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Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014
YGYNO-976740; No. of pages: 9; 4C: Gynecologic Oncology xxx (2017) xxx–xxx
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014 Mette Tuxen Faber a, Kirsten Frederiksen b, Allan Jensen a, Peter Bo Aarslev a, Susanne K. Kjaer a,c,⁎ a b c
Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark Statistics and Pharmacoepidemiology, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark Gynecologic Clinic, Juliane Marie Center, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
H I G H L I G H T S • In the last three decades the incidence of type 1 endometrial cancer decreased. • The incidence of type 2 endometrial cancer incidence increased substantially. • Type 1 and type 2 endometrial cancer incidence should be evaluated separately.
a r t i c l e
i n f o
Article history: Received 6 February 2017 Received in revised form 1 May 2017 Accepted 9 May 2017 Available online xxxx Keywords: Endometrial cancer Incidence Hysterectomy-corrected Denmark Epidemiology
a b s t r a c t Objective. To investigate time trends in the incidence of overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, correcting for hysterectomy. Methods. Based on the Danish Cancer Registry and the Danish National Patient Registry we calculated hysterectomy-corrected incidence rates of overall, type 1 and type 2 endometrial cancer. Separate analyses for women b55 years (defined as pre- and perimenopausal age) and women aged ≥55 years (defined as postmenopausal age) and analyses allowing for different time trends before and after the study period midyear 1996 were performed. Log-linear Poisson models were used to estimate annual percentage change (APC) in incidence with 95% confidence intervals (CI). Results. The overall incidence of endometrial cancer decreased slightly from 1978 to 1995, but in the last two decades of the study period the incidence has been stable (APC = 0.16; 95% CI: −0.19; 0.50). In the study period (1978–2014) type 1 endometrial cancer incidence decreased slightly (APC = −0.67; 95% CI:−0.83; −0.52), whereas the incidence of type 2 endometrial cancer increased substantially (APC = 4.85; 95% CI: 4.47; 5.23). The decrease in type 1 endometrial cancer was most pronounced before 1996 in women younger than 55 years (APC = −2.79; 95% CI: −3.65; −1.91), while the largest increase in type 2 endometrial cancer was observed after 1996 (APC = 6.42; 95% CI: 5.72; 7.12). Conclusions. Over a period of more than 35 years, the incidence of type 1 endometrial cancer decreased, mainly in pre- and perimenopausal women, while type 2 endometrial cancer incidence increased. © 2017 Elsevier Inc. All rights reserved.
1. Introduction With almost 168,000 new cases and 35,000 deaths annually, cancer of the corpus uteri is the fourth commonest cancer type and the tenth leading cause of cancer death in women living in more developed countries [1]. Endometrial cancer can be divided into two distinct types in relation to histology, risk factors, and prognosis [2,3]. Type 1 endometrial cancer ⁎ Corresponding author at: Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. E-mail address: [email protected] (S.K. Kjaer).
constitutes 80–90% of all endometrial cancers. It is mainly diagnosed in relatively young women [3,4], and the prognosis is good (overall 5-year survival rate N80%) [3]. Type 1 endometrial cancer is estrogendependent, of endometrioid histology, and strongly linked to obesity [3]. Type 2 endometrial cancer is suggested to be less hormonedependent and non-endometrioid. It is comprised of higher grade histologies, particularly papillary serous carcinomas and clear-cell carcinomas [3–5]. Type 2 tumors have a high rate of recurrence and more often metastasize and present with a high grade at diagnosis compared with type 1 tumors [3,5]. Type 2 endometrial cancer typically occurs in women who are postmenopausal and multiparous [4,6]. Although type 2 endometrial cancer only constitutes 10–20% of all endometrial
http://dx.doi.org/10.1016/j.ygyno.2017.05.015 0090-8258/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: M.T. Faber, et al., Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.05.015
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cancers, it accounts for the majority of endometrial cancer deaths as it has a worse prognosis than type 1 endometrial cancer (overall 5-year survival rate is around 50%) [4,7]. Some studies have suggested different risk factor patterns for type 1 and type 2 endometrial cancer [5,6], but a recent pooled analysis showed that the two endometrial cancer types shared many common etiologic factors [8]. According to Ewertz & Jensen, the incidence rates of endometrial cancer increased markedly in Denmark from 1943 to 1980, particularly among women aged 50 years and older [9]. A recent study reported that the incidence rates of endometrial cancer among Danish women aged 55 years and older declined during the 1980s and early 1990s followed by a moderate increase from the late 1990s to 2004 [10]. A consistent increase in the incidence of endometrial cancer among postmenopausal women has been observed in Norway, Sweden, and Finland over the last 50 years [10] and also in other European countries [11,12]. However, a limitation of the majority of previous studies, but not all [13–16], is that they have not examined incidence rates separately for the two types of endometrial cancer. A further limitation of most previous incidence studies [10–16], but not all [17–19], is that they estimated endometrial cancer incidence rates without eliminating hysterectomized women from the population at risk. Women who have had a hysterectomy are no longer at risk of endometrial cancer and failure to remove these women from the population at risk implies an underestimation of the endometrial cancer incidence rates. Furthermore, when hysterectomy prevalence changes over time and differentially among age groups, estimation of time trends without taking hysterectomies into account may lead to false conclusions. In Denmark, we have a unique opportunity to take hysterectomies into account and to distinguish between type 1 and type 2 when calculating endometrial cancer incidence rates by use of data from two population-based registries; the Danish Cancer Registry and the Danish National Patient Registry. Using these data sources we report trends in hysterectomy-corrected age-standardized incidence rates of overall, type 1, and type 2 endometrial cancer in Denmark from 1978 to 2014. Furthermore, to evaluate time trends in pre- and perimenopausal women and postmenopausal women separately, trends for women younger than 55 years and women aged 55 years and older were estimated. Finally, to investigate possible changes in time trends in Denmark around the mid-1990s, as observed by Lindemann et al. [10], we provided estimates before and after 1996. 2. Material and methods 2.1. Data sources Information on all incident cases of endometrial cancer in Denmark was obtained from the Danish Cancer Registry, which contains nationwide information about all incident cancer cases diagnosed in Denmark since 1943. The Danish Cancer Registry is linked annually to the Causes of Death Registry and the Danish National Patient Registry to ensure completeness of data. It is considered to be 95–98% complete and contains information about e.g. date of birth, topography, morphology, and date of diagnosis for all cancer patients. In the Danish Cancer Registry, a data conversion has taken place on data from 1978 to 2003 so that all diagnoses have been converted from the modified International Classification of Diseases, 7th edition (ICD-7) to ICD-10. This means that from 1978 and onwards the registry is coded in accordance with ICD-10 for diagnosis and the International Classification of Diseases of Oncology, 3rd edition (ICD-O-3) for morphology [20]. From the Danish Cancer Registry, we retrieved data on all endometrial cancers diagnosed from January 1, 1978 to December 31, 2014 based on the ICD-10 codes C54 = malignant neoplasm of corpus uteri (except code C54.2 = myometrium) and C55 = malignant neoplasm of uterus, part unspecified. All cases were further classified according to the ICD-O-3 morphology codes as type 1, type 2, or ‘other’ endometrial cancers. Only invasive cancers
(i.e. with ‘3’ as the last digit in the morphology code) were included. Type 1 included common carcinomas such as endometrioid carcinomas, mucinous carcinomas, and adenocarcinomas, while type 2 encompassed the more uncommon and aggressive carcinomas including serous carcinomas, clear-cell carcinomas, carcinosarcomas, and malignant mixed Müllerian tumors [21]. Unspecified carcinomas and other types of endometrial carcinomas that are distinct from the two main types described above were classified as ‘other’ endometrial cancers. Finally, all sarcomas (except adenosarcoma and carcinosarcoma) and lymphomas, as well as non-epithelial endometrial carcinomas were not considered as endometrial cancers and were thus excluded from the analyses. Likewise, carcinomas with missing or undetermined histology were excluded from the analyses. Information on hysterectomies was obtained from the Danish National Patient Registry, which comprises information on surgical procedures for all somatic conditions in Denmark since 1977 [22]. From 1977 to 2012 a total of 226,333 hysterectomies were performed in women with a valid personal identification number. This information together with the age- and calendar specific mortality-rates for women derived from Statistics Denmark enabled us to estimate the age- and calendar year specific proportion of women that should be removed from the population-at-risk denominator when calculating incidence rates.
2.2. Statistical analysis Annual incidence rates for the period 1978 to 2014 were calculated per 100,000 women-years at risk and age-standardized according to the World Standard Population [23,24] using direct standardization. Risk time was estimated both uncorrected using the annual midyear female population size obtained from Statistics Denmark, as well as hysterectomy-corrected. Women having undergone total hysterectomy are no longer at risk of developing endometrial cancer and should be removed from the risk time from the age at hysterectomy until the age at death. To do this, the age- and calendar year specific hysterectomy prevalence, that is the proportion of women alive in a given year and being hysterectomized before a given age, was estimated in an illness-death model assuming the transition intensities to be piecewise constant in one year intervals [25]. Mortality intensity (before as well as after hysterectomy) was estimated using the age- and calendar year specific mortality rates for women provided by Statistics Denmark. Hysterectomy rates were estimated using the information about the number of total hysterectomies in the Danish National Patient Registry with the rates observed in 1978 extrapolated back and the rates observed in 2012 extrapolated forward in time. Internal validation of the model by comparing the model-based age-specific prevalence estimates for those below 70 years of age in the year 2012 where full information from the registers exist with the actual observed proportion of women hysterectomized after 1977 and still alive showed very good agreement. Additionally, sensitivity analyses with halving respectively doubling the age-specific hysterectomy rates before 1978 were performed to investigate whether changing the assumption that the age-specific hysterectomy rates before 1978 was at the same level as in 1978 affects the conclusion. We estimated hysterectomy-corrected incidence rates of overall, type 1 and type 2 endometrial cancer. Separate trends for women younger than 55 years (defined as pre- and perimenopausal age) and women aged 55 years and older (defined as postmenopausal age) were also estimated. To evaluate incidence trends over time, the annual percentage change (APC) in incidence with corresponding 95% confidence intervals (CIs) was calculated based on a log-linear Poisson regression model with age in 5-year groups and the association with year in one year groups specified as linear or piecewise linear with a knot in the midyear 1996. A statistical significance level of 5% was used. All analyses were performed using the SAS software package (version 9.3.; SAS Institute, Cary, NC, USA).
Please cite this article as: M.T. Faber, et al., Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.05.015
M.T. Faber et al. / Gynecologic Oncology xxx (2017) xxx–xxx
3. Results During the study period from 1978 to 2014, 25,313 women were registered with cancer of the corpus uteri in the Danish Cancer Registry. Of these, 1416 women were excluded because they were registered with unspecified carcinomas, sarcomas, lymphomas, non-epithelial endometrial carcinomas, or carcinomas with missing or undetermined histology, leaving. 23,897 women for analyses; 21,243 women were classified with type 1, 2294 women were classified with type 2, and 360 women were classified with ‘other’ endometrial cancer (Table 1). Given the low number of ‘other’ endometrial cancers and the diversity of tumor types included in this category the remaining part of the article will focus on the incidence of overall (including ‘other’ endometrial cancer), type 1, and type 2 endometrial cancer only. In Table 1, the number of overall, type 1 and type 2 endometrial cancer cases by calendar year and age is presented. The number of overall and type 1 endometrial cancer cases increased slightly from the period 1978–1995 to the period 1996–2014, while the number of type 2 endometrial cancer cases increased markedly. The mean age at diagnosis of overall and type 1 endometrial cancer was 66 years and the mean age at diagnosis of type 2 endometrial cancer was 69 years. A total of 99.06 million women-years contributed to the risk time. When hysterectomies were taken into account, there were 91.53 million womenyears. Table 1 also shows the age-standardized incidence rates of endometrial cancer for the entire study period. The overall uncorrected, agestandardized incidence rate of endometrial cancer was 13.6 per 100,000, while the hysterectomy-corrected, age-standardized incidence rate was 16.4. Age-standardized incidence rates, uncorrected and hysterectomy-corrected, were 12.2 and 14.8, respectively, for type 1 endometrial cancer and 1.2 and 1.4, respectively, for type 2 endometrial cancer (Table 1). All remaining incidence rates presented in the article are hysterectomy-corrected. Fig. 1A shows the hysterectomy-corrected, age-standardized incidence rate of overall endometrial cancer in Denmark from 1978 to 2014. The age-standardized incidence rate decreased slightly between 1978 and 2014 from 16.7 to 15.9 per 100,000 women-years corresponding to an annual percentage change of −0.24 (95% CI: −0.39; −0.08). Fig. 1A also presents the uncorrected, age-standardized incidence rate of overall endometrial cancer. The difference between the uncorrected and corrected incidence rates was constant over time, i.e. the gradient of the curve was unchanged, which was reflected by a minor change only in the APC-value for the uncorrected, age-standardized incidence rate (APC = −0.15; 95% CI: −0.30; 0.01). This tendency was also observed for type 1 and type 2 endometrial cancer and for overall, type 1 and type 2 endometrial cancer according to age (data not shown) and
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the remaining incidence rates presented in the article are hysterectomy-corrected. Incidence rates of overall endometrial cancer among women younger than 55 years and women aged 55 years and older, respectively, are shown in Fig. 1B and C. Among women younger than 55 years of age the incidence decreased significantly from 1978 to 2014 (APC = −1.57; 95% CI: −1.99; −1.15), whereas for women of postmenopausal age (55 years and older) the incidence of endometrial cancer remained virtually unchanged during the study period (APC = − 0.04; 95% CI: −0.20; 0.12). The hysterectomy-corrected, age-standardized incidence rate of type 1 endometrial cancer in Denmark 1978–2014 is presented in Fig. 2A. The incidence decreased from 15.8 per 100,000 women-years in 1978 to 12.9 per 100,000 women-years in 2014 (APC = − 0.67; 95% CI: −0.83; −0.52). We also assessed the incidence of type 1 endometrial cancer among women younger than 55 years and women aged 55 years and older separately (Fig. 2B and C). The incidence decreased for both groups, but the decrease was more pronounced among women younger than 55 years (APC = − 1.69; 95% CI: − 2.11; − 1.28) than among women aged 55 years and older (APC = −0.52; 95% CI: −0.68; −0.35). Fig. 3A shows the hysterectomy-corrected, age-standardized incidence rate of type 2 endometrial cancer from 1978 to 2014. The incidence rate increased from 0.5 per 100,000 women-years in 1978 to 2.9 per 100,000 women-years in 2014. When estimated in a Poisson regression analysis this development represented an annual percentage change of 4.85 (95% CI: 4.47; 5.23). Separate incidence rates of type 2 endometrial cancer for women younger than 55 years and women aged 55 years and older are presented in Fig. 3B and C. For both groups, the incidence rates increased over time, but the increase was more substantial for postmenopausal women (APC = 5.01; 95% CI: 4.62; 5.40) than for pre- and perimenopausal women (APC = 2.75; 95% CI: 1.39; 4.13). Table 2 presents time trends for the incidence of overall, type 1 and type 2 endometrial cancer according to age and calendar year allowing for a shift in trend in the study period midyear 1996. The overall endometrial cancer incidence decreased before 1996, both among all women (APC = − 0.65; 95% CI: − 1.01; − 0.29) and among women younger than 55 years (APC = −2.84; 95% CI: −3.71; −1.96), whereas the incidence remained stable from 1996 and onwards. For type 1 endometrial cancer, a major decrease was observed before 1996 among the youngest women (APC = −2.79; 95% CI: −3.65; −1.91), while analyses for type 2 endometrial cancer revealed a marked increase after 1996 both among women younger than 55 years (APC = 4.01; 95% CI: 1.45; 6.63) and among women aged 55 years and older (APC = 6.59; 95% CI: 5.87; 7.32).
Table 1 Number of endometrial cancer cases and age-standardized incidence rates (uncorrected and corrected for hysterectomy) in Denmark by age at diagnosis and calendar year. 1978–2014 n
Overall endometrial cancera All b55 years 55+ years Type 1 endometrial cancer All b55 years 55+ years Type 2 endometrial cancer All b55 years 55+ years
1978–1995 %
Age-standardized incidence rate per 100,000 women-years Uncorrected for hysterectomy
Corrected for hysterectomy
1996–2014
n
%
n
%
23,897 3188 20,709
100.0 13.3 86.7
13.6 3.2 72.5
16.4 3.6 89.1
11,281 1577 9704
100.0 14.0 86.0
12,616 1611 11,005
100.0 12.8 87.2
21,243 2980 18,263
100.0 14.0 86.0
12.2 3.0 64.7
14.8 3.4 79.5
10,422 1489 8933
100.0 14.3 85.7
10,821 1491 9330
100.0 13.8 86.2
2294 160 2134
100.0 7.0 93.0
1.2 0.16 6.8
1.4 0.18 8.5
631 50 581
100.0 7.9 92.1
1663 110 1553
100.0 6.6 93.4
Number of endometrial cancer cases. a As overall endometrial cancer also includes ‘other’ endometrial cancers (n = 360), the number of Type 1 and Type 2 cases do not add up to the overall.
Please cite this article as: M.T. Faber, et al., Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.05.015
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M.T. Faber et al. / Gynecologic Oncology xxx (2017) xxx–xxx
Please cite this article as: M.T. Faber, et al., Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.05.015
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4. Discussion In this population-based study of hysterectomy-corrected endometrial cancer incidence in Denmark we found that the overall incidence of endometrial cancer decreased slightly from 1978 to 1995, but thereafter the incidence was stable. As one of the first studies we were able to distinguish between the incidence of type 1 and type 2 endometrial cancer. Type 1 endometrial cancer showed a decreasing trend over time, whereas a marked increase in the incidence of type 2 endometrial cancer was found from 1978 to 2014. The decrease in type 1 endometrial cancer was most pronounced in women younger than 55 years of age and mainly took place before 1996, while we observed an increase in type 2 endometrial cancer initially only among postmenopausal women, but after 1996 a significant increase was observed both in pre-perimenopausal and in postmenopausal women. In line with our results, some studies have found a stable incidence of overall endometrial cancer [12,15], while other studies reported an increasing incidence over time [10,13,16–18]. Of these, two studies [17,18] provided hysterectomy-corrected estimates. The decrease in type 1 endometrial cancer observed in our study is in line with a recent study by Temkin et al. [19] who reported a decrease in the hysterectomy-corrected incidence rate of overall and type 1 endometrial cancer among white US women. In contrast, some other studies have found that the incidence of type 1 endometrial cancer increased during the last two to three decades [13–16]. The increase in type 2 endometrial cancer incidence observed in our study is compatible with results from two studies [26,27]. In a Japanese study, Honda et al. [26] found a statistically significant increase in the incidence of type 2 endometrial cancer from the period 1990–2000 to the period 2001–2010. Likewise, a study from the United States [27] revealed increased rates of advancedstage endometrial cancers and high-risk histologies, including serous carcinoma, clear cell carcinoma, and sarcoma, from 1988 to 2001. Conversely, other recent studies from the Netherlands [13,14], United Kingdom [16] and the United States [15] found that type 2 endometrial cancer incidence rates decreased or remained relatively unchanged during the last two to three decades. None of these studies [13–16,26,27] estimated hysterectomy-corrected incidence rates. Looking at the endometrial cancer incidence over the entire study period according to age, we found either no change or a slight decrease in the incidence of overall and type 1 endometrial cancer among women aged 55 years and older. In line with our results, Temkin et al. [19] reported a decrease in the incidence of overall and type 1 endometrial cancer among white women aged 50 years and older. This is in contrast to the findings of some other studies where increasing trends in postmenopausal women were found [10–12,14,16,28]. However, the decreasing trends in type 1 endometrial cancer among pre- and perimenopausal women that we observed are in accordance with several studies [11,12,28]. In contrast, our study is the first to assess agespecific incidence rates of type 2 endometrial cancer, and so our finding of a statistically significant increase in type 2 endometrial cancer incidence is new. The variation in endometrial cancer incidence across studies may reflect inherent differences in study characteristics such as study period and age and race of the included women. Furthermore, not all studies corrected for hysterectomy. Therefore direct comparisons between studies may be difficult. Hysterectomy is a common surgical procedure for women, but the absolute frequency of hysterectomy and changes in hysterectomy rates over time are important factors and these both vary within and between countries. In the United States, where N30% of all women have had a hysterectomy by age 60, recent declines in hysterectomy rates have been observed [19]. In Denmark, the age-adjusted incidence of hysterectomy decreased from 1977 to 2010 and only 6% of
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women at any age underwent hysterectomy in 2010 [29]. Different national coding practices may also explain the differences in the incidence of the two types of endometrial cancer in the respective studies, particularly if there was a change in coding over time. Some of the increase in type 2 endometrial cancer found in our study may potentially be attributed to changes in detection rates, changes in diagnostic practices, or improvements of the histopathologic diagnosis over time. Furthermore, the increase may be attributable to a more refined pathology diagnosis of type 2 lesions, which may be related to awareness of the disease in training or more access to biomarkers. Lastly, it should be noted that type 2 endometrial cancer is a rare diagnosis and therefore the results for this type are based on a limited number of cases. Other factors may also contribute to the time trends observed in endometrial cancer incidence. Previously it has been suggested that the risk factor pattern differs between type 1 and type 2 endometrial cancers. However, still only few studies have examined epidemiological differences between these two types of cancers, and the results are equivocal. It is well established that oral contraceptive use has a protective effect on risk of type 1 endometrial cancer [30], but this has also been shown for type 2 endometrial cancer [5,8]. Since their release in 1966, oral contraceptives have become increasingly popular in Denmark and today Denmark has one of the highest percentages of oral contraceptive use in Europe [31]. In relation to HRT use, one recent meta-analysis made the conclusion that there is no significantly different effect of hormones according to histologic subtypes [32]. Other studies reported that use of HRT increases the risk of type 1 endometrial cancer [33], whereas HRT use does not seem to have a major impact on the risk of type 2 endometrial cancer [5,6]. Since the mid-1990s, HRT use has declined in Denmark [34]. Tobacco smoking has been reported to decrease the risk of endometrial cancer through its antiestrogenic effects [35] and therefore was anticipated to be most strongly related to type 1 tumors, but recent studies have shown that smoking decreases the risk of both type 1 and type 2 endometrial cancer [5,8]. Despite a significant reduction in the proportion of female smokers in the study period, smoking is still common among Danish women (17% in 2016) [36]. Additional risk factors for endometrial cancer are obesity [35,37] and diabetes [35,38] both of which have been shown to contribute to type 1 and type 2 endometrial cancer in some studies [5,8]. Thus, risk factor profiles for type 1 and type 2 endometrial cancer may be overlapping, implying that not only type 1 but also type 2 endometrial cancer may be estrogen-dependent. To support this, a recent study [39] found that there was no statistically significant difference in the serum levels of sex hormones (estradiol, progesterone, testosterone, FSH and LH) between patients with type 1 and type 2 endometrial cancer regardless of menopausal status. Furthermore, the majority of type 2 endometrial cancer were estrogen receptor and progesterone receptor positive. These results suggest that excess estrogen may also be involved in the pathogenesis of type 2 endometrial cancer and that type 2 endometrial cancer is not completely estrogen-independent. Lastly, as newly suggested by Suarez et al. [40], the dualistic view of endometrial cancer, originally proposed by Bokhman [2], may be challenged by new insights on risk factors and new histologic categories, and this calls for further investigation. This study is based on high-quality population-based, nationwide data and covered a period of N35 years. Additional key strengths include the ability to distinguish between type 1 and type 2 endometrial cancer and to correct for hysterectomy. Elimination of hysterectomized women is important to avoid an underestimation of endometrial cancer incidence rates and to make sure that time trends in endometrial cancer incidence are not influenced by changes in hysterectomy prevalence over time. Our estimates of hysterectomy prevalence were based on information about hysterectomies from a 36 year period obtained from a
Fig. 1. Age-standardized incidence rates (World Standard Population) of overall endometrial cancer 1978–2014 for all women, hysterectomy-corrected and uncorrected (A) and for women divided according to age b55 years, hysterectomy-corrected (B) and ≥55 years, hysterectomy-corrected (C). Note that the scale on the y-axis is different in Figure A, B and C. APC = Annual percentage change.
Please cite this article as: M.T. Faber, et al., Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.05.015
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Fig. 2. Hysterectomy-corrected, age-standardized incidence rates (World Standard Population) of type 1 endometrial cancer 1978–2014 for all women (A) and for women divided according to age b 55 years (B) and ≥55 years (C). Note that the scale on the y-axis is different in Figure A, B and C. APC = Annual percentage change.
Please cite this article as: M.T. Faber, et al., Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.05.015
M.T. Faber et al. / Gynecologic Oncology xxx (2017) xxx–xxx
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Fig. 3. Hysterectomy-corrected, age-standardized incidence rates (World Standard Population) of type 2 endometrial cancer 1978–2014 for all women (A) and for women divided according to age b 55 years (B) and ≥55 years (C). Note that the scale on the y-axis is different in Figure A, B and C. APC = Annual percentage change.
Please cite this article as: M.T. Faber, et al., Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.05.015
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Table 2 Annual percentage change (APC) and 95% confidence intervals (CI) for overall, type 1 and type 2 endometrial cancer by age and calendar year. 1978–1995
Overall All b55 years ≥55 years Type 1 All b55 years ≥55 years Type 2 All b55 years ≥55 years
1996–2014
APC
(95% CI)
APC
(95% CI)
−0.65 −2.84 −0.29
(−1.01; −0.29) (−3.71; −1.96) (−0.66; 0.08)
0.16 −0.22 0.19
(−0.19; 0.50) (−1.15; 0.72) (−0.16; 0.55)
−0.68 −2.79 −0.32
(−1.03; −0.33) (−3.65; −1.91) (−0.70; 0.05)
−0.67 −0.52 −0.70
(−1.02; −0.31) (−1.45; 0.41) (−1.07; −0.34)
2.39 1.01 2.50
(1.43; 3.36) (−2.19; 4.31) (1.51; 3.51)
6.42 4.01 6.59
(5.72; 7.12) (1.45; 6.63) (5.87; 7.32)
population-based hospital registry. To take into account hysterectomies performed before the start of the registry, hysterectomy rates from 1978 were extrapolated back in time. This assumption could potentially have affected the estimated time trends. However, sensitivity analyses with halving respectively doubling the age-specific hysterectomy rates back in time did not alter the main conclusions. A potential limitation is that even though tumors registered in the Danish Cancer Registry are morphologically verified by a pathologist we cannot exclude the possibility of misclassification of type 1 and type 2 endometrial cancer. However, this would only impact the results if the misclassification differed over time. In conclusion, we found that the incidence of overall and type 1 endometrial cancer decreased slightly from 1978 to 2014, while there was a marked increase in the incidence of type 2 endometrial cancer. The incidence of overall and type 1 endometrial cancer mainly decreased in the first part of the study period among pre- and perimenopausal women, while the highest increase in type 2 endometrial cancer was observed in the last part of the study period both among pre- and perimenopausal women and postmenopausal women. Given the differences in the incidence of type 1 and type 2 endometrial cancer, future studies should consider type 1 and type 2 endometrial cancers as separate diseases. In addition, further studies are needed to gain knowledge about the etiology of type 1 and type 2 endometrial cancer. Funding statement This research received no specific financial support from any funding agency in the public, commercial, or not-for-profit sectors. Conflict of interest statement The authors declare no conflicts of interest.
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Please cite this article as: M.T. Faber, et al., Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.05.015
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Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014 Mette Tuxen Faber a, Kirsten Frederiksen b, Allan Jensen a, Peter Bo Aarslev a, Susanne K. Kjaer a,c,⁎ a b c
Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark Statistics and Pharmacoepidemiology, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark Gynecologic Clinic, Juliane Marie Center, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
H I G H L I G H T S • In the last three decades the incidence of type 1 endometrial cancer decreased. • The incidence of type 2 endometrial cancer incidence increased substantially. • Type 1 and type 2 endometrial cancer incidence should be evaluated separately.
a r t i c l e
i n f o
Article history: Received 6 February 2017 Received in revised form 1 May 2017 Accepted 9 May 2017 Available online xxxx Keywords: Endometrial cancer Incidence Hysterectomy-corrected Denmark Epidemiology
a b s t r a c t Objective. To investigate time trends in the incidence of overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, correcting for hysterectomy. Methods. Based on the Danish Cancer Registry and the Danish National Patient Registry we calculated hysterectomy-corrected incidence rates of overall, type 1 and type 2 endometrial cancer. Separate analyses for women b55 years (defined as pre- and perimenopausal age) and women aged ≥55 years (defined as postmenopausal age) and analyses allowing for different time trends before and after the study period midyear 1996 were performed. Log-linear Poisson models were used to estimate annual percentage change (APC) in incidence with 95% confidence intervals (CI). Results. The overall incidence of endometrial cancer decreased slightly from 1978 to 1995, but in the last two decades of the study period the incidence has been stable (APC = 0.16; 95% CI: −0.19; 0.50). In the study period (1978–2014) type 1 endometrial cancer incidence decreased slightly (APC = −0.67; 95% CI:−0.83; −0.52), whereas the incidence of type 2 endometrial cancer increased substantially (APC = 4.85; 95% CI: 4.47; 5.23). The decrease in type 1 endometrial cancer was most pronounced before 1996 in women younger than 55 years (APC = −2.79; 95% CI: −3.65; −1.91), while the largest increase in type 2 endometrial cancer was observed after 1996 (APC = 6.42; 95% CI: 5.72; 7.12). Conclusions. Over a period of more than 35 years, the incidence of type 1 endometrial cancer decreased, mainly in pre- and perimenopausal women, while type 2 endometrial cancer incidence increased. © 2017 Elsevier Inc. All rights reserved.
1. Introduction With almost 168,000 new cases and 35,000 deaths annually, cancer of the corpus uteri is the fourth commonest cancer type and the tenth leading cause of cancer death in women living in more developed countries [1]. Endometrial cancer can be divided into two distinct types in relation to histology, risk factors, and prognosis [2,3]. Type 1 endometrial cancer ⁎ Corresponding author at: Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. E-mail address: [email protected] (S.K. Kjaer).
constitutes 80–90% of all endometrial cancers. It is mainly diagnosed in relatively young women [3,4], and the prognosis is good (overall 5-year survival rate N80%) [3]. Type 1 endometrial cancer is estrogendependent, of endometrioid histology, and strongly linked to obesity [3]. Type 2 endometrial cancer is suggested to be less hormonedependent and non-endometrioid. It is comprised of higher grade histologies, particularly papillary serous carcinomas and clear-cell carcinomas [3–5]. Type 2 tumors have a high rate of recurrence and more often metastasize and present with a high grade at diagnosis compared with type 1 tumors [3,5]. Type 2 endometrial cancer typically occurs in women who are postmenopausal and multiparous [4,6]. Although type 2 endometrial cancer only constitutes 10–20% of all endometrial
http://dx.doi.org/10.1016/j.ygyno.2017.05.015 0090-8258/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: M.T. Faber, et al., Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.05.015
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cancers, it accounts for the majority of endometrial cancer deaths as it has a worse prognosis than type 1 endometrial cancer (overall 5-year survival rate is around 50%) [4,7]. Some studies have suggested different risk factor patterns for type 1 and type 2 endometrial cancer [5,6], but a recent pooled analysis showed that the two endometrial cancer types shared many common etiologic factors [8]. According to Ewertz & Jensen, the incidence rates of endometrial cancer increased markedly in Denmark from 1943 to 1980, particularly among women aged 50 years and older [9]. A recent study reported that the incidence rates of endometrial cancer among Danish women aged 55 years and older declined during the 1980s and early 1990s followed by a moderate increase from the late 1990s to 2004 [10]. A consistent increase in the incidence of endometrial cancer among postmenopausal women has been observed in Norway, Sweden, and Finland over the last 50 years [10] and also in other European countries [11,12]. However, a limitation of the majority of previous studies, but not all [13–16], is that they have not examined incidence rates separately for the two types of endometrial cancer. A further limitation of most previous incidence studies [10–16], but not all [17–19], is that they estimated endometrial cancer incidence rates without eliminating hysterectomized women from the population at risk. Women who have had a hysterectomy are no longer at risk of endometrial cancer and failure to remove these women from the population at risk implies an underestimation of the endometrial cancer incidence rates. Furthermore, when hysterectomy prevalence changes over time and differentially among age groups, estimation of time trends without taking hysterectomies into account may lead to false conclusions. In Denmark, we have a unique opportunity to take hysterectomies into account and to distinguish between type 1 and type 2 when calculating endometrial cancer incidence rates by use of data from two population-based registries; the Danish Cancer Registry and the Danish National Patient Registry. Using these data sources we report trends in hysterectomy-corrected age-standardized incidence rates of overall, type 1, and type 2 endometrial cancer in Denmark from 1978 to 2014. Furthermore, to evaluate time trends in pre- and perimenopausal women and postmenopausal women separately, trends for women younger than 55 years and women aged 55 years and older were estimated. Finally, to investigate possible changes in time trends in Denmark around the mid-1990s, as observed by Lindemann et al. [10], we provided estimates before and after 1996. 2. Material and methods 2.1. Data sources Information on all incident cases of endometrial cancer in Denmark was obtained from the Danish Cancer Registry, which contains nationwide information about all incident cancer cases diagnosed in Denmark since 1943. The Danish Cancer Registry is linked annually to the Causes of Death Registry and the Danish National Patient Registry to ensure completeness of data. It is considered to be 95–98% complete and contains information about e.g. date of birth, topography, morphology, and date of diagnosis for all cancer patients. In the Danish Cancer Registry, a data conversion has taken place on data from 1978 to 2003 so that all diagnoses have been converted from the modified International Classification of Diseases, 7th edition (ICD-7) to ICD-10. This means that from 1978 and onwards the registry is coded in accordance with ICD-10 for diagnosis and the International Classification of Diseases of Oncology, 3rd edition (ICD-O-3) for morphology [20]. From the Danish Cancer Registry, we retrieved data on all endometrial cancers diagnosed from January 1, 1978 to December 31, 2014 based on the ICD-10 codes C54 = malignant neoplasm of corpus uteri (except code C54.2 = myometrium) and C55 = malignant neoplasm of uterus, part unspecified. All cases were further classified according to the ICD-O-3 morphology codes as type 1, type 2, or ‘other’ endometrial cancers. Only invasive cancers
(i.e. with ‘3’ as the last digit in the morphology code) were included. Type 1 included common carcinomas such as endometrioid carcinomas, mucinous carcinomas, and adenocarcinomas, while type 2 encompassed the more uncommon and aggressive carcinomas including serous carcinomas, clear-cell carcinomas, carcinosarcomas, and malignant mixed Müllerian tumors [21]. Unspecified carcinomas and other types of endometrial carcinomas that are distinct from the two main types described above were classified as ‘other’ endometrial cancers. Finally, all sarcomas (except adenosarcoma and carcinosarcoma) and lymphomas, as well as non-epithelial endometrial carcinomas were not considered as endometrial cancers and were thus excluded from the analyses. Likewise, carcinomas with missing or undetermined histology were excluded from the analyses. Information on hysterectomies was obtained from the Danish National Patient Registry, which comprises information on surgical procedures for all somatic conditions in Denmark since 1977 [22]. From 1977 to 2012 a total of 226,333 hysterectomies were performed in women with a valid personal identification number. This information together with the age- and calendar specific mortality-rates for women derived from Statistics Denmark enabled us to estimate the age- and calendar year specific proportion of women that should be removed from the population-at-risk denominator when calculating incidence rates.
2.2. Statistical analysis Annual incidence rates for the period 1978 to 2014 were calculated per 100,000 women-years at risk and age-standardized according to the World Standard Population [23,24] using direct standardization. Risk time was estimated both uncorrected using the annual midyear female population size obtained from Statistics Denmark, as well as hysterectomy-corrected. Women having undergone total hysterectomy are no longer at risk of developing endometrial cancer and should be removed from the risk time from the age at hysterectomy until the age at death. To do this, the age- and calendar year specific hysterectomy prevalence, that is the proportion of women alive in a given year and being hysterectomized before a given age, was estimated in an illness-death model assuming the transition intensities to be piecewise constant in one year intervals [25]. Mortality intensity (before as well as after hysterectomy) was estimated using the age- and calendar year specific mortality rates for women provided by Statistics Denmark. Hysterectomy rates were estimated using the information about the number of total hysterectomies in the Danish National Patient Registry with the rates observed in 1978 extrapolated back and the rates observed in 2012 extrapolated forward in time. Internal validation of the model by comparing the model-based age-specific prevalence estimates for those below 70 years of age in the year 2012 where full information from the registers exist with the actual observed proportion of women hysterectomized after 1977 and still alive showed very good agreement. Additionally, sensitivity analyses with halving respectively doubling the age-specific hysterectomy rates before 1978 were performed to investigate whether changing the assumption that the age-specific hysterectomy rates before 1978 was at the same level as in 1978 affects the conclusion. We estimated hysterectomy-corrected incidence rates of overall, type 1 and type 2 endometrial cancer. Separate trends for women younger than 55 years (defined as pre- and perimenopausal age) and women aged 55 years and older (defined as postmenopausal age) were also estimated. To evaluate incidence trends over time, the annual percentage change (APC) in incidence with corresponding 95% confidence intervals (CIs) was calculated based on a log-linear Poisson regression model with age in 5-year groups and the association with year in one year groups specified as linear or piecewise linear with a knot in the midyear 1996. A statistical significance level of 5% was used. All analyses were performed using the SAS software package (version 9.3.; SAS Institute, Cary, NC, USA).
Please cite this article as: M.T. Faber, et al., Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.05.015
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3. Results During the study period from 1978 to 2014, 25,313 women were registered with cancer of the corpus uteri in the Danish Cancer Registry. Of these, 1416 women were excluded because they were registered with unspecified carcinomas, sarcomas, lymphomas, non-epithelial endometrial carcinomas, or carcinomas with missing or undetermined histology, leaving. 23,897 women for analyses; 21,243 women were classified with type 1, 2294 women were classified with type 2, and 360 women were classified with ‘other’ endometrial cancer (Table 1). Given the low number of ‘other’ endometrial cancers and the diversity of tumor types included in this category the remaining part of the article will focus on the incidence of overall (including ‘other’ endometrial cancer), type 1, and type 2 endometrial cancer only. In Table 1, the number of overall, type 1 and type 2 endometrial cancer cases by calendar year and age is presented. The number of overall and type 1 endometrial cancer cases increased slightly from the period 1978–1995 to the period 1996–2014, while the number of type 2 endometrial cancer cases increased markedly. The mean age at diagnosis of overall and type 1 endometrial cancer was 66 years and the mean age at diagnosis of type 2 endometrial cancer was 69 years. A total of 99.06 million women-years contributed to the risk time. When hysterectomies were taken into account, there were 91.53 million womenyears. Table 1 also shows the age-standardized incidence rates of endometrial cancer for the entire study period. The overall uncorrected, agestandardized incidence rate of endometrial cancer was 13.6 per 100,000, while the hysterectomy-corrected, age-standardized incidence rate was 16.4. Age-standardized incidence rates, uncorrected and hysterectomy-corrected, were 12.2 and 14.8, respectively, for type 1 endometrial cancer and 1.2 and 1.4, respectively, for type 2 endometrial cancer (Table 1). All remaining incidence rates presented in the article are hysterectomy-corrected. Fig. 1A shows the hysterectomy-corrected, age-standardized incidence rate of overall endometrial cancer in Denmark from 1978 to 2014. The age-standardized incidence rate decreased slightly between 1978 and 2014 from 16.7 to 15.9 per 100,000 women-years corresponding to an annual percentage change of −0.24 (95% CI: −0.39; −0.08). Fig. 1A also presents the uncorrected, age-standardized incidence rate of overall endometrial cancer. The difference between the uncorrected and corrected incidence rates was constant over time, i.e. the gradient of the curve was unchanged, which was reflected by a minor change only in the APC-value for the uncorrected, age-standardized incidence rate (APC = −0.15; 95% CI: −0.30; 0.01). This tendency was also observed for type 1 and type 2 endometrial cancer and for overall, type 1 and type 2 endometrial cancer according to age (data not shown) and
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the remaining incidence rates presented in the article are hysterectomy-corrected. Incidence rates of overall endometrial cancer among women younger than 55 years and women aged 55 years and older, respectively, are shown in Fig. 1B and C. Among women younger than 55 years of age the incidence decreased significantly from 1978 to 2014 (APC = −1.57; 95% CI: −1.99; −1.15), whereas for women of postmenopausal age (55 years and older) the incidence of endometrial cancer remained virtually unchanged during the study period (APC = − 0.04; 95% CI: −0.20; 0.12). The hysterectomy-corrected, age-standardized incidence rate of type 1 endometrial cancer in Denmark 1978–2014 is presented in Fig. 2A. The incidence decreased from 15.8 per 100,000 women-years in 1978 to 12.9 per 100,000 women-years in 2014 (APC = − 0.67; 95% CI: −0.83; −0.52). We also assessed the incidence of type 1 endometrial cancer among women younger than 55 years and women aged 55 years and older separately (Fig. 2B and C). The incidence decreased for both groups, but the decrease was more pronounced among women younger than 55 years (APC = − 1.69; 95% CI: − 2.11; − 1.28) than among women aged 55 years and older (APC = −0.52; 95% CI: −0.68; −0.35). Fig. 3A shows the hysterectomy-corrected, age-standardized incidence rate of type 2 endometrial cancer from 1978 to 2014. The incidence rate increased from 0.5 per 100,000 women-years in 1978 to 2.9 per 100,000 women-years in 2014. When estimated in a Poisson regression analysis this development represented an annual percentage change of 4.85 (95% CI: 4.47; 5.23). Separate incidence rates of type 2 endometrial cancer for women younger than 55 years and women aged 55 years and older are presented in Fig. 3B and C. For both groups, the incidence rates increased over time, but the increase was more substantial for postmenopausal women (APC = 5.01; 95% CI: 4.62; 5.40) than for pre- and perimenopausal women (APC = 2.75; 95% CI: 1.39; 4.13). Table 2 presents time trends for the incidence of overall, type 1 and type 2 endometrial cancer according to age and calendar year allowing for a shift in trend in the study period midyear 1996. The overall endometrial cancer incidence decreased before 1996, both among all women (APC = − 0.65; 95% CI: − 1.01; − 0.29) and among women younger than 55 years (APC = −2.84; 95% CI: −3.71; −1.96), whereas the incidence remained stable from 1996 and onwards. For type 1 endometrial cancer, a major decrease was observed before 1996 among the youngest women (APC = −2.79; 95% CI: −3.65; −1.91), while analyses for type 2 endometrial cancer revealed a marked increase after 1996 both among women younger than 55 years (APC = 4.01; 95% CI: 1.45; 6.63) and among women aged 55 years and older (APC = 6.59; 95% CI: 5.87; 7.32).
Table 1 Number of endometrial cancer cases and age-standardized incidence rates (uncorrected and corrected for hysterectomy) in Denmark by age at diagnosis and calendar year. 1978–2014 n
Overall endometrial cancera All b55 years 55+ years Type 1 endometrial cancer All b55 years 55+ years Type 2 endometrial cancer All b55 years 55+ years
1978–1995 %
Age-standardized incidence rate per 100,000 women-years Uncorrected for hysterectomy
Corrected for hysterectomy
1996–2014
n
%
n
%
23,897 3188 20,709
100.0 13.3 86.7
13.6 3.2 72.5
16.4 3.6 89.1
11,281 1577 9704
100.0 14.0 86.0
12,616 1611 11,005
100.0 12.8 87.2
21,243 2980 18,263
100.0 14.0 86.0
12.2 3.0 64.7
14.8 3.4 79.5
10,422 1489 8933
100.0 14.3 85.7
10,821 1491 9330
100.0 13.8 86.2
2294 160 2134
100.0 7.0 93.0
1.2 0.16 6.8
1.4 0.18 8.5
631 50 581
100.0 7.9 92.1
1663 110 1553
100.0 6.6 93.4
Number of endometrial cancer cases. a As overall endometrial cancer also includes ‘other’ endometrial cancers (n = 360), the number of Type 1 and Type 2 cases do not add up to the overall.
Please cite this article as: M.T. Faber, et al., Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.05.015
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Please cite this article as: M.T. Faber, et al., Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.05.015
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4. Discussion In this population-based study of hysterectomy-corrected endometrial cancer incidence in Denmark we found that the overall incidence of endometrial cancer decreased slightly from 1978 to 1995, but thereafter the incidence was stable. As one of the first studies we were able to distinguish between the incidence of type 1 and type 2 endometrial cancer. Type 1 endometrial cancer showed a decreasing trend over time, whereas a marked increase in the incidence of type 2 endometrial cancer was found from 1978 to 2014. The decrease in type 1 endometrial cancer was most pronounced in women younger than 55 years of age and mainly took place before 1996, while we observed an increase in type 2 endometrial cancer initially only among postmenopausal women, but after 1996 a significant increase was observed both in pre-perimenopausal and in postmenopausal women. In line with our results, some studies have found a stable incidence of overall endometrial cancer [12,15], while other studies reported an increasing incidence over time [10,13,16–18]. Of these, two studies [17,18] provided hysterectomy-corrected estimates. The decrease in type 1 endometrial cancer observed in our study is in line with a recent study by Temkin et al. [19] who reported a decrease in the hysterectomy-corrected incidence rate of overall and type 1 endometrial cancer among white US women. In contrast, some other studies have found that the incidence of type 1 endometrial cancer increased during the last two to three decades [13–16]. The increase in type 2 endometrial cancer incidence observed in our study is compatible with results from two studies [26,27]. In a Japanese study, Honda et al. [26] found a statistically significant increase in the incidence of type 2 endometrial cancer from the period 1990–2000 to the period 2001–2010. Likewise, a study from the United States [27] revealed increased rates of advancedstage endometrial cancers and high-risk histologies, including serous carcinoma, clear cell carcinoma, and sarcoma, from 1988 to 2001. Conversely, other recent studies from the Netherlands [13,14], United Kingdom [16] and the United States [15] found that type 2 endometrial cancer incidence rates decreased or remained relatively unchanged during the last two to three decades. None of these studies [13–16,26,27] estimated hysterectomy-corrected incidence rates. Looking at the endometrial cancer incidence over the entire study period according to age, we found either no change or a slight decrease in the incidence of overall and type 1 endometrial cancer among women aged 55 years and older. In line with our results, Temkin et al. [19] reported a decrease in the incidence of overall and type 1 endometrial cancer among white women aged 50 years and older. This is in contrast to the findings of some other studies where increasing trends in postmenopausal women were found [10–12,14,16,28]. However, the decreasing trends in type 1 endometrial cancer among pre- and perimenopausal women that we observed are in accordance with several studies [11,12,28]. In contrast, our study is the first to assess agespecific incidence rates of type 2 endometrial cancer, and so our finding of a statistically significant increase in type 2 endometrial cancer incidence is new. The variation in endometrial cancer incidence across studies may reflect inherent differences in study characteristics such as study period and age and race of the included women. Furthermore, not all studies corrected for hysterectomy. Therefore direct comparisons between studies may be difficult. Hysterectomy is a common surgical procedure for women, but the absolute frequency of hysterectomy and changes in hysterectomy rates over time are important factors and these both vary within and between countries. In the United States, where N30% of all women have had a hysterectomy by age 60, recent declines in hysterectomy rates have been observed [19]. In Denmark, the age-adjusted incidence of hysterectomy decreased from 1977 to 2010 and only 6% of
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women at any age underwent hysterectomy in 2010 [29]. Different national coding practices may also explain the differences in the incidence of the two types of endometrial cancer in the respective studies, particularly if there was a change in coding over time. Some of the increase in type 2 endometrial cancer found in our study may potentially be attributed to changes in detection rates, changes in diagnostic practices, or improvements of the histopathologic diagnosis over time. Furthermore, the increase may be attributable to a more refined pathology diagnosis of type 2 lesions, which may be related to awareness of the disease in training or more access to biomarkers. Lastly, it should be noted that type 2 endometrial cancer is a rare diagnosis and therefore the results for this type are based on a limited number of cases. Other factors may also contribute to the time trends observed in endometrial cancer incidence. Previously it has been suggested that the risk factor pattern differs between type 1 and type 2 endometrial cancers. However, still only few studies have examined epidemiological differences between these two types of cancers, and the results are equivocal. It is well established that oral contraceptive use has a protective effect on risk of type 1 endometrial cancer [30], but this has also been shown for type 2 endometrial cancer [5,8]. Since their release in 1966, oral contraceptives have become increasingly popular in Denmark and today Denmark has one of the highest percentages of oral contraceptive use in Europe [31]. In relation to HRT use, one recent meta-analysis made the conclusion that there is no significantly different effect of hormones according to histologic subtypes [32]. Other studies reported that use of HRT increases the risk of type 1 endometrial cancer [33], whereas HRT use does not seem to have a major impact on the risk of type 2 endometrial cancer [5,6]. Since the mid-1990s, HRT use has declined in Denmark [34]. Tobacco smoking has been reported to decrease the risk of endometrial cancer through its antiestrogenic effects [35] and therefore was anticipated to be most strongly related to type 1 tumors, but recent studies have shown that smoking decreases the risk of both type 1 and type 2 endometrial cancer [5,8]. Despite a significant reduction in the proportion of female smokers in the study period, smoking is still common among Danish women (17% in 2016) [36]. Additional risk factors for endometrial cancer are obesity [35,37] and diabetes [35,38] both of which have been shown to contribute to type 1 and type 2 endometrial cancer in some studies [5,8]. Thus, risk factor profiles for type 1 and type 2 endometrial cancer may be overlapping, implying that not only type 1 but also type 2 endometrial cancer may be estrogen-dependent. To support this, a recent study [39] found that there was no statistically significant difference in the serum levels of sex hormones (estradiol, progesterone, testosterone, FSH and LH) between patients with type 1 and type 2 endometrial cancer regardless of menopausal status. Furthermore, the majority of type 2 endometrial cancer were estrogen receptor and progesterone receptor positive. These results suggest that excess estrogen may also be involved in the pathogenesis of type 2 endometrial cancer and that type 2 endometrial cancer is not completely estrogen-independent. Lastly, as newly suggested by Suarez et al. [40], the dualistic view of endometrial cancer, originally proposed by Bokhman [2], may be challenged by new insights on risk factors and new histologic categories, and this calls for further investigation. This study is based on high-quality population-based, nationwide data and covered a period of N35 years. Additional key strengths include the ability to distinguish between type 1 and type 2 endometrial cancer and to correct for hysterectomy. Elimination of hysterectomized women is important to avoid an underestimation of endometrial cancer incidence rates and to make sure that time trends in endometrial cancer incidence are not influenced by changes in hysterectomy prevalence over time. Our estimates of hysterectomy prevalence were based on information about hysterectomies from a 36 year period obtained from a
Fig. 1. Age-standardized incidence rates (World Standard Population) of overall endometrial cancer 1978–2014 for all women, hysterectomy-corrected and uncorrected (A) and for women divided according to age b55 years, hysterectomy-corrected (B) and ≥55 years, hysterectomy-corrected (C). Note that the scale on the y-axis is different in Figure A, B and C. APC = Annual percentage change.
Please cite this article as: M.T. Faber, et al., Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.05.015
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M.T. Faber et al. / Gynecologic Oncology xxx (2017) xxx–xxx
Fig. 2. Hysterectomy-corrected, age-standardized incidence rates (World Standard Population) of type 1 endometrial cancer 1978–2014 for all women (A) and for women divided according to age b 55 years (B) and ≥55 years (C). Note that the scale on the y-axis is different in Figure A, B and C. APC = Annual percentage change.
Please cite this article as: M.T. Faber, et al., Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.05.015
M.T. Faber et al. / Gynecologic Oncology xxx (2017) xxx–xxx
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Fig. 3. Hysterectomy-corrected, age-standardized incidence rates (World Standard Population) of type 2 endometrial cancer 1978–2014 for all women (A) and for women divided according to age b 55 years (B) and ≥55 years (C). Note that the scale on the y-axis is different in Figure A, B and C. APC = Annual percentage change.
Please cite this article as: M.T. Faber, et al., Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.05.015
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M.T. Faber et al. / Gynecologic Oncology xxx (2017) xxx–xxx
Table 2 Annual percentage change (APC) and 95% confidence intervals (CI) for overall, type 1 and type 2 endometrial cancer by age and calendar year. 1978–1995
Overall All b55 years ≥55 years Type 1 All b55 years ≥55 years Type 2 All b55 years ≥55 years
1996–2014
APC
(95% CI)
APC
(95% CI)
−0.65 −2.84 −0.29
(−1.01; −0.29) (−3.71; −1.96) (−0.66; 0.08)
0.16 −0.22 0.19
(−0.19; 0.50) (−1.15; 0.72) (−0.16; 0.55)
−0.68 −2.79 −0.32
(−1.03; −0.33) (−3.65; −1.91) (−0.70; 0.05)
−0.67 −0.52 −0.70
(−1.02; −0.31) (−1.45; 0.41) (−1.07; −0.34)
2.39 1.01 2.50
(1.43; 3.36) (−2.19; 4.31) (1.51; 3.51)
6.42 4.01 6.59
(5.72; 7.12) (1.45; 6.63) (5.87; 7.32)
population-based hospital registry. To take into account hysterectomies performed before the start of the registry, hysterectomy rates from 1978 were extrapolated back in time. This assumption could potentially have affected the estimated time trends. However, sensitivity analyses with halving respectively doubling the age-specific hysterectomy rates back in time did not alter the main conclusions. A potential limitation is that even though tumors registered in the Danish Cancer Registry are morphologically verified by a pathologist we cannot exclude the possibility of misclassification of type 1 and type 2 endometrial cancer. However, this would only impact the results if the misclassification differed over time. In conclusion, we found that the incidence of overall and type 1 endometrial cancer decreased slightly from 1978 to 2014, while there was a marked increase in the incidence of type 2 endometrial cancer. The incidence of overall and type 1 endometrial cancer mainly decreased in the first part of the study period among pre- and perimenopausal women, while the highest increase in type 2 endometrial cancer was observed in the last part of the study period both among pre- and perimenopausal women and postmenopausal women. Given the differences in the incidence of type 1 and type 2 endometrial cancer, future studies should consider type 1 and type 2 endometrial cancers as separate diseases. In addition, further studies are needed to gain knowledge about the etiology of type 1 and type 2 endometrial cancer. Funding statement This research received no specific financial support from any funding agency in the public, commercial, or not-for-profit sectors. Conflict of interest statement The authors declare no conflicts of interest.
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Please cite this article as: M.T. Faber, et al., Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978–2014, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.05.015