Download Reproduction-related Risk Factors for Mucinous and Nonmucinous

American Journal of Epidemiology
Copyright © 2001 by The Johns Hopkins University School of Hygiene and Public Health
All rights reserved
Vol. 153, No. 9
Printed in U.S.A.
Risk Factors for Mucinous and Nonmucinous Ovarian Cancer Purdie et al.
Reproduction-related Risk Factors for Mucinous and Nonmucinous Epithelial
Ovarian Cancer
David M. Purdie,1 Victor Siskind,1 Christopher J. Bain,2 Penelope M. Webb,1 and Adèle C. Green1
The proposition that mucinous ovarian cancer has an etiology distinct from that of other histologic types has
been evaluated using data from a population-based case-control study of epithelial ovarian cancer conducted in
1990–1993 among Australian women aged 18–79 years. The protective effects of parity and oral contraceptive
use were greater in nonmucinous than in mucinous ovarian tumors. However, these differences appeared to be
driven largely by the effect of ovulatory life, which was positively associated with nonmucinous tumors only. An
association with family history of breast and/or ovarian cancer also appeared to be restricted to nonmucinous
cancers. These results lend support to the hypothesis that mucinous and nonmucinous ovarian tumors develop
via different causal mechanisms. Am J Epidemiol 2001;153:860–4.
contraceptives, oral; histology; ovarian neoplasms; parity
In a recent paper, Risch et al. (1) proposed that epithelial
ovarian cancer is not a homogeneous entity from an etiologic
point of view. In particular, they presented evidence suggesting that parity, oral contraceptive use, and family history of
ovarian cancer have a different relation to carcinomas of the
mucinous subtype than they do to other histologic types. A
number of other studies have presented similar findings
(2–4). A more recent publication (5), however, did not support this proposition, although differences in other reproductive factors, such as histories of infertility or hysterectomy,
were suggested. Moreover, our analysis of the association
between oral contraceptives and ovarian cancer showed that
the odds ratio of mucinous carcinoma for a year of oral contraceptive use, adjusted for the number of lifetime ovulatory
cycles, was very similar to that of both serous and endometrioid types (6). To clarify whether mucinous tumors do
constitute a distinct etiologic subgroup, we present here a
comparison of mucinous versus other types of epithelial
ovarian cancer combined with respect to their reproductive
and gynecologic risk factor profiles.
states. Women diagnosed in 1991 and 1992 were recruited
in New South Wales and Victoria; in Queensland, where the
cancer registry was an additional source, women diagnosed
in these 2 years and also in 1993 and the latter part of 1990
were eligible for enrollment. A specialist gynecologic
pathologist in each state conducted an independent histologic review of all specimens. A detailed description of the
study has been published (6, 7). Briefly, after consent from
the attending doctor, research assistants invited all eligible
cases (those aged between 18 and 79 years and competent to
complete a questionnaire) to participate either prior to discharge or while attending the clinic for follow-up.
Controls were selected from the electoral roll by a random procedure designed to yield an age and regional distribution similar to that of the cases; enrollment to vote is
compulsory in Australia. Women with a history of ovarian
cancer or bilateral oophorectomy, or who were incapable of
completing the questionnaire, were ineligible for inclusion
in the control series. Two cases and two controls whose calendars contained insufficient information on contraceptive
practices were excluded, as were those cases known to be
not on the electoral roll. Ethical approval for the study was
obtained from all participating hospitals and institutions,
and all women in the study, as well as all treating doctors,
provided informed consent.
Trained interviewers administered a standard questionnaire in person either in the clinic (cases) or in the woman’s
home (some cases, all controls). The topics covered included
demography, medical and surgical history, and family history
of cancer. We collected details of each woman’s reproductive
experience by means of a pregnancy and lactation record,
including the time to return of menses following pregnancy,
and a month-by-month calendar dealing with contraception
and attempts to become pregnant during the reproductive
years. The questionnaire used is available from the study’s
web site: http://www.qimr.edu.au/research/labs/davidp/swh.
MATERIALS AND METHODS
We ascertained all histologically confirmed incident cases
of primary epithelial ovarian cancer registered in all major
gynecologic-oncology treatment centers in three Australian
Received for publication February 11, 2000, and accepted for
publication September 18, 2000.
Abbreviation: CI, confidence interval.
1
Queensland Institute of Medical Research, Brisbane,
Queensland, Australia.
2
Department of Social and Preventive Medicine, The University of
Queensland, Brisbane, Queensland, Australia.
Reprint requests to Dr. David Purdie, Queensland Institute of
Medical Research, Post Office, Royal Brisbane Hospital, Brisbane,
Queensland 4029, Australia (e-mail: [email protected]).
860
Risk Factors for Mucinous and Nonmucinous Ovarian Cancer 861
This procedure yielded 791 cases of epithelial ovarian
cancer and 853 controls with data suitable for analysis,
reflecting response rates of 90 percent and 73 percent,
respectively. Based on histologic review, cases were classified into the following subtypes: 114 (14.4 percent) as mucinous, 415 (52.5 percent) as serous, 99 (12.5 percent) as
endometrioid, and 57 (7.2 percent) as clear cell. The remainder (n 106, 13.4 percent) were mainly of mixed or undifferentiated histologic type, two being transitional cell
(Brenner) tumors.
The factors examined were duration of oral contraceptive
use, parity, breastfeeding, tubal sterilization, hysterectomy,
history of breast or ovarian cancer in a first-degree relative,
and infertility as measured by self-reported difficulty in conceiving (7). For each woman we also calculated her ovulatory life within each decade of life between the age at
menarche and the age at menopause (8), diagnosis, or interview, as appropriate. From the length of each full or partial
decade we subtracted the total reported anovulatory period
in that decade due to pregnancy, postpartum amenorrhea,
oral contraceptive use, and/or amenorrhea due to illness,
underweight, or other causes. We then weighted the results
from each decade by the intensity of ovulation in that
decade of life applicable to this population (9) and summed.
We adjusted the total number of ovulations upward or downward depending on the extent to which each participant’s
reported average menstrual interval was proportionately
lower or higher, respectively, than a standard 4 weeks. The
total number of ovulations was then divided by 13, the average number of menstrual cycles per year, to create the variable “ovulation years.”
Age, years of oral contraceptive use (among users), and
ovulation years were all approximately normally distributed,
so mean differences were assessed using Student’s t test.
Differences in the prevalence of exposure between cases with
mucinous and nonmucinous ovarian tumors were tested using
Pearson’s chi-square statistic.
Multivariate analysis was by means of polytomous logistic
regression in which the response categories were mucinous
cancers, nonmucinous cancers, and controls. We conducted
two analyses that differed only in that the factor ovulatory
years was omitted in the first model but included in the second. Additional covariates were age in years and its square,
body mass index (split at the 65th and 85th percentiles),
smoking (current; past; never), alcohol consumption (none;
0.1–2.5 g/day; >2.5 g/day; unknown), and hormone replacement therapy, all of which have previously been found to be
associated with disease status in these data (6, 7, 10). Agesquared was included to allow for residual confounding inadequately accounted for by the linear age term. This had the
same effect as adjusting for age in 5-year bands with greater
statistical efficiency. The net effect of ovulation years on the
risk of mucinous and nonmucinous tumors was assessed in a
model not including factors from which it was constructed,
namely, duration of oral contraceptive use, parity, and breastfeeding. Significance levels for the comparisons between
mucinous and nonmucinous forms of ovarian cancer were
derived from a similar logistic model comparing mucinous
with nonmucinous cancers in the absence of the control
Am J Epidemiol Vol. 153, No. 9, 2001
group. The statistical software packages SAS (11) and
SUDAAN (12) were used to conduct all analyses.
RESULTS
Table 1 lists the percentages of cases of mucinous and
other histologic types, along with controls, according to
their risk factor profile. Means, along with 95 percent confidence intervals, for age, duration of oral contraceptive use
(among users), and years of ovulatory life are also presented
for the three groups. Women with mucinous ovarian tumors
were in general considerably younger than were cases with
nonmucinous tumors or controls, although mucinous tumors
did occur in women over the whole age range. The percentage of mucinous tumors that were of borderline malignancy
was significantly higher than that for nonmucinous tumors
(table 1).
Crudely, significant differences between mucinous and
nonmucinous tumors were seen for breastfeeding, family
history of ovarian cancer, menopausal status, ever use of
oral contraceptives, and mean duration of ovulatory life.
Some of these differences, in particular the last three, can be
attributed to the 10-year mean age difference between cases
with mucinous and nonmucinous tumors.
The odds ratios (and 95 percent confidence intervals) of
mucinous and nonmucinous tumors versus controls for the
factors included in the polytomous logistic regression models are presented in table 2, along with the significance level
of the mucinous versus nonmucinous comparison (i.e., without controls). The duration of oral contraceptive use had a
lesser protective effect, at a marginally significant level,
among cases with mucinous cancer than among other cases.
The protective effects for parity were also smaller in the
mucinous group, albeit not significantly so. Differences
between the mucinous and nonmucinous groups with
respect to hysterectomy, tubal sterilization, and breastfeeding were not significant. A history of self-reported infertility
was positively associated with the occurrence of nonmucinous tumors only. The difference between mucinous and
nonmucinous tumors, however, was not significant. A history of breast or ovarian cancer in a first-degree relative
showed a significant positive association with nonmucinous
tumors only.
The odds ratios associated with each year’s ovulation
assessed without adjusting for oral contraceptive use, parity,
and breastfeeding were 1.01 (95 percent confidence interval
(CI): 0.98, 1.04) for mucinous and 1.05 (95 percent CI: 1.04,
1.07) for nonmucinous tumors (p value for difference 0.003). In light of this difference, we conducted a second
analysis to examine the effects of the reproductive variables
with the inclusion of ovulatory years in the multivariate
model (table 2).
Once ovulation years were taken into consideration, there
was no longer a meaningful difference between the two histologic groups in their odds ratios for the duration of oral
contraceptive use, and there was less difference between the
coefficients for parity. The odds ratios for hysterectomy,
tubal sterilization, breastfeeding, self-reported infertility,
and history of breast or ovarian cancer in a first-degree rel-
862
Purdie et al.
TABLE 1. Distribution of demographic and risk factor data for cases with mucinous and nonmucinous
ovarian tumors and controls, Australia, 1990–1993
Factor
Controls
(n = 853)
(%)
Mucinous
(n = 114)
(%)
Nonmucinous
(n = 677)
(%)
p
value*,†
64
57
40
11
68
<0.01
<0.01
15
8
31
46
62
70
20
23
7
23
16
25
36
65
58
14
13
7
22
13
29
35
44
64
14
13
13
0.81
<0.01
<0.01
0.97
0.96
0.06
7
4
13
<0.01
Borderline
Postmenopausal
Parity
0
1
2
3 or more
Ever oral contraceptive use
Ever breastfed
Hysterectomy
Tubal sterilization
Self-reported infertility
Family history of breast or
ovarian cancer
Controls
(n = 853)
Mean
Age (years)
Oral contraceptives (years of
use among users)
Ovulation (years)
95% CI§
Mucinous
(n = 114)
Nonmucinous
(n = 677)
Mean
95% CI
Mean
95% CI
p
value*,‡
55
54, 56
47
45, 50
57
56, 58
<0.01
7.6
20
7.1, 8.1
19, 21
6.5
21
5.3, 7.7
19, 23
5.6
29
5.0, 6.1
28, 30
0.15
<0.01
* Mucinous versus nonmucinous ovarian tumors.
† Pearson’s chi-square test of association.
‡ Student’s t test.
§ CI, confidence interval.
ative were not materially affected by the inclusion of ovulation years (table 2).
Because ovulatory life is closely associated with age in
premenopausal women, but not in postmenopausal women,
and because women with mucinous tumors were considerably younger on average than were women with nonmucinous tumors, the analysis was repeated for pre- and postmenopausal women separately. The differences between
mucinous and nonmucinous tumors seen overall did not
appear to differ within the two menopausal groups. In addition, because of the excess of borderline tumors among
those of mucinous histology, we repeated the analysis separately for borderline (n 139) and frankly malignant (n 652) tumors. Nearly identical effects were seen for mucinous and nonmucinous tumors among the borderline and
malignant tumor groups. For instance, the odds ratio associated with each year’s ovulation in borderline tumors was
1.01 for mucinous (95 percent CI: 0.98, 1.05) and 1.07 for
nonmucinous (95 percent CI: 1.03, 1.10) tumors, while
among frankly malignant tumors, the risks were 1.01 for the
mucinous subtype (95 percent CI: 0.97, 1.04) and 1.05 for
nonmucinous subtypes (95 percent CI: 1.04, 1.07).
DISCUSSION
A number of authors have compared the effects of reproduction-related exposures on the risk of mucinous and nonmucinous ovarian tumors (1–5). The most consistent differences
appear to be that the protective effects of parity and oral con-
traceptives may be restricted to the nonmucinous forms. Most
of these studies, however, have had small numbers of cases of
mucinous histology and have relied on hospital records for
classification of tumor types. These deficiencies could reduce
the ability of these studies to detect any true differences in risk
factors between the tumor types.
Our findings (unadjusted for ovulation years) are consistent with those reported previously in that the effects of parity and oral contraceptive use were less marked in mucinous
than in nonmucinous tumors. However, both increasing parity and longer duration of use of oral contraceptives were
negatively associated with the occurrence of both tumor
groups. We took the analysis a step further and observed that
the differences between them appeared to be driven by a significant difference in the effect of ovulation. The increasing
number of lifetime ovulations appeared to increase the risk
of nonmucinous tumors only and, once this was taken into
account, the differences between the risks of mucinous and
nonmucinous tumors associated with the duration of oral
contraceptive use and pregnancy diminished. Mucinous
ovarian tumors are histologically and clinically similar to
adenocarcinomas of the uterine cervix (13), and these
tumors may also share some risk factors. The risk of cervical adenocarcinoma is not reduced by oral contraceptive
usage (14) or by parity (15).
Previous studies have also shown a low occurrence of
mucinous tumors among women with a family history of
ovarian cancer (1, 16–19). This finding was supported in our
data, with a positive association being seen between a famAm J Epidemiol Vol. 153, No. 9, 2001
Risk Factors for Mucinous and Nonmucinous Ovarian Cancer 863
TABLE 2. Multivariate odds ratios and their 95 percent confidence intervals for mucinous and
nonmucinous forms of epithelial ovarian cancer compared with controls according to
reproductive risk factors, by control of lifetime ovulations, Australia, 1990–1993
Mucinous
Factor
OR†,‡
Nonmucinous
95% CI†
OR‡
95% CI
p
value*
Without control for number of lifetime ovulations
Parity
0
1
2
3 or more
Ever use of oral contraceptives
Duration of oral contraceptive
use (per year)
Ever breastfed
Hysterectomy
Tubal sterilization
Self-reported infertility
Family history of breast or
ovarian cancer
1.00
2.06
0.89
0.91
0.62
0.94,
0.38,
0.39,
0.37,
4.49
2.11
2.11
1.04
1.00
1.08
0.59
0.41
0.52
0.66,
0.37,
0.26,
0.39,
1.75
0.92
0.66
0.68
0.15§
0.14
0.29
0.04
0.41
0.95
0.86
0.89
0.41
0.79
0.91,
0.48,
0.50,
0.23,
0.34,
0.99
1.54
1.58
0.76
1.88
0.92
1.12
0.58
0.61
1.21
0.89,
0.80,
0.42,
0.45,
0.81,
0.94
1.56
0.79
0.84
1.81
0.09
0.40
0.24
0.12
0.18
0.66
0.25, 1.73
1.87
1.29, 2.71
0.03
With control for number of lifetime ovulations
Parity
0
1
2
3 or more
Ever use of oral contraceptives
Duration of oral contraceptive
use (per year)
Ever breastfed
Hysterectomy
Tubal sterilization
Self-reported infertility
Family history of breast or
ovarian cancer
1.00
1.95
0.84
0.80
0.61
0.90,
0.36,
0.35,
0.36,
4.21
1.96
1.85
1.04
1.00
1.12
0.61
0.45
0.64
0.69,
0.39,
0.28,
0.48,
1.82
0.96
0.72
0.85
0.35§
0.24
0.38
0.11
0.98
0.92
0.84
0.87
0.42
0.77
0.88,
0.47,
0.49,
0.23,
0.32,
0.97
1.51
1.56
0.78
1.83
0.93
1.12
0.59
0.60
1.24
0.90,
0.80,
0.43,
0.44,
0.83,
0.96
1.56
0.80
0.83
1.85
0.97
0.38
0.31
0.14
0.17
0.67
0.26, 1.77
1.88
1.30, 2.73
0.03
* Mucinous versus nonmucinous ovarian tumors.
† OR, odds ratio; CI, confidence interval.
‡ Adjusted for age in years, age squared, body mass index, smoking, and alcohol consumption as well as all
other variables listed in the table (years of oral contraceptive use were not included in the model examining the
effect of ever use of oral contraceptives).
§ Overall significance level for parity.
ily history of breast or ovarian cancer and nonmucinous
tumors only.
There was a nonsignificant difference seen between the
effect of a reported history of infertility and the two tumor
classes, with a positive association seen in nonmucinous
tumors only. This finding is in contrast to that reported by
Wittenberg et al. (5) who found that the risk associated with
infertility was restricted to mucinous tumors only. It should
be noted here that women’s self reported difficulty in conceiving is subject to variable interpretation. Infertility is a
heterogeneous combination of disorders, which may have
very different etiologies.
No significant differences were observed between the
risks of mucinous and nonmucinous tumors for tubal sterilization, hysterectomy, and breastfeeding. Wittenberg et al.
(5) found an inverse association with hysterectomy among
Am J Epidemiol Vol. 153, No. 9, 2001
women with mucinous tumors only; however, in our data
the protective effect of hysterectomy, if anything, was
greater in nonmucinous tumors. Differences in the effect of
these factors on the occurrence of mucinous and nonmucinous ovarian tumors have never been seen consistently, and
any observed differences seem quite likely to be due to random variation.
In conclusion, this study has provided evidence to support the conclusions reached by Risch et al. (1) that ovarian
cancer is an etiologically heterogeneous collection of
tumors, and important risk factors such as ovulation and
genetic susceptibility may apply only to a subset of ovarian
cancers, namely, the nonmucinous subtypes. Data we have
presented elsewhere (10), with respect to the effects of
exposure to hormone replacement therapy, also fit with this
interpretation.
864
Purdie et al.
ACKNOWLEDGMENTS
Funding for this study was provided by the Australian
National Health and Medical Research Council and the
Queensland Cancer Fund.
The contribution made by other members of the Survey of
Women’s Health Study Group has been acknowledged previously (7).
8.
9.
10.
11.
12.
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