GYNECOLOGIC ONCOLOGY 2,122-129 (1974)

Risk Factors for Endometrial Cancer]

BRIAN MACMAHON, M.D.

Department of Epidemiology, Harvard School of Public Health,

Boston, Massachusetts 02115

Received March I,1974

Three categories of risk factors for endometrial cancer are reviewed. The first con- sists of what may be considered as variations in normal anatomy or physiology. Risk factors of this type for endometrial cancer include overweight, nulliparity, and late menopause. Second, certain frank disease states are associated with increased risk of endometrial cancer. These include diabetes mellitus, hypertension, Stein- Lever&al syndrome, and cancers of other sites, particularly of the breast and ovary. Last, exposure to known external causes of a disease may be considered as risk factors. In the context of endometrial cancer, pelvic irradiation and prolonged ex- ogenous estrogen administration are likely risk factors. While the above character- istics serve to focus attention on certain categories of high-risk women they provide no basis for limiting screening to any subgroup of the population.

Disease risk factors may be thought of as demographic or personal. The former are variables such as age, sex, race, and place of residence, on which mortality and census data are assembled routinely. The latter are those char- acteristics that distinguish one individual from others of the same demogra- phic group living in the same area at the same time. The distinction is not clear-cut, but it will serve the present purpose in that other speakers have dealt with the former category and this paper deals primarily with the latter.

Identification of personal risk factors usually requires special studies in which information from affected and unaffected individuals is compared. In this paper, particular use will be made of such a study recently undertaken in Boston by Kaplan and Cole [l], since this study was based on cases in a defined population and provides estimates of the frequency of relevant risk factors.

Again somewhat arbitrarily, personal risk factors can be divided into three groups-variations of normal anatomy or physiology, the presence of frank abnormality or disease, and exposure to known external causes of disease. In the context of endometrial cancer, there are examples in all three categories. The variations in normal anatomy or physiology will be considered first.

r Presented at Conference on “New Directions for Research on Endometrial Cancer” Marco Island, Florida, December 3-5, 1973.

122

Copyright @ 1974 by Academic Press, Inc. All rights of reproduction in any form reserved.

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RISK FACTORS

Overweight

Clinicians have been impressed by the high proportion of overweight women among patients with endometrial cancer and there are many series in which a high proportion of “obese” women has been reported. In some, “obesity” has been defined, in others it has not. In few reports has an ade- quate comparison series been available.

In 1960, Damon [23 studied patients with cancers of the endometrium, breast, and other parts of the reproductive system, as well as age-matched con- trols without cancer or other known disease. The mean body weight of the en- dometrial cancer patients was 13% greater than that of the controls, in spite of similarity in height. Blind readings of somatotype showed a substantial excess of “endomorphic” (high fat relative to bone and muscle) body types among the endometrial cancer patients. This study clearly substantiated the clinical impressions of association between obesity and endometrial cancer risk. Unfortunately, the data are presented in terms only of means and measures of statistical variation. No distributions by measures of body weight were given, and one cannot estimate from these carefully collected data the degree of increased risk associated with various degrees of obesity.

In a study in which cases and controls were asked their weight at age 25-29, Wynder et al. [3] found that, among the cases, 21% were between 21 and 50 lb overweight, and 9% were more than 50 lb overweight. Corresponding per- centages in the controls were 8% and l%, respectively. These figures would suggest that women who were 21-50 lb overweight were approximately three times, and those more than 50 lb overweight approximately 10 times, as likely to develop endometrial cancer as women of normal or below nomal weight.

Using the Khosla-Lowe Index (Wt/Ht*), and controlling for age and socio- economic status, it was found in the Boston study that women in the upper third of the weight distribution had 1.8 times the risk of those in the lower two thirds, and those in the top 15% of the weight distribution had 2.4 times the risk of those in the lower two thirds. There was no variation in risk by weight within the population in the lower two thirds of the weight distribution,

One of the objectives in identifying high-risk groups is to focus screening programs on their members. In this instance the heaviest one third of the pop- ulation would be considered the high-risk group. However, in the Boston study only half the total endometrial cancer cases in the population occurred in the heaviest one third. Thus, even though overweight is a strong risk factor for endometrial cancer, there is no basis for restricting screening to over- weight women.

Nulliparity

Nulliparity is another long-recognized characteristic of patients with en- dometrial cancer [3,41. In the Boston study, rates for nulliparous women were

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twice as high as those for women with one child and more than three times as high as for those with five or more children.

In view of the recent observation that the inverse association between parity and breast cancer risk results from a positive association between cancer risk and age at first birth, it is of interest to examine the latter variable in the context of endometrial cancer. Wynder et al. [31 found no difference between cases and controls with respect to this variable, and in the data of Kaplan and Cole 111 the trend is irregular. This question warrants further in- vestigation, but existing data do not suggest the type of association that has been observed for cancer of the breast.

Once again, limitation of a screening program to the high-risk group- in this instance, the nulliparous, comprising about 24% of the popula- tion- would result in the identification of only 48% of all cases occurring in the population.

Late Menopause

Several investigators have noted that the average age of menopause among patients with endometrial cancer is higher than in normal women [3,5-71. Kaplan and Cole found a 2.4-fold risk of endometrial cancer among women whose menopause occurred at 52 or older relative to those whose menopause occurred prior to age 49. One difficulty in interpreting this association is the possibility that prolongation of menstrual bleeding may reflect the presence of early neoplastic or preneoplastic changes in the uterus, rather than prolongation of ovarian activity. However, if this is so, the uterine changes must antedate the diagnosis of endometrial cancer by a considerable time, since in the Boston study increased risk associated with late menopause was found for women 60-69 and 70 or more at the time of diagnosis of the endome- trial cancer.

Association with early onset of menarche was also found in the Boston study, but this has been less frequently studied and the data are more subject to errors of anamnesis.

Available data do not permit examination of the effects of these “physio- logic” variations in combination. It would, for example, be of interest to know whether the risk for women who are both overweight and nulliparous and have late menopause is greater, less or the same as would be expected if the factors were acting independently. According to the Boston data, and on the assumption of independence, women who were nulliparous, in the top 15% of the weight distribution, and had menopause at 52 or older would be expected to have more than five times the risk of parous women in the lower two thirds of the weight distribution who had menopause prior to age 49. The assumption of independence of the action of these risk factors is, however, questionable.

Diabetes mellitus

The frank abnormality that is most clearly a risk factor for endometrial cancer is diabetes mellitus. The confusing literature on the relationship

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between these two conditions has been reviewed by Kessler 181. Comparison groups are lacking or inadequate in most reports; nevertheless, a high frequency of diabetes-whether diagnosed by history or by abnormal glucose- tolerance test at the time of diagnosis of the endometrial cancer- is reported so consistently that it seems most likely that diabetes is associated with increased risk of endometrial cancer. After controlling for age, body weight, and socioeconomic status, Kaplan and Cole found a relative risk of 2.8 as- sociated with a history of diabetes [ll. Most perplexing is Kessler’s own re- trospective follow-up study of a large group of diabetics among whom fewer-though not significantly fewer-deaths from endometrial cancer were observed than would have been expected on the basis, of age, sex, and time- specific mortality rates in the general population 191. No convincing explana- tion of this negative result in a methodologically sound study has been forth- coming.

Hypertension

High blood pressure has been reported as characteristic of endometrial cancer patients, but the data are less convincing than for the four factors already discussed. Wynder et al. found a higher proportion of cases than con- trols with high blood pressure, but there was a similar excess of patients with low pressures and the mean pressure did not differ between cases and con- trols [3]. In the data of Kaplan and Cole, the relative risk associated with a his- tory of hypertension, after controlling for age and weight, was 1.5, but this did not differ significantly from unity.

Stein-Leoenthal Syndrome

The Stein-Leventhal syndrome [lo] is a rare disorder comprising anovula- tion with associated menstrual irregularities and infertility, obesity, male hir- sutism, and, less regularly, acne, hypertension, and lack of breast develop- ment. There have been several case reports ill-141 and one series of 16 patients [15] of women with endometrial cancer associated with this syn- drome. The Stein-Lever&al syndrome usually manifests itself in the decade or so after puberty, and most of the reported endometrial cancers have been in patients under 40 yr of age-an age when endometrial cancer is not common.

One cannot obtain from the literature any idea as to the size of the risk of en- dometrial cancer experienced by patients with Stein-Leventhal syndrome. The infrequency of endometrial cancer under age 40 and the even greater rar- ity of the Stein-Leventhal syndrome suggest a substantial risk for such pa- tients. Dockerty et al. [16] suggested that clinical evidence of the syndrome is found in 20% of patients with endometrial cancer under 40 yr of age. On the other hand, Jackson and Dockerty [15] f ound only 16 instances of association of endometrial cancer with Stein-Leventhal syndrome in a search that in- cluded review of surgical specimens from “several thousand” patients (all ages) who had had endometrial cancers removed. In 1958, Lever&al 1171 stated that in their combined experience neither he nor Stein had seen en-

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dometrial cancer in association with the syndrome. Part of the difficulty in reconciling such observations is the variation in criteria for the presence or absence of Stein-Leventhal syndrome.

Neither has knowledge of this association - assuming that it indeed exists to some degree-yet helped to elucidate the mechanism of carcinogenesis in the endometrium. The basic hormonal environment produced by the syndrome is usually considered to be one of continuous estrogen stimulation unopposed by progesterone. However, the hirsutism suggests that more complex interac- tions are occurring. The association is compatible with a role for estrogen stimulation in endometrial cancer, but does not provide convincing evidence in favor of such a role.

Cancers of Other Sites

There is little doubt that cancers of the endometrium and breast and of the endometrium and ovary tend to occur in the same women more frequently than would be expected by chance [l&25]. The associations are not strong, and the possibility cannot be ruled out that they result simply from the demographic and personal factors that are common to women with the three diseases. Association of cancers of the endometrium and bowel has also been reported [26].

Other Diseases

Wynder et al. reported a higher frequency of hypothyroidism and goiter among cases than among controls [3] and Kaplan and Cole a higher frequency of arthritis [l]. These observations are unsubstantiated by other investigators and are of unknown significance.

Familial History

There is some evidence for familial aggregation of endometrial cancer [21,27]. However, the association is not strong, and, since endometrial cancer is also much less common than cancer of the breast, it does not seem useful to regard women with a family history of endometrial cancer as a high-risk group in the same sense that women with familial history of breast cancer are at high risk for that disease.

Radiation Exposure

Exposure to large doses of radiation in the course of medical therapy is the best documented of the exogenous risk factors for endometrial cancer [28-341. However, the problem of interpretation exists as in the association with late menopause -therapeutic irradiation may be prompted by the early manifesta- tions of endometrial cancer [35,36]. Wagoner and Connelly reported a follow- up study of 5749 women receiving pelvic irradiation for benign or malignant disease between 1935 and 1964 [37]. On the basis of age and time-specific rates in the general population, 1.8 cases of endometrial cancer were expected in the cohort, but 16 were observed. The excess was observed both in those

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receiving radiation for benign conditions and those irradiated for cancer. Belief that the excess represents a causal association between irradiation and endometrial cancer is strengthened by the observation of a relationship between radiation dose and cancer risk, and by the fact that the excess is ob- served among women who did not receive radiation for diseases of the uterus 1371. Malignant endometrial tumors have also been produced by radium and X-rays in rats [33].

Endometrial cancers appearing after radiation exposure include a high proportion of sarcomas and mixed carcinosarcomas 133,371.

Exogenous Estrogen

Another exogenous factor suspected of causal relationship to endometrial cancer is estrogen therapy [38-401. Cutler et al. reported two patients with en- dometrial cancer among 24 cases of gonadal dysgenesis treated with stilbes- trol for 5 yr or more [41]. As noted by Cutler et al., the early age at which es- trogen-associated endometrial tumors are detected suggests that the estrogens play a causal role in the disease.

DISCUSSION

The studies reviewed above suggest that, in a clinical context, particular attention should be paid to the possibility of endometrial cancer in women with certain characteristics-obesity, nulliparity, late menopause, diabetes, and so on. However, in the context of a screening program, the available data provide no basis for limiting screening to any high-risk group in the popula- tion-except, perhaps, a group defined on the basis of age, for example over 50.

It has been noted frequently that endometrial and breast cancers share cer- tain risk factors in common, and this has led to speculation that a particular hormonal or other endogenous milieu may be common to the two cancers. It is true that body weight and parity show superficially similar relationships to both diseases, but closer examination indicates important dissimilarities. With respect to weight, in endometrial cancer it is the excessively overweight woman who is at high risk, there being little risk difference between the un- derweight and those in the normal range. For breast cancer, on the other hand, the greatest differential is between the lowest weight group and those in the normal range, with little increase in risk with increase in weight above the lowest weight group [42]. The dissimilarity with respect to the association with parity is even more explicit. For breast cancer it has been shown that the protective effect of pregnancy is a function of the age at first birth and that by age 30 pregnancy is no longer protective [43]. The question of whether en- dometrial cancer risk varies with age at first birth is not closed, but the data of Kaplan and Cole indicate a sharply lower risk for parous than for nulliparous women even when the first birth occurred after 30 yr of age 111. Too much should, therefore, not be read into the superficial similarity of risk factors for breast and endometrial cancer.

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