European Journal of Cancer (2013) 49, 150– 155

Available at www.sciencedirect.com

journal homepage: www.ejcancer.info

Sex difference in the incidence of nasopharyngeal carcinoma

in Hong Kong 1983–2008: Suggestion of a potential protective role
of oestrogen

Shao-Hua Xie a, Ignatius Tak-Sun Yu a, Lap-Ah Tse a,⇑, Oscar Wai-kong Mang b, Li Yue c

a
School of Public Health and Primary Care, The Chinese of Hong Kong, Hong Kong SAR, China
b
Hong Kong Cancer Registry, Hospital Authority, Hong Kong SAR, China
c
Workplace Safety and Insurance Board, Toronto, ON, Canada

Available online 11 August 2012

KEYWORDS Abstract Background: Nasopharyngeal carcinoma (NPC) shows a male predominance in

Nasopharyngeal carci- incidence while the underlying reasons have rarely been explored.
noma Methods: We analysed incident cases of NPC recorded in Hong Kong Cancer Registry during
Sex ratio the period 1983–2008. All cases were divided into 5-year age groups. Age group specific inci-
Sex difference dence rates of NPC by sex and male to female ratios in incidence rate by age group were cal-
Aetiology culated. A curve fitting approach was taken to quantitatively describe the age-specific
Oestrogen incidence rates of NPC using non-linear regressions.
Results: During the period 1983–2008, a total of 27,579 new cases of NPC were identified
(20,060 males and 7519 females) in Hong Kong. The overall male to female ratio of the annual
age-standardised incidence rates of NPC ranged 2.2–3.1. The male to female ratio of NPC
incidence increased with age until peaking at ages 55–59 years and showed a decline thereafter.
An additional minor increase at ages 15–19 years was also observed. Modelling of the age-spe-
cific incidence curves suggested divergent slopes for men and women and a delay in increasing
incidence with age among females, by around 5–10 years before menopause ages.
Conclusion: The age-dependent pattern of the sex difference in the incidence of NPC could not
be completely explained by known risk factors for NPC. The contributions of intrinsic expo-
sures, such as sex hormones, merit consideration and further investigations.
Ó 2012 Elsevier Ltd. All rights reserved.

⇑ Corresponding author: Address: School of Public Health, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China. Tel.: +86 852
22528791; fax: +86 852 21457489.
E-mail address: shelly@cuhk.edu.hk (L.-A. Tse).

0959-8049/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ejca.2012.07.004
 S.-H. Xie et al. / European Journal of Cancer 49 (2013) 150–155
1. Introduction
Nasopharyngeal carcinoma (NPC) is a malignancy
with remarkable ethnic and geographical variations in
incidence. NPC is rare in most parts of the world with
age-adjusted incidence rates less than 1 per 100,000 per-
sons per year irrespective of sex.1 However, high incidence
rates of NPC are noted in certain areas, especially in
Southern China and Hong Kong. The age-adjusted inci-
dence rates of NPC among males and females in Hong
Kong in 2008 were 14.9 and 4.8 per 100,000, respectively.2
NPC has been for decades a leading cause for cancer inci-
dence among Hong Kong males under the age of 50 years.3
The age-specific curve of incidence rates of NPC
differed greatly across different populations. In most
low-risk populations, the incidence rate of NPC mono-
tonically increases with age, which is similar to that of
most types of epithelia cancers.4–6 However, in high-risk
regions, such as Southern China and Hong Kong, it
increases with age until peaking around ages 50–59 years
and then declines with age.7,8 A minor peak among ado-
lescents and young adults was also observed in several
populations with low risk of NPC.1,4,9–11 The distinct
features of age distributions of incidence rates of NPC
suggest different aetiological profiles that are related to age.
A common feature of the incidence rates of NPC
across populations is the male predominance. In most
populations, the male to female ratio of incidence rate
of NPC is approximately 2–3:1.1,6 Such a male predom-
inance in incidence of NPC may be partly explained by
differences between the sexes in the prevalence of some
environmental risk factors, such as smoking and hazard-
ous occupational exposures. It is also possible that some
intrinsic exposures, such as sex hormones, could account
for the observed male predominance by a protective
effect of endogenous oestrogen but this postulation has
been rarely examined.
In the present study, we described the sex difference in
the incidence of NPC in Hong Kong during the period
1983–2008. We also examined the putative effect of oest-
rogen, using age as a proxy, on the incidence of NPC. It
was hypothesised that a protective effect of oestrogen on
the development of NPC would be reflected by a decline
in the male to female sex ratio of the NPC incidence
after usual menopausal ages due to decreased hormonal
protection in females. This study also aimed to examine
whether the male predominance in NPC incidence is
related to a delayed development in females, as previ-
ously suggested in upper gastrointestinal adenocarcino-
mas which are also cancers with remarkable male
predominance.12,13 Aetiological implications of the
results are discussed hereby.
2. Materials and Methods
All newly diagnosed NPC cases during 1983–2008
were identified from Hong Kong Cancer Registry, a
151
population-based cancer registry. It is a member of the
International Association of Cancer Registries (IACR)
and contributes regularly to “Cancer Incidence in Five
Continents” publications of the IACR. Population data
during the corresponding period were obtained from the
Hong Kong Census and Statistics Department.
Cases were divided into five-year groups beginning
from ages 0–4 years. All cases aged 85 years or older
were combined as one group. For each age group, the
incidence rate of NPC was calculated separately for each
sex by dividing the number of cases by the correspond-
ing population. The male to female ratios of incidence
rates of NPC were calculated by dividing the incidence
rates in males by those in females, and then plotted
against age group. To evaluate potential time period
effects, results were stratified into three periods: 1983–
1991, 1992–2000, and 2000–2008. We also performed
subgroup analyses stratified by histological subtype.
A curve fitting approach was taken to quantitatively
describe the age-specific incidence rates of NPC by sex
using non-linear regressions.12–14 The equation
I(t) = a  (t d)b
(1 kt) modified from previous stud-
ies was fitted to age-specific incidence data using the
SOLVER function of Microsoft Excel. In this equation,
I(t) is the age-specific incidence rate of NPC (1/100,000
person-years) at age t (the mean age of the group), a is
a scaling factor, b is a power term, d is the a delay term
for the time between birth and age of increased incidence
above zero and k is an empirical term to be described. A
logic “if” function was used in Excel such that when
t < d, I(t) = 0. Thus only when d > t was I(t) > 0.
3. Results
During the period 1983–2008, a total of 27,579 new
cases of NPC were identified (20,060 males and 7519
females). The crude annual incidence rates of NPC ran-
ged 20.6–31.9 per 100,000 and 6.7–11.9 per 100,000 for
males and females, respectively. The age-standardised
incidence rates with the World Health Organisation
(WHO) standard population (2000) as reference steadily
decreased from 35.6 per 100,000 person-years in 1983 to
14.9 per 100,000 person-years in 2008 for males, and
from 12.7 per 100,000 person-years in 1983 to 4.8 per
100,000 person-years in 2008 for females.
The age-group specific incidence rates of NPC and
the male to female ratios in the incidence rate during
1983–1008 are shown in Table 1. The incidence rate of
NPC increased with age until it peaked between the ages
50–54 years in males and 50–64 years in females, and
subsequently declined at older ages. The incidence rate
in females at the ages of 20–49 (adulthood before men-
opause age) was lower than that at the ages of 50 or
above (after menopause age) and the difference was sta-
tistically significant (P < 0.01). The overall male to
female ratio of the annual age-standardised incidence
152 S.-H. Xie et al. / European Journal of Cancer 49 (2013) 150–155

Table 1
Distribution of nasopharyngeal carcinoma in different age groups,
stratified by sex, in Hong Kong during the period 1983–2008.
Age groups Male Female Male to
a b a b female ratio
No. IR No. IR
10–14 12 0.2 6 0.1 1.9
15–19 65 1.1 25 0.4 2.4
20–24 147 2.3 118 1.8 1.3
25–29 527 7.7 264 3.5 2.2
30–34 1162 16.2 615 7.8 2.1
35–39 2221 31.4 951 12.6 2.5
40–44 2923 44.8 1087 16.6 2.7
45–49 2999 52.7 1014 18.9 2.8
50–54 2853 60.2 857 19.8 3.0
55–59 2315 58.9 666 18.8 3.1
60–64 1849 56.5 607 20.0 2.8
Fig. 2. Male to female ratios in smoking prevalence and the incidence
65–69 1378 49.4 527 18.9 2.6
rate of nasopharyngeal carcinoma over time in Hong Kong, 1983–
70–74 898 42.2 366 15.4 2.7
2008.
75–79 435 32.3 221 12.6 2.6
80–84 196 29.1 118 10.6 2.7
85+ 61 16.6 65 7.2 2.3
All ages 20060 25.0c 7519 9.3c 2.7
21.8d 8.1d 2.7
a
Number of cases.
b
Incidence rate (1/100,000 person-years).
c
Crude incidence rate (1/100,000 person-years).
d
Age-standardised incidence rate using World Health Organisation
(WHO) World Standard Population 2000 as the reference (1/100,000
person-years).

Fig. 3. Male to female ratios in the incidence rate of nasopharyngeal

carcinoma by histological subtype.

Fig. 1. Male to female ratios in the incidence rate of nasopharyngeal

carcinoma by age groups in Hong Kong, 1983–2008.

rates of NPC ranged 2.2–3.1. Similar to the age-specific

incidence, the male to female ratio of NPC incidence
increased with age until peaking at ages 55–59 years
and showed a decline thereafter (Table 1, Fig. 1). A
sudden increase at ages 15–19 years was also observed.
Age-specific sex ratio curves of the three different peri-
ods display approximately the same overall pattern in
the three periods although the sex ratios of incidence
in the period 2000–2008 were higher than those in the
two previous periods at all age groups (Fig. 1). The
overall male to female ratio in the incidence of NPC
Fig. 4. Modelling of age-specific incidence rates of nasopharyngeal
carcinoma by sex in Hong Kong, 1983–2008.
has slightly increased since the late 1990s (Fig. 2).
Age-specific sex ratio curves of different histological sub-
types showed a similar pattern whereas the ratio of the
keratinising squamous cell carcinoma peaked at earlier
 S.-H. Xie et al. / European Journal of Cancer 49 (2013) 150–155
ages than that of the non-keratinising carcinoma
(Fig. 3).
Results of the curve fitting analysis which described
the age-specific incidence rates of NPC by sex using
non-linear regressions are shown in Fig. 4. The ages at
which the age-incidence curve rose above zero were
similar in males (28.5 years) and in females (23.8 years).
However, modelling of the curves suggested divergent
slopes for men and women (P = 0.02) with a delay in
increasing incidence with age among females by
5–10 years before menopause ages.
4. Discussion
The present study confirmed the long-recognised
male predominance in the incidence rate of NPC. It also
suggested that the male to female ratio of NPC inci-
dence was age-dependent where it increased with age
until peaking at ages 55–59 years and declined thereaf-
ter, in addition to a minor peak among adolescents.
The male predominance in the incidence of NPC was
related to a delayed development in female, especially
before menopause.
The aetiology of NPC has not been completely under-
stood yet. Previous lines of evidence have strongly indi-
cated that Epstein-Barr virus (EBV) infection might play
a crucial role in the development of NPC,1,15–17
although it was not considered to be a sufficient cause
of NPC since EBV is ubiquitous and more than 90%
adults all over the world are healthy carriers of EBV
yet only a very small proportion of the population
develop NPC.1,18 Some other non-viral factors have also
been associated with elevated NPC risk, including inap-
propriate diet,19–21 active smoking,22,23 environmental
tobacco smoke (ETS),23 occupational exposures to
formaldehyde and dusts,24,25 as well as some genetic pre-
dispositions.26–28 The sex difference in incidence of NPC
may be attributable to some of these environmental
exposures which are unequally distributed across sexes.
An alternative explanation is the ‘X-linked recessive
mutation’ hypothesis with the involvement of X-chro-
mosome with EBV infection in the development of
NPC.29 In support of this, Wee et al. have also traced
ancient migration histories and modern genetic signa-
tures and suggested a plausible female transmission.30
The major findings of the present study that both the
incidence rates of NPC and its male to female ratio
increased with age until peaking around ages 55–
59 years and declined at older ages seem not to be
explained by EBV infection because EBV infection per-
sists life-long and does not differ across the sexes.18,31 It
is also less likely to be explained by dietary factors,
active smoking, ETS, or indoor air pollution since there
is no strong evidence supporting declines in the preva-
lence of these exposures after around ages 55–59 years
which are more marked in males. Hazardous occupa-
tional exposures may, at least partly, explain this finding
153
because they are generally more common in men than
women and decrease after ages 55–59 years, the normal
retirement ages. However, occupational exposures may
only explain a small proportion because exposures to
specific carcinogens are generally rare in the population.
The possible explanation of competing risk of deaths on
the declines after ages 55–59 years in the incidence rates
of NPC and its male to female ratio could not be ruled
out. However, during the study period 1983–2008, the
overall mortality rates after the age of 75 years were
approximately 7% and 6% for males and females,
respectively but only 0.4% and 0.2% for males and
females, respectively, before the age of 75 years.32 Since
the competing risk of deaths on disease rates is usually
evident at very old ages while the observed declines
occurred at somewhat earlier ages, the influence of com-
peting risk of deaths on the incidence rates of NPC and
its sex ratio would be minor. In addition, because the life
expectancies for both sexes in Hong Kong have steadily
increased during the past several decades,33 this influ-
ence is expected to be even weaker in the future.
The contributions of intrinsic exposures merit consid-
eration. The hypothesis of a protective effect of oestro-
gen on the risk of developing NPC is supported by the
age-dependent sex ratio in the incidence of NPC with
an inflection at menopause ages and a delay in the devel-
opment of NPC in females before menopause observed
in this study, although the observed decrease in the inci-
dence rate of NPC in females after 60 years old did not
speak for a strong effect of oestrogen. To our knowl-
edge, the association between sex hormone exposures
and the risk of NPC in humans has not been examined
in epidemiological studies till now, which need further
investigations in the future. In addition, this hypothesis
is actually plausible based on biological evidences. For
example, oestrogen is known to mediate inhibition of
inflammatory responses which are important contribut-
ing factors to carcinogenesis.34–36 Furthermore, oestro-
gen is known to exert its biological actions through
the activation of oestrogen receptors (ERs) and ERs
have been identified in NPC tissues.37 A repressor of
ERs, the NAG7, was also found to be a negative regu-
lator of nasopharyngeal carcinoma cell growth.38 Thus,
if the speculated protective effect on NPC risk really
exists, it may be mediated by ERs.
The minor increase in the male to female ratio
in NPC incidence at ages 15–19 observed in the
present study reminds of additional peaks among late
adolescents/young adults in age-incidence curves of
NPC previously reported in several populations.1,4,9–11
The early peaks in the bimodal age-specific curves of
both incidence and sex ratio in incidence could imply
roles of exposures in early life that are differentially
distributed among the two sexes, including changes in
sex hormones. However, because of the relative rarity
of NPC among adolescents/young adults, the early peak
in the age-specific curve of male to female ratio in NPC
154 S.-H. Xie et al. / European Journal of Cancer 49 (2013) 150–155
Table 2
Proportions of the population born in different places in Hong Kong
(%).
Year Male Female
*
Hong China Elsewhere Hong China*
Kong Kong
1991 60.1 36.5 3.5 59.4 34.8
1996 61.7 34.3 4.0 58.9 33.2
2001 62.5 33.7 3.7 57.0 33.8
2006 64.2 32.4 3.4 56.8 34.5
*
Other than Hong Kong.
incidence observed in our study may be due to unstable
incidence rates resulting from small numbers of cases
in these younger age groups, and thus, needs to be
interpreted with caution.
The slightly increased male to female ratio in NPC
incidence in the latest period 2000–2008 observed in this
study might not be explained by the changes in the
smoking prevalence over time in the population. As
shown in Fig. 2, the male to female ratio in smoking
prevalence of the population has declined steadily in
recent 20 years,39 which was the opposite of that in
NPC incidence. However, it is possibly due to the
increased male to female ratio in the smoking prevalence
before the 1990s if there was a latent period between the
exposure to tobacco smokes and the onset of NPC.
Based on the speculated protective role of oestrogen,
the increased male to female ratio in NPC incidence
may be explained by the increased prevalence of oral
contraceptives use, which may have resulted in a
decrease of NPC incidence. According to reports from
The Family Planning Association of Hong Kong, the
proportion of women desiring to have a/another child
in Hong Kong has decreased from 29.1% in 1987 to
12.7% in 2007. Taking oral contraceptives is still a com-
mon practice, which was used by approximately 36% of
women at childbearing ages in Hong Kong.40 The
increased male to female ratio is also possibly explained
by the changes in the population structure. As shown in
Table 2, the proportion of the population born in Hong
Kong has declined in females but increased in males in
recent years.41 Female Hong Kong residents migrated
from other places, probably from low-risk regions of
NPC, may have ‘diluted’ the observed incidence rates
of NPC in females and led to an increased male to
female ratio in NPC incidence.
It was also noted that the male to female ratio in the
incidence rate of keratinising squamous cell carcinoma
peaked at earlier ages than that of non-keratinising car-
cinoma, suggesting different aetiological profiles of these
two histological subtypes of NPC. The observed earlier
peak in the sex ratio in the incidence rate of keratinising
squamous cell carcinoma could be explained by some
environmental exposures at earlier life which are more
prevalent among males, such as smoking22,23,42 and con-
sumption of Cantonese-styled salted fish1,6,19 at early
ages. Although the association between EBV infection
and the risk of keratinising squamous cell carcinoma
remains controversial,43 the keratinising squamous cell
carcinoma appears to be with a stronger relationship
Elsewhere with cigarette smoking than non-keratinising carci-
noma.42 Unfortunately, few previous studies have
5.8 addressed the risk factors of NPC by histological sub-
8.0 type. Future aetiological studies need to take into
9.3
8.8
account the histology given that different histological
subtypes of NPC should not be considered as aetiologi-
cally homogenous.
In summary, this study displayed the age-dependent
pattern of the sex difference in the incidence of NPC
in Hong Kong during the period 1983–2008. This obser-
vation could not be completely explained by known risk
factors for NPC and requires consideration and further
investigations on the roles of intrinsic exposures, such as
sex hormones, in the development of NPC.
Conflict of interest statement
The authors declare that there are no conflicts of
interest.
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