1 INSERM (National Institute of Health and Medical Research) U170 - IFR69, Villejuif, France
2 Laboratory of Anatomy and Cytopathology, Nouméa, New Caledonia
3 Pasteur Institute of New Caledonia, Nouméa, New Caledonia
Reprint requests to Dr. Pascal Guénel, INSERM U170, 16 avenue Paul Vaillant-Couturier, 94807 Villejuif Cedex, France (e-mail: guenel{at}vjf.inserm.fr).
Received for publication October 18, 2004. Accepted for publication January 26, 2005.
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ABSTRACT |
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case-control studies; goiter; menarche; menopause; New Caledonia; pregnancy; thyroid neoplasms
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INTRODUCTION |
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Because thyroid cancer is generally three times more frequent in women than in men, and because the incidence in women peaks during the reproductive years (5), hormonal changes related to the menstrual cycle, pregnancy, menopause, and hormone use have been suggested as etiologic factors. Goiter, which is intimately related to hormonal and reproductive events, may also predispose to thyroid cancer. Purported mechanisms of carcinogenicity involve elevated levels of thyroid-stimulating hormone that stimulates thyroid hyperplasia. High levels of this hormone have been reported during puberty, pregnancy, and oral contraceptive use (6
, 7
). Estrogens have also been shown to promote thyroid tumor growth via estrogen receptors present in thyroid tissue (8
, 9
), supporting the hypothesis that sex hormones, and therefore menstrual and reproductive events, may modify thyroid cancer risk in women.
Several epidemiologic studies have been conducted to investigate thyroid cancer risk in relation to goiter and to menstrual and reproductive factors in the United States (1020
), Europe (21
31
), and Asia (32
35
). Fourteen case-control studies conducted prior to 1997 (10
16
, 25
, 26
, 28
, 29
, 32
) were pooled in an analysis including a large number of thyroid cancer cases (2,247 women) and controls (3,699 women) (36
). Goiter was strongly and consistently associated with thyroid cancer (17
, 19
, 21
, 23
, 33
, 37
). The associations between thyroid cancer and menstrual or reproductive factors were generally weak or nonexistent, with the exception of miscarriage as the outcome of the first pregnancy and artificial menopause (25
, 38
) or hysterectomy (17
, 18
). Parity was not associated with thyroid cancer in the pooled analysis (38
), but, in recent studies, elevated risks during the 5 years postpartum have been reported (18
, 20
, 34
). Exogenous hormone use was associated with marginally increased odds ratios in the pooled analysis (39
). To investigate the remarkably high incidence of thyroid cancer and to clarify the role of certain risk factors for thyroid cancer in general, a countrywide population-based case-control study was conducted in New Caledonia. This paper reports on goiter, menstrual and reproductive events, and exogenous hormone use on the basis of the data collected on New Caledonian women.
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MATERIALS AND METHODS |
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The cases were identified from the pathology records kept by the two histopathology laboratories, one public and one private, operating in New Caledonia. All pathology reports including a diagnosis of thyroid cancer were retrieved by manual or electronic searches. The cancer diagnoses were made by the local pathologists. Most of the histologic slides were also reviewed by the Pathology Department of the Royal Prince Alfred Hospital in Sydney, Australia. The case list was cross-checked with the New Caledonia cancer registry, which collects information on cancer diagnoses from medical facilities throughout the country. However, no additional case of thyroid cancer was detected. All of the pathology reports were retrieved in order to code the histology, number, and size of the cancerous nodules. Mixed papillary-follicular cases were included in the papillary group (40). If insufficient information had been included in the initial report (e.g., unspecified tumor size), the histologic slide was reviewed to obtain the missing information. The thyroid cancer cases were classified according to histology and size of the largest cancerous nodule.
All cases diagnosed during the 5-year period before the start of data collection in 1998 and all cases newly diagnosed up to the end of the study period in 1999 were recruited for the study. The good prognosis of differentiated thyroid tumors, and residential stability, enabled subject enrollment several years after the initial diagnosis.
Of 324 cases of thyroid cancer in women, 31 (10 percent) were not included because the subject refused to participate (n = 8), had died (n = 18), could not be contacted (n = 4), or was too ill (n = 1). The study population thus consisted of 293 cases, 255 with papillary carcinoma and 38 with follicular carcinoma (table 1). More than 54 percent of the papillary carcinomas were less than or equal to 10 mm in diameter.
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Of 405 eligible controls, 51 (13 percent) did not participate because they refused (n = 19), had died (n = 11), or could not be contacted (n = 18) or for another reason (n = 3). The remaining 354 controls were included in the analyses.
Data collection
Trained interviewers conducted a face-to-face interview with the cases and controls at their home address, using a structured questionnaire, after having obtained informed consent. The interviewers elicited information on sociodemographic characteristics, diet, alcohol drinking, tobacco smoking, anthropometric factors, gynecologic and reproductive history, medical conditions, medical x-ray exposure, occupational and residential history, and familial history of thyroid cancer. Benign thyroid disease history, menstrual and reproductive factors, and exogenous hormone use are reported herein. Participants were asked whether the goiter was diagnosed by a physician and how it was treated. Goiters not reported by the participants as medically confirmed were excluded. Since detection of thyroid cancer may be enhanced following diagnosis of goiter, the odds ratio for goiter may be overestimated. To minimize this potential surveillance bias, only those goiters diagnosed at least 1 year before the reference date were considered in the analyses. Different lag times between goiter and cancer, and carcinoma size, were also taken into account to assess surveillance bias, assuming that this bias would more strongly affect carcinomas less than or equal to 10 mm in diameter diagnosed shortly after goiter.
Women were considered postmenopausal if they reported that they had not menstruated for at least 1 year as of the reference date. Menopausal status was initially regarded as unknown for women who used hormone replacement therapy before the end of menstruation. To reduce the number of women of unknown menopausal status, all women older than age 55 years (90th percentile of age at menopause for women with a natural menopause) were subsequently classified as having undergone a natural menopause. Artificial menopause was defined as the cessation of menses induced by surgical removal of the ovaries or uterus.
Statistical analysis
The odds ratios were calculated by unconditional logistic regression (41), using SAS version 8.2 software (SAS Institute, Inc., Cary, North Carolina). All odds ratios were adjusted for age (5-year age groups) and ethnic group (European, Melanesian, other). Potential confounding between hormonal and reproductive factors was investigated in multivariate models. Nonordinal polytomous logistic regression (42
) was carried out in the analyses by using two case groups defined by carcinoma size (
10 mm or >10 mm) and histologic subtype (papillary or follicular). All of the analyses were also conducted after stratification by ethnicity and by age group (<45 years,
45 years). This cutpoint was chosen to categorize women according to reproductive or postreproductive age, assuming that the reproductive period may modify the relation between hormonal factors and thyroid cancer risk. Tests for trend were calculated by fitting models with continuous exposure variables, assuming a log-linear relation between exposure and cancer risk.
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RESULTS |
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A history of miscarriage was associated with an odds ratio of 1.4 (table 6) that reached 2.3 for miscarriage during the first pregnancy. Voluntary abortion was associated with an odds ratio of 3.1. Voluntary abortion was more strongly associated with papillary microcarcinoma (OR = 4.1) than with larger tumors (OR = 1.7) (table 7). Seven cases and no controls had had a voluntary abortion in the 5-year period before the reference date. Because a history of voluntary abortion was related to the number of full-term pregnancies, multivariate models including both variables were fitted, but the odds ratios were not modified by mutual adjustment (results not shown).
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DISCUSSION |
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Strengths and limitations of the study
The methodological strengths of the study are a population-based design, exhaustive identification of cases over the study period, and high response rates among cases (90 percent) and controls (87 percent). Another important feature is a thorough review of the histologic diagnoses and of tumor size, which, to our knowledge, was determined for the first time in a case-control study. The study also has some limitations. Electoral rolls may not be a perfect population register to use to recruit population controls. However, the rolls were updated just before study initiation and were believed to be almost complete. We did not take into account exposure to ionizing radiation during childhood, one of the few recognized risk factors. However, this exposure was probably too low to affect the risk of thyroid cancer at a detectable level and to confound the reported associations. Recall bias may have occurred, particularly for previous thyroid disorders such as goiter, if cases were more prone than controls to declare goiter. Taking into account only those goiters reported by the participant as medically confirmed should have minimized this potential bias. Another problem, referred to below as surveillance bias, may have occurred if diagnosis of goiter, or another medical condition, led to intensive cancer screening and diagnosis of thyroid carcinomas that would otherwise have remained undetected. The elevated proportion of papillary microcarcinomas in our case group (over 54 percent vs. 1724 percent in a cancer-registry-based study (43)) may reflect high screening levels in New Caledonia and indicate that some degree of surveillance bias did occur. Stratification on size of the carcinoma to study hormonal and reproductive risk factors permitted assessment of a possible effect of a surveillance bias.
History of benign thyroid disease
Goiter was associated with a fourfold increase in the risk of thyroid cancer in New Caledonian women. This finding is in line with the results of previous studies conducted in Italy (21, 28
), Switzerland (23
), the United States (10
, 13
, 14
, 17
, 19
), Japan (33
), and China (32
) that reported odds ratios ranging from 4 to 7 for women with a history of goiter. In a pooled analysis of 12 case-control studies, the odds ratio was 5.9 (37
). These findings may support the assumption that goiter facilitates thyroid tumor growth, or they may reflect an upward bias of the odds ratio due to surveillance bias. Two studies have reported that the association between goiter and thyroid cancer is particularly elevated if the cancer is diagnosed shortly after goiter, that is, during a period when cancer screening is more active (17
, 37
), suggesting some surveillance bias. In contrast, the New Caledonian study showed a higher odds ratio when goiter was diagnosed 5 or more years before cancer than when it occurred closer to the time of cancer diagnosis. Furthermore, microcarcinomas, which are unlikely to be detected without screening, were as strongly associated with goiter as large thyroid tumors. If surveillance bias were acting fully, a stronger association with small carcinomas would be expected. These findings suggest that the reported odds ratio cannot be entirely accounted for by surveillance bias and thus provide further evidence that goiter predisposes to thyroid cancer.
Menstrual factors
The relation between thyroid function and menstruation, puberty, and menopause has long been recognized (44, 45
). The thyroid gland enlarges during the menstrual cycle (46
), and it has been shown that estrogen 17ß-estradiol has a growth-promoting effect on thyroid tumor cells, mainly via estrogen receptors present in thyroid tissue (8
, 9
).
Age at menarche.
Late menarche was weakly associated with thyroid cancer (OR = 1.2) in a pooled analysis of 14 case-control studies conducted worldwide (38). In New Caledonia, late menarche (age >15 years) was strongly associated with thyroid cancer in European women (OR = 3.4) and, to a lesser degree, in Melanesian women (OR = 1.5), whereas an inverse association was observed for other ethnic groups, including Polynesian and Asian women (OR = 0.2). It is possible that ethnic-specific risk factors for thyroid cancer also influencing age at menarche, such as dietary or genetic factors, explain the different odds ratios for the various ethnic groups. If late menarche increases the risk of thyroid cancer in Melanesian women, it may play a role in the elevated incidence observed in this group because menarche occurred noticeably later in Melanesian women than in other ethnic groups (for 46 percent of Melanesian and 13 percent of European controls, age at menarche was
15 years).
Irregular menstruation.
For women aged less than 45 years who had never menstruated regularly, the odds ratio was 3.6. Because this association did not change with cancer size, surveillance bias was not a likely explanation. No data on menstrual disorders were reported in the pooled analysis (38). An odds ratio of 2.2 (95 percent confidence interval: 0.9, 6.1), consistent with the present finding, was observed for women aged less than 35 years in a US study (17
). Again, a link between menstrual disorders and thyroid dysfunction (44
) may explain the observed association.
Menopausal status.
No evidence that thyroid cancer was associated with menopausal status or with age at menopause emerged in our data. There was some evidence that hysterectomy, but not ovariectomy, was related to thyroid cancer, particularly when hysterectomy occurred at a young age. In the pooled analysis (38), artificial menopause was associated with an odds ratio of 1.8 (95 percent confidence interval: 1.4, 2.4), but the types of surgical procedures, hysterectomy or bilateral ovariectomy, were not distinguished. In two recent case-control studies (17
, 18
), and in a cohort study of hysterectomized women (47
), an approximately twofold excess risk of thyroid cancer was reported for hysterectomy. This association may be related to surveillance bias because women undergoing surgical procedures may be more carefully monitored for thyroid disorders. However, it has also been suggested that hysterectomy may be an indicator of prolonged menstrual disturbances that may share a common etiology with thyroid cancer (47
). For example, uterine fibroma, which induces hyperestrogenism, is an indication for hysterectomy (38
). The higher risk of thyroid cancer associated with hysterectomy at a younger age reported herein may reflect more serious menstrual disorders.
Reproductive factors
Parity.
Parity among women aged less than 45 years was associated with an odds ratio of 1.8 (95 percent confidence interval: 0.9, 3.6), whereas parity did not increase the risk for older women. An association between thyroid cancer and parity has been reported in some (13, 14
, 22
, 31
33
, 48
) but not all (11
, 15
, 17
, 18
, 20
, 24
27
, 29
) studies, resulting in an approximately 20 percent increased odds ratio for parous versus nulliparous women in the pooled analysis (38
), making a conclusion difficult. The very high birth rates observed in our study population, particularly among Melanesian women, provided a unique opportunity to investigate the effect of high parity on thyroid cancer. For example, 18 percent of the European and 48 percent of the Melanesian controls had had at least four full-term pregnancies. A statistically significant 8 percent increase in risk (p = 0.01) for each additional pregnancy was observed, resulting in a 2.2-fold increase for women having had eight or more pregnancies. The trend was also more marked among women of reproductive age, although not statistically significant. These findings are in line with the results of a previous case-control study in Kuwait in which the risk was increased approximately twofold for women having had 11 or more pregnancies (34
). They strongly support the existence of a link between parity and thyroid cancer.
Time-dependent factors.
High levels of estrogen, human chorionic gonadotropin, and thyroid-stimulating hormone during pregnancy are responsible for direct thyroid stimulation and may promote tumor growth (68
). This mechanism may account for an increased risk of thyroid cancer in the period following delivery and is compatible with our observation of an increased risk for women of reproductive age. A time-dependent risk pattern after a livebirth, with increased risk over the first years postpartum, followed by a downward trend, has also been reported in several studies (18
, 20
, 31
, 34
, 48
). In New Caledonia, this pattern was observed for uniparous women, although the transient increase in risk following delivery and the downward trend thereafter were not statistically significant.
Interestingly, a transient increase in risk after the first childbirth, attributed to increased cell proliferation during pregnancy, was reported for breast cancer (49, 50
). There is also evidence that women with a thyroid carcinoma have a greater than expected risk of developing breast carcinoma, particularly young premenopausal women (51
, 52
), suggesting that breast and thyroid cancers may share common etiologic factors. Although several factors such as parity or age at menarche seem to have opposite effects on thyroid and on breast cancers (53
), the transient increase in risk following childbirth is a common feature that might explain a link between the two tumors.
Miscarriage and abortion.
New Caledonian women with miscarriage as the outcome of the first pregnancy had a marked increased risk of thyroid cancer (OR = 2.3). This factor was consistently associated with thyroid cancer in previous epidemiologic studies (13, 15
, 25
, 32
, 38
). The mechanism leading from miscarriage during the first pregnancy to thyroid cancer has not been elucidated, but it is possible that miscarriage may be induced by thyroid disorders or hormonal dysfunction (44
).
This study demonstrated a clear association between voluntary abortion and thyroid cancer. However, this finding may reflect a surveillance bias, since women undergoing voluntary abortion may be more actively screened for thyroid disorders. This hypothesis is supported by a strong association with microcarcinomas and by the short lag time between abortion and cancer diagnosis.
Exogenous hormone use.
Our results do not show an association with the use of oral contraceptives or hormone replacement therapy in New Caledonian women. In addition, they do not confirm the weak association observed for current oral contraceptive users in the pooled analysis (39).
Conclusion
This study provides additional evidence that factors related to hormonal, menstrual, or reproductive life in women are associated with thyroid cancer. The development of thyroid carcinoma may share common mechanisms with goiter, miscarriage, or conditions leading to hysterectomy that might explain the observed associations between these factors and thyroid cancer. Alternatively, the association between voluntary abortion and thyroid cancer could be explained by an increased detection of thyroid cancer in women undergoing that surgical procedure. High parity and late menarche are of particular interest, since they are both associated with thyroid cancer risk and are highly prevalent among Melanesian women compared with European women. High parity in particular may explain, in part, the high thyroid cancer incidence observed among Melanesian women in New Caledonia.
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ACKNOWLEDGMENTS |
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The authors thank Danièle Luce and Diane Cyr. They gratefully acknowledge Michèle Reynier for her invaluable help in data collection in New Caledonia.
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References |
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