birth

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D. Maxwell Parkin, F. Bray / Vaccine 24S3 (2006) S3/11S3/25

cohorts to better understand how sexual behaviour of different populations subjects women to an increasingly higher
average risk of cervical cancer in certain countries relative to
others.
In a health services context, it is important to know
how many cases are being prevented by screening and how
many cases may be prevented in the future. Studies in England and Wales [41] have attempted such a quantification,
where an improved programme has successfully countered
increases. In estimating the cases prevented in the past,
one must specify an appropriate model and provide information on the historical screening process. However, precise quantitative information on organised screening practices is difficult to obtain, and there is little information
on the extent and distribution of opportunistic screening
[5].

5. Trends in other HPV-related cancers

There are few systematic studies of time trends of cancers of the external genitalia. In Norway, marked increases
in the incidence of VIN were observed, but not of invasive
cancer between 1973 and 1992 [42]; a similar observation
was observed in the US [43]. Possibly early diagnosis and

treatment of in situ carcinoma reduces increases in invasive vulvar carcinoma incidence. For anal cancers, there have
been marked incidence increases for over 50 years [44]. Conversely, there have been recent declines in mortality rates
from oral and pharyngeal cancers in many European countries, as well as in Australia and North America (coinciding
with lung cancer); however, they are still rising in most of
Central and Eastern Europe, and until very recently, in Japan
[45].
In the context of examining the impact of HPV, it is interesting to compare cervical cancer trends in the absence of
screening, with those of the external genitalia and of the
mouth and of the pharynx. The observation of simple associations between these trends would be expected if a substantial
proportion of cancers at these sites due to infection with the
same HR-HPV types. In Fig. 11, there are no striking resemblances in the trends in HPV-related cancers and cervical
cancer in the four countries studied. However, there is some
correlation between the temporal patterns of cervical cancer and those for cancers of the penis and of other female
genitalia, at least in the Colombian, Chinese and Indian populations. This may be anticipated given that the PAR estimates
indicate that about two-fifths of these cancers can probably
be attributed to HPV (40%), whereas the proportion is much
lower for mouth and pharyngeal cancer.

Fig. 11. Time trends in age-truncated (World, ages 3064) incidence rates of five HPV-related cancers in four cancer registries accepted in successive Volumes
of Cancer Incidence in Five Continents [48].

D. Maxwell Parkin, F. Bray / Vaccine 24S3 (2006) S3/11S3/25

S3/23

Table 3
Predicted number of cervical cancer cases in 2010 and 2020 by world area and age. Projections assume rates estimated for 2002 hold into the future. Adapted
from [2]
2002

2002 (% burden of
cervix cancer 2002)

2010 (% change
from 2002)

2020 (% change
from 2002)

2020 (% burden of
cervix cancer 2020)

World
Women aged <65
Women aged 65

493,000
396,500
96,500

100
80
20

584,500 (19%)
470,000 (19%)
114,500 (18%)

702,500 (42%)
549,000 (38%)
153,500 (59%)

100
78
22

Less developed areas

Women aged <65
Women aged 65

409,000
336,000
73,000

83
82
18

505,500 (23%)
413,500 (23%)
92,000 (25%)

639,500 (56%)
507,500 (51%)
132,000 (80%)

83
79
21

More developed areas

Women aged <65
Women aged 65

83,000
60,000
23,000

17
72
28

89,000 (06%)
63,500 (05%)
25,222 (09%)

92,500 (11%)
62,500 (03%)
30,000 (31%)

17
67
33

6. Projections of HPV-related cancers

Planning cancer services requires knowledge of the current and likely future patterns of occurrence. Predictions can
be used to make decisions on future provision of services
(or post hoc, to investigate why their expected impact was
not achieved). Both screening and HPV infection will influence future rates, and accurate predictions will depend upon
information on both changing levels of persistent infection
with HR-HPVs and the relative impact of interventions in the
population. The assessment of the impact (epidemiologically
and economically) of HPV vaccine, requires fairly complex mathematical modelling with a scenario-based approach
[46].
Simpler approaches usually involve a projection based
on past trends that represent the composite effect of changing risk and preventive interventions. Here the APC model
is commonly applied, wherein the period and birth cohort
effects are proxies for events that cannot be measured directly
[47]. The cancer burden measured by the number of new
cases, is calculated by multiplying the predicted cancer rates
with population forecasts.
In countries where the HPV vaccine is likely to be introduced, predicted numbers based on such extrapolations are
likely to become increasingly inaccurate; however, they do
serve to quantify the effectiveness of a proposed vaccine by
comparison of the numbers predicted in its absence with those
actually observed subsequently.
6.1. Global projections of cervix cancer 2010 and 2020
We assume here that current incidence rates will apply in
the future, and calculate expected numbers using appropriate population forecasts. Anything more complex would be
hard to justify, given past trends are quite different between
and within world regions, and the temporal landscape will
surely be radically altered by the aforementioned interventions. Irrespective of changing risk, population growth and
ageing are extremely important in determining likely future
burden, and demographic changes will continue to have major

consequences over the next half-century, particularly in the

developing world.
Table 3 shows the predicted number of new cases of cervical cancer based on the estimated incidence rates in 2002
applied to short-term population projections in 2010 and
2020. In the absence of changing risk or intervention, it is
projected that by 2020, 0.7 million cases will occur, about
a 40% increase from 2002. Four-fifths of the cervical cancer cases worldwide in 2002 were in less-developed regions,
and, as a result of the much more rapid ageing and population
growth in these areas, this proportion could increase to over
90% by 2020. The biggest relative increase will occur among
the elderlyan 80% increase from 410,000 cases to 640,000
by 2020.

Disclosed potential conicts of interest

Authors have disclosed no potential conflicts of interests.

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