Introduction

Endometrial carcinoma (EC) is one of the most common gynecological malignancies. Surprisingly, the incidence rate of EC has continued to increase in both developing and developed countries [1]. The exact pathogenesis is still unclear despite advances in modern medicine, and most scholars believe that EC, especially endometrial adenocarcinoma (type I), is related to a series of endocrine and metabolic disorders [2–4].

Metabolic syndrome (MS), including obesity, hypertension, insulin resistance, diabetes, and dyslipidemia, increases the risk of developing multiple types of cancer, including liver, colorectal, and bladder cancers in men, and endometrial, pancreatic, breast post-menopausal, and colorectal cancers in women [5–7]. However, the role played by each single component of the syndrome on cancer risk is still unclear. For endometrial cancer, obesity and/or high circumference waist explain all the risk associated with the full metabolic syndrome. Observations that link blood pressure, glucose metabolism, and insulin resistance to endometrial cancer have come mostly from retrospective studies. These retrospective studies have provided less conclusive results because of self-reported disease history and anthropometry or an absence of adjustment for body mass. In fact, many metabolic disorders may influence estrogen/progesterone levels and expose women to a permanent hormonal imbalance, which may increase the risk of malignant endometrial changes. However, few reports on the relationship between MS and the prognosis of endometrial adenocarcinoma exist in the literature. This retrospective study compared the prognosis of patients with endometrial adenocarcinoma who also have MS with that of patients who only have EC. At the same time, we assessed the relationship between MS and clinicopathological features of patients with endometrial adenocarcinoma.

Materials and methods

A total of 385 patients with histologically confirmed endometrial adenocarcinoma (type I) were selected from January 2001 to December 2008 at the Department of Gynecologic Oncology, Zhejiang Cancer Hospital, in China. The study protocol was approved by the Ethics Committee of Zhejiang Cancer Hospital, and informed consent was obtained from each patient enrolled in the study. The median age at the start of the first treatment was 55.0 years (range 40–72 years). Patients were divided into two groups based on the presence of comorbidities (Group 1: EC and MS, Group 2: EC alone). We selected all patients with International Federation of Gynecology and Obstetrics (FIGO) stages I, II, III, and IV according to the 2009 version of the FIGO staging system. Overall survival (OS) was defined as the time from the date of surgery to the date of the last follow-up examination or death. The follow-up deadline was December 2013. The range of the follow-up period was 2–144 months. None of the patients had any other malignant tumors and none used oral contraceptives (OC) or hormone replacement therapy (HRT) for at least a year before admission. They had all undergone laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, or retroperitoneal lymphadenectomy therapy. Adjuvant treatment was recommended after surgery depending on surgical findings and disease stage. Self-reported information on height and weight at different ages was collected. Waist circumference (2 cm above the umbilicus) was also measured. A history of medical conditions, including type 2 diabetes, clinical obesity, drug-treated hypertension, and drug-treated or clinical diagnosis of hyperlipidemia, was self-reported and included age at first diagnosis. Patients with diseases with an onset <1 year before hospital admission were not considered for this study. Body mass index (BMI) was calculated according to Quetelet’s index (weight/height2, kg/m2). The values of CA19-9 and CA125 were pre-surgery values.

MS was defined as a combination of the presence of the following: (1) type 2 diabetes (2) history of drug-treated hypertension (as an alternative indicator of elevated blood pressure), (3) history of a clinical diagnosis of or drug-treated hyperlipidemia [as a proxy indicator of increased low-density lipoprotein/reduced high-density lipoprotein (HDL) cholesterol levels], and (4) (abdominal) obesity. Using different proposed definitions of MS, (abdominal) obesity was defined as a waist circumference ≥80 cm or BMI ≥28 kg/m2 for women who did not provide their waist circumference. A summary indicator of MS was also defined according to the International Diabetes Federation criteria, and was adapted to our data, as the simultaneous presence of (abdominal) obesity plus at least two other components of MS [8].

Results

We first analyzed the correlation between MS and OS in endometrial carcinoma using the Kaplan–Meier method and compared the survival curves using the log-rank test. Of the 385 patients, 129 patients with endometrial adenocarcinoma also had MS, while 256 patients had endometrial adenocarcinoma but did not have MS. The OS rate among patients with MS was 74.42 % (96/129), and the OS rate among patients without MS was 87.89 % (225/256). A univariate analysis demonstrated that the OS rate among the patients with endometrial adenocarcinoma and MS was significantly worse than that among the patients without MS for all 385 samples (P = 0.001) (Fig. 1). Furthermore, multivariate Cox proportional hazards regression analyses showed that stage (P = 0.001), lymphatic metastasis (P = 0.021), and MS (P = 0.049) were independent prognostic factors for endometrial adenocarcinoma (Table 1). These results suggest that MS is a prognostic factor for endometrial adenocarcinoma patients.

Fig. 1
figure 1

Univariate analyses of factors that were associated with OS in patients with and without MS according to the Kaplan–Meier method and the log-rank test

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Table 1 Multivariate analyses of the factors that were associated with OS in the patients with endometrial adenocarcinoma according to a Cox proportional hazard regression model performed in a stepwise manner (forward: condition, entry α = 0.05, stay α = 0.1)
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To investigate the significance of MS in endometrial adenocarcinoma, we next compared the relationship between MS and clinicopathological features. Statistical analyses demonstrated that MS was closely related to the FIGO stage (P = 0.021), grade (P = 0.022), vascular invasion (P = 0.044), tumor size (P = 0.035), and lymphatic metastasis (P = 0.014) but not with age at the start of the first treatment (Table 2). These results suggest that MS may be associated with multiple clinicopathological features in endometrial adenocarcinoma.

Table 2 Relationship between MS and clinicopathological features of patients with endometrial adenocarcinoma
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Finally, in the univariate analysis of the OS rate among the 129 patients with endometrial adenocarcinoma and MS, higher stage (P = 0.001), vascular invasion (P = 0.049), tumor size >2 cm (P = 0.028), lymphatic metastasis (P = 0.002), and CA19-9 >37 U/ml (P = 0.002) all showed significantly low P values for OS (Table 3). These results suggest that MS in particular may negatively affect the prognosis of human endometrial adenocarcinoma to a greater extent than the stage, vascular invasion status, tumor size, lymph node status, and CA19-9 value.

Table 3 Univariate analysis of the OS rate among the patients with endometrial adenocarcinoma and MS
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Discussion

On the basis of differences in histology and clinical outcomes, ECs have long been divided into two types [9–11]. Type I tumors, comprise the large majority of ECs, are mostly endometrial adenocarcinomas, are associated with unopposed estrogen stimulation, and are often preceded by endometrial hyperplasia. Type II tumors, are predominantly serous carcinomas, are commonly described as estrogen-independent, arise in atrophic endometrium, and are derived from intraepithelial carcinoma, a precancerous lesion. Many studies have shown that multiple factors characterize the initiation, development, and poor prognosis of endometrial cancers [12]. Thus, it is urgent to find new prognostic factors that are involved in EC to improve the survival of patients.

MS is a cluster of risk factors including obesity, hypertension, insulin resistance, and dyslipidemias for cardiovascular disease and type 2 diabetes and constitutes a growing problem worldwide [13].

Individual components of MS have previously been linked to the development of various types of cancer. Evidence has begun to emerge that links MS with certain types of cancer [14, 15], but data are still sparse [16, 17]. Cust et al. [18] recently reported on MS and the risk of EC in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition. MS was found to be directly associated with endometrial cancer, and the risk increased with the number of MS factors present. A large prospective study also showed direct associations between MS, as well as between individual MS factors (except for cholesterol), and the risk of endometrial carcinoma. This study offers further evidence that the influence of MS with respect to the risk of EC extends beyond the risk conferred by obesity alone, particularly in women with a high BMI [19]. Our results confirmed that MS may be incorporated into the screening of individuals for endometrial adenocarcinoma [20]. However, the prognostic value of MS in human endometrial adenocarcinoma remains unknown.

It is generally accepted that the factors that affect the prognosis of EC include age, grade, vascular and myometrial invasion, tumor size, and lymph node status. In the current study, we attempted to determine the association between MS and the prognosis of endometrial adenocarcinoma. A univariate analysis demonstrated that MS significantly affected the prognosis of endometrial adenocarcinoma. Furthermore, through an analysis of the correlation between different variables and OS, we found that MS was an independent prognostic factor for endometrial adenocarcinoma. This result was consistent with the findings of Bjorge T., who examined the association between MS and the risk of fatal uterine corpus cancer in a large prospective cohort study. Approximately 290,000 women from Austria, Norway, and Sweden were enrolled during the years 1974–2005. They found an increased risk of fatal uterine corpus cancer in women with MS [relative risk = 1.56, 95 % confidence interval (CI): 1.32, 1.84] [19].

The mechanisms that link MS and endometrial adenocarcinoma are not fully understood. Mechanisms that may contribute to the adverse impact of MS and its components on the risk of endometrial carcinoma include insulin resistance [21–24], a proinflammatory milieu that favors the development of neoplastic transformation [24], and mechanisms related to the metabolism of sex steroids [25].

To explore the manner in which MS affects the prognosis of endometrial carcinoma, we compared the relationship between MS and the clinicopathological features of patients with endometrial adenocarcinoma. We found that the presence of the following factors was significant when they were individually evaluated in patients with endometrial adenocarcinoma and MS: higher stages, low differentiation, vascular invasion, tumor size >2 cm, and lymphatic metastasis. MS may be an important etiologic factor in the development and progression of endometrial adenocarcinoma, as well as in overall cancer mortality. But the causation between MS and these clinicopathological features is open to speculation.

In clinical practice, we sometimes encounter patients with endometrial adenocarcinoma and MS whose prognosis is rather favorable. To determine what factors may predict a favorable outcome, we analyzed 8 clinicopathological prognostic factors in patients with endometrial adenocarcinoma and MS. Most of the factors that were examined in this analysis were shown to have a significant effect on the prognosis of endometrial adenocarcinoma. However, we initially conjectured that MS may be such a critical prognostic factor that none of the other clinicopathological factors would be significant in our case analysis. In fact, according to the univariate analysis of the clinicopathological prognostic factors in endometrial adenocarcinoma cases with MS, higher stage, vascular invasion, tumor size >2 cm, lymphatic metastasis, and CA19-9 values >37 U/ml were the factors that showed significantly low P values for OS. Therefore, the absence of these factors suggests a relatively favorable prognosis in patients with endometrial adenocarcinoma and MS.

However, the current study is limited because of its retrospective nature and because of the all Chinese patient population. In addition, further work, such as a prospective study and an investigation of the associated molecular mechanisms, should be performed to clarify issues that were not explored in this study. Moreover, we should treat patients in a different way based on the presence of MS.

In conclusion, we clarified that MS is associated with FIGO stage, grade, vascular invasion, tumor size, and lymphatic metastasis. We also confirmed that MS leads to a poor outcome in patients with endometrial adenocarcinoma. Moreover, MS is an independent prognostic factor in patients with endometrial adenocarcinoma. Thus, MS potentially offers clinical value in the personal treatment of patients with endometrial adenocarcinoma.