Type I and II endometrial cancer: Both types of endometrial cancer have many common causes

Type I and Type II Endometrial Cancer: Do They Have Different Risk Factors?

objective

Endometrial cancer has long been divided into estrogen-dependent type I and estrogen-independent type II, which is less clinically aggressive. Little is known about the risk factors for type II tumors, as most studies lack enough cases to study these less common tumors individually. We looked at whether so-called classic endometrial cancer risk factors also affect the risk of type II tumours.

Patients and methods

We pooled individual-level data from 10 cohort studies and 14 case-control studies from the Consortium for Endometrial Cancer Epidemiology. A total of 14,069 cases of endometrial cancer and 35,312 controls were included. We classified endometrioid carcinoma (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and squamous differentiated adenocarcinoma (n = 777) as type I tumors, serous (n = 508) and mixed cells (n = 346) as type II tumors.

outcome

Fertility, oral contraceptives, smoking, age at menarche, and diabetes mellitus are similarly associated with type I and type II tumors. However, BMI had a greater effect on type I tumors than on type II tumors: odds ratio (OR) for every 2 kg/m2 increase in type I and 1.12 (95% CI, 1.19 to 1.21) for each 2 kg/m2 increase in type II (P heterogeneity< 0001). The pattern of risk factors for high-grade endometrioid tumors and type II tumors is similar.

conclusion

The results of this pooled analysis suggest that both types of endometrial cancer share many common causes. Thus, the etiology of type II tumors may not be entirely estrogen-independent as previously thought.

introduce

Endometrial cancer has long been classified into two types based on differences in histological and clinical outcomes. Type I tumors, which account for the vast majority of endometrial cancers, are mostly endometrioid adenocarcinomas, are associated with unopposed estrogen stimulation and usually precede endometrial hyperplasia. Type II tumors are predominantly serous carcinomas, often described as estrogen-independent, occurring in atrophic endometrium and arising from precancerous intraepithelial carcinomas. Type II tumors are generally poorly differentiated, have a worse prognosis than type I tumors, and account for a disproportionate proportion of endometrial cancer deaths (40% of deaths compared to only 10% to 20% of cases). The different genetic alterations found in type I and type II tumors suggest that these subtypes may have different etiologies.

Many of the known risk factors for type I endometrial cancer are associated with imbalances in estrogen and progesterone exposure, including obesity and the use of non-counter-estrogen therapy. The use of combined oral contraceptives (OCs) associated with progestogen dominance reduces the risk of endometrial cancer. Other risk factors include nulliparity, early menarche, and late menopause, while smoking is associated with a reduced risk. Little is known about the risk factors for type II tumors, mainly because most epidemiological studies lack enough cases to study these less common tumors alone.

In this study, we integrated individual data from 24 epidemiological studies participating in the Endometrial Cancer Epidemiology Consortium (E2C2) and performed a pooled analysis of 854 type II and 12,853 type I cases and 35,312 controls. E2C2 is an international consortium that aims to aggregate data to identify genetic and environmental risk factors for endometrial cancer that cannot be addressed by a single study. The large number of cases and controls in E2C2 allowed us to assess risk factors for type II tumors and associations for specific histological subtypes.

discuss

In this large pooled analysis, we observed that most of the classic endometrial cancer risk factors (i.e., obesity, age at menarche, fertility, use of oral contraceptives, smoking, and diabetes) were associated with less common and more clinically aggressive type II tumors (serous and mixed cellular). In addition, we observed similar patterns of risk factors for high-grade endometrioid tumors and type II tumors, while risk factors for clear cell tumors appeared to differ from those for other histological types of endometrial cancer.

The first epidemiological study to investigate risk factors for specific histological subtypes of endometrial cancer was a case-control study of 26 serous carcinomas and 328 endometrioid carcinomas. This study found that BMI, menopausal estrogen use, age at menarche, and number of births were associated with endometrioid tumors, but not serous tumors. Oral contraceptive use and smoking are associated with a reduced risk of both tumor types. The study also found significant differences in age- and BMI-adjusted serum endogenous estrogen and sex hormone-binding globulin (SHBG) levels between patients with endometrioid tumors and patients with serous tumors. Despite its small size, this study raises the possibility that the risk factors for serous tumors may be different from those for endometrioid tumors. The data from this study were combined with other clinicopathological and molecular data to propose a binary model of endometrial carcinogenesis.

Since the initial study, five epidemiological studies have investigated risk factors for type II tumors, two of which have focused on BMI. Similar to our findings, the largest study of 992 cases of type II tumors (including papillary, serous, clear cell, and some poorly differentiated cancers) found that BMI was associated with both type II tumors and type I tumors (including endometrioid and mucinous adenocarcinomas), and that the risk of type I tumors was slightly higher than that of type II tumors. However, the study did not control for potential confounders (i.e., reproductive history, use of exogenous hormones, and smoking) and therefore had a potential for bias, thus weakening the validity of its findings. Another BMI study of 970 cases of type II tumors had limited statistical power, but they also found that BMI was associated with type II tumors.

It is generally accepted that the classic endometrial cancer risk factor works through an estrogen mechanism that either increases estrogen exposure or counteracts the effects of estrogen. Obesity is associated with higher circulating estrogen levels in postmenopausal women and lower levels of progesterone in premenopausal women. Obesity is also associated with lower levels of SHBG, a protein that binds to and regulates estrogen biological activity. Oral contraceptives contain a progestin that directly counteracts the effects of estrogen on the lining of the uterus. Smoking lowers estrogen levels by lowering the age of menopause and altering estrogen metabolism. Hyperinsulinemia is a common feature of type 2 diabetes, and it can increase bioactive estrogen levels by lowering SHBG levels.

Type II tumors are often described as estrogen-independent, so estrogen and anti-estrogen exposure can be expected to be independent of their risk. However, our pooled analysis found an association between estrogen and anti-estrogen factors and type II tumor risk, suggesting that estrogen-driven proliferation associated with risk factors is also important for type II tumors, or that related mechanisms other than estrogen also drive these associations. For example, mechanisms associated with BMI/obesity, such as hyperinsulinemia, chronic inflammation, or oxidative activity, may be important. Hyperinsulinemia is also a hallmark of type 2 diabetes, and we found that it is associated with type II tumors, not BMI. Smoking has been shown to increase progesterone receptor (PGR) and homeobox A10 (HOXA10) expression in human endometrium and endometrial cells. In the etiology of endometrial cancer, further consideration of the role of other possible mechanisms is needed.

The advantages of this study include: large sample size and greater statistical power than most previous studies in examining the effect of specific histological types; Publication bias was minimal, if any, because our inclusion of a study in the analysis did not depend on whether the results had already been published; Comparisons between studies because we use individual-level data to standardize the definition and modeling of exposures and potential confounders, which is not possible in meta-analyses based on published estimates. Nonetheless, differences in exposure assessments in each study were a limitation of pooled analysis. Due to the lack of detailed menopausal hormone data (time and duration of use for specific hormone types), we were unable to examine this important association, which was a limitation of our analysis.

Histological sources of information do not appear to influence our results, but there may be some degree of misclassification of tumor types. Centralized pathology review including staining with key markers such as p53 is not possible, and the inclusion of certain type I tumors in the type II group may partially explain the observed type II tumor associations. However, almost all common associations for type I and type II tumors are equally strong. If our findings are the result of misclassification of tumor types, then almost all type II tumors must be type I tumors, and the BMI results should be the same for both tumor types. However, BMI associations are statistically distinctly different, clearly supporting a different classification. Pathologists generally agree that the main problem of misclassification is the diagnosis of low-grade endometrioid tumors while ignoring high-grade tumors29, and that misdiagnosis of tumors as serous tumors is unlikely to produce enough misclassification to explain the results obtained here. However, it is clear that future research will require the use of pathological examinations and molecular diagnostics to accurately define tumor types.

In conclusion, this large pooled analysis provides epidemiological evidence that in many ways, the risk factor profiles of type II and type I tumors are very similar, suggesting that they share some common etiological pathways. Thinking about the aggressive histological subtypes of endometrial cancer, it is best to get rid of the traditional distinction between type I and type II.

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