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Recent trends in the incidence and mortality of cancer of the uterine corpus in Connecticut
GYNECOLOGIC
ONCOLOGY
Recent
LORAINE
6, 183-195 (1978)
Trends in the Incidence of the Uterine Corpus
and Mortality in Connecticut
of Cancer
D. MARRETT, PH.D.,‘~~ J. MARK ELWOOD, M.B., S. M. EPID., J. WISTER MEIGS, M.D.,2 AND JOHN T. FLANNERY, B.S.2
Connecticut Cancer Epidemiology Unit, Yale University, New Haven, Connecticut, 06.510, Department ofHealth Care and Epidemiology, University of British Columbia, Vancouver, British Columbia V6T I W5, and Connecticut Tumor Registry, State Department of Health, Hartford, Connecticut 06115 Received November 29, 1977 Incidence rates for invasive cancer of the uterine corpus (including cancer of the uterus, not otherwise specified) have been calculated according to stage of disease (localized, nonlocalized) based on cases reported to the Connecticut Tumor Registry between 1960and 1975. 1960-64 and 1965-69 rates were very similar for both disease stages. However, in 1970-75 the incidence of localized corpus cancer was 26% higher than in either of the preceding quinquennia, while the rate of nonlocalized disease remained about the same as previously. Women aged 50-59 experienced the largest increase in localized disease, although all other age groups over 50 also had higher rates in the most recent period of diagnosis. No increases were evident in women under 50 years of age. In addition, the frequency of the diagnosis of carcinoma in situ of the endometrium increased gradually over the 16-year period, and mortality from corpus cancer declined slightly. The possible effects of increasing exogenous estrogen use by menopausal and postmenopausal women, changes in diagnostic practices leading to earlier diagnosis, diagnostic criteria, and decreasing numbers of women with intact uteri as a result of increasing hysterectomy rates are considered in the interpretation of these recent trends in the incidence and mortality of cancer of the uterine corpus in Connecticut.
Although the incidence of endometrial cancer in Connecticut changed little between 1935and 1969 [I], a recent report indicates that incidence rates have risen since 1969, not only in Connecticut, but also in several areas of the United States possessing population-based tumor registries [2]. The increase is of particular significance when viewed in conjunction with the reported association between the occurrence of carcinoma of the corpus uteri in middle-aged women and prior administration of exogenous estrogens [3-71. The purpose of this paper is to present data reported to the Connecticut Tumor Registry (CTR) on the incidence of cancer of the uterine corpus in Connecticut I Address reprint requests to Dr. L. Marrett, Connecticut Cancer Epidemiology Unit, Yale University, 30 College Street, New Haven, Connecticut 06510 aSupported by contracts NOI CP 33235 and NO1 CP 43203 with the National Cancer Institute. 183 0090~8258/78/0062-0183$0 I .00/O Copyright @ 1978 by Academic Press, Inc. All rights of reproduction in any form reserved.
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according to age, stage of disease, and time of diagnosis and the mortality from this tumor by age and time of death since 1960. These data are then interpreted in terms of the explanatory hypotheses which appear consistent with them. MATERIALS
AND METHODS
The CTR contains data on new cases of malignant neoplasms which have been reported to it from all hospitals within the State since 1935. In addition, several major hospitals located in adjacent states but proximate to the Connecticut border report tumors diagnosed in Connecticut residents. Historical details of reporting mechanisms and requirements have been described elsewhere 183.Reporting is thought to have been reasonably complete for at least 30 years. Since 1960, death certificate and autopsy diagnoses have accounted for less than 3% of cases. Between 1960and 1975, there were 5 101 cases of invasive cancer of the corpus uteri (primary site 182, International Classification of Diseases, 9th Revision) diagnosed in women resident in Connecticut. There were also 540 invasive tumors recorded as “uterus, not otherwise specified” (uterus NOS, primary site 179, International Classification of Diseases, 9th Revision). There were 365 cases of carcinoma in situ (CIS) reported, with primary site corpus uteri in 349 of them and uterus NOS in 16. An intensive review of Connecticut cases diagnosed between 1935 and 1951 indicated that of the uterus NOS tumors diagnosed during life for which actual primary site could be determined, 90% arose in the corpus uteri 191. Therefore, all tumors of the uterus NOS are included in the results presented here. The proportion of tumors specified only as uterus has been declining steadily over the period of time reported here, from 16.5% of cases diagnosed in 1960-64 to less than 5% in 1970-75. Of the 540 invasive tumors of the uterus NOS reported in 1960-75, 62 were first diagnosed at death. There is considerable doubt about the true site of origin of these cases [9]. However, since they comprise only 1% of the total number of corpus cancer cases, the effect of incorrectly classifying a portion of them as corpus rather than cervix should be small. Sarcomas and mixed tumors comprised 8.5% (480 cases) of the invasive corpus cancers diagnosed in 1960-75. These will not be analyzed separately at this time. Stage of disease at time of diagnosis is determined by registry staff using “all clinical, X-ray, gross, and microscopic findings within the first course of planned medical care and instituted no later than 4 months from the accepted date of diagnosis; for untreated cases first hospitalization or date of diagnosis is used,” as stated in the CTR Coding Manual. The coding of stage of disease has for the most part been uniform since 1935. A tumor is considered to be in situ if it fulfills all microscopic criteria for malignancy except invasion and has been histologically confirmed. An invasive tumor is designated to be either localized if it is restricted to the organ of origin or nonlocalized if known spread has occurred. Over 95% of the cases of invasive disease diagnosed in 1960-75 have been staged. Incidence rates have been calculated for localized, nonlocalized, and all invasive (localized, nonlocalized, and stage unknown) corpus cancer in Connecticut according to time of diagnosis and age at diagnosis for the period 1960- 1975. Mortality rates have also been computed by time period and age at death for the years 1960 through 1974, based on the numbers of incident cases of cancer of the uterine corpus (including uterus NOS) who have died and had cancer of the corpus
CANCER
OF THE
UTERINE
CORPUS
185
IN CONNECTICUT
uteri or uterus NOS coded as the underlying cause of death by the Connecticut Registrar of Vital Statistics. All rates are average annual rates per 100,000Connecticut women; all ages rates are age standardized by the direct method to the U.S. 1970 Census Population. Age-specific Connecticut female populations used for intercensal years are as estimated by the Public Health Statistics Section of the Connecticut State Department of Health [IO]. RESULTS
The age-adjusted incidence rates for cancer of the uterine corpus in Connecticut were comparable in the two periods 1960-64 and 196549 for each stage of invasive disease (Table 1). However, the age-adjusted incidence of invasive disease was nearly 20% higher in 1970-75 than in either of these two earlier periods. TABLE
1
AVERAGE ANNUAL INCIDENCE RATES PER 100,000 WOMEN, CANCER OF THE UTERINE CORPUS, BY AGE AND STAGE OF DISEASE, CONNECTICUT, 1960-1975
Time of diagnosis 1965-69
1960-64
1970-75
Stage of disease
Age at diagnosis”
Number of cases
Rate
Number of cases
Rate
Number of cases
Rate
Localized
20-29 30-39 40-49 so-59 60-69 70-79 80+ All ages”
3 42 206 333 333 201 54 1172
0.4 4.5 22.3 47.1 61.1 60.6 42.8 16.3
5 29 200 395 374 229 58 1292
0.5 3.3 20.7 48.5 63.9 60.9 36.3 16.3
6 58 234 755 636 335 II7 2141
0.4 5.2 20.4 69.8 80.9 67.0 52.2 20.5
Nonlocalized
20-29 30-39 40-49 50-59 60-69 70-79 80+ All ages”
0 3 28 49 77 68 24 249
0 0.3 3.0 6.9 14.1 20.5 19.0 3.5
I 6 22 57 73 57 22 238
0.1 0.7 2.3 7.0 12.5 15.1 13.8 3.0
2 4 24 97 91 94 29 341
0.1 0.4 2.1 9.0 11.6 18.8 12.9 3.2
All invasive’
20-29 30-39 40-49 50-59 60-69 70-79 80+ All ages”
3 46 238 391 423 286 97 1485
0.4 5.0 25.8 55.3 77.6 86.2 76.9 20.7
6 37 223 468 458 302 97 I593
0.6 4.2 23.1 57.5 78.3 80.2 60.7 20. I
8 64 263 866 741 448 173 2563
0.5 5.7 22.9 80.1 94.2 89.6 77.2 24.5
” In addition, there were three cases diagnosed in women under 20 years old. ’ All ages rates have been age standardized by the direct method to the U.S. 1970 Census Population. (’ Includes cases with unknown stage.
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This excess reflects the higher rate of localized corpus cancer observed in the most recent time period, for the incidence of tumors with regional or distant spread remained unchanged. Women in all age groups 50 and over experienced higher rates of localized disease in 1970-75 than in either previous diagnostic period. Those aged 50-59 had the greatest increase, with an average annual rate for 1970-75 that exceeded the largest of the two earlier rates by 21.3 cases of disease per 100,000 women (43.9%). A substantial rise also occurred amongst 60- to 69-year-old women. Although the older women (70-79 and 80+) showed moderate increases in their rates of localized disease, these age groups contain proportionally more unstaged cases than younger age groups, so that the increases in localized disease could reflect more accurate staging rather than true increases in the risk of disease. In fact, increases in the rates for all invasive disease in these age groups are small. Examination of the stage-specific time trends since 1970in more detail (Table 2) reveals that the age-adjusted rates of localized disease have increased consistently with each 2-year period of diagnosis since 1970. In addition, every age group 50 and over, except 70-79, experienced this consistent rise. Although there are no general time trends evident in the incidence of nonlocalized corpus cancer, the rate of regional or distant disease in women aged 50-59 is higher in each of the 2-year diagnostic periods since 1970 than it was in either of the preceding quinquennia. The diagnosis of carcinoma in situ of the endometrium has been reported with increasing frequency since 1960, rising from an average of 13.2 cases per year in 1960-64 to 20.6 cases annually in 1965-69 and 32.7 in 1970-75. Mortality rates from cancer of the uterine corpus appear to have declined slightly over the 15-year period 1960-74 (Table 3). Only in the age group 60-69 is 1970-74 mortality greater than that in both preceding quinquennia. DISCUSSION
The incidence of cancer of the corpus uteri is currently increasing in several areas of the United States 121.In Connecticut this increase is entirely due to rising rates of localized disease since 1970in women aged 50 and over. It is unlikely that such results have been produced by changes in the reporting or coding practices of the CTR, as these practices have been consistent, essentially complete, and of good quality over the 16-year period reported here. The strong associations of endometrial cancer with menopausal and postmenopausal exogenous estrogen exposure reported in several retrospective studies [3-71 have already led to the hypothesis that increasing incidence is due to increase in such exposure 121. However, the interpretation of a change in incidence must take into account other possible influences, including changing rates of hysterectomy, changes in diagnostic techniques, with earlier diagnosis, diagnostic criteria, and changes in the prevalence of other risk factors for endometrial cancer. Changing Rates of Hysterectomy Changes in the rates of hysterectomy over time make the interpretation of time trends in the rates of uterine malignancies difficult, because the correct de-
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TABLE 2 AVERAGE ANNUAL INCIDENCE RATES PER 100,000 WOMEN, CANCER OF THE UTERINE CORPUS, BY AGE AND STAGE OF DISEASE, CONNECTICUT, 1970-75 Time of diagnosis 1970-7 1
1974-75
1972-73
Stage of disease
Age at diagnosis
Number of cases
Rate
Number of cases
Rate
Number of cases
Rate
Localized
20-29 30-39 40-49 so-59 60-69 70-79 i$o+ All ages”
I I7 66 204 180 101 31 600
0.2 4.8 16.7 57.4 72.6 61.9 42.2 17.7
4 I8 96 243 206 121 38 726
0.8 4.8 25.0 67.3 78.5 72.5 50.7 20.9
I 23 72 308 250 II3 48 815
0.2 5.9 19.4 84.4 90.6 66.5 63.5 22.9
Nonlocalized
20-29 30-39 40-49 50-59 60-69 70-79 80+ All ages”
0 0 5 32 28 33 9 107
0 0 I.3 9.0 11.3 20.2 12.2 3.1
I 2 9 26 37 34 9 118
0.2 0.5 2.3 7.2 14.1 20.4 12.0 3.3
I 2 10 39 26 27 II II6
0.2 0.5 2.7 10.7 9.4 15.9 14.6 3.2
All invasive”
20-29 30-39 40-49 50-59 60-69 70-79 80+ All ages”
I I7 72 243 213 143 48 737
0.2 4.8 18.3 68.3 85.9 87.6 65.3 21.7
5 20 108 271 246 162 54 866
1.0 5.3 28.1 75. I 93.7 97.1 72. I 24.9
2 27 83 352 282 143 71 960
0.4 6.9 22.4 96.5 102.2 84.2 93.9 26.9
li All ages rates have been age standardized tion. e Includes cases with unknown stage.
by the direct method to the U.S. 1970 Census Popula-
nominators for these disease rates are the numbers of women with intact uteri. Hysterectomy rates for U.S. women increased through the 1960sand early 1970s (Table 4) [I I- 161.Lyon and Gardner have estimated the effects of this increase in terms of the age-specific proportions of women with uteri since 1960 [15]. When Connecticut incidence rates of invasive corpus cancer are adjusted for prior hysterectomy in those years for which estimates of the proportions of women without uteri have been published [ 151,a gradual increase between 1960and 1970is evident (Fig. 1). Although population data on the incidence of hysterectomy prior to 1960 are not available, one can infer from published data that the rates for this operation were in fact rising. For example, the percentage of women aged 65+ having undergone operative menopause prior to 1960-62 was less than that for younger
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TABLE 3 AVERAGEANNUAL MORTALITY RATES PER 100,000 WOMEN, CANCEROF THE UTERINE CORPUS,’ CONNECTICUT,1960-1974 Period of death 1960-64
1970-74
1965-69
Age at death”
Number of deaths
Rate
Number of deaths
Rate
20-29 30-39 40-49 50-59 60-69 70-79 80+ All ages’
0 2 19 56 85 108 54 325
0 0.2 2.1 7.9 15.6 32.5 42.8 4.6
0 3 10 28 101 110 53 306
0 0.3 1.0 3.4 17.3 29.2 33.2 3.8
Number of deaths 0
1 10 56 120 109 64 360
Rate 0
0.1 1.0 6.2 18.6 26.3 34.4 4.0
0 Includes all women diagnosed as having cancer of the corpus uteri or uterus NOS who died of either of these causes. * In addition, there were two deaths among women under 20 years old. c Age standardized by the direct method to the U.S. 1970 Census Population.
women [ 171.These data, although incomplete, are consistent with rising hysterectomy rates in Connecticut from the mid 1940sthrough the early 1970s.The resulting reductions in the population of middle-aged and older women with intact uteri would have masked an increase in uterine cancer among women still at risk which probably began in Connecticut 25 or more years ago. As this ongoing increase in corpus cancer has become apparent in reported rates TABLE 4 CRUDE ANNUAL HYSTERECTOMYOPERATIVERATES PER 100,000 WOMEN, UNITED STATES, 1965-1975, AS ESTIMATED BY THE PROFESSIONAL ACTIVITY STUDY (PAS) [16] AND THE HOSPITALDISCHARGE SURVEY(HDS) [ll-14,183 Source Year
PAS
HDS
I965 1968 1970 1971 1972 1973 1974 1975
N/A” N/A 602 640” 670” 720” 715” 727
439 484 N/A 544 614 648 648 N/A
‘I N/A, not available. b Estimated by eye from Illustration I [16].
,
CANCER OF THE UTERINE
of
' 1960
CORPUS IN CONNECTICUT
I 1965 YEAR
I I970
189
J 1975
OF DIAGNOSIS
FIG. 1. Incidence of invasive cancer of the uterine corpus, Connecticut, 1960-1975. Ageadjusted rates (U.S. 1970 population), unadjusted and adjusted for prior hysterectomy.
only since 1970, then either rates of hysterectomy have been decelerating or the true rates of corpus cancer have been accelerating since that time, or both. The Connecticut incidence of cancer of the uterine corpus adjusted for prior hysterectomy has clearly accelerated since 1970 (Fig. 1). However, the adjusted rates shown in Fig. 1 should be considered to be indicative only of the probable pattern of increase in Connecticut and not of the actual magnitude of this increase, since their calculations are based on the assumption that national and Connecticut hysterectomy rates have been comparable during the last 15 or 20 years. Although there are no data to directly evaluate the validity of this assumption, for those years in which region-specific hysterectomy data are available (1970, 197I, 1975), the northeast region has had a consistently lower rate of hysterectomy than the country as a whole [13, 161.In addition, data from both the Professional Activity Study and the Hospital Discharge Survey indicate that national hysterectomy rates have stabilized since 1973 (Table 4) [ 13, 16, 181, which is contrary to the assumption of continuing increase on which the 1974 and 1975 adjustments for prior hysterectomy are based [15]. Finally, there is evidence that hysterectomy rates might have started to decelerate even earlier in the northeast, since the rates for this operation in the northeast region increased proportionately less than nationwide rates between 1970 and 1975 [16]. There are two other effects of hysterectomy rates on uterine cancer incidence which must be mentioned. First, an increase in the number of hysterectomies for noncancerous reasons means that fewer cases of cancer should be found in future than would otherwise be expected. From a public health viewpoint this is obvi-
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ously important, but it makes it difficult for the epidemiologist to identify secular trends in true disease rates which might lead to suggested etiologic agents. For example, if the prevalence of women with uteri had not been decreasing during the 1960s then the incidence rates, unadjusted for prior hysterectomy, would have reflected the true pattern of disease occurrence, namely a secular increase, and perhaps the endometrial cancer-exogenous estrogen association would have been epidemiologically’investigated sooner than it was. Second, unsuspected tumors are occasionally found at hysterectomy, and increasing numbers of hysterectomies should result in an increased number of such incidental findings. Assuming that the rate of incidental findings in the hysterectomized population of women aged 45-64 is the same as the rate of incident endometrial cancer in the general population of women of the same age, we would expect to find less than 65 unsuspected tumors per 100,000operations (0.065%) in the 1960s. Thus, with a 1965 hysterectomy rate of 761 per 100,000 women aged 45-64, incidental findings might be expected to account for 0.6 cases of disease per 100,000 women. The effect in other age groups would be even less. Even with the higher rates of both hysterectomy and disease in 1973,one could attribute only one tumor per 100,000women aged 45-64 to incidental findings at hysterectomy. Thus, the increasing rate of hysterectomy could be expected to result in an increase of about 0.4 cases of disease per 100,000women (1 .O-0.6) in this age group between 1965and 1973due to incidental findings. Since the rate of corpus cancer in this age group has increased by about 20 cases per 100,000 women during this time, this effect of increasing numbers of hysterectomies is relatively unimportant. Changes in Diagnostic Practices Increases restricted to the two early stages of disease, in situ and localized, make it apparent that more cancer of the corpus uteri is being detected at earlier stages of development. This is likely to be at least partly attributable to recent improvements in the methods available for diagnosis. Several reasonably reliable techniques can now be performed in the physician’s office with no anesthetic [19-261; the disease state of asymptomatic or mildly symptomatic women can thus be readily determined. As a result, there is increasing encouragement to screen menopausal and postmenopausal women for this disease [27, 281. The potential effect of such changes in diagnostic practices can be seen in the time trends of the stage distribution of invasive cervical cancer in Connecticut subsequent to the introduction of the Pap smear as a diagnostic tool (Table 5). Initially, the proportion of tumors diagnosed in the localized stage increased, as early asymptomatic lesions were picked up and a mixture of prevalent and incident cases were being diagnosed. However, once most of these prevalent early cases were removed from the population at risk of diagnosis, the proportion of tumors diagnosed in the localized stage began declining [29]. California experience was comparable with respect to increases in localized cervical cancer, but stage-specific data are available only through 1963 [30]. Diagnostic Criteria There is ample discussion in the recent literature about precursors to endometrial cancer and their definitions [3 11.The diagnosis of carcinoma in situ seems to
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TABLE 5 DISTRIBUTION OF CASES OF INVASIVE CERVICAL CANNER BY STAGE AND TIME PERIOD, CONNECTICUT, 1940-74 [29] Number
of
Period of diagnosis
Percentage localized
Percentage nonlocalized
staged invasive tumors
1940-44 1945-49 19.50-54 1955-59 1960-64 1965-69” 1970-74”
68 70 72 70 66 61 59
32 30 28 30 34 39 41
784 880 903 953 891 859 840
ClData for 1969-1974 from the Connecticut Tumor Registry
be gaining in acceptability, so that its increasing frequency in Connecticut may reflect not only more widespread diagnostic testing but also increasing recognition of CIS as a diagnostic entity with some potential for progression to carcinoma. More diagnoses of CIS imply that pathologists are probably receiving increasing numbers of specimens from early and borderline tumors which must be classified as either CIS or early invasive endometrial cancer. The actual effect of their diagnostic decisions on the rates of early invasive cancer is at present indeterminate, but it is possible that some morphologic but not biologic cancers which might have regressed would be labeled as carcinoma [27]. Increased Prevalence of Other Risk Factors Factors associated with an increased risk of endometrial cancer, such as overweight, nulliparity, late menopause, diabetes mellitus, hypertension, SteinLeventhal syndrome, cancers of other sites, pelvic irradiation, and administration of estrogens have been recently reviewed [32]. There is no evidence that the prevalences of any of these, apart from estrogen use, have increased much in the age groups that have shown recent rises in corpus cancer incidence. Increasing Use of Exogenous Estrogens Studies of both humans and animals have demonstrated that estrogens, endogenous and exogenous, have an important role in producing or promoting the development of endometrial cancer [3-7, 33-431. There is some evidence that tumors induced by exogenous estrogens, in humans at least, may be less likely to invade other tissues than other endometrial tumors 17, 281. Exogenous estrogen use may also promote earlier diagnosis in diseased women either through the production of symptoms, usually bleeding, from an extant but previously asymptomatic lesion or through more frequent patient-physician contact 128,441. There is also evidence that exogenous estrogens can produce endometrial changes which could be incorrectly labeled as cancer; these changes sometimes disappear after removal of the estrogenic stimulation [28, 44-461. Estrogens have been used for replacement therapy since the 1930s; by 1958, 1.6 million prescriptions were being filled nationally per year [5]. This figure changed
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little between 1958and 1965but had doubled by 1966; this new higher level of use was maintained until 1971, after which time it began to increase again 15, 473. These data, viewed in conjunction with the increase in incidence of endometrial cancer which began in 1970, would lead to an estimated latency period of 4 to 8 years between initiation of drug exposure and diagnosis of cancer. This is consistent with estimates of the latency period derived from clinical sources. For example, the median time between first exposure and diagnosis in a series of 23 endometrial cancer patients who had been using exogenous estrogens for at least 1 year immediately prior to diagnosis was 6 years [48]; in one of the recent case-control studies [7], 12 out of the 16 endometrial cancer cases who had used conjugated estrogens for 6 months or more beginning at least 1year prior to diagnosis had in fact started using them 5-10 years before diagnosis [49]. The Connecticut Tumor Registry should therefore have begun to report increasing incidence of endometrial cancer by the late 1940s at least. We have presented incomplete evidence on hysterectomy rates suggesting that a rise in incidence probably did occur in earlier years of the Registry but was obscured by the gradual reduction in the true at-risk population. The recent sharp rise in disease rates is compatible with a large increase in drug use beginning in the mid 1960s. Available data suggest that women aged 50-59 and 60-69 were the greatest consumers of exogenous estrogens in the late 1960s [501. With a latent period as short as indicated, the largest effect on disease rates could be expected to occur in these and slightly older age groups, with a smaller increase among the oldest women. Connecticut experience since 1970 of increases in these age groups but restricted to localized tumors is consistent not only with a short latent period, but also with a shorter period for development of localized than of more advanced lesions. If estrogens do produce endometrial abnormalities which are sometimes incorrectly labeled as cancer [28,44-461, then the rapid increase in estrogen use which occurred during the late 1960scould be expected to result in a similar trend in the reported incidence of localized tumors of the uterine corpus due to this effect alone but to have no impact on mortality rates; Connecticut experience is consistent with this. Although we cannot as yet assessthe contribution of this effect, the finding that the association of exogenous estrogen use with endometrial cancer is seen for deeply invasive tumors [40] and after pathological review 1511suggests that it cannot be the only factor. In summary, the recent increase in the incidence of localized invasive endometrial cancer in women 50 and over in Connecticut is likely to be at least partially due to the increasing use of estrogen therapy. However, the trend is also influenced by hysterectomy rates and by diagnostic practices and criteria, and additional information on these factors as well as on drug use in Connecticut is necessary for further evaluation. The fact that neither mortality from corpus cancer nor nonlocalized disease incidence has increased in Connecticut since 1960 suggests that estrogen therapy may be predominantly associated with tumors that can be readily diagnosed at an early stage. This is consistent with the results of some case-control studies [5, 7, 281. Thus, the risk to the patient of such therapy may be reduced by close medical supervision and the physician may choose to
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UTERINE
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accept such a controllable risk in light of the potential benefits of exogenous estrogen administration to the patient [52]. It remains to be seen if medical practices will be adequate to prevent the increase in mortality rates from endometrial cancer which would be expected on the basis of the currently rising incidence. ACKNOWLEDGMENT The authors would like to express their appreciation to Dr. J. McL. Morris, John Slade Ely Professor of Gynecology, Yale University School of Medicine, for his many helpful discussions and suggestions during the preparation of this manuscript.
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18. Leaverton, P. Estimated number and rate of hysterectomies: United States, 1974, Persona1 communication, Division of Health Resources Utilization Statistics, Hospital Care Statistics Branch. 19. Cohen, C. J., Gusberg, S. B., and Koffler, D. Histologic screening for endometrial cancer, Gynecol. Oncol. 2, 279-286 (1974). 20. Creasman, W. T., and Weed, J. C., Jr. Screening techniques in endometrial cancer, Cancer 38, 436-440 ( 1976). 21. “Current Status of Endometrial Carcinoma” in Mediscope, the American Cancer Society, Connecticut Division, Issue No. 15 (1976). 22. McGowan, L. Cytologic methods for the detection of endometrial cancer, Gynecol. Oncol. 2, 272-278 (1974). 23. Ng, A. B. P. The cellular detection of endometrial carcinoma and its precursors, Gynecol. Oncol. 2, 162-179 (1974). 24. Popkin, D. R. Endometrial cancer: The present status of diagnosis, Canad. Med. Assoc. J. 115, 596-600 ( 1976). 25. Walters, D., Robinson, D., Park, R. C., and Patow, W. E. Diagnostic outpatient aspiration curettage, Obstet. Gynecol. 46, 160-164 (1975). 26. Webb, M. J., and Gaffey, T. A. Outpatient diagnostic aspiration curettage, Obster. Gynecol. 47, 239-242 (1976). 27. Cramer, D. W. Interpreting trends in the incidence and mortality of endometrial cancer. Presented to the Obstetrics and Gynecology Advisory Committee of the Food and Drug Administration, Rockville, Maryland (December 16, 1975). 28. Kistner, R. W. Estrogens and endometrial cancer, Obstet. Gynecot. 48, 479-482 (1976). 29. Meigs, J. W., Laskey, P. W., and Flannery, J. T. Evidence for regression of carcinoma-in-siru and for a second form of invasive cervical cancer, Connecticut 1935-73, Geburtsh. Frauenheilk. 36, 554-569 (1976). 30. Linden, G., and Dunn, J. E., Jr. Earlier diagnosis of cervical cancer: An analysis of reports to the California Tumor Registry from 1942 to 1963, Calif. Med. 105, 331-336 (1966). 3 I. Vellios, F. Endometrial hyperplasia and carcinoma in-situ, Gynecol. Oncol. 2, 152-161 (1974). 32. MacMahon, B. Risk factors for endometrial cancer, Gynecol. Oncot. 2, 122-129 (1974). 33. Fechner, R. E., and Kaufman, R. H. Endometrial adenocarcinoma in Stein-Leventhal syndrome, Cancer 34, 444-452 (1974). 34. Gusberg, S. B., and Kardon, P. Proliferative endometrial response to theta-granulosa cell tumors, Amer. J. Obstet. Gynecol.
111, 633-643 (1971).
35. Cutler, B. S., Forbes, A. P., Ingersoll, F. M., and Scully, R. E. Endometrial carcinoma after stilbestrol therapy in gonadal dysgenesis, N. Engl. J. Med. 287, 628-631 (1972). 36. Dewhurst, C. J., deKoos, E. B., and Haines, R. M. Replacement hormone therapy in gonadal dysgenesis, Brit. J. Obstet. Gynecol. 82, 412-416 (1975). 37. Roberts, G., and Wells, A. L. Oestrogen-induced endometrial carcinoma in a patient with gonadal dysgenesis, Brit. J. Obset. Gynecol. 82, 417-420 (1975). 38. Hoover, R., Fraumeni, J. F., Jr., Everson, R., and Myers, M. H. Cancer of the uterine corpus after hormonal treatment for breast cancer, Lancet 1, 885-887 (1976). 39. Larson, J. A. Estrogens and endometrial carcinoma, Obstet. Gynecol. 3, 551-572 (1954). 40. Ziel, H. K., and Finkle, W. D. Correspondence, N. Engl. J. Med. 294, 848 (1976). 41. Evaluation of carcinogenic risk of chemicals to man: Sex hormones. International Agency for Research on Cancer Monographs, Vol. 6, Lyon (1974). 42. Griffiths, C. T., Craig, J. M., Kistner, R. W., Rothman, K. J., Steiner, G. J., and Tomic, M. Effect of castration, estrogen, and timed progestins on induced endometrial carcinoma in the rabbit, Gynecol. Oncol. 3, 259-275 (1975). 43. Meissner, W. A., Sommers, S. C., and Sherman, G. Endometrial hyperplasia, endometrial carcinoma, and endometriosis produced experimentally by estrogen, Cancer 10,500-509 (1957). 44. Jensen, E. I., and Ostergaard, E. Clinical studies concerning the relationship of estrogens to the development of cancer of the corpus uteri, Amer. J. Obstet. Gynecol. 67, 1094-I 102 (1954). 45. Sommers, S. C. Report on estrogens and endometrial cancer. Presented to the Obstetrics and Gynecology Advisory Committee of the Food and Drug Administration, Rockville, Maryland (December 16, 1975).
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OF
THE
UTERINE
CORPUS
IN
CONNECTICUT
195
46. Ostergaard, E. Malignant and pseudomalignant hyperplasia adenomatosa of the endometrium in postmenopausal women treated with oestrogen, Acta Ohret. Gynecol. Stand. 53, 97-102 (1974). 47. Current Industrial Reports, U.S. Department of Commerce, Bureau of the Census, Series M28G (1962-67) and Ma28G (1%8-73). 48. Gusberg, S. B., and Hall, R. E. Precursors of corpus cancer. III. The appearance of cancer of the endometrium in estrogenicahy conditioned patients, Obster. Gynecol. 17, 397-412 (1961). 49. Annegers, J. F. Personal communication. 50. Pfeffer, R. I. Estrogen use in postmenopausal women, Amer. J. Epidemio/. 105, 21-29 (1977). 51. Gordon, J., Reagan, J. W., Finkle, W. D., and Ziel, H. K. Estrogen and endometrial carcinoma: An independent pathology review supporting original risk estimate, N. Engl. J. Med. 297, 570-571 (1977). 52. Weiss, N. S. Risks and benefits of estrogen use, N. Engl. J. Med. 293, 1200-1202 (1975).
ONCOLOGY
Recent
LORAINE
6, 183-195 (1978)
Trends in the Incidence of the Uterine Corpus
and Mortality in Connecticut
of Cancer
D. MARRETT, PH.D.,‘~~ J. MARK ELWOOD, M.B., S. M. EPID., J. WISTER MEIGS, M.D.,2 AND JOHN T. FLANNERY, B.S.2
Connecticut Cancer Epidemiology Unit, Yale University, New Haven, Connecticut, 06.510, Department ofHealth Care and Epidemiology, University of British Columbia, Vancouver, British Columbia V6T I W5, and Connecticut Tumor Registry, State Department of Health, Hartford, Connecticut 06115 Received November 29, 1977 Incidence rates for invasive cancer of the uterine corpus (including cancer of the uterus, not otherwise specified) have been calculated according to stage of disease (localized, nonlocalized) based on cases reported to the Connecticut Tumor Registry between 1960and 1975. 1960-64 and 1965-69 rates were very similar for both disease stages. However, in 1970-75 the incidence of localized corpus cancer was 26% higher than in either of the preceding quinquennia, while the rate of nonlocalized disease remained about the same as previously. Women aged 50-59 experienced the largest increase in localized disease, although all other age groups over 50 also had higher rates in the most recent period of diagnosis. No increases were evident in women under 50 years of age. In addition, the frequency of the diagnosis of carcinoma in situ of the endometrium increased gradually over the 16-year period, and mortality from corpus cancer declined slightly. The possible effects of increasing exogenous estrogen use by menopausal and postmenopausal women, changes in diagnostic practices leading to earlier diagnosis, diagnostic criteria, and decreasing numbers of women with intact uteri as a result of increasing hysterectomy rates are considered in the interpretation of these recent trends in the incidence and mortality of cancer of the uterine corpus in Connecticut.
Although the incidence of endometrial cancer in Connecticut changed little between 1935and 1969 [I], a recent report indicates that incidence rates have risen since 1969, not only in Connecticut, but also in several areas of the United States possessing population-based tumor registries [2]. The increase is of particular significance when viewed in conjunction with the reported association between the occurrence of carcinoma of the corpus uteri in middle-aged women and prior administration of exogenous estrogens [3-71. The purpose of this paper is to present data reported to the Connecticut Tumor Registry (CTR) on the incidence of cancer of the uterine corpus in Connecticut I Address reprint requests to Dr. L. Marrett, Connecticut Cancer Epidemiology Unit, Yale University, 30 College Street, New Haven, Connecticut 06510 aSupported by contracts NOI CP 33235 and NO1 CP 43203 with the National Cancer Institute. 183 0090~8258/78/0062-0183$0 I .00/O Copyright @ 1978 by Academic Press, Inc. All rights of reproduction in any form reserved.
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according to age, stage of disease, and time of diagnosis and the mortality from this tumor by age and time of death since 1960. These data are then interpreted in terms of the explanatory hypotheses which appear consistent with them. MATERIALS
AND METHODS
The CTR contains data on new cases of malignant neoplasms which have been reported to it from all hospitals within the State since 1935. In addition, several major hospitals located in adjacent states but proximate to the Connecticut border report tumors diagnosed in Connecticut residents. Historical details of reporting mechanisms and requirements have been described elsewhere 183.Reporting is thought to have been reasonably complete for at least 30 years. Since 1960, death certificate and autopsy diagnoses have accounted for less than 3% of cases. Between 1960and 1975, there were 5 101 cases of invasive cancer of the corpus uteri (primary site 182, International Classification of Diseases, 9th Revision) diagnosed in women resident in Connecticut. There were also 540 invasive tumors recorded as “uterus, not otherwise specified” (uterus NOS, primary site 179, International Classification of Diseases, 9th Revision). There were 365 cases of carcinoma in situ (CIS) reported, with primary site corpus uteri in 349 of them and uterus NOS in 16. An intensive review of Connecticut cases diagnosed between 1935 and 1951 indicated that of the uterus NOS tumors diagnosed during life for which actual primary site could be determined, 90% arose in the corpus uteri 191. Therefore, all tumors of the uterus NOS are included in the results presented here. The proportion of tumors specified only as uterus has been declining steadily over the period of time reported here, from 16.5% of cases diagnosed in 1960-64 to less than 5% in 1970-75. Of the 540 invasive tumors of the uterus NOS reported in 1960-75, 62 were first diagnosed at death. There is considerable doubt about the true site of origin of these cases [9]. However, since they comprise only 1% of the total number of corpus cancer cases, the effect of incorrectly classifying a portion of them as corpus rather than cervix should be small. Sarcomas and mixed tumors comprised 8.5% (480 cases) of the invasive corpus cancers diagnosed in 1960-75. These will not be analyzed separately at this time. Stage of disease at time of diagnosis is determined by registry staff using “all clinical, X-ray, gross, and microscopic findings within the first course of planned medical care and instituted no later than 4 months from the accepted date of diagnosis; for untreated cases first hospitalization or date of diagnosis is used,” as stated in the CTR Coding Manual. The coding of stage of disease has for the most part been uniform since 1935. A tumor is considered to be in situ if it fulfills all microscopic criteria for malignancy except invasion and has been histologically confirmed. An invasive tumor is designated to be either localized if it is restricted to the organ of origin or nonlocalized if known spread has occurred. Over 95% of the cases of invasive disease diagnosed in 1960-75 have been staged. Incidence rates have been calculated for localized, nonlocalized, and all invasive (localized, nonlocalized, and stage unknown) corpus cancer in Connecticut according to time of diagnosis and age at diagnosis for the period 1960- 1975. Mortality rates have also been computed by time period and age at death for the years 1960 through 1974, based on the numbers of incident cases of cancer of the uterine corpus (including uterus NOS) who have died and had cancer of the corpus
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UTERINE
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uteri or uterus NOS coded as the underlying cause of death by the Connecticut Registrar of Vital Statistics. All rates are average annual rates per 100,000Connecticut women; all ages rates are age standardized by the direct method to the U.S. 1970 Census Population. Age-specific Connecticut female populations used for intercensal years are as estimated by the Public Health Statistics Section of the Connecticut State Department of Health [IO]. RESULTS
The age-adjusted incidence rates for cancer of the uterine corpus in Connecticut were comparable in the two periods 1960-64 and 196549 for each stage of invasive disease (Table 1). However, the age-adjusted incidence of invasive disease was nearly 20% higher in 1970-75 than in either of these two earlier periods. TABLE
1
AVERAGE ANNUAL INCIDENCE RATES PER 100,000 WOMEN, CANCER OF THE UTERINE CORPUS, BY AGE AND STAGE OF DISEASE, CONNECTICUT, 1960-1975
Time of diagnosis 1965-69
1960-64
1970-75
Stage of disease
Age at diagnosis”
Number of cases
Rate
Number of cases
Rate
Number of cases
Rate
Localized
20-29 30-39 40-49 so-59 60-69 70-79 80+ All ages”
3 42 206 333 333 201 54 1172
0.4 4.5 22.3 47.1 61.1 60.6 42.8 16.3
5 29 200 395 374 229 58 1292
0.5 3.3 20.7 48.5 63.9 60.9 36.3 16.3
6 58 234 755 636 335 II7 2141
0.4 5.2 20.4 69.8 80.9 67.0 52.2 20.5
Nonlocalized
20-29 30-39 40-49 50-59 60-69 70-79 80+ All ages”
0 3 28 49 77 68 24 249
0 0.3 3.0 6.9 14.1 20.5 19.0 3.5
I 6 22 57 73 57 22 238
0.1 0.7 2.3 7.0 12.5 15.1 13.8 3.0
2 4 24 97 91 94 29 341
0.1 0.4 2.1 9.0 11.6 18.8 12.9 3.2
All invasive’
20-29 30-39 40-49 50-59 60-69 70-79 80+ All ages”
3 46 238 391 423 286 97 1485
0.4 5.0 25.8 55.3 77.6 86.2 76.9 20.7
6 37 223 468 458 302 97 I593
0.6 4.2 23.1 57.5 78.3 80.2 60.7 20. I
8 64 263 866 741 448 173 2563
0.5 5.7 22.9 80.1 94.2 89.6 77.2 24.5
” In addition, there were three cases diagnosed in women under 20 years old. ’ All ages rates have been age standardized by the direct method to the U.S. 1970 Census Population. (’ Includes cases with unknown stage.
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This excess reflects the higher rate of localized corpus cancer observed in the most recent time period, for the incidence of tumors with regional or distant spread remained unchanged. Women in all age groups 50 and over experienced higher rates of localized disease in 1970-75 than in either previous diagnostic period. Those aged 50-59 had the greatest increase, with an average annual rate for 1970-75 that exceeded the largest of the two earlier rates by 21.3 cases of disease per 100,000 women (43.9%). A substantial rise also occurred amongst 60- to 69-year-old women. Although the older women (70-79 and 80+) showed moderate increases in their rates of localized disease, these age groups contain proportionally more unstaged cases than younger age groups, so that the increases in localized disease could reflect more accurate staging rather than true increases in the risk of disease. In fact, increases in the rates for all invasive disease in these age groups are small. Examination of the stage-specific time trends since 1970in more detail (Table 2) reveals that the age-adjusted rates of localized disease have increased consistently with each 2-year period of diagnosis since 1970. In addition, every age group 50 and over, except 70-79, experienced this consistent rise. Although there are no general time trends evident in the incidence of nonlocalized corpus cancer, the rate of regional or distant disease in women aged 50-59 is higher in each of the 2-year diagnostic periods since 1970 than it was in either of the preceding quinquennia. The diagnosis of carcinoma in situ of the endometrium has been reported with increasing frequency since 1960, rising from an average of 13.2 cases per year in 1960-64 to 20.6 cases annually in 1965-69 and 32.7 in 1970-75. Mortality rates from cancer of the uterine corpus appear to have declined slightly over the 15-year period 1960-74 (Table 3). Only in the age group 60-69 is 1970-74 mortality greater than that in both preceding quinquennia. DISCUSSION
The incidence of cancer of the corpus uteri is currently increasing in several areas of the United States 121.In Connecticut this increase is entirely due to rising rates of localized disease since 1970in women aged 50 and over. It is unlikely that such results have been produced by changes in the reporting or coding practices of the CTR, as these practices have been consistent, essentially complete, and of good quality over the 16-year period reported here. The strong associations of endometrial cancer with menopausal and postmenopausal exogenous estrogen exposure reported in several retrospective studies [3-71 have already led to the hypothesis that increasing incidence is due to increase in such exposure 121. However, the interpretation of a change in incidence must take into account other possible influences, including changing rates of hysterectomy, changes in diagnostic techniques, with earlier diagnosis, diagnostic criteria, and changes in the prevalence of other risk factors for endometrial cancer. Changing Rates of Hysterectomy Changes in the rates of hysterectomy over time make the interpretation of time trends in the rates of uterine malignancies difficult, because the correct de-
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TABLE 2 AVERAGE ANNUAL INCIDENCE RATES PER 100,000 WOMEN, CANCER OF THE UTERINE CORPUS, BY AGE AND STAGE OF DISEASE, CONNECTICUT, 1970-75 Time of diagnosis 1970-7 1
1974-75
1972-73
Stage of disease
Age at diagnosis
Number of cases
Rate
Number of cases
Rate
Number of cases
Rate
Localized
20-29 30-39 40-49 so-59 60-69 70-79 i$o+ All ages”
I I7 66 204 180 101 31 600
0.2 4.8 16.7 57.4 72.6 61.9 42.2 17.7
4 I8 96 243 206 121 38 726
0.8 4.8 25.0 67.3 78.5 72.5 50.7 20.9
I 23 72 308 250 II3 48 815
0.2 5.9 19.4 84.4 90.6 66.5 63.5 22.9
Nonlocalized
20-29 30-39 40-49 50-59 60-69 70-79 80+ All ages”
0 0 5 32 28 33 9 107
0 0 I.3 9.0 11.3 20.2 12.2 3.1
I 2 9 26 37 34 9 118
0.2 0.5 2.3 7.2 14.1 20.4 12.0 3.3
I 2 10 39 26 27 II II6
0.2 0.5 2.7 10.7 9.4 15.9 14.6 3.2
All invasive”
20-29 30-39 40-49 50-59 60-69 70-79 80+ All ages”
I I7 72 243 213 143 48 737
0.2 4.8 18.3 68.3 85.9 87.6 65.3 21.7
5 20 108 271 246 162 54 866
1.0 5.3 28.1 75. I 93.7 97.1 72. I 24.9
2 27 83 352 282 143 71 960
0.4 6.9 22.4 96.5 102.2 84.2 93.9 26.9
li All ages rates have been age standardized tion. e Includes cases with unknown stage.
by the direct method to the U.S. 1970 Census Popula-
nominators for these disease rates are the numbers of women with intact uteri. Hysterectomy rates for U.S. women increased through the 1960sand early 1970s (Table 4) [I I- 161.Lyon and Gardner have estimated the effects of this increase in terms of the age-specific proportions of women with uteri since 1960 [15]. When Connecticut incidence rates of invasive corpus cancer are adjusted for prior hysterectomy in those years for which estimates of the proportions of women without uteri have been published [ 151,a gradual increase between 1960and 1970is evident (Fig. 1). Although population data on the incidence of hysterectomy prior to 1960 are not available, one can infer from published data that the rates for this operation were in fact rising. For example, the percentage of women aged 65+ having undergone operative menopause prior to 1960-62 was less than that for younger
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ET AL.
TABLE 3 AVERAGEANNUAL MORTALITY RATES PER 100,000 WOMEN, CANCEROF THE UTERINE CORPUS,’ CONNECTICUT,1960-1974 Period of death 1960-64
1970-74
1965-69
Age at death”
Number of deaths
Rate
Number of deaths
Rate
20-29 30-39 40-49 50-59 60-69 70-79 80+ All ages’
0 2 19 56 85 108 54 325
0 0.2 2.1 7.9 15.6 32.5 42.8 4.6
0 3 10 28 101 110 53 306
0 0.3 1.0 3.4 17.3 29.2 33.2 3.8
Number of deaths 0
1 10 56 120 109 64 360
Rate 0
0.1 1.0 6.2 18.6 26.3 34.4 4.0
0 Includes all women diagnosed as having cancer of the corpus uteri or uterus NOS who died of either of these causes. * In addition, there were two deaths among women under 20 years old. c Age standardized by the direct method to the U.S. 1970 Census Population.
women [ 171.These data, although incomplete, are consistent with rising hysterectomy rates in Connecticut from the mid 1940sthrough the early 1970s.The resulting reductions in the population of middle-aged and older women with intact uteri would have masked an increase in uterine cancer among women still at risk which probably began in Connecticut 25 or more years ago. As this ongoing increase in corpus cancer has become apparent in reported rates TABLE 4 CRUDE ANNUAL HYSTERECTOMYOPERATIVERATES PER 100,000 WOMEN, UNITED STATES, 1965-1975, AS ESTIMATED BY THE PROFESSIONAL ACTIVITY STUDY (PAS) [16] AND THE HOSPITALDISCHARGE SURVEY(HDS) [ll-14,183 Source Year
PAS
HDS
I965 1968 1970 1971 1972 1973 1974 1975
N/A” N/A 602 640” 670” 720” 715” 727
439 484 N/A 544 614 648 648 N/A
‘I N/A, not available. b Estimated by eye from Illustration I [16].
,
CANCER OF THE UTERINE
of
' 1960
CORPUS IN CONNECTICUT
I 1965 YEAR
I I970
189
J 1975
OF DIAGNOSIS
FIG. 1. Incidence of invasive cancer of the uterine corpus, Connecticut, 1960-1975. Ageadjusted rates (U.S. 1970 population), unadjusted and adjusted for prior hysterectomy.
only since 1970, then either rates of hysterectomy have been decelerating or the true rates of corpus cancer have been accelerating since that time, or both. The Connecticut incidence of cancer of the uterine corpus adjusted for prior hysterectomy has clearly accelerated since 1970 (Fig. 1). However, the adjusted rates shown in Fig. 1 should be considered to be indicative only of the probable pattern of increase in Connecticut and not of the actual magnitude of this increase, since their calculations are based on the assumption that national and Connecticut hysterectomy rates have been comparable during the last 15 or 20 years. Although there are no data to directly evaluate the validity of this assumption, for those years in which region-specific hysterectomy data are available (1970, 197I, 1975), the northeast region has had a consistently lower rate of hysterectomy than the country as a whole [13, 161.In addition, data from both the Professional Activity Study and the Hospital Discharge Survey indicate that national hysterectomy rates have stabilized since 1973 (Table 4) [ 13, 16, 181, which is contrary to the assumption of continuing increase on which the 1974 and 1975 adjustments for prior hysterectomy are based [15]. Finally, there is evidence that hysterectomy rates might have started to decelerate even earlier in the northeast, since the rates for this operation in the northeast region increased proportionately less than nationwide rates between 1970 and 1975 [16]. There are two other effects of hysterectomy rates on uterine cancer incidence which must be mentioned. First, an increase in the number of hysterectomies for noncancerous reasons means that fewer cases of cancer should be found in future than would otherwise be expected. From a public health viewpoint this is obvi-
190
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ET AL.
ously important, but it makes it difficult for the epidemiologist to identify secular trends in true disease rates which might lead to suggested etiologic agents. For example, if the prevalence of women with uteri had not been decreasing during the 1960s then the incidence rates, unadjusted for prior hysterectomy, would have reflected the true pattern of disease occurrence, namely a secular increase, and perhaps the endometrial cancer-exogenous estrogen association would have been epidemiologically’investigated sooner than it was. Second, unsuspected tumors are occasionally found at hysterectomy, and increasing numbers of hysterectomies should result in an increased number of such incidental findings. Assuming that the rate of incidental findings in the hysterectomized population of women aged 45-64 is the same as the rate of incident endometrial cancer in the general population of women of the same age, we would expect to find less than 65 unsuspected tumors per 100,000operations (0.065%) in the 1960s. Thus, with a 1965 hysterectomy rate of 761 per 100,000 women aged 45-64, incidental findings might be expected to account for 0.6 cases of disease per 100,000 women. The effect in other age groups would be even less. Even with the higher rates of both hysterectomy and disease in 1973,one could attribute only one tumor per 100,000women aged 45-64 to incidental findings at hysterectomy. Thus, the increasing rate of hysterectomy could be expected to result in an increase of about 0.4 cases of disease per 100,000women (1 .O-0.6) in this age group between 1965and 1973due to incidental findings. Since the rate of corpus cancer in this age group has increased by about 20 cases per 100,000 women during this time, this effect of increasing numbers of hysterectomies is relatively unimportant. Changes in Diagnostic Practices Increases restricted to the two early stages of disease, in situ and localized, make it apparent that more cancer of the corpus uteri is being detected at earlier stages of development. This is likely to be at least partly attributable to recent improvements in the methods available for diagnosis. Several reasonably reliable techniques can now be performed in the physician’s office with no anesthetic [19-261; the disease state of asymptomatic or mildly symptomatic women can thus be readily determined. As a result, there is increasing encouragement to screen menopausal and postmenopausal women for this disease [27, 281. The potential effect of such changes in diagnostic practices can be seen in the time trends of the stage distribution of invasive cervical cancer in Connecticut subsequent to the introduction of the Pap smear as a diagnostic tool (Table 5). Initially, the proportion of tumors diagnosed in the localized stage increased, as early asymptomatic lesions were picked up and a mixture of prevalent and incident cases were being diagnosed. However, once most of these prevalent early cases were removed from the population at risk of diagnosis, the proportion of tumors diagnosed in the localized stage began declining [29]. California experience was comparable with respect to increases in localized cervical cancer, but stage-specific data are available only through 1963 [30]. Diagnostic Criteria There is ample discussion in the recent literature about precursors to endometrial cancer and their definitions [3 11.The diagnosis of carcinoma in situ seems to
CANCER OF THE UTERINE
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191
TABLE 5 DISTRIBUTION OF CASES OF INVASIVE CERVICAL CANNER BY STAGE AND TIME PERIOD, CONNECTICUT, 1940-74 [29] Number
of
Period of diagnosis
Percentage localized
Percentage nonlocalized
staged invasive tumors
1940-44 1945-49 19.50-54 1955-59 1960-64 1965-69” 1970-74”
68 70 72 70 66 61 59
32 30 28 30 34 39 41
784 880 903 953 891 859 840
ClData for 1969-1974 from the Connecticut Tumor Registry
be gaining in acceptability, so that its increasing frequency in Connecticut may reflect not only more widespread diagnostic testing but also increasing recognition of CIS as a diagnostic entity with some potential for progression to carcinoma. More diagnoses of CIS imply that pathologists are probably receiving increasing numbers of specimens from early and borderline tumors which must be classified as either CIS or early invasive endometrial cancer. The actual effect of their diagnostic decisions on the rates of early invasive cancer is at present indeterminate, but it is possible that some morphologic but not biologic cancers which might have regressed would be labeled as carcinoma [27]. Increased Prevalence of Other Risk Factors Factors associated with an increased risk of endometrial cancer, such as overweight, nulliparity, late menopause, diabetes mellitus, hypertension, SteinLeventhal syndrome, cancers of other sites, pelvic irradiation, and administration of estrogens have been recently reviewed [32]. There is no evidence that the prevalences of any of these, apart from estrogen use, have increased much in the age groups that have shown recent rises in corpus cancer incidence. Increasing Use of Exogenous Estrogens Studies of both humans and animals have demonstrated that estrogens, endogenous and exogenous, have an important role in producing or promoting the development of endometrial cancer [3-7, 33-431. There is some evidence that tumors induced by exogenous estrogens, in humans at least, may be less likely to invade other tissues than other endometrial tumors 17, 281. Exogenous estrogen use may also promote earlier diagnosis in diseased women either through the production of symptoms, usually bleeding, from an extant but previously asymptomatic lesion or through more frequent patient-physician contact 128,441. There is also evidence that exogenous estrogens can produce endometrial changes which could be incorrectly labeled as cancer; these changes sometimes disappear after removal of the estrogenic stimulation [28, 44-461. Estrogens have been used for replacement therapy since the 1930s; by 1958, 1.6 million prescriptions were being filled nationally per year [5]. This figure changed
192
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ET AL.
little between 1958and 1965but had doubled by 1966; this new higher level of use was maintained until 1971, after which time it began to increase again 15, 473. These data, viewed in conjunction with the increase in incidence of endometrial cancer which began in 1970, would lead to an estimated latency period of 4 to 8 years between initiation of drug exposure and diagnosis of cancer. This is consistent with estimates of the latency period derived from clinical sources. For example, the median time between first exposure and diagnosis in a series of 23 endometrial cancer patients who had been using exogenous estrogens for at least 1 year immediately prior to diagnosis was 6 years [48]; in one of the recent case-control studies [7], 12 out of the 16 endometrial cancer cases who had used conjugated estrogens for 6 months or more beginning at least 1year prior to diagnosis had in fact started using them 5-10 years before diagnosis [49]. The Connecticut Tumor Registry should therefore have begun to report increasing incidence of endometrial cancer by the late 1940s at least. We have presented incomplete evidence on hysterectomy rates suggesting that a rise in incidence probably did occur in earlier years of the Registry but was obscured by the gradual reduction in the true at-risk population. The recent sharp rise in disease rates is compatible with a large increase in drug use beginning in the mid 1960s. Available data suggest that women aged 50-59 and 60-69 were the greatest consumers of exogenous estrogens in the late 1960s [501. With a latent period as short as indicated, the largest effect on disease rates could be expected to occur in these and slightly older age groups, with a smaller increase among the oldest women. Connecticut experience since 1970 of increases in these age groups but restricted to localized tumors is consistent not only with a short latent period, but also with a shorter period for development of localized than of more advanced lesions. If estrogens do produce endometrial abnormalities which are sometimes incorrectly labeled as cancer [28,44-461, then the rapid increase in estrogen use which occurred during the late 1960scould be expected to result in a similar trend in the reported incidence of localized tumors of the uterine corpus due to this effect alone but to have no impact on mortality rates; Connecticut experience is consistent with this. Although we cannot as yet assessthe contribution of this effect, the finding that the association of exogenous estrogen use with endometrial cancer is seen for deeply invasive tumors [40] and after pathological review 1511suggests that it cannot be the only factor. In summary, the recent increase in the incidence of localized invasive endometrial cancer in women 50 and over in Connecticut is likely to be at least partially due to the increasing use of estrogen therapy. However, the trend is also influenced by hysterectomy rates and by diagnostic practices and criteria, and additional information on these factors as well as on drug use in Connecticut is necessary for further evaluation. The fact that neither mortality from corpus cancer nor nonlocalized disease incidence has increased in Connecticut since 1960 suggests that estrogen therapy may be predominantly associated with tumors that can be readily diagnosed at an early stage. This is consistent with the results of some case-control studies [5, 7, 281. Thus, the risk to the patient of such therapy may be reduced by close medical supervision and the physician may choose to
CANCER
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UTERINE
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accept such a controllable risk in light of the potential benefits of exogenous estrogen administration to the patient [52]. It remains to be seen if medical practices will be adequate to prevent the increase in mortality rates from endometrial cancer which would be expected on the basis of the currently rising incidence. ACKNOWLEDGMENT The authors would like to express their appreciation to Dr. J. McL. Morris, John Slade Ely Professor of Gynecology, Yale University School of Medicine, for his many helpful discussions and suggestions during the preparation of this manuscript.
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