GYNECOLOGIC
ONCOLOGY
41, 1-16 (1991)
REVIEW The Epidemiology of Endometrial Cancer FABIO PARAZZINI,*
CARLO LA VECCHIA,*‘-~ LUCA BOCCIOLONE,* AND SILVIA FRANCE~CHI~
*Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy; tlnstitute of Social and Preventive Medicine, University of Lausanne, 1005 Lausanne, Switzerland; and $Centro di Riferimento Oncologico, Via Pedemontana Occidentale, Aviano, Italy
Received July 18, 1990
and analytical epidemiology of endometrial cancer is reviewed. Over the last few decades, age-standardized incidence rates have been rising in several countries. The rise has been even greater in terms of absolute numbers of cases, and hence public health implications, due to the aging of the population. Although endometrial cancer rates were found to be higher in richer countries and urban populations, there is now evidence of somechanges in the socioeconomic determinants of the disease in developed countries. In etiological terms, any factor that increases exposure to unopposed estrogens (such as menopausal replacement treatment, obesity, and irregular menstrual cycles) tends to increase the risk of the disease,while factors that decrease exposure to estrogensor increase progesterone levels (such as oral contraceptives or smoking) tend to be protective. Less well delined, or more difficult to explain in biological terms, is the role of other factors, such as births, miscarriages, or diabetes and hypertension, and only suggestive evidence is available on diet from analytical epidemiology. The data reviewed herein are discussedin terms of models of carclnogenesis, as well as attributable risks and public health implications. o PM Academic press, The descriptive
IX.
women endometrial cancer is reportedly more frequent in women with Stein Leventhal syndrome (characterized by high levels of estrogens) [5-71 and estrogen producing ovarian tumors [8]. In the postmenopausal period the risk of the disease is elevated in hormonal replacement therapy users and rises with the duration of use [9]. Similarly, obese women, who have high levels of available peripheral estrogens [lo], show a higher frequency of endometrial cancer. Animal data have also produced some evidence that exogenous and endogenous estrogens stimulate mitotic activity of the endometrial cells, while progestogen reduces this activity, mainly by lowering the concentration of estrogen receptors and to a lesser extent by increasing the metabolism of estradiol to the less active estrone and by stimulating differentiation of endometrial cells to a secretory state [11,12]. The impact of these factors, however, differs in various populations. In Northern Italy, for instance, established risk factors for endometrial cancer account only for about 50% of the cases [13]. Various other factors, such as early menarche or late menopause, nulliparity, history of diabetes and hypertension, and dietary fat intake, have been associated with the risk of endometrial cancer. Thus, several questions are still open, and in some cases available evidence is controversial in quantitative and qualitative terms. This article reviews published data on the descriptive and analytical epidemiology of endometrial cancer.
Together with lung and cervical cancer, endometrial cancer is one of the malignancies for which epidemiological data have offered the most important and definite etiological clues [l]. In terms of descriptive epidemiology and ecological studies, it is known that cancer of the corpus uteri is a disease of affluent societies, and its incidence rates are strongly correlated with gross internal product and other environmental factors, such as fat intake [2], in different populations. The slope of the age curve of endometrial cancer incidence flattens off around DESCRIPTIVE EPIDEMIOLOGY menopause, when female hormone levels decrease [3]. In relation to etiological inferences, the role of estrogens, About 150,000 new cases of endometrial cancer are particularly together with that of reduced progesterone diagnosed every year worldwide; thus, endometrial cancer levels, in endometrial carcinogenesis was suggested in the is the fifth leading cancer in women [14]. late 1940s [4] and is now clearly established. In young There is a wide difference in its incidence in various
All
oo90-825a91s1.50 Copyright 0 1991by AcademicRess, Inc. rights of reproduction
in any fomt reserved.
2
PARAZZINI
ET AL.
TABLE 1 Age-Standardized Incidence rates/100,000 Women of Endometrial Cancer (and Percentage Incidence of All Cases of Cancer in Women) in Developed Countries (on the Basis of the World Standard Population Age-Standardized Rates) Percentage Incidence of all cancer Rate/1OO,OUO cases in women women” Europe Zurich, Switzerland Neuchatel, Switzerland Vas, Hungary Denmark Geneva, Switzerland Saarland, FRG GDR Base& Switzerland Slovakia, Czechoslovakia Parma, Italy Iceland Sweden Vaud, Switzerland Bas-Rhin, France Navarra, Spain Varese, Italy Ragusa, Italy Finland Norway Slovenia, Yugoslavia North Scotland, UK Tarragona, Spain Hamburg, FRG Oxford, UK Eindhoven, Netherlands South Western UK Isere , France Doubs, France Calvados, France Warsaw City, Poland Trent, UK South Thames, UK Cracow City, Poland Birmingham, UK
16.9 16.8 15.3 15.3 15.2 14.3 13.9 13.7 13.7 13.4 13.4 13.2 12.8 12.7 12.5 12.5 12.3 12.2 12.1 11.6 11.5 11.3 11.3 10.4 10.3 9.9 9.7 9.6 9.4 9.3 9.2 9.2 9.2 9.1
8.4 7.5 9.3 6.3 6.8 6.7 7.5 6.7 8.3 6.7 5.7 5.9 6.4 6.3
8.1 6.1 6.9 6.9 5.7 7.3 5.5 7.4 5.3 6.1 5.0 5.0 5.8 5.6 5.8 5.9 4.4 4.9 5.0 4.8
Europe South East Scotland, UK Szabolcs, Hungary North East Scotland, UK Zaragoza, Spain Mersey, UK East Scotland, UK West Scotland, UK North Western UK Southern Ireland County Cluj, Romania Nowy Sacz, Poland North America Canada Manitoba Ontario Quebec
Alberta British Columbia United States Seattle Los Angeles (whites) Detroit (whites) Connecticut (whites) Iowa New York State (less City) Japan Nagasaki Miyagi Osaka Australia North South West New Zealand-Maori
Rate/100,000 women
Percentage Incidence of all cancer cases in women
7.8 7.8 7.6 7.5 7.4 6.8 5.7 5.5 5.4 4.4 4.3
3.3 6.8 3.5 5.9 3.4 3.0 2.6 2.7 3.0 3.3 3.4
19.8 17.4 17.1 15.6 14.7
7.6 7.2 7.2 7.4 6.5
25.0 24.1 22.0 19.3 19.3 16.7
9.5 8.7 8.3 7.3
8.1 6.6
3.0 2.8 2.4
1.8 1.9 1.6
8.3 15.4
4.0 5.2
Source. Ref. [15]. ’ Nonmelanomatous skin cancer excluded.
countries (Table 1). According to data for 1978-1982, the highest risk areas were the United States and Canada. In Europe higher rates are reported from cancer registries in Switzerland and Germany, while Southern European countries (France and Spain), the UK, and East European countries show lower rates, with a ratio of about 4 between highest and lowest incidence areas. Developing countries (and Japan) have incidence rates about four to five times lower, the areas with the lowest incidence rates being India and South Asia (Table 2). However, registration deficiencies, especially failure to distinguish cancer of the corpus and cervix uteri where
the latter is very common, should always be considered in the interpretation of these data. In the United States and Canada endometrial cancer accounts for about 810% of all incident cancers in women. Similar high rates were found in Western European and temperate South American population groups. In low-risk areas endometrial cancer represents only 2-4% of all cancers. Although endometrial cancer seems a prominent public health problem confined to Western society or developed countries, more than 30% of new cases diagnosed worldwide are in developing countries [14]. Furthermore, endometrial cancer is a tumor of elderly women, so its
EPIDEMIOLOGY
OF ENDOMETRIAL
TABLE 2 Incidence of Endometrial Cancer (and Percentage Incidence of All Cases of Cancer in Women) in Selected Developing Areas, 1980 Crude rates/ 100,000 women
Percentage incidence all cancer cases in women
4.6 3.4 3.0 1.6 1.5
4.3 3.9 4.0 2.2 2.6
Central/South America Temperate South America Tropical South America Caribbean Central America
22.7 6.7 5.0 3.0
9.3 4.1 3.9 3.8
Asia USSR Micro Polynesia China Melanesia Western Asia Other East Asia South Eastern South Asia Southern Asia
17.4 3.8 3.3 3.0 2.6 2.2 2.2 0.9
9.7 4.4 3.0 3.2 2.9 2.0 2.5 1.1
Africa Middle Northern Southern Eastern Western
3
CANCER
impact will increase, in absolute terms, as the population grows older. The evidence of higher incidences of endometrial cancer in “Westernized” populations is indirectly confirmed by the consistent intracountry observation that, within each country, higher rates are generally found in urban than in rural populations (Table 3). Considering the incidence data from 18 regions in the world [15] higher rates of endometrial cancer in urban populations were reported in 12; the excesswas about 20-40%, irrespective of whether the region was in a high- or low-incidence area. In regard to racial differences, the incidence of endometrial cancer is approximately double in whites compared to that in blacks in six out of seven areas covered by the Surveillance Epidemiology and End Results programs, the sole exception being the New Orleans area [15,16]. TRENDS IN ENDOMETRIAL
CANCER INCIDENCE
Available incidence trends of endometrial cancer in the last 20 years are presented in Table 4. In the high-risk areas of North America endometrial cancer incidence tended to rise from the early 1960s to the mid 1970s but flattened off in the early 1980s [B-18]. Conversely, in low- and middle-risk areas the trends were generally increasing.
Source. Ref. [14].
TABLE 3 Age-Standardized Endometrial Cancer Incidence Rate/lOO,OOOWomen in Urban and Rural Populations in Selected Countries 1975
Fukuoka, Japan Miyagi, Japan Osaka, Japan Slovakia, Czechoslovakia Finland Bas-Rhin, France Calvados, France Doubs, France Szabolcs, Hungary Norway Cieszow, Poland Katowice, Poland Zaragoza, Spain Vaud, Switzerland England and Wales, UK New South Wales, Australia Saarland, FRG County Cluj , Romania Source. Refs. [15,94]. ’ North western.
Urban
Rural
1.6 2.3 1.4 13.7 11.9 18.2
1.0 1.5 0.8 11.2 9.6 13.6
11.9 9.4 10.5 6.6 8.0 7.2 16.1 5.4 8.0
21.8 8.1 11.4 4.2 7.4 7.0 16.6 4.0 7.3
1980 (Ratio)
Urban
Rural
(Ratio)
(1.5) 1.8)
3.3
2.2
(1.5)
(1.2) (1.2)
16.9
13.3
(1.3)
8.2 9.8 10.0 12.5
11.5 9.2 7.2 11.7
(0.7) (1.1) (1.4) (1.1)
13.9 8.0 8.3 14.3 5.6
12.1 9.1 8.5 14.0 3.0
(0.9) (0.9) (1.0) (1.9)
(1.6)
(1.3) (0.5)
(1.2) (0.9)
(1.6)
(1.1) (1.0) (1.0)
(1.4) (1.1)
(1.1)
4
PARAZZINI
ET AL.
TABLE
4
Trends in Incidence of Endometrial Cancer in Selected Areas, MO-1980 (Rate/lOO,OOOWomen Standardized to the World Standard Population) I%5
Canada Manitoba Quebec Alberta Saskatchewan United States HawaiiXaucasian -Japanese -Chinese -Hawaian -Filipino Alameda-White -Black Connecticut New York State Cali, Colombia Jamaica Puerto Rico Miyagi, Japan Bombay, India Singapore-Chinese Israel-all Jews Hamburg, FRG Slovenia GDR Hungary Sxabolcs Vas Poland Warsaw Cracow Denmark Finland Norway Sweden UK Oxford Liverpool (Mersey in 1975 and 1980) Birmingham New Zealand-Non-Maori -Maori
1975
1980
14.3 12.5 15.4
16.5 11.3 12.0 19.1
14.2 13.5 15.2 17.3
19.2 14.3 19.8 18.7
19.8 17.1 15.6 15.8
15.6 9.8 18.1 -
17.5 10.8 19.5 23.9 16.2 16.8 18.1 15.3 6.8 6.4 4.6 1.3 1.5 8.8 6.9 12.0
28.8 15.6 19.7 31.8 11.2 33.3 13.6 17.8 12.7 5.1 6.3 6.1 1.3 1.3 4.9 10.8 8.9 9.1 13.0
34.8 19.4 28.5 34.6 14.8 38.5 10.5 21.3 18.8 4.3 7.8 6.3 2.0 1.4 4.1 9.9 10.3 14.3
23.4 15.5 18.7 25.2 11.0 24.8 10.8 16.7 6.0 8.0 2.8 2.0 5.1 9.8 11.3 11.6 13.9
7.8 8.6
7.0 12.3
8.3 12.4
7.8 15.3
4.6 7.0 11.0 8.6 8.2 12.0
7.7 6.6 11.4 9.6 9.7 12.1
9.7 9.8 13.0 10.9 11.0 13.0
9.3 9.2 15.3 12.2 12.1 13.2
9.1 9.7 9.0 10.6 10.4
9.4 8.6 8.5 22.3 10.6
10.7 8.1 9.4 11.2 18.4
10.4 7.4 9.1 10.0 15.4
12.8 12.0 8.1 4.3 3.0 2.0 4.2 10.1 9.2 5.9 -
10.7 9.2 7.7 11.1
8.4 8.1 21.0
Source. Refs. [15-181.
Differences in diagnostic and registration accuracy aside, at least two underlying determinants must be taken into consideration in interpreting temporal trends or geographic differences in endometrial cancer incidence. First, hysterectomy rates appear to be decreasing, after having been very high,. in the United States and Canada, but are probably increasing in Southern European countries [19]. Above all, however, the use of estrogens in the peri- and postmenopausal period has also been declining in those countries where it first became popular (i.e., the United States and Canada) since the recognition in the middle
1970s of a causal link. between hormonal replacement therapy and endometrial cancer [20,21]. Such factors obviously operate on the above mentioned downward trend in North America and the upward trend in some European areas in opposite ways. RISK FACTORS Socioeconomic Indicators
A socioeconomic gradient in risk of endometrial cancer (i.e., upper class women have higher risks) was suggested
EPIDEMIOLOGY
OF ENDOMETRIAL
by descriptive epidemiological data and has also been indicated, at individual levels, by analytical case-control studies. Higher education was reported to be associated with a greater frequency of endometrial cancer in a casecontrol study conducted in the United States: compared with women with only primary schooling, the risk was about 50% higher for a grade-5 schooling increase [22]. Similarly, higher income was associated with an elevated risk of the disease in a case-control study conducted in the United States [23]. These findings, however, were not confirmed in two other case-control studies [24,25]. These discrepancies can be at least partly explained by other known risk factors for endometrial cancer, for example the more widespread use of hormonal replacement therapy among higher social class women, particularly in earlier calendar period, and differences in the distribution of overweight across social classes in different areas [26,27]. Anthropometric
Variables
With estrogen replacement therapy, overweight is the best defined and most important risk factor for endometrial cancer and has been recognized for over 30 years [28] (Table 5). Although different measures and cutoff points were utilized in the 18 reports reviewed, the frequency of overweight and obesity was systematically and substantially greater in casesthan in controls. The relative risks (RR) ranged between 2 and 10, in relation to the categories chosen and the characteristics of the populations studied. Interestingly, the relation with overweight is stronger in women who have never used estrogen replacement treatments [29], suggesting that obesity and hormonal replacement therapy act with similar mechanisms and probably on the same stage of a multistage process of carcinogenesis [30]. The association between weight and endometrial cancer risk has generally been explained in terms of an increased availability of unopposed peripheral estrogens (particularly in the postmenopause period, when aromatization of androgens to estrogens in adipose tissue is the major source of estrogens [ll] and progesterone is completely lacking) and a lower concentration of sex hormone binding globulin (SHBG) in obese women, leading to an increased availability of peripheral estrogens to hormoneresponsive tissues such as endometrium [lo]. At least two studies found elevated risks of endometrial cancer in premenopausal obese women as well. In one from California [31], the RR was 17.7 for women weighing 2190 pounds compared with those weighing ~130, and in the second, conducted in Italy [24], the RR was 20.3 (95% CI 4.0-103.5) for those with Quetelet’s Index (QI kgm-‘) 230 compared with those with QI 200 pounds (P < 0.001) RR = 2.3 for women weighing ~57 kg vs S75 kg; significant trend in risk RR = 17.7 for women weighing >190 pounds vs 165 pounds Mean QI was 31.1 in the study group vs 26.7 in the control group RR = 11.6 for weight 381.6 kg vs
ONCOLOGY
41, 1-16 (1991)
REVIEW The Epidemiology of Endometrial Cancer FABIO PARAZZINI,*
CARLO LA VECCHIA,*‘-~ LUCA BOCCIOLONE,* AND SILVIA FRANCE~CHI~
*Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy; tlnstitute of Social and Preventive Medicine, University of Lausanne, 1005 Lausanne, Switzerland; and $Centro di Riferimento Oncologico, Via Pedemontana Occidentale, Aviano, Italy
Received July 18, 1990
and analytical epidemiology of endometrial cancer is reviewed. Over the last few decades, age-standardized incidence rates have been rising in several countries. The rise has been even greater in terms of absolute numbers of cases, and hence public health implications, due to the aging of the population. Although endometrial cancer rates were found to be higher in richer countries and urban populations, there is now evidence of somechanges in the socioeconomic determinants of the disease in developed countries. In etiological terms, any factor that increases exposure to unopposed estrogens (such as menopausal replacement treatment, obesity, and irregular menstrual cycles) tends to increase the risk of the disease,while factors that decrease exposure to estrogensor increase progesterone levels (such as oral contraceptives or smoking) tend to be protective. Less well delined, or more difficult to explain in biological terms, is the role of other factors, such as births, miscarriages, or diabetes and hypertension, and only suggestive evidence is available on diet from analytical epidemiology. The data reviewed herein are discussedin terms of models of carclnogenesis, as well as attributable risks and public health implications. o PM Academic press, The descriptive
IX.
women endometrial cancer is reportedly more frequent in women with Stein Leventhal syndrome (characterized by high levels of estrogens) [5-71 and estrogen producing ovarian tumors [8]. In the postmenopausal period the risk of the disease is elevated in hormonal replacement therapy users and rises with the duration of use [9]. Similarly, obese women, who have high levels of available peripheral estrogens [lo], show a higher frequency of endometrial cancer. Animal data have also produced some evidence that exogenous and endogenous estrogens stimulate mitotic activity of the endometrial cells, while progestogen reduces this activity, mainly by lowering the concentration of estrogen receptors and to a lesser extent by increasing the metabolism of estradiol to the less active estrone and by stimulating differentiation of endometrial cells to a secretory state [11,12]. The impact of these factors, however, differs in various populations. In Northern Italy, for instance, established risk factors for endometrial cancer account only for about 50% of the cases [13]. Various other factors, such as early menarche or late menopause, nulliparity, history of diabetes and hypertension, and dietary fat intake, have been associated with the risk of endometrial cancer. Thus, several questions are still open, and in some cases available evidence is controversial in quantitative and qualitative terms. This article reviews published data on the descriptive and analytical epidemiology of endometrial cancer.
Together with lung and cervical cancer, endometrial cancer is one of the malignancies for which epidemiological data have offered the most important and definite etiological clues [l]. In terms of descriptive epidemiology and ecological studies, it is known that cancer of the corpus uteri is a disease of affluent societies, and its incidence rates are strongly correlated with gross internal product and other environmental factors, such as fat intake [2], in different populations. The slope of the age curve of endometrial cancer incidence flattens off around DESCRIPTIVE EPIDEMIOLOGY menopause, when female hormone levels decrease [3]. In relation to etiological inferences, the role of estrogens, About 150,000 new cases of endometrial cancer are particularly together with that of reduced progesterone diagnosed every year worldwide; thus, endometrial cancer levels, in endometrial carcinogenesis was suggested in the is the fifth leading cancer in women [14]. late 1940s [4] and is now clearly established. In young There is a wide difference in its incidence in various
All
oo90-825a91s1.50 Copyright 0 1991by AcademicRess, Inc. rights of reproduction
in any fomt reserved.
2
PARAZZINI
ET AL.
TABLE 1 Age-Standardized Incidence rates/100,000 Women of Endometrial Cancer (and Percentage Incidence of All Cases of Cancer in Women) in Developed Countries (on the Basis of the World Standard Population Age-Standardized Rates) Percentage Incidence of all cancer Rate/1OO,OUO cases in women women” Europe Zurich, Switzerland Neuchatel, Switzerland Vas, Hungary Denmark Geneva, Switzerland Saarland, FRG GDR Base& Switzerland Slovakia, Czechoslovakia Parma, Italy Iceland Sweden Vaud, Switzerland Bas-Rhin, France Navarra, Spain Varese, Italy Ragusa, Italy Finland Norway Slovenia, Yugoslavia North Scotland, UK Tarragona, Spain Hamburg, FRG Oxford, UK Eindhoven, Netherlands South Western UK Isere , France Doubs, France Calvados, France Warsaw City, Poland Trent, UK South Thames, UK Cracow City, Poland Birmingham, UK
16.9 16.8 15.3 15.3 15.2 14.3 13.9 13.7 13.7 13.4 13.4 13.2 12.8 12.7 12.5 12.5 12.3 12.2 12.1 11.6 11.5 11.3 11.3 10.4 10.3 9.9 9.7 9.6 9.4 9.3 9.2 9.2 9.2 9.1
8.4 7.5 9.3 6.3 6.8 6.7 7.5 6.7 8.3 6.7 5.7 5.9 6.4 6.3
8.1 6.1 6.9 6.9 5.7 7.3 5.5 7.4 5.3 6.1 5.0 5.0 5.8 5.6 5.8 5.9 4.4 4.9 5.0 4.8
Europe South East Scotland, UK Szabolcs, Hungary North East Scotland, UK Zaragoza, Spain Mersey, UK East Scotland, UK West Scotland, UK North Western UK Southern Ireland County Cluj, Romania Nowy Sacz, Poland North America Canada Manitoba Ontario Quebec
Alberta British Columbia United States Seattle Los Angeles (whites) Detroit (whites) Connecticut (whites) Iowa New York State (less City) Japan Nagasaki Miyagi Osaka Australia North South West New Zealand-Maori
Rate/100,000 women
Percentage Incidence of all cancer cases in women
7.8 7.8 7.6 7.5 7.4 6.8 5.7 5.5 5.4 4.4 4.3
3.3 6.8 3.5 5.9 3.4 3.0 2.6 2.7 3.0 3.3 3.4
19.8 17.4 17.1 15.6 14.7
7.6 7.2 7.2 7.4 6.5
25.0 24.1 22.0 19.3 19.3 16.7
9.5 8.7 8.3 7.3
8.1 6.6
3.0 2.8 2.4
1.8 1.9 1.6
8.3 15.4
4.0 5.2
Source. Ref. [15]. ’ Nonmelanomatous skin cancer excluded.
countries (Table 1). According to data for 1978-1982, the highest risk areas were the United States and Canada. In Europe higher rates are reported from cancer registries in Switzerland and Germany, while Southern European countries (France and Spain), the UK, and East European countries show lower rates, with a ratio of about 4 between highest and lowest incidence areas. Developing countries (and Japan) have incidence rates about four to five times lower, the areas with the lowest incidence rates being India and South Asia (Table 2). However, registration deficiencies, especially failure to distinguish cancer of the corpus and cervix uteri where
the latter is very common, should always be considered in the interpretation of these data. In the United States and Canada endometrial cancer accounts for about 810% of all incident cancers in women. Similar high rates were found in Western European and temperate South American population groups. In low-risk areas endometrial cancer represents only 2-4% of all cancers. Although endometrial cancer seems a prominent public health problem confined to Western society or developed countries, more than 30% of new cases diagnosed worldwide are in developing countries [14]. Furthermore, endometrial cancer is a tumor of elderly women, so its
EPIDEMIOLOGY
OF ENDOMETRIAL
TABLE 2 Incidence of Endometrial Cancer (and Percentage Incidence of All Cases of Cancer in Women) in Selected Developing Areas, 1980 Crude rates/ 100,000 women
Percentage incidence all cancer cases in women
4.6 3.4 3.0 1.6 1.5
4.3 3.9 4.0 2.2 2.6
Central/South America Temperate South America Tropical South America Caribbean Central America
22.7 6.7 5.0 3.0
9.3 4.1 3.9 3.8
Asia USSR Micro Polynesia China Melanesia Western Asia Other East Asia South Eastern South Asia Southern Asia
17.4 3.8 3.3 3.0 2.6 2.2 2.2 0.9
9.7 4.4 3.0 3.2 2.9 2.0 2.5 1.1
Africa Middle Northern Southern Eastern Western
3
CANCER
impact will increase, in absolute terms, as the population grows older. The evidence of higher incidences of endometrial cancer in “Westernized” populations is indirectly confirmed by the consistent intracountry observation that, within each country, higher rates are generally found in urban than in rural populations (Table 3). Considering the incidence data from 18 regions in the world [15] higher rates of endometrial cancer in urban populations were reported in 12; the excesswas about 20-40%, irrespective of whether the region was in a high- or low-incidence area. In regard to racial differences, the incidence of endometrial cancer is approximately double in whites compared to that in blacks in six out of seven areas covered by the Surveillance Epidemiology and End Results programs, the sole exception being the New Orleans area [15,16]. TRENDS IN ENDOMETRIAL
CANCER INCIDENCE
Available incidence trends of endometrial cancer in the last 20 years are presented in Table 4. In the high-risk areas of North America endometrial cancer incidence tended to rise from the early 1960s to the mid 1970s but flattened off in the early 1980s [B-18]. Conversely, in low- and middle-risk areas the trends were generally increasing.
Source. Ref. [14].
TABLE 3 Age-Standardized Endometrial Cancer Incidence Rate/lOO,OOOWomen in Urban and Rural Populations in Selected Countries 1975
Fukuoka, Japan Miyagi, Japan Osaka, Japan Slovakia, Czechoslovakia Finland Bas-Rhin, France Calvados, France Doubs, France Szabolcs, Hungary Norway Cieszow, Poland Katowice, Poland Zaragoza, Spain Vaud, Switzerland England and Wales, UK New South Wales, Australia Saarland, FRG County Cluj , Romania Source. Refs. [15,94]. ’ North western.
Urban
Rural
1.6 2.3 1.4 13.7 11.9 18.2
1.0 1.5 0.8 11.2 9.6 13.6
11.9 9.4 10.5 6.6 8.0 7.2 16.1 5.4 8.0
21.8 8.1 11.4 4.2 7.4 7.0 16.6 4.0 7.3
1980 (Ratio)
Urban
Rural
(Ratio)
(1.5) 1.8)
3.3
2.2
(1.5)
(1.2) (1.2)
16.9
13.3
(1.3)
8.2 9.8 10.0 12.5
11.5 9.2 7.2 11.7
(0.7) (1.1) (1.4) (1.1)
13.9 8.0 8.3 14.3 5.6
12.1 9.1 8.5 14.0 3.0
(0.9) (0.9) (1.0) (1.9)
(1.6)
(1.3) (0.5)
(1.2) (0.9)
(1.6)
(1.1) (1.0) (1.0)
(1.4) (1.1)
(1.1)
4
PARAZZINI
ET AL.
TABLE
4
Trends in Incidence of Endometrial Cancer in Selected Areas, MO-1980 (Rate/lOO,OOOWomen Standardized to the World Standard Population) I%5
Canada Manitoba Quebec Alberta Saskatchewan United States HawaiiXaucasian -Japanese -Chinese -Hawaian -Filipino Alameda-White -Black Connecticut New York State Cali, Colombia Jamaica Puerto Rico Miyagi, Japan Bombay, India Singapore-Chinese Israel-all Jews Hamburg, FRG Slovenia GDR Hungary Sxabolcs Vas Poland Warsaw Cracow Denmark Finland Norway Sweden UK Oxford Liverpool (Mersey in 1975 and 1980) Birmingham New Zealand-Non-Maori -Maori
1975
1980
14.3 12.5 15.4
16.5 11.3 12.0 19.1
14.2 13.5 15.2 17.3
19.2 14.3 19.8 18.7
19.8 17.1 15.6 15.8
15.6 9.8 18.1 -
17.5 10.8 19.5 23.9 16.2 16.8 18.1 15.3 6.8 6.4 4.6 1.3 1.5 8.8 6.9 12.0
28.8 15.6 19.7 31.8 11.2 33.3 13.6 17.8 12.7 5.1 6.3 6.1 1.3 1.3 4.9 10.8 8.9 9.1 13.0
34.8 19.4 28.5 34.6 14.8 38.5 10.5 21.3 18.8 4.3 7.8 6.3 2.0 1.4 4.1 9.9 10.3 14.3
23.4 15.5 18.7 25.2 11.0 24.8 10.8 16.7 6.0 8.0 2.8 2.0 5.1 9.8 11.3 11.6 13.9
7.8 8.6
7.0 12.3
8.3 12.4
7.8 15.3
4.6 7.0 11.0 8.6 8.2 12.0
7.7 6.6 11.4 9.6 9.7 12.1
9.7 9.8 13.0 10.9 11.0 13.0
9.3 9.2 15.3 12.2 12.1 13.2
9.1 9.7 9.0 10.6 10.4
9.4 8.6 8.5 22.3 10.6
10.7 8.1 9.4 11.2 18.4
10.4 7.4 9.1 10.0 15.4
12.8 12.0 8.1 4.3 3.0 2.0 4.2 10.1 9.2 5.9 -
10.7 9.2 7.7 11.1
8.4 8.1 21.0
Source. Refs. [15-181.
Differences in diagnostic and registration accuracy aside, at least two underlying determinants must be taken into consideration in interpreting temporal trends or geographic differences in endometrial cancer incidence. First, hysterectomy rates appear to be decreasing, after having been very high,. in the United States and Canada, but are probably increasing in Southern European countries [19]. Above all, however, the use of estrogens in the peri- and postmenopausal period has also been declining in those countries where it first became popular (i.e., the United States and Canada) since the recognition in the middle
1970s of a causal link. between hormonal replacement therapy and endometrial cancer [20,21]. Such factors obviously operate on the above mentioned downward trend in North America and the upward trend in some European areas in opposite ways. RISK FACTORS Socioeconomic Indicators
A socioeconomic gradient in risk of endometrial cancer (i.e., upper class women have higher risks) was suggested
EPIDEMIOLOGY
OF ENDOMETRIAL
by descriptive epidemiological data and has also been indicated, at individual levels, by analytical case-control studies. Higher education was reported to be associated with a greater frequency of endometrial cancer in a casecontrol study conducted in the United States: compared with women with only primary schooling, the risk was about 50% higher for a grade-5 schooling increase [22]. Similarly, higher income was associated with an elevated risk of the disease in a case-control study conducted in the United States [23]. These findings, however, were not confirmed in two other case-control studies [24,25]. These discrepancies can be at least partly explained by other known risk factors for endometrial cancer, for example the more widespread use of hormonal replacement therapy among higher social class women, particularly in earlier calendar period, and differences in the distribution of overweight across social classes in different areas [26,27]. Anthropometric
Variables
With estrogen replacement therapy, overweight is the best defined and most important risk factor for endometrial cancer and has been recognized for over 30 years [28] (Table 5). Although different measures and cutoff points were utilized in the 18 reports reviewed, the frequency of overweight and obesity was systematically and substantially greater in casesthan in controls. The relative risks (RR) ranged between 2 and 10, in relation to the categories chosen and the characteristics of the populations studied. Interestingly, the relation with overweight is stronger in women who have never used estrogen replacement treatments [29], suggesting that obesity and hormonal replacement therapy act with similar mechanisms and probably on the same stage of a multistage process of carcinogenesis [30]. The association between weight and endometrial cancer risk has generally been explained in terms of an increased availability of unopposed peripheral estrogens (particularly in the postmenopause period, when aromatization of androgens to estrogens in adipose tissue is the major source of estrogens [ll] and progesterone is completely lacking) and a lower concentration of sex hormone binding globulin (SHBG) in obese women, leading to an increased availability of peripheral estrogens to hormoneresponsive tissues such as endometrium [lo]. At least two studies found elevated risks of endometrial cancer in premenopausal obese women as well. In one from California [31], the RR was 17.7 for women weighing 2190 pounds compared with those weighing ~130, and in the second, conducted in Italy [24], the RR was 20.3 (95% CI 4.0-103.5) for those with Quetelet’s Index (QI kgm-‘) 230 compared with those with QI 200 pounds (P < 0.001) RR = 2.3 for women weighing ~57 kg vs S75 kg; significant trend in risk RR = 17.7 for women weighing >190 pounds vs 165 pounds Mean QI was 31.1 in the study group vs 26.7 in the control group RR = 11.6 for weight 381.6 kg vs
