Download Age-Incidence Curves of Nasopharyngeal Carcinoma Worldwide

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Age-Incidence Curves of Nasopharyngeal Carcinoma
Worldwide: Bimodality in Low-Risk Populations
and Aetiologic Implications
Freddie Bray,1,2 Marion Haugen,2 Tron A. Moger,2,3 Steinar Tretli,1
Odd O. Aalen,1,2 and Tom Grotmol1
1
The Cancer Registry of Norway, Institute of Population-Based Cancer Research, and 2Department of Biostatistics, Institute for
Basic Medical Sciences, and 3Institute of Health Management and Health Economics, University of Oslo, Oslo, Norway
Abstract
The distinct geographic variation in the global incidence of nasopharyngeal carcinoma reflects a complex
etiology involving viral, environmental, and genetic
components. The high to intermediate rates observed in
endemic areas contrast markedly with the uniformly
low rates seen in much of the world. An interesting
epidemiologic observation is the early peak in ageincidence curves observed in certain geographically
disparate populations, suggestive of distinct causal
entities and the possible exhaustion of susceptible
individuals from the population at a certain age. The
aim of this study was to systematically evaluate the
age-incidence profiles of NPC worldwide on partitioning populations according to level of risk, in an effort
to provide clues about the importance of early-in-life
factors and genetic susceptibility. Using data from 23
high-quality population-based cancer registries for
the period 1983-1997, a key finding was the consistent
pattern of bimodality that emerged across low-risk
populations, irrespective of geographic location.
Continual increases in NPC risk by age up to a
first peak in late adolescence/early adulthood (ages
15-24 years) were observed, followed by a second peak
later in life (ages 65-79 years). No such early peak in
NPC incidence by age group was evident among the
high-risk populations studied. These findings are
discussed according to existing lines of biological and
epidemiologic evidence related to level of population
risk, age at diagnosis, and histologic subtype. A
modified model for NPC tumor development is
proposed on the basis of these observations. (Cancer
Epidemiol Biomarkers Prev 2008;17(9):2356 – 65)
Introduction
The incidence of nasopharyngeal carcinoma (NPC) has a
rather distinct and geographically well-defined distribution worldwide. High to intermediate rates are observed
in certain populations and regions in China, Southeast
Asia, Northern Africa; among the Inuit populations of
Alaska, Greenland, and Northern Canada; and in
migrants of Chinese and Filipino descent (1-6). Outside
of these endemic areas, however, NPC can be considered
a rather rare neoplasm. To illustrate, incidence rates in
high-risk Hong Kong were between 30 and 60 times
those in equivalent national or regional registry populations in Colombia, the United States, Finland, Zimbabwe,
India, and Japan over the period 1998-2002 (4).
The etiology of NPC, described by several experts as
enigmatic (7, 8), has viral, environmental, and genetic
components. Whereas the EBV is considered a critical
step in the progression of NPC from precancerous lesion
to malignancy, only a fraction of the EBV-infected
population go on to develop NPC, and early seroepidemiologic surveys showed the virus to be both a lifelong
infection and one that is ubiquitous in most areas of the
Received 5/20/08; revised 6/18/08; accepted 6/30/08.
Grant support: (sfi)2—Statistics for Innovation (M. Haugen).
Requests for reprints: Freddie Bray, The Cancer Registry of Norway, Institute of
Population-based Cancer Research, Montebello, N-0310 Oslo, Norway. Phone:
47-23-33-39-15; Fax: 47-22-45-13-70. E-mail: [email protected]
Copyright D 2008 American Association for Cancer Research.
doi:10.1158/1055-9965.EPI-08-0461
world (9). That persons migrating from high- to low-risk
countries retained incidence rates that were intermediate
between natives of their host country and their country
of origin (10) has long implied a role for other
contributory factors, including environmental and host
(genetic) factors, possibly interacting with EBV.
Much of our understanding of the underlying
risk determinants of NPC, including the role of a
nitrosamine-rich diet, has arisen from studies based
on individuals from populations at high to intermediate
risk. The two comprehensive epidemiologic reviews
of NPC in the recent past have noted the need for
further elucidation of the risk factors at play in low-risk
populations (8, 11). In particular, there is a need
to identify sources of variability that may provide
clues to the determinants of NPC in nonendemic
populations, and how they contrast with NPC cases
in high-risk populations. Some of the recent developments in our understanding of NPC etiology have
arisen following stratification by degree of risk—often
characterized by geographic location—and histologic
subtype of diagnosis, as defined in the recent WHO
classification (12).
An investigation of the properties of the age-incidence
curves of NPC in different populations can be informative. Rates of NPC are often described as constantly
increasing with age in the epidemiologic review literature (6, 8), although earlier peaks in both high- and
low-risk regions have been reported (8, 13-17). The
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Table 1. Characteristics of the registry populations by region and risk group
Mean annual
population
coverage, 1983-1997
Low-risk
India
Chennai*
Mumbai*
Japan
Miyagi
Osaka
North America
Canada
SEER White
North West Europe
Denmark
Estonia
c
Switzerland, Zurich
UK, Birmingham
UK, Merseyside
UK, North Western
b
UK, Oxford
UK, South Thames
UK, Yorkshire
UK, Scotland
Australia
New South Wales
South
Victoria
High-risk
Philippines, Manila*
Thailand, Chiang Mai*
Singapore: Chinesex
Singapore: Malayx
Mean annual
no. cases,
1983-1997
119.8
13.5
3.8
9.8
10.9
2.2
8.7
46.7
27.6
19.1
37.6
5.2
1.5
1.1
5.3
2.4
4.0
2.6
6.7
3.7
5.1
11.6
5.8
1.4
4.3
8.4
4.5
1.3
2.1
0.4
584
51
19
32
55
11
44
262
179
83
145
22
8
4
18
12
16
8
24
11
22
75
42
6
27
464
153
29
269
13
ASR, 1983-1997
Age (y)
Males
Females
1st peak
2nd peak
0.5
0.6
0.7
0.6
0.6
0.5
0.6
0.7
0.8
0.5
0.4
0.4
0.6
0.4
0.4
0.5
0.4
0.3
0.4
0.3
0.5
0.7
0.9
0.5
0.8
8.4
7.5
2.9
17.4
5.9
0.2
0.3
0.3
0.2
0.2
0.2
0.2
0.3
0.3
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.2
0.2
0.3
0.1
0.3
3.2
3.0
1.4
6.6
1.9
15-19
15-19
65-69
65-69
15-19
65-69
15-19
65-69
15-19
70-74
15-19
75-79
—
—
—
—
—
—
—
—
45-49
55-59
Abbreviations: ASR, age-standardized rate; SEER, Surveillance, Epidemiology, and End Results.
* Population data available in 16 age groups (0.4, 5-9,. . ., 70-74, 75+).
cIncidence data available for the years of diagnosis 1983-1996.
bIncidence data available for the years of diagnosis 1985-1997.
x Population data available in 17 age groups (0.4, 5-9,. . ., 75-79, 80+).
bimodality of disease rates, a phenomenon commonly
observed for Hodgkin lymphoma, suggests the possibility of distinct causal entities (18) and the exhaustion of a
pool of susceptible individuals, leaving a group who are,
in theory at least, initially nonsusceptible (19). For NPC, a
systematic evaluation of the age-incidence profiles
according to level of risk may provide clues about the
importance of early-life environmental factors and
genetic susceptibility.
This descriptive study thus critically examines
the shape of cross-sectional age-incidence curves in
13 countries across four continents. Data from 23
high-quality population-based cancer registries over the
diagnostic period 1983-1997 are dichotomized into those
considered at low and high risk of NPC. The results are
interpreted using existing lines of biological and epidemiologic evidence, in relation to level of population risk,
age, and microscopic subtype.
Subjects and Methods
The Cancer Incidence in Five Continents (CI5) Vol. I to VIII
ADDS database contains global cancer incidence
data from consistently high-quality population-based
registries that have provided histologic data covering a
minimum span of 12 consecutive years (3), as part of
their submission to successive CI5 Volumes. We initially
extracted diagnoses of nasopharyngeal cancer (ICD-10
C11) for 72 cancer registries, together with the
corresponding population data by year of diagnosis,
sex, age, and, where available, ethnicity. Whereas
we extracted nasopharyngeal ‘‘cancers’’ rather than
‘‘carcinomas,’’ the term NPC is used here to identify
the latter, given that carcinomas represent the vast
majority of nasopharyngeal tumors, and the subset for
which most epidemiologic studies have focused.
We restricted analyses to the period 1983-1997 to
enable a sufficiently long span of data available that
allowed as many registries to contribute as possible. To
remove some of the uncertainty in the rates by age and
over time, we excluded registries with an average annual
population coverage of less than 1 million inhabitants
across the 15-y period. We retained registry data on the
Malay population of Singapore however, given its
relatively high NPC incidence. We used U.S. incidence
data (for Whites only) based on the Surveillance,
Epidemiology, and End Results 9 registries, and national
data for Canada. Because there were only six NPC
diagnoses in the Quito Registry in Ecuador 1983-1997,
this population was excluded from further analyses.
For the remaining 23 registry populations, incidence
data were available by 5-y age group and sex for each of
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Age-Incidence Curves of NPC Worldwide
the years of diagnosis 1983-1997 and available for
18 age groups (0.4, 5-9,. . ., 80-84, 85+; see footnotes of
Table 1 for exceptions). The mean number of NPC cases
diagnosed annually during the period 1983-1997 varied
from 4 in Zurich, Switzerland (mean annual population
of 1.1 million) through to 269 among the Chinese
population of Singapore (mean annual population of
2.1 million). Regional registries were aggregated to
national or larger area levels on the basis of geographic
area, thus enabling sufficient numbers for meaningful
age-specific analyses. Age-specific rates were calculated
and were summarized as age-standardized rates using
the weights from the world standard population (20, 21).
Those populations with age-adjusted rates of >2.5 were
then identified as ‘‘high-risk’’ countries, with the
remainder considered as ‘‘low-risk’’ (rates V2.5). Further
analyses and the presentation of results reflect this
stratification (Table 1; Fig. 1). The low-risk and high-risk
age-standardized rates were based on simple averages of
the age-standardized rates in the respective registry
populations. To assess relative changes over time, trends
of age-standardized rates by 5-y period are presented on
a semi-log scale by area, sex, and risk group.
The aggregated age-specific rates were calculated by
weighting the counts and person-years of the constituent
registry populations by the square root of the personyears, allowing smaller populations to attain a relatively
higher weighting in the rate calculation. Graphs of rates
versus age are presented on a semi-log scale to convey
the structure and relative magnitude of the age curves
by geographic area and sex, stratified by risk status. The
overall low-risk age-specific rates are based on 18 age
groups, but incidence in the last age group (75+) is
excluded for the two registry populations missing
population data. The overall age-specific rates in
high-risk populations are based on the 16 age groups
for which rates could be calculated in each of the
four comprising populations.
Results
Geographic Variations 1983-1997. For the entire study
period, the four high-risk populations in Table 1
contribute f44% of the 1,048 mean annual number
NPC cases, but only 6.5% of the mean annual personyears at risk (f128 million). In the low-risk areas, the
aggregated age-adjusted rates in men and women are
uniformly low at 0.5 and 0.2 (per 100,000), respectively,
with an f3-fold variation in rates between populations,
observed in both sexes.
There is greater variation in the rates in the Asian
populations comprising the high-risk group (Fig. 1), with
the highest rate of 17.4 observed among the Chinese
population of Singapore and the lowest in Chiang Mai,
Thailand (2.9). Rates in the high-risk group are thus four
to eight times higher than those comprising the lowrisk group. In women in the high-risk areas, rates are
lower and there is less variation, although the rank
ordering of registries (according to the magnitude of
their rates) is similar to that of men. The male/female
ratio tends to vary uniformly from 2 to 3, irrespective
of risk group, with no emerging patterns related to geographic location.
Age-Specific Rates 1983-1997
Low-Risk Populations. The age-specific incidences rates
of NPC by 5-year age group in the five low-risk
countries/regions (and overall) are shown in Fig. 2A,
and the observed peaks are noted in Table 1. A consistent
pattern across populations emerges from continual
increases in NPC risk by age up to a first peak in late
adolescence/early adulthood followed by a second peak
later in life (ages 65-79 years). This observation tends to be
clearer among men, but is still apparent in women,
although the reverse is true in North America, with the
peak and decline more evident in female rates. The first
low-risk peak commonly occurs in the age group 15-19
years, and is followed by a subsequent decline that is
Figure 1. NPC age-standardized incidence rates (per 100,000 person-years at risk) according to the studied registry population and
sex. The two risk groups are indicated, as is the magnitude of the rates in selected populations.
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observed to vary from 5 to 10 years in Australia, Northern
and Western Europe, and North America to up to 20 years
in the low-risk Asian populations in this study (India and
Japan). It is also notable that male/female rate ratios up to
the age of 30 years are above unity (closer to 2) in most of
the low-risk populations in Fig. 2A.
In general, a ‘‘second wave’’ involves rates of NPC
continually increasing from the age 30 to 39 years,
toward a further peak at an elderly age. This second
maximum is observed to vary between countries and
regions, occurring at 65 to 69 years in North American
men, for example, but some 10 to 15 years later in
Australia and Northern Europe.
High-Risk Populations. No such early peak in NPC
incidence with age is evident in the four high-risk
populations (Fig. 2B), although a slight kink in the
continual increase in rates by age may be observed, most
notably among Thai men. What is more apparent is
an earlier decline in age-incidence (in middle-age, ages
45-60 years) than seen in any low-risk population
under study. This is most striking among the Chinese
population of Singapore in both sexes, with a peak and
subsequent decline beginning in the rates of the age
group 45-49 years. Such an observation is less discernible
in the incidence rates in the Thai and Filipino men and
women, although there seems to be an early plateau in
the rates in the former population.
Time Trends 1983-1997. Figure 3 shows the all-ages
standardized rates in consecutive 3-year periods. The
time trends for the period 1983 through to 1997 are
generally flat in both low- and high-risk populations.
There is, however, some evidence of a minor decline
among women in the late 1980s and early 1990s, most
notably among the Chinese population of Singapore and
residents of Chiang Mai, Thailand. Trends restricted to
NPC at younger ages (ages under 50 years) are not
dissimilar, although declines in both sexes are more
visible in recent periods in the Singapore Chinese and
Filipino populations (data not shown).
Discussion
This descriptive study has compared international
age curves of NPC incidence 1983-1997 on the basis of
high-quality cancer registration data worldwide. On
dichotomizing these populations according to the
magnitude of their rates, the key finding is that
there exists distinctive age-incidence curve for NPC for
low- and high-risk groups, respectively, and in particular, that the age-incidence curves seem to be uniformly
bimodal in every low-risk population, irrespective of
geographic location and sex. This finding is perhaps at
odds with the widely held concept that NPC incidence
increases monotonically with age in the majority of
low-risk populations, as reported in recent comprehensive reviews (6, 8). The low-risk curves shown in
this study convey a systematic pattern of continual
increases in risk by age up to a first peak in late
adolescence/early adulthood (ages 15-24 years), a
subsequent decline in risk of up to the ages 30-39 years,
followed by increasing risk with age to a second peak
later in life (ages 65-79 years).
The bimodality property of the NPC incidence rates has
previously been described in selected low-risk populations including (in both Whites and Blacks) the United
States (13), Malaysia (22), and among a hospital series in
Mumbai, India (14). Given the relative rarity of NPC
incidence in nonendemic areas and the random variation
inherent in the age curves, it is perhaps not surprising that
a more general observation of bimodality has not been
reported previously. Evidence for such an attribute was
achieved only on aggregating incidence and person-years
over a number of registries across a 15-year span, and a
limitation of this study is the necessity of doing so.
Registry data were collapsed on the basis of geographic proximity rather than a priori knowledge of a
correspondence in underlying risk determinants for
NPC between populations. Further, basing the rates on
diagnoses 1983-1997 may have led to a distortion in the
age curves where trends diverge by age group during
this calendar period, as would be evident if strong birth
cohort effects were present, markers of corresponding
changes in the prevalence of underlying risk factors. Both
the age-adjusted and age-specific trends seemed to be
rather stable among the low-risk populations, however,
and given the similarity in magnitude and structure of
the registry population age-incidence curves within a
predefined geographic area, it seemed reasonable to
aggregate the data for the predefined purposes. It is
also evident that the broad dichotomization of risk levels
into only two categories is a rather crude maneuver,
particularly given the wide variation observed in rates
among populations within the high-risk group, although,
however, this was necessary simplification, given the
limited data available.
The first peak of the bimodal age-incidence curve in
low-risk populations is similar to that of clear cell
adenocarcinoma of the vagina. This condition is caused
by diethylstilboestrol exposure during pregnancy,
and there is thus reason to believe that a similar time
frame is underlying the early peak of the current NPC
age-incidence curve. The first ‘‘hit’’ in individuals
diagnosed with NPC in late adolescence/early adulthood
in the low-risk group, is most likely a germ-line alteration
(major gene transmission) according to the current model
for the development of NPC (Chan et al., 2004 in ref. 12).
The molecular mechanisms pertaining to these early
events in the low-risk populations, however, are not very
well characterized. The familial cases compose the
majority within this group of NPC, which supports the
notion that susceptibility genes play an important role.
In adult NPC, EBV infection is well established as a
causative agent, being responsible for the second hit
in the pathogenesis. On the molecular level, 10 of the
100 EBV genes incorporated in latently infected cells are
expressed, the membrane protein LMP1 being the most
important with its oncogenic properties. Recent evidence
suggests a similar role for EBV infection in the
pathogenesis of NPC occurring in late adolescence/early
adulthood [reviewed by Ayan et al. (22), and references
therein]. The novel finding of an early peak in low-risk
populations implies a role for susceptibility genes in the
pathogenesis and would hopefully stimulate research
aimed at identification of such genes. Several susceptibility genes have already been implicated in the etiology
of NPC, such as certain alleles of the human leukocyte
antigen classes I and II. Human leukocyte antigen
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Age-Incidence Curves of NPC Worldwide
Figure 2. A. NPC incidence rates (per 100,000
person-years at risk) versus age (5-y groupings)
by registry population in
each of the low-risk
countries/regions, by
sex. The aggregated rates
are in bold, and were
calculated by weighting
the counts and personyears by the square root
of the total population
1983-1997. Vertical lines
are included to highlight
the rates in age groups
15-24 and 65-74 y.
plays an important role in presenting the viral antigens
to the T cells of the immune system, and it has been
shown that alleles less efficient at inducing CTL responses are more frequent in high-risk than in low-risk
populations (23). It is plausible that polymorphisms in
human leukocyte antigen, as well as in other relevant
susceptibility genes, play a role for the development of
NPC among adolescents in these populations. Our
consistent finding of higher NPC incidence rates among
younger men than younger women (aged <30 years),
however, could also imply a role for early-in-life environmental factors that are differentially distributed
among the sexes.
Of recent interest has been the relationship of age
and pathologic subtype, and in Table 2, the three sets of
age-incidence patterns observed in this article are linked
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Figure 2 Continued. B.
NPC incidence rates (per
100,000 person-years at
risk) versus age (5-y
groupings) by registry
population in each of the
high-risk countries/
regions, by sex. The aggregated rates are in bold,
and were calculated by
weighting the counts and
p e r s o n -y e a r s b y t he
square root of the total
population 1983-1997.
Vertical lines are included
to highlight the rates in
age groups 15-24 and 4549 y.
to established or putative risk factors for the three
distinct histopathologic entities developed by the WHO
(12). In the WHO system, the first two groups of NPC are
moderately differentiated squamous cell carcinomas
with keratin production (type I) or nonkeratinizing (type
II), with a third group containing undifferentiated
carcinomas or lymphoepitheliomas (type III). There
are a number of intriguing epidemiologic differences
between these subtypes in low-risk populations. Type I is
more common in low-incidence populations (13, 24) and
nonfamilial cases (25) and is associated with an older age
at diagnosis. Type I is also the only subtype that has been
associated with alcohol and cigarette consumption (24),
and in an occupational study examining subtype, type I
(but not types II and III) has been linked with
formaldehyde exposure (26).
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Age-Incidence Curves of NPC Worldwide
Figure 3. Trends in agestandardized (world) NPC
incidence rates (per
100,000 person-years at
risk) by calendar period
in countries/region classified as low or high risk,
by sex. Rates are based on
3-y nonoverlapping aggregates of annual data over
the period 1983-1997.
It may be that the increases in risk in low-incidence
populations in later ages—following the first peak to a
second maximum during, or soon after, the onset of
elderly age—are the result of sporadic NPC development
associated with environmental and lifestyle-related risk
factors postulated for NPC. Heavy tobacco (24, 27) and
alcohol use (24) have been associated with an increased
risk of overall NPC, with the association most notable
among those diagnosed at ages z50 years (24). A decline
in smoking has been hypothesized as a contributor to the
overall decline in incidence trends among U.S. men (28).
The contribution of occupational exposure such as
formaldehyde and NPC risk remains unresolved. Whereas an IARC Monograph Working Group concluded that
there was ‘‘sufficient epidemiologic evidence that formaldehyde causes NPC in humans’’ (29), other reviews
(e.g., refs. 8, 30) have considered the evidence of an
association inconsistent.
Perhaps because of the relative rarity of NPC, there
has been little breakthrough in explaining younger cases
of NPC in low-risk populations, although they tend to be
more often familial cases diagnosed with type II or type
III NPC, with the latter the more commonly diagnosed
type in children (31). Undifferentiated nasopharyngeal
carcinoma may thus develop through exposure to factors
early in life, in particular EBV infection, affecting
genetically susceptible individuals. Types II and III are
more commonly associated with elevated EBV titers,
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Table 2. Risk factors associated with NPC according to WHO microscopic type and population level of risk
WHO type
Putative risk factors
Type I, keratinizing squamous cell
Smoking
Type II, nonkeratinizing
squamous cell, differentiated
Type III, nonkeratinizing
squamous cell, undifferentiated
Mainly affecting low-risk
populations and older ages
EBV?
Formaldehyde?
Nonfamilial factors
EBV
Familial factors
Preserved foods?
EBV
Risk group/age affected
5% of all cases
Mainly affecting high-risk
populations, as well as children
(irrespective of level of risk in population)
Preserved foods
Familial factors
with EBV detection in type I less consistent (8). A study
of NPC cases in low-risk setting (the United States) has
also reported an increased risk of types II and III with
frequent consumption of preserved meat (32).
Among high- to intermediate-risk populations, type III
tumors predominate (28, 33). The age-incidence curves in
this study exhibit a single peak with a decline observed
earlier than in the low-incidence populations. Whereas a
bimodal relation has been reported in several intermediate-risk populations in Northern Africa (15) and Western
Asia (8, 16, 17), the unimodal age pattern in the highestrisk populations is well established. The decline with age
seen in Singapore Chinese, for instance, beginning at the
age of 50 years, has been postulated as compatible with
either a viral or carcinogenic exposure early in life, or
an exhaustion of the pool of genetically susceptible
individuals (34). Whereas trends in NPC have been
reported as rather stable in Southern China (35), declines
have been noted in a number of populations of Chinese
origin over the last 20 years (28, 33, 36-38). Interestingly,
those studies that were able to stratify by histologic
category reported that the observed decreases were
largely restricted to type I tumors (28, 33), suggesting
that it is the changing prevalence of type I risk factors
that dominates the trends.
Numerous studies have reported increased risks
associated with certain foods eaten in high-risk areas
including salted fish, various preserved foods, and hot
spices, which are high in nitroso compounds and volatile
nitrosamines (see ref. 8), and it is possible that such a
chronic dietary exposure over a sustained period of time
may explain the age curves seen in high-risk populations.
Figure 4. Three pathways leading to the development of NPC,
modified from Chan
et al., 2004 in chapter 2
of ref. 12.
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Exposure to such foods during the time window that
includes weaning and childhood may be particularly
important (39, 40). The time of infection with EBV in
early life may also be critical; a Danish study reported
evidence of children from the high-risk Eskimo population in Greenland becoming infected with EBV at an
earlier age than children in low-risk Denmark (41).
Conversely, in low-risk populations, the diagnosis of
infectious mononucleosis, a marker of late infection with
EBV, has been linked with decreased NPC risk (24).
It can be hypothesized that bimodality is an inherent
feature of NPC age-incidence curves irrespective of level
of risk, and that the first peak is simply masked in the
Filipino, Singaporean, and Thai populations by genetic
and epigenetic factors associated with their high-risk
status. That the apparent kink in the age-incidence
curves at ages 15-24 years in the intermediate-risk groups
(Chiang Mai and Singapore Malay) is not evident among
the highest-risk Singapore Chinese would tend to
support this. Less speculatively, real differences in the
NPC rates between low-, intermediate-, and high-risk
populations at younger ages should primarily relate to
early events in the tumorigenesis pathway, and would
likely comprise differentials in both susceptibility to
genetic damage and exposures to environmental causes.
Loss of heterozygosity on chromosomes 3p and 9p is
such an early event that is linked to dietary habits,
including salted fish intake (42). Further, the combined
frequency for loss of heterozygosity on 3p and 9p in
histologically normal nasopharyngeal epithelium has
been shown to be much higher in high-risk than in
low-risk populations (43). More generally, there are
aspects of the rationale for bimodality in low-risk
populations, including germ-line mutations and human
leukocyte antigen associations, which would also,
given the current evidence, apply in intermediate- and
high-risk groups.
This descriptive study has presented the age-incidence
curves of NPC partitioned into level of risk, with a novel
finding that there is clear evidence of uniform bimodality
in low-risk populations worldwide, irrespective of place
of residence and sex. The early peak in incidence,
although unexplained, suggests a role for major susceptibility genes in the pathogenesis, possibly mediated
by other factors including EBV infection, for which
age at infection may be critical. The second peak in
low-incidence populations may owe more to the classic
risk factors for NPC, heavy smoking, high alcohol
consumption, and possibly long-term exposure to certain
occupational carcinogens; other unexplained factors,
however, may also be in operation. The observed curves
in high-risk populations are unimodal, although a
masking of the first peak via early epigenetic events is
a possible explanation for the lack of bimodality.
In summary, Fig. 4 provides an adapted and
simplified model for the development of NPC along
three pathways and incorporates level of risk, age, and
pathologic subtype. In brief, type I tumors, which
predominate in low-risk populations, are considered as
mainly occurring through environmental exposures such
as smoking, with the presence of latent EBV infection
indicated as a potentially important step in the pathway.
The pathogenesis of NPC at young ages, which are
mainly type II/III tumors, includes EBV infection at a
critical later step following either germ-line mutations of
individuals with familial predisposition or polymorphic
variants involving minor genes. Finally, the pathway for
type III tumors, common in high-risk populations,
includes an initial genetic polymorphism associated with
chronic (dietary) exposure to nitrosamine compounds.
EBV infection is also considered a critical step in the
pathway of undifferentiated malignancies.
Further studies of the age-incidence curves according
to WHO histologic type would certainly seem to be
warranted. Another aspect of the age-incidence curves
that could be further explored involves the concept of
‘‘frailty’’ or, in terms of incidence, ‘‘susceptibility’’ to the
development of NPC. A frailty effect is one that
describes the influence of individual selection in the
general population. As an example, one explanation for
the first peak in low-incidence populations could be the
exhaustion of a fixed number of susceptible individuals
in the population at a given age, with the decline in rates
being the result of the remaining group remaining at low
risk at given age at diagnosis (in theory, they are
nonsusceptible). Frailty models have been developed
and successfully applied to better understand the
biological and etiologic mechanisms involved in the
development of testicular cancer (44, 45), and it would
seem to be appropriate to apply such a frailty modeling
approach to rates of NPC. Model-based estimates of the
proportion susceptible to NPC, and the approximate
number of genetic events required for the tumor to
develop would better quantify and aid interpretation of
the apparent differences in age-incidence by geographical area and sex.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgments
The costs of publication of this article were defrayed in part by
the payment of page charges. This article must therefore be
hereby marked advertisement in accordance with 18 U.S.C.
Section 1734 solely to indicate this fact.
We thank the numerous population-based cancer registries
worldwide that have contributed their data to successive
volumes of Cancer Incidence in Five Continents, thus making the
present study possible.
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2365
Age-Incidence Curves of Nasopharyngeal Carcinoma
Worldwide: Bimodality in Low-Risk Populations and
Aetiologic Implications
Freddie Bray, Marion Haugen, Tron A. Moger, et al.
Cancer Epidemiol Biomarkers Prev 2008;17:2356-2365.
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