IJC International Journal of Cancer
Reproductive and menstrual factors and risk of differentiated thyroid carcinoma: The EPIC study Raul Zamora-Ros1*, Sabina Rinaldi1*, Carine Biessy1, Anne Tjïnneland2, Jytte Halkjær2, Agnes Fournier3,4, T. Fortner5, Heiner Boeing6, Jana Fo €rster6, Marie-Christine Boutron-Ruault3,4, Sylvie Mesrine3,4, Kaja Tikk5, Renee 7,8 7,8,9 7 10 Antonia Trichopoulou , Dimitrios Trichopoulos , Eleni-Maria Papatesta , Giovanna Masala , Giovanna Tagliabue11, 12 13 Salvatore Panico , Rosario Tumino , Silvia Polidoro14, Petra H.M. Peeters15,16, H.B(as) Bueno-de-Mesquita16,17,18, €elles23, Antonio Agudo24, Esther Molina-Montes25,26, Elisabete Weiderpass19,20,21,22, Eiliv Lund19, Marcial Argu 26,27,28 26,29 ~aga26,30, Jonas Manjer31, Martin Almquist32, Carmen Navarro , Aurelio Barricarte , Nerea Larran 33 34 €m , Joakim Hennings , Konstantinos K. Tsilidis35,36, Julie A. Schmidt35, Kay-Thee Khaw37, Maria Sandstro Nicholas J. Wareham38, Isabelle Romieu1, Graham Byrnes1, Marc J. Gunter16, Elio Riboli16 and Silvia Franceschi1 1
International Agency for Research on Cancer (IARC), Lyon, France Danish Cancer Society Research Center, Copenhagen, Denmark 3 Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Villejuif, France 4 Paris South University, UMRS Inserm 1018 Team 9, Villejuif, France 5 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany 6 €cke, Nuthetal, Germany Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbru 7 Hellenic Health Foundation, Athens, Greece 8 Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece 9 Department of Epidemiology, Harvard School of Public Health, Boston, MA 10 Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute – ISPO, Florence, Italy 11 Lombardy Cancer Registry Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy 12 Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy 13 Cancer Registry and Histopathology Unit, “Civic M.P. Arezzo” Hospital, ASP Ragusa, Italy 14 Laboratory of Molecular Epidemiology, Human Genetics Foundation (HuGeF), Torino, Italy 15 Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands 16 School of Public Health, Imperial College London, London, United Kingdom 17 National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands 18 Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands 19 Department of Community Medicine, University of Tromsï, Tromsï, Norway 20 Cancer Registry of Norway, Oslo, Norway 21 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden 22 Samfundet Folkh€alsan, Helsinki, Finland 23 Public Health Directorate, Asturias, Spain 24 Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, Barcelona, Spain 25 Andalusian School of Public Health, Granada, Spain
Short Report
2
Key words: reproductive factors, menstrual factors, hormone use, differentiated thyroid carcinoma, EPIC Conflict of interest: Nothing to report *R.Z.-R. and S.R. contributed equally to this work Grant sponsors: This work was supported by the European Commission: Public Health and Consumer Protection Directorate 1993 to 2004; Research Directorate-General 2005; the French National Cancer Institute (L’Institut National du Cancer; INCA); Grant Number: 2009-139; Grant sponsors: Ligue contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l’Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid; German Cancer Research Center (DKFZ); German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund (FIS) of the Spanish Ministry of Health (RTICC (DR06/0020/ 0091); the participating regional governments from Asturias, Andalucıa, Murcia, Navarra and Vasco Country and the Catalan Institute of Oncology of Spain; Cancer Research UK; Medical Research Council, UK; the Stroke Association, UK; British Heart Foundation; Department of Health, UK; Food Standards Agency, UK; the Wellcome Trust, UK; the Hellenic Health Foundation; Italian Association for Research on Cancer; Compagnia San Paolo, Italy; Dutch Ministry of Public Health, Welfare and Sports; Dutch Ministry of Health; Dutch Prevention Funds; LK Research Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); Statistics Netherlands (The Netherlands); Swedish Cancer Society; Swedish Scientific Council; Regional Government of Skane, Sweden; Nordforsk—Centre of Excellence programme; Some authors are partners of ECNIS, a network of excellence of the 6FP of the EC. DOI: 10.1002/ijc.29067 History: Received 29 Apr 2014; Accepted 11 June 2014; Online 8 July 2014 Correspondence to: Dr. Sabina Rinaldi, International Agency for Research on Cancer, Lyon, France, E-mail: [email protected]
C 2014 UICC Int. J. Cancer: 136, 1218–1227 (2015) V
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Zamora-Ros et al.
26
blica (CIBERESP), Madrid, Spain CIBER Epidemiologıa y Salud Pu Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain 28 Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain 29 Public Health Institute of Navarra, Pamplona, Spain 30 Public Health Division of Gipuzkoa, Regional Government of the Basque Country, San Sebastian, Spain 31 € University Hospital, Malmo €, Sweden Deparment of Surgery, Malmo 32 Department of Surgery, University Hospital Lund, Lund, Sweden 33 Department for Radiation Sciences, Oncology Umea˚ University, Umea˚, Sweden 34 Department of Surgical and Perioperative Sciences, Umea˚ University, Umea˚, Sweden 35 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom 36 Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece 37 Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom 38 MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom 27
Differentiated thyroid carcinoma (TC) is threefold more common in women than in men and, therefore, a role of female hormones in the etiology of differentiated TC has been suggested. We assessed these hypotheses in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Among 345,157 women (mean age 51) followed for an average of 11 years, 508 differentiated TC cases were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models. No significant associations were observed between differentiated TC risk and number of pregnancies, breast feeding, menopausal status, and age at menarche and at menopause. Significant associations were found with history of infertility problems (HR 1.70; 95% CI 1.12–2.60), a recent pregnancy (HR for 5 vs. >5 years before recruitment 3.87; 95% CI 1.43–10.46), menopause type (HR for surgical vs. natural menopause: 2.16; 95% CI 1.41– 3.31), oral contraceptive (OC) use at recruitment (HR: 0.48; 95% CI 0.25–0.92) and duration of OC use (HR for 9 vs. 1 year: 0.66; 95% CI: 0.50–0.89). An increased risk was also found with hormone replacement therapy use at recruitment (HR 5 1.30, 95% CI 1.02–1.67), but this was not significant after adjustment for type of menopause (HR 5 1.22, 95% CI 0.95– 1.57). Overall, our findings do not support a strong role of reproductive and menstrual factors, and female hormone use in the etiology of differentiated TC. The few observed associations may be real or accounted for by increased surveillance in women who had infertility problems, recent pregnancies or underwent surgical menopause.
Thyroid carcinoma (TC) is the most common cancer of the endocrine system and the second most common cancer (after breast) among young women in high-income countries.1,2 TC incidence has increased markedly worldwide over the last decades, and this increase is only partially explained by increased surveillance of thyroid nodules. Thus, TC has now become an important clinical and economic burden.2 The only well-known risk factors for TC are ionizing radiation exposure, especially during childhood, and benign thyroid disease. Evidence from large epidemiological studies also shows that height and weight may play a role.3,4 The incidence of TC is about threefold higher in women than in men,1 and the excess in TC risk in women is the largest during women’s reproductive years.5,6 Therefore, facC 2014 UICC Int. J. Cancer: 136, 1218–1227 (2015) V
tors related to reproductive and menstrual history have been suggested to be relevant to TC etiology. However, results from case–control6–15 and prospective studies16–22 showed weak and inconsistent results on the associations between pregnancy, parity, menstrual cycle regularity, exogenous hormone use and menopausal status and TC risk. The aim of our study was to investigate prospectively the association between reproductive and menstrual factors, and exogenous hormones use with the risk of differentiated TC in women who participated in a large European cohort, the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Because of its large sample size and the high number of cases cumulated, we were able to evaluate these relationships in all women combined and separately for young women.
Short Report
What’s new? Differentiated thyroid carcinoma (TC) is three-fold more common in women than in men. This raises the question: Do female hormones play a role in the pathogenesis of TC? In this large, prospective study, the authors did not find any strong association between reproductive or menstrual factors and TC risk. They did, however, identify positive associations between infertility, recent pregnancy, or surgical menopause and TC risk, and also detected an inverse association with prolonged use of oral contraceptives.
1220
Material and Methods Subjects and study design
The EPIC project is a European network of prospective cohorts that was set up to examine relationships between diet and environmental factors and cancer risk. The EPIC cohort includes about half a million men and women, recruited from 23 regional and national research centers located in ten western European countries: Denmark, France, Germany, Greece, Italy, Norway, Spain, Sweden, The Netherlands and United Kingdom. The rationale and study design were previously described in detail.23 All participants provided written informed consent, and the Internal Review Boards of the International Agency of Research on Cancer and all boards from recruitment centers approved the EPIC project. The present study is based on data from a population of 345,157 women after excluding those with prevalent cancer other than non-melanoma skin cancer at baseline. Participants were also excluded if they had missing lifestyle (n 5 573) or anthropometry data (n 5 819).
Short Report
Identification and selection of thyroid cancer cases
In most of the EPIC countries (Denmark, France, Italy, Norway, Spain, Sweden, The Netherlands and United Kingdom), data on vital status were ascertained by record linkage with regional and/or national mortality registries. In Greece, Germany and Naples (Italy) data on vital status were continuously collected through active follow-up.23 In all centers except those in Greece, Germany and France, incident cancer cases were identified through record linkage with regional cancer registries. In France, Germany and Greece, follow-up for cancer incidence was based on a combination of methods, including the use of health insurance records, contacts with cancer and pathology registries and active follow-up through study participants and their next-of-kin. Closure dates for our study were defined as the latest date of complete followup for both cancer incidence and vital status. The follow-up spans ended between December 2006 and December 2009, depending on the EPIC center. A total of 537 first primary incident TC cases (codes “C73” as per the tenth Revision of the International Statistical Classification of Diseases, Injury and Causes of Death) in women were identified within the EPIC cohort at the time of analyses. TC cases with medullary cancer (n 5 22), undifferentiated cancers (n 5 4, anaplastic), lymphoma (n 5 1) and other specific morphologies (n 5 2, squamous cell and large cell carcinomas) were excluded from our study. Overall, 508 female first primary incident differentiated TC cases were included in our study. Reproductive and lifestyle characteristics
Baseline questionnaire data (including detailed questions about current habitual diet, menstrual and reproductive history, lifetime history of tobacco smoking, consumption of alcoholic beverages and physical activity) and anthropometric
Reproductive factors and differentiated thyroid carcinoma in women
measurements were collected from study participants in the period 1992–2000.23,24 Information on age at menarche and at menopause, age at first and last full-term pregnancy, spontaneous or induced abortion, breast feeding, exogenous hormones use [oral contraceptives (OC) and hormone replacement therapy (HRT)] and fertility problems were recorded in all centers (except in Sweden, where information on surgical menopause was not collected). The number of full-term pregnancies was calculated as the sum of live born children and stillbirths. Except from Norway and Umeå (Sweden), where information about twin pregnancies was available, the number of full-term pregnancies is overestimated, as twin pregnancies counted twice. Women were considered premenopausal if reporting menstrual periods over the past 12 months before recruitment, or when they were below the age of 46 years, and had either a hysterectomy or missing information on menopausal status. Women were considered as postmenopausal when they reported (i) no menses over the past 12 months before recruitment or (ii) bilateral ovariectomy or (iii) either a hysterectomy or missing information on menopausal status at age 55 years or above. Other women were considered as perimenopausal/unknown menopause status, and are referred to as perimenopausal throughout the article. Statistical analyses
Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) of TC for each hormonal, reproductive and menstrual factor. Tests and graphs based on Schoenfeld residuals were used to assess the proportional hazards assumption, which was satisfied. Age was used as underlying primary dependent time variable, with entry time defined as the subject’s age at recruitment and exit time as age at TC diagnosis, death or censoring date (lost or end of follow-up), whichever occurred first. All statistical models were stratified by study center and by age at recruitment (1-year category). Potential confounders included educational level (no formal education, primary, technical/professional school, secondary, university and not specified), smoking status (never, former and current smokers), alcohol intake (0, >0–15, >15–29.9 and 30 g/day), Cambridge physical activity index (inactive, moderately inactive, moderately active, active and unknown)24 and body mass index (10% change in HRs; therefore, all presented models were unadjusted. Trend tests across levels of exposure categories were performed on continuous variables, whereas for categorical variables the test has been computed by assigning consecutive scores to the categories as an ordinal variable. All associations were examined for differentiated TC in all women and separately in women below age 50 and for papillary TC only. All statistical analyses were performed using the Statistical Analysis System (SAS) software package, Version 9.3 (SAS Institute). C 2014 UICC Int. J. Cancer: 136, 1218–1227 (2015) V
50.9 (9.9) 11.0 (2.7) 402
Mean age recruitment (SD) (years)
Mean length of follow-up (SD) (years)
No. of cases (papillary)
15.7 41.2 27.6
1
2
3
C 2014 UICC Int. J. Cancer: 136, 1218–1227 (2015) V
29.3
29.5 38.6
74.1
Never
46.5 18.9
Postmenopausal
Perimenopausal
7.5
Surgical
Short Report
92.5
Natural
Type of menopause (%)3
34.6
Premenopausal
Menopausal status (%)
25.9
Ever
6.6
93.4
15.4
77.4
7.2
55.2
44.8
41.7
41.5
Never
Use of hormone replacement therapy (%)1
58.3
58.5
Ever
Use of oral contraceptives (%)
99.8
94.9
>5
1
0.2
5.1
5
Years since last pregnancy (%)1
26
28.2
31.9
23–25
6.5
93.6
27.9
46.1
26.0
68.7
31.3
39.1
60.9
99.0
1.0
36.9
34.1
29.0
29.2
27.3
42.5
44.6
16.6
9.7
178
10.4 (2.6)
52.7 (6.6)
n 5 206 712,698
France
45.4
15.7
11.7
12
11.0 (2.4)
56.8 (4.4)
n 5 16 323,411
Denmark
0–15
31.6
24.7
43.7
16.1
14.2
2.8
16.6
0
Alcohol consumption (g/day) (%)
30
34.3
56.2
18.5–25
50.4
2.1
1.2
9.2
44.4
46.4
Reproductive and menstrual factors and risk of differentiated thyroid carcinoma: The EPIC study Raul Zamora-Ros1*, Sabina Rinaldi1*, Carine Biessy1, Anne Tjïnneland2, Jytte Halkjær2, Agnes Fournier3,4, T. Fortner5, Heiner Boeing6, Jana Fo €rster6, Marie-Christine Boutron-Ruault3,4, Sylvie Mesrine3,4, Kaja Tikk5, Renee 7,8 7,8,9 7 10 Antonia Trichopoulou , Dimitrios Trichopoulos , Eleni-Maria Papatesta , Giovanna Masala , Giovanna Tagliabue11, 12 13 Salvatore Panico , Rosario Tumino , Silvia Polidoro14, Petra H.M. Peeters15,16, H.B(as) Bueno-de-Mesquita16,17,18, €elles23, Antonio Agudo24, Esther Molina-Montes25,26, Elisabete Weiderpass19,20,21,22, Eiliv Lund19, Marcial Argu 26,27,28 26,29 ~aga26,30, Jonas Manjer31, Martin Almquist32, Carmen Navarro , Aurelio Barricarte , Nerea Larran 33 34 €m , Joakim Hennings , Konstantinos K. Tsilidis35,36, Julie A. Schmidt35, Kay-Thee Khaw37, Maria Sandstro Nicholas J. Wareham38, Isabelle Romieu1, Graham Byrnes1, Marc J. Gunter16, Elio Riboli16 and Silvia Franceschi1 1
International Agency for Research on Cancer (IARC), Lyon, France Danish Cancer Society Research Center, Copenhagen, Denmark 3 Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Villejuif, France 4 Paris South University, UMRS Inserm 1018 Team 9, Villejuif, France 5 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany 6 €cke, Nuthetal, Germany Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbru 7 Hellenic Health Foundation, Athens, Greece 8 Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece 9 Department of Epidemiology, Harvard School of Public Health, Boston, MA 10 Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute – ISPO, Florence, Italy 11 Lombardy Cancer Registry Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy 12 Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy 13 Cancer Registry and Histopathology Unit, “Civic M.P. Arezzo” Hospital, ASP Ragusa, Italy 14 Laboratory of Molecular Epidemiology, Human Genetics Foundation (HuGeF), Torino, Italy 15 Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands 16 School of Public Health, Imperial College London, London, United Kingdom 17 National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands 18 Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands 19 Department of Community Medicine, University of Tromsï, Tromsï, Norway 20 Cancer Registry of Norway, Oslo, Norway 21 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden 22 Samfundet Folkh€alsan, Helsinki, Finland 23 Public Health Directorate, Asturias, Spain 24 Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, Barcelona, Spain 25 Andalusian School of Public Health, Granada, Spain
Short Report
2
Key words: reproductive factors, menstrual factors, hormone use, differentiated thyroid carcinoma, EPIC Conflict of interest: Nothing to report *R.Z.-R. and S.R. contributed equally to this work Grant sponsors: This work was supported by the European Commission: Public Health and Consumer Protection Directorate 1993 to 2004; Research Directorate-General 2005; the French National Cancer Institute (L’Institut National du Cancer; INCA); Grant Number: 2009-139; Grant sponsors: Ligue contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l’Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid; German Cancer Research Center (DKFZ); German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund (FIS) of the Spanish Ministry of Health (RTICC (DR06/0020/ 0091); the participating regional governments from Asturias, Andalucıa, Murcia, Navarra and Vasco Country and the Catalan Institute of Oncology of Spain; Cancer Research UK; Medical Research Council, UK; the Stroke Association, UK; British Heart Foundation; Department of Health, UK; Food Standards Agency, UK; the Wellcome Trust, UK; the Hellenic Health Foundation; Italian Association for Research on Cancer; Compagnia San Paolo, Italy; Dutch Ministry of Public Health, Welfare and Sports; Dutch Ministry of Health; Dutch Prevention Funds; LK Research Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); Statistics Netherlands (The Netherlands); Swedish Cancer Society; Swedish Scientific Council; Regional Government of Skane, Sweden; Nordforsk—Centre of Excellence programme; Some authors are partners of ECNIS, a network of excellence of the 6FP of the EC. DOI: 10.1002/ijc.29067 History: Received 29 Apr 2014; Accepted 11 June 2014; Online 8 July 2014 Correspondence to: Dr. Sabina Rinaldi, International Agency for Research on Cancer, Lyon, France, E-mail: [email protected]
C 2014 UICC Int. J. Cancer: 136, 1218–1227 (2015) V
1219
Zamora-Ros et al.
26
blica (CIBERESP), Madrid, Spain CIBER Epidemiologıa y Salud Pu Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain 28 Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain 29 Public Health Institute of Navarra, Pamplona, Spain 30 Public Health Division of Gipuzkoa, Regional Government of the Basque Country, San Sebastian, Spain 31 € University Hospital, Malmo €, Sweden Deparment of Surgery, Malmo 32 Department of Surgery, University Hospital Lund, Lund, Sweden 33 Department for Radiation Sciences, Oncology Umea˚ University, Umea˚, Sweden 34 Department of Surgical and Perioperative Sciences, Umea˚ University, Umea˚, Sweden 35 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom 36 Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece 37 Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom 38 MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom 27
Differentiated thyroid carcinoma (TC) is threefold more common in women than in men and, therefore, a role of female hormones in the etiology of differentiated TC has been suggested. We assessed these hypotheses in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Among 345,157 women (mean age 51) followed for an average of 11 years, 508 differentiated TC cases were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models. No significant associations were observed between differentiated TC risk and number of pregnancies, breast feeding, menopausal status, and age at menarche and at menopause. Significant associations were found with history of infertility problems (HR 1.70; 95% CI 1.12–2.60), a recent pregnancy (HR for 5 vs. >5 years before recruitment 3.87; 95% CI 1.43–10.46), menopause type (HR for surgical vs. natural menopause: 2.16; 95% CI 1.41– 3.31), oral contraceptive (OC) use at recruitment (HR: 0.48; 95% CI 0.25–0.92) and duration of OC use (HR for 9 vs. 1 year: 0.66; 95% CI: 0.50–0.89). An increased risk was also found with hormone replacement therapy use at recruitment (HR 5 1.30, 95% CI 1.02–1.67), but this was not significant after adjustment for type of menopause (HR 5 1.22, 95% CI 0.95– 1.57). Overall, our findings do not support a strong role of reproductive and menstrual factors, and female hormone use in the etiology of differentiated TC. The few observed associations may be real or accounted for by increased surveillance in women who had infertility problems, recent pregnancies or underwent surgical menopause.
Thyroid carcinoma (TC) is the most common cancer of the endocrine system and the second most common cancer (after breast) among young women in high-income countries.1,2 TC incidence has increased markedly worldwide over the last decades, and this increase is only partially explained by increased surveillance of thyroid nodules. Thus, TC has now become an important clinical and economic burden.2 The only well-known risk factors for TC are ionizing radiation exposure, especially during childhood, and benign thyroid disease. Evidence from large epidemiological studies also shows that height and weight may play a role.3,4 The incidence of TC is about threefold higher in women than in men,1 and the excess in TC risk in women is the largest during women’s reproductive years.5,6 Therefore, facC 2014 UICC Int. J. Cancer: 136, 1218–1227 (2015) V
tors related to reproductive and menstrual history have been suggested to be relevant to TC etiology. However, results from case–control6–15 and prospective studies16–22 showed weak and inconsistent results on the associations between pregnancy, parity, menstrual cycle regularity, exogenous hormone use and menopausal status and TC risk. The aim of our study was to investigate prospectively the association between reproductive and menstrual factors, and exogenous hormones use with the risk of differentiated TC in women who participated in a large European cohort, the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Because of its large sample size and the high number of cases cumulated, we were able to evaluate these relationships in all women combined and separately for young women.
Short Report
What’s new? Differentiated thyroid carcinoma (TC) is three-fold more common in women than in men. This raises the question: Do female hormones play a role in the pathogenesis of TC? In this large, prospective study, the authors did not find any strong association between reproductive or menstrual factors and TC risk. They did, however, identify positive associations between infertility, recent pregnancy, or surgical menopause and TC risk, and also detected an inverse association with prolonged use of oral contraceptives.
1220
Material and Methods Subjects and study design
The EPIC project is a European network of prospective cohorts that was set up to examine relationships between diet and environmental factors and cancer risk. The EPIC cohort includes about half a million men and women, recruited from 23 regional and national research centers located in ten western European countries: Denmark, France, Germany, Greece, Italy, Norway, Spain, Sweden, The Netherlands and United Kingdom. The rationale and study design were previously described in detail.23 All participants provided written informed consent, and the Internal Review Boards of the International Agency of Research on Cancer and all boards from recruitment centers approved the EPIC project. The present study is based on data from a population of 345,157 women after excluding those with prevalent cancer other than non-melanoma skin cancer at baseline. Participants were also excluded if they had missing lifestyle (n 5 573) or anthropometry data (n 5 819).
Short Report
Identification and selection of thyroid cancer cases
In most of the EPIC countries (Denmark, France, Italy, Norway, Spain, Sweden, The Netherlands and United Kingdom), data on vital status were ascertained by record linkage with regional and/or national mortality registries. In Greece, Germany and Naples (Italy) data on vital status were continuously collected through active follow-up.23 In all centers except those in Greece, Germany and France, incident cancer cases were identified through record linkage with regional cancer registries. In France, Germany and Greece, follow-up for cancer incidence was based on a combination of methods, including the use of health insurance records, contacts with cancer and pathology registries and active follow-up through study participants and their next-of-kin. Closure dates for our study were defined as the latest date of complete followup for both cancer incidence and vital status. The follow-up spans ended between December 2006 and December 2009, depending on the EPIC center. A total of 537 first primary incident TC cases (codes “C73” as per the tenth Revision of the International Statistical Classification of Diseases, Injury and Causes of Death) in women were identified within the EPIC cohort at the time of analyses. TC cases with medullary cancer (n 5 22), undifferentiated cancers (n 5 4, anaplastic), lymphoma (n 5 1) and other specific morphologies (n 5 2, squamous cell and large cell carcinomas) were excluded from our study. Overall, 508 female first primary incident differentiated TC cases were included in our study. Reproductive and lifestyle characteristics
Baseline questionnaire data (including detailed questions about current habitual diet, menstrual and reproductive history, lifetime history of tobacco smoking, consumption of alcoholic beverages and physical activity) and anthropometric
Reproductive factors and differentiated thyroid carcinoma in women
measurements were collected from study participants in the period 1992–2000.23,24 Information on age at menarche and at menopause, age at first and last full-term pregnancy, spontaneous or induced abortion, breast feeding, exogenous hormones use [oral contraceptives (OC) and hormone replacement therapy (HRT)] and fertility problems were recorded in all centers (except in Sweden, where information on surgical menopause was not collected). The number of full-term pregnancies was calculated as the sum of live born children and stillbirths. Except from Norway and Umeå (Sweden), where information about twin pregnancies was available, the number of full-term pregnancies is overestimated, as twin pregnancies counted twice. Women were considered premenopausal if reporting menstrual periods over the past 12 months before recruitment, or when they were below the age of 46 years, and had either a hysterectomy or missing information on menopausal status. Women were considered as postmenopausal when they reported (i) no menses over the past 12 months before recruitment or (ii) bilateral ovariectomy or (iii) either a hysterectomy or missing information on menopausal status at age 55 years or above. Other women were considered as perimenopausal/unknown menopause status, and are referred to as perimenopausal throughout the article. Statistical analyses
Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) of TC for each hormonal, reproductive and menstrual factor. Tests and graphs based on Schoenfeld residuals were used to assess the proportional hazards assumption, which was satisfied. Age was used as underlying primary dependent time variable, with entry time defined as the subject’s age at recruitment and exit time as age at TC diagnosis, death or censoring date (lost or end of follow-up), whichever occurred first. All statistical models were stratified by study center and by age at recruitment (1-year category). Potential confounders included educational level (no formal education, primary, technical/professional school, secondary, university and not specified), smoking status (never, former and current smokers), alcohol intake (0, >0–15, >15–29.9 and 30 g/day), Cambridge physical activity index (inactive, moderately inactive, moderately active, active and unknown)24 and body mass index (10% change in HRs; therefore, all presented models were unadjusted. Trend tests across levels of exposure categories were performed on continuous variables, whereas for categorical variables the test has been computed by assigning consecutive scores to the categories as an ordinal variable. All associations were examined for differentiated TC in all women and separately in women below age 50 and for papillary TC only. All statistical analyses were performed using the Statistical Analysis System (SAS) software package, Version 9.3 (SAS Institute). C 2014 UICC Int. J. Cancer: 136, 1218–1227 (2015) V
50.9 (9.9) 11.0 (2.7) 402
Mean age recruitment (SD) (years)
Mean length of follow-up (SD) (years)
No. of cases (papillary)
15.7 41.2 27.6
1
2
3
C 2014 UICC Int. J. Cancer: 136, 1218–1227 (2015) V
29.3
29.5 38.6
74.1
Never
46.5 18.9
Postmenopausal
Perimenopausal
7.5
Surgical
Short Report
92.5
Natural
Type of menopause (%)3
34.6
Premenopausal
Menopausal status (%)
25.9
Ever
6.6
93.4
15.4
77.4
7.2
55.2
44.8
41.7
41.5
Never
Use of hormone replacement therapy (%)1
58.3
58.5
Ever
Use of oral contraceptives (%)
99.8
94.9
>5
1
0.2
5.1
5
Years since last pregnancy (%)1
26
28.2
31.9
23–25
6.5
93.6
27.9
46.1
26.0
68.7
31.3
39.1
60.9
99.0
1.0
36.9
34.1
29.0
29.2
27.3
42.5
44.6
16.6
9.7
178
10.4 (2.6)
52.7 (6.6)
n 5 206 712,698
France
45.4
15.7
11.7
12
11.0 (2.4)
56.8 (4.4)
n 5 16 323,411
Denmark
0–15
31.6
24.7
43.7
16.1
14.2
2.8
16.6
0
Alcohol consumption (g/day) (%)
30
34.3
56.2
18.5–25
50.4
2.1
1.2
9.2
44.4
46.4
