Trends in Endometrial Cancer Incidence Rates in the United States,1999

Abstract

Background:

Risk factors for endometrial cancer, such as hormone replacement therapy (HRT) and obesity, have changed significantly in the last decade. We investigated trends in endometrial cancer histologic subtypes on a national level during 1999–2006.

Methods:

Data covering 88% of the U.S. population were from central cancer registries in the National Program of Cancer Registries (NPCR) and Surveillance, Epidemiology, and End Results (SEER) programs that met high-quality United States Cancer Statistics (USCS) criteria. Our analyses included females with microscopically confirmed invasive uterine cancer (n=257,039). Age-adjusted incidence rates and trends for all invasive uterine cancers and by endometrial cancer histologic subtypes (type I and II) were assessed.

Results:

There were 145,922 cases of type I endometrial cancers and 15,591 cases of type II for 1999–2006. We found that type I endometrial cancers have been increasing, whereas type II endometrial cancers and all invasive uterine cancers have been relatively stable throughout the 1999–2006 period.

Conclusions:

During the past decade, the overall burden of uterine cancer has been stable, although there have been changes in underlying histologies (e.g., endometrial). Changes in trends for underlying histologies may be masked when reviewing trends irrespective of histologic subtypes. Our findings suggest the need to examine trends of uterine cancer by histologic subtype in order to better understand the burden of endometrial cancer in relation to these subtypes to help women at increased risk for developing more aggressive types of endometrial cancer (e.g., type II).

Introduction

In the United States in 2006, 12% of all cancers diagnosed in women were invasive neoplasms of the female genital system.¹ Uterine cancer, specifically endometrial cancer, is the most commonly diagnosed of all these malignancies.^2,3 It is the fourth most common cancer, accounting for 6% of female cancers, following breast, lung, and colorectal cancer.² However, since most women present with an early stage of endometrial cancer, this results in only 3% of all cancer-related deaths in women. Pathologic features that affect the behavior of endometrial cancer include stage at diagnosis, tumor grade, histologic type, uterine size, depth of myometrial invasion, microscopic involvement of vascular spaces in the uterus by the tumor, and spread of the tumor outside the uterus.⁴ Older women tend to be diagnosed with a higher stage and grade of endometrial cancer than younger women.^4

–7 In addition, white women have better survival from endometrial cancer than black women, which is partially explained by the higher stage and grade of tumors found in black women.^4,7

Endometrial cancer develops along two distinct pathways with defined molecular alterations and distinct histologic and clinical features.^8

–13 This dualistic model has been firmly established and is widely accepted.^5,6,8,9,14 The majority of endometrial cancers (approximately 70%–80%) are type I and have endometrioid differentiation, while type II cancers account for 10%–20% of the endometrial cancers and are classified as serous and clear cell.^{5
–7,9,11,12,15,16} Type I endometrial cancers are estrogen dependent and develop through the hyperplasia-carcinoma sequence, whereas type II cancers are not estrogen dependent and develop independently of the endometrial hyperplasia pathway.^5,7,9,17 Type I endometrial cancers have a favorable prognosis.^{4

–7,9

–13} Type II endometrial carcinomas, including papillary serous carcinomas and clear cell carcinomas, have poorer prognoses.^{4

–7,9

–13}

Previous studies have examined uterine cancer incidence using population-based data,^2,18

–22 but few studies have investigated endometrial cancer incidence by histologic subtypes on a population level.^20
–22 Results from some studies have indicated that changes in endometrial cancer incidence could be expected because of declining use of hormone replacement therapy (HRT) and increasing obesity rates, with differing effects on type I and II subtypes.^12,23

–26 Data indicate that the total number of U.S. prescriptions for combined estrogen and progestin (HRT) dropped from 20 million in 1999 to 10 million in 2003, while the prevalence of obesity has doubled in US adults during the period 1980–2002.^26,27 Consequently, changes in the prevalence of these hormonal exposures might be expected to have greater impact on the incidence of the hormonally mediated type I endometrial cancer subtype and little impact on the incidence of the hormone-independent type II subtype. As HRT and obesity are important risk factors for development of endometrial cancer,^{4
–6,9,11,24,27

–36} this analysis provides a unique opportunity to assess trends in endometrial cancer incidence by histologic subtypes in light of these changes. The present study is intended to augment the current literature on endometrial cancer subtypes by providing incidence and trends on a national level. Thus, these analyses will focus on endometrial cancer incidence by histologic subtype and will evaluate trends in endometrial cancer subtypes for diagnosis years 1999–2006.

Materials and Methods

In this study, incident invasive uterine cancer cases were identified from population-based cancer registries that participated in the Centers for Disease Control and Prevention's (CDC) National Program of Cancer Registries (NPCR) or the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) Program.^37
–39 Together, NPCR and SEER collect cancer incidence data for the entire U.S. population.^38,39 These data were submitted to NPCR in January 2009 and to SEER in November 2008. Data included uterine cancer cases (n=257,039) diagnosed from 1999 through 2006 in central cancer registries (CCRs) in 42 states that met case ascertainment and quality criteria for all eight years.³⁸ These data cover approximately 88% of the U.S. population for all years. Data from CCRs in eight states and the District of Columbia were excluded because they did not meet the case ascertainment and quality criteria for all eight years. We included all female invasive uterine cancers (site code C54.0-54.9), excluding lymphomas, leukemias, mesotheliomas, Kaposi sarcomas, and related cancers.^40,41 In addition, we excluded cases of uterine cancers with a site code of not otherwise specified (NOS) (C55.9) because it is unknown whether these cases were uterine or cervical cancers. All data analyses for this database were performed using SEER*Stat version 6.6.2.⁴²

Uterine cancer histologic groupings were coded according to the version of the International Classification of Disease for Oncology (ICD-O) used at the time of diagnosis.^40,41 As a result, for 1999–2006 analyses, uterine cancer cases diagnosed from 1999 to 2000 used the ICD-O second edition (ICD-O-2), and 2001–2006 cases used the ICD-O third edition (ICD-O-3); data from the 1999–2000 diagnosis years were converted to the ICD-O-3 codes. Table 1 shows the histology categories and ICD-O-3 codes used to define type I and II endometrial cancers.⁴¹ The uterine cancer histologies that were not endometrioid, serous, or clear cell were grouped into the all other invasive uterine cancer category.

Table 1.

Histology Categories and International Classification of Diseases for Oncology, 3rd ed., Codes Used to Define Type I and II Endometrial Cancers in Females, United States, 1999–2006

Endometrial carcinoma histology definitions	ICD-O-3 codes	Frequency
Endometrioid adenocarcinoma (type I)^a	8262, 8380, 8382, 8383, 8570	145,922
Villous adenocarcinoma	8262	87
Endometrioid adenocarcinoma, NOS	8380	142,726
Endometrioid adenocarcinoma, secretory variant	8382	488
Endometrioid adenocarcinoma, ciliated variant	8383	125
Adenocarcinoma with squamous metaplasia	8570	2,496
Serous adenocarcinomas (type II)^b	8441, 8460, 8461	12,041
Serous cystadenocarcinoma, NOS	8441	2,938
Papillary serous cystadenocarcinoma	8460	7,778
Serous surface papillary carcinoma	8461	1,325
Clear cell adenocarcinoma^c (type II)^b	8310, 8313	3,550

The analyses were limited to microscopically confirmed endometrial carcinomas.

Type I indicates estrogen-dependent tumors.

Type II indicates nonestrogen-dependent tumors.

Clear cell adenocarcinomas comprise clear cell adenocarcinoma, not otherwise specified (NOS), and clear cell adenocarcinofibroma.

Cancer stage was assigned as SEER summary stage 1977 (SS77) for cases diagnosed before 2001, as SEER summary stage 2000 for cases diagnosed in 2001–2003, and as derived summary stage using the collaborative stage algorithm for cases diagnosed in 2004 or later.⁴³ These data were then aggregated to obtain an overall frequency count for stage. Stage was categorized as in situ, localized, regional, distant, or unstaged/unknown. Cancers reported as regional were also subclassified as regional with direct extension only (RE), regional lymph nodes only (RN), regional direct extension and lymph nodes (RE+RN), and regional not otherwise specified (RNOS). Grade was categorized as I (well differentiated), II (moderately differentiated), III (poorly differentiated), IV (undifferentiated/anaplastic), and unknown.

We examined cases by race, including white, black, American Indian/Alaska Native (AI/AN), Asian/Pacific Islander (API), and other/unknown race. To increase the accuracy of the AI/AN designation, linkages between the CCRs and the Indian Health Service (IHS) database were completed before data submission to NPCR and SEER. Ethnicity was categorized as Hispanic or non-Hispanic. Race and ethnicity were not mutually exclusive.

We presented distributions of endometrial cancer histologic subtypes (type I and II) by demographic and tumor characteristics. We then calculated age-adjusted incidence rates with 95% confidence intervals (95% CI) by endometrial histologic subtypes (type I and II), all other invasive uterine cancers, and all invasive uterine cancers combined. Rates were estimated per 100,000 women and age-adjusted using the U.S. 2000 population standard (19 age groups, Census P25-1130). Counts and rates based on <16 cases were not presented to ensure rate stability and confidentiality. Lastly, annual percent change (APC) and percent change between years were calculated based on invasive endometrial cancer histologic subtype (types I and II), all other invasive uterine cancers, and all invasive uterine cancer cases over time. APC was calculated using the weighted least squares method. The APC estimates were not presented if there were <16 cases in a single year within diagnoses years 1999–2006.

Results

Table 2 shows demographic and tumor characteristics by endometrial histologic subtype. Type I (endometrioid) accounted for 145,922 (90.3%) of all endometrial cases, and there were 15,591 (9.7%) type II (serous and clear cell) endometrial cases. Women with type II endometrial tumors tended to be older at diagnosis than women with type I endometrial tumors (68.2% vs. 41.6% age ≥65 at diagnosis, respectively) and were more likely to be black (17.5% vs. 5.7%, respectively). Type II endometrial tumors were more likely to be higher-grade tumors, with 62.7% at grade III or IV, compared to type I tumors, where only 15.1% were grade III or IV. Women with type II endometrial tumors were less likely to present at a localized stage than were women with type I, 37.8% and 76.5%, respectively.

Table 2.

Demographic and Tumor Characteristics of Type I and II Endometrial Cancers in Females, United States, 1999–2006

	Type I n (%)	Type II n (%)
Total	145,922 (100.0)	15,591 (100.0)
Age at diagnosis, years
0–49	22,010 (15.1)	529 (3.4)
50–64	63,259 (43.4)	4,429 (28.4)
65–79	46, 317 (31.7)	7,916 (50.8)
≥80	14, 336 (9.8)	2,717 (17.4)
Race
White	131,118 (89.9)	12,288 (78.8)
Black	8,249 (5.7)	2,720 (17.5)
AI/AN	554 (0.4)	55 (0.4)
API	3,978 (2.7)	389 (2.5)
Other unspecified/unknown race	2,023 (1.4)	139 (0.9)
Ethnicity^a
Hispanic	8,818 (6.0)	977 (6.3)
Non-Hispanic	137,104 (94.0)	14,614 (93.7)
Region
Northeast	42,781 (29.3)	4,643 (29.8)
Midwest	37,893 (26.0)	3,912 (25.1)
South	35,393 (24.3)	4,083 (26.2)
West	29,855 (20.5)	2,953 (18.9)
Grade
I	67,113 (46.0)	384 (2.5)
II	48,685 (33.4)	1,394 (8.9)
III	20,288 (13.9)	7,758 (49.8)
IV	1,673 (1.2)	2,011 (12.9)
Unknown	8,163 (5.6)	4,044 (25.9)
Stage at diagnosis^b
In situ (IS)	0 (0.0)	0 (0.0)
Localized (L)	111,660 (76.5)	5,896 (37.8)
Regional (R)	23,925 (16.4)	5,505 (35.3)
RE	16,908 (11.6)	3,021 (19.4)
RN	3,086 (2.1)	778 (5.0)
RE+RN	3,483 (2.4)	1,567 (10.1)
RNOS	448 (0.3)	139 (0.9)
Distant	4,609 (3.2)	3,515 (22.5)
Unstaged/unknown (U)	5,725 (3.9)	675 (4.3)
Diagnosis year
1999	12,536 (8.6)	1,751 (11.2)
2000	14,065 (9.6)	1,729 (11.1)
2001	17,216 (11.8)	1,914 (12.3)
2002	18,069 (12.4)	1,814 (11.6)
2003	18,864 (12.9)	1,953 (12.5)
2004	20,626 (14.1)	2,105 (13.5)
2005	21,658 (14.8)	2,156 (13.8)
2006	22,888 (15.7)	2,169 (13.9)

Counts pertain to 88% of U.S population covered by eligible cancer registries. Data from eight states and the District of Columbia are not included.

Percentages may not add to 100% because of rounding.

Race and ethnicity are not mutually exclusive.

SEER summary stage 1977 was used for 1999–2000 cases, SEER summary stage 2000 was used for 2001–2003 cases, and derived summary stage 2000 (also known as collaborative stage) was used for 2004–2006 cases. Stage information was missing for 3 cases of endometrioid histology.

AI/AN, American Indian/Alaska Native; API, Asian/Pacific Islander; RE, regional direct extension only; RN, regional lymph nodes only; RE+RN, regional direct extension and lymph nodes; RNOS, regional not otherwise specified; SEER, National Cancer Institute's Surveillance, Epidemiology, and End Results Program.

Table 3 shows the change in incidence rates over time, comparing uterine cancers by type I and type II endometrial cancer cases, all other invasive uterine cancers, and all invasive uterine cancer cases combined. Rates of invasive type I endometrial cancers increased from 1999 to 2006, whereas type II endometrial cancers remained relatively stable over this time period. The total percent change from 1999 to 2006 was greater for type I endometrial cancers (60.9%) compared to type II (12.8%). In addition, the APC was greater for type I endometrial carcinomas (6.3%; 95% CI: 4.1, 8.5) than for type II (2.2%; 95% CI: 0.9, 3.5), p=0.002. For all other invasive uterine cancers, the total percent change for 1999 to 2006 was −49.4%, and the APC was −9.5% (95% CI: −10.9, −8.1). When all invasive uterine cancers were combined, the APC was not statistically significant (−0.1%; 95% CI: −0.6, 0.4), and the total percent change during this period was −0.3%.

Table 3.

Age-Adjusted Uterine Cancer Incidence Rates by Diagnosis Year in Females, United States, 1999–2006

	Endometrioid—Type I			Serous and clear cell—Type II			All other invasive uterine cancers			All invasive uterine cancers
Diagnosis year	Case ^a	Rate (95% CI) ^b	Percent change	Case	Rate (95% CI)	Percent change	Case	Rate (95% CI)	Percent change	Case	Rate (95% CI)	Percent change
1999	12,536	9.6 (9.5,9.8)		1,751	1.3 (1.2,1.4)		16,209	12.3 (12.2,12.5)		30,496	23.3 (23.0,23.5)
2000	14,065	10.6 (10.5,10.8)	10.4	1,729	1.3 (1.2,1.3)	0.0	14,710	11.0 (10.9,11.2)	−10.6	30,504	22.9 (22.7,23.2)	−1.7
2001	17,216	12.8 (12.6,13.0)	20.8	1,914	1.4 (1.3,1.4)	7.7	12,674	9.4 (9.2,9.5)	−14.5	31,804	23.6 (23.3,23.8)	3.1
2002	18,069	13.2 (13.0,13.4)	3.1	1,814	1.3 (1.2,1.4)	−7.1	12,126	8.8 (8.6,9.0)	−6.4	32,009	23.3 (23.0,23.5)	−1.3
2003	18,864	13.5 (13.3,13.7)	2.3	1,953	1.4 (1.3,1.4)	7.7	10,760	7.7 (7.5,7.8)	−12.5	31,577	22.6 (22.3,22.8)	−3.0
2004	20,626	14.5 (14.3,14.7)	7.4	2,105	1.5 (1.4,1.5)	7.1	9,965	7.0 (6.8,7.1)	−9.1	32,696	22.9 (22.7,23.2)	1.3
2005	21,658	15.0 (14.8,15.2)	3.4	2,156	1.5 (1.4,1.5)	0.0	9,848	6.8 (6.6,6.9)	−2.9	33,662	23.2 (22.9,23.4)	1.3
2006	22,888	15.5 (15.3,15.7)	3.3	2,169	1.5 (1.4,1.5)	0.0	9,234	6.3 (6.1,6.4)	−7.4	34,291	23.2 (22.9,23.4)	0.0
Annual percent change^c		6.3^d (4.1,8.5)			2.2^d (0.9,3.5)			−9.5^d (−10.9, −8.1)			−0.1 (−0.6,0.4)
Total percent change		60.9			12.8			−49.4			−0.3

Counts pertain to 88% of U.S population covered by eligible cancer registries. Data from eight states and the District of Columbia are not included.

Rates are per 100,000 women and age-adjusted to the 2000 U.S. standard population (19 age groups, Census P25-1130).

95% confidence interval (CI) calculated using the Tiwari modification.

Annual percent change (APC) was calculated using weighted least squares method.

The APC is significantly different from zero (p<0.05).

Table 3 also shows that the incidence of type I endometrial cancers has increased since 1999 from a rate of 9.6/100,000 women to 15.5/100,000 women in 2006 compared to all other invasive uterine cancers, which have decreased from a rate of 12.3/100,000 women in 1999 to 6.3/100,000 women in 2006. In contrast, the incidence of type II endometrial cancers has been relatively stable (average of 1.4/100,000 women) throughout the 1999–2006 period. Similarly, when type I and type II endometrial cancers are combined with all other invasive uterine cancers, a stable trend (approximately 23.0/100,000 women) is seen for the 1999–2006 diagnosis years.

Discussion

We assessed changes over time in cancer incidence trends for all invasive uterine cancers and by endometrial cancer histologic subtype. We found that the age-adjusted incidence of all invasive uterine cancers remained stable during 1999–2006. This finding is consistent with findings of other studies.^2,19,20 Analyses of endometrial cancer histologic subtypes showed that the incidence of type I endometrial cancers increased during the 1999–2006 diagnosis years compared to type II endometrial cancers, which remained relatively stable during this period. However, a decrease in all other invasive uterine cancers occurred during the same period in which an increase in type I cancers was observed. These opposing trends in rates may indicate that some of the histologies found in all other invasive uterine cancers could have moved into the type I endometrial category over time. Alternatively, it could be possible that observed trends between type I and all other invasive uterine cancers reflect the true increase and decrease in these histologies, respectively. When all other invasive uterine cancers were further examined, it was apparent that adeocarcinoma, NOS (8140), accounted for the majority of this decrease, 54,428 cases of the total 95,526 cases of all other invasive uterine cancers. In fact, in 1999, adenocarcinomas, NOS, accounted for 11,427 cases and decreased steadily to 3,785 cases in 2006. This decrease may be the result of more definitive histologic classifications available in ICD-O-3 effective in 2001. Studies that focus on reabstraction of cases to examine the coding of endometrial histologic subtypes over these time periods may be warranted in the future to determine if these changes are real or an artifact of better coding of histologies. Despite the overall observed trends in endometrial cancers, it is important that incidence be monitored to assess temporal changes in specific histologic subtypes that affect the risk of morbidity and mortality in specific populations, particularly as risk factors change over time.

Studies examining overall trends in uterine cancer have been conducted.^2,19,20 These studies have indicated that uterine cancer incidence has been relatively stable over the last two decades, which is similar to our findings. A review of the literature found no studies that evaluate overall trends in endometrial cancer by histologic subtypes on a national level, although there have been several studies that have evaluated endometrial cancer subtype by race/ethnicity, grade, and survival. A study by Plaxe and Saltzstein²¹ found that a greater proportion of black women had high-risk lesions classified as grade >2 endometrioid carcinomas, papillary serous, clear cell carcinomas, and adenosquamous histologies than white women. Similarly, they found that black women have a significantly higher incidence of high-risk tumors compared to white women.²¹ Additional studies have analyzed the aggressiveness and mortality outcomes by type II endometrial tumors. These studies indicate that disparities in incidence of mortality by race and histologic subtypes exist.^22,44 A study by Madison et al.²² found that women with more aggressive histologic subtypes (type II) tended to be older than women with less aggressive histologic subtypes (type I). These studies, along with our findings, indicate that it may be important to evaluate type I and type II endometrial cancers as separate diseases, as it appears that these histologic subtypes have quite different risk factors.

Various factors, including trends in HRT use and the rise of obesity in the United States, may contribute to endometrial cancer incidence, especially by histologic subtype. Thomas et al.³¹ found that very obese women aged 20–54 years have an elevated endometrial cancer risk, which appears heightened by early menopause. McCullough et al.²⁴ found that obesity was associated with a greater risk of both types I and II endometrial cancers, although the association with type II cancers was driven by high-grade endometrioid tumors; the small number of cases with serous, clear cell, and papillary histology precluded meaningful analysis using this stricter definition. Analyses have also been conducted on obesity in relation to the combined synergistic effects with HRT on endometrial cancer development.^11,24,32 These studies found that the effects of obesity were mitigated by the use of estrogen plus progestin.^11,24,32 The recent decline in estrogen plus progestin use among women after the Women's Health Initiative (WHI) study contrasted with the rise of obesity²⁷ in the United States draws further attention to the need for understanding the associations among various etiologic factors that may contribute to increased risk of endometrial cancer, especially among histologic subtypes that may have significant implications for future research and prevention efforts.¹¹ In addition, results from the WHI study showed that the biologic roles of estrogen plus progestin in tumorigenesis are different between breast and endometrial cancer, although both are considered estrogen-dependent tissues. Future analyses should focus on the clinical significance of these findings.^45,46

Other studies on endometrial cancers by histologic subtype include an analysis by the Nurses' Health Study, which examined the association between reproductive factors and HRT and found that reproductive risk factors are likely risk factors for invasive type I endometrial cancer because they are linked to endogenous hormone levels.²⁸ As formulations of both oral contraceptives and HRT continue to evolve, trending toward lower-dose estrogens with increased knowledge of the effects of these therapies, it is important that analyses be conducted on histologic subtypes of endometrial cancer because types I and II cancers differ etiologically.^47,48

Our findings should be considered in light of several limitations. Data were not analyzed from CCRs in eight states and the District of Columbia. The exclusion of these CCRs may have influenced the reported incidence rates; however, our study included data for 88% of the U.S. population. Moreover, our analyses could not identify which risk factors were influencing changes in the rates of endometrial tumors. Our analyses assessed trends in endometrial cancer incidence over the time during which HRT use is known to have declined and obesity rates to have increased without establishing a cause and effect relationship. Moreover, we were unable to determine if these trends were related to changes in classification of certain histologies by pathologists.

Our study provides the first population-based analysis of type I and II endometrial cancer incidence that covers approximately 88% of the U.S. population for the 1999–2006 period. These analyses contribute to a more detailed understanding of current trends by endometrial histologic subtype on a national level. In addition, as type II cancers are less common, our analyses provide a robust sample size to observe trends in incidence of this particular histology. Most importantly, we were able to assess the incidence rates separately for endometrial type I and type II cancers to provide further insight into endometrial cancer incidence and trends in the United States.

Conclusions

During the past decade, the overall burden of uterine cancer has been stable, although there have been changes in underlying histologies (e.g., endometrial). Changes in trends for underlying histologies may be masked when reviewing trends irrespective of histologic subtypes. Our findings suggest the need to examine trends of uterine cancer by histologic subtypes in order to better understand the burden of endometrial cancer in relation to these subtypes to help women at increased risk for developing more aggressive types of endometrial cancer (e.g., type II).

Footnotes

Acknowledgments

We would like to acknowledge the contribution of CCR staff who collected the data used in this study. These data were provided by the CCRs participating in the NPCR and were submitted to CDC in the January 2009 data submission or to the SEER Program in the November 2008 submission. The dataset includes data for diagnosis years 1998–2006 (excluding SEER-Metro Registry data). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Disclosure Statement

All authors state that no competing financial interests exist.

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