According to the National Cancer Statistics, endometrial cancer is the most prevalent gynecologic cancer in the western world and the fourth most common malignancy in women worldwide [1]. Endometrial cancer is a surgically staged disease. Fortunately the majority of patients are diagnosed at an early stage. This provides the opportunity to cure a great amount of these women. However, to find the right treatment for every individual patient on one side and to prevent overtreatment on the other requires reliable factors that help us to predict prognosis and course of disease.

1 Classic Risk Factors

At present, the following factors are clinically used to assess the individual patient’ prognosis and, based upon the risk assessment, further therapeutic decisions and treatment regimens are initiated.

1.1 FIGO Stage

The aim of staging cancers by assessing spread and size of disease is to establish prognosis. Surgical stage is the most important prognostic factor for survival in endometrial cancer. Since the revision of the FIGO classification in 2009 parametrial infiltration is also incorporated in the staging. Almost 71% of patients with endometrial cancer are diagnosed in stage I. Patients with early-stage disease show a 5-year-survival rate of at least 85.4% depending on histologic subtype. This declines to 20.1% in stage IV [2].

1.2 Tumor Grade

Poor tumor differentiation is associated with decreased survival. For patients with grade 2 and grade 3 cancers survival is significantly reduced compared to grade 1 tumors (hazard ratio 1.4 and 2.8 respectively) [2], as detailed in Table. 14.1. Tumor grade is also related with deeper myometrial invasion and increased likelihood of lymph node metastasis.

Table 14.1 5-year survival rate depending on grade [2]
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1.3 Histologic Subtype

According to histologic differentiation , various subtypes such as endometrioid, mucinous, squamous, serous-papillary, or clear-cell carcinoma can be distinguished.

Depending on the histologic subtype, the 5-year-survival rate differs significantly. It is substantially lower for patients with serous carcinomas with 52.6% compared to those with endometrioid subtypes with a 83.2% 5-year-survival rate [2].

Bokhman further classified endometrial carcinomas on the basis of two distinct pathologic subtypes: Type-I tumors are usually of endometrioid subtype, arise from endometrial hyperplasia as precursor lesions, are estrogen-dependent and are associated with a favorable prognosis. Type-II cancers are of more aggressive behavior caused by higher tumor grade, poor differentiation, deeper myometrial infiltration and therefore prognosis is poor [3].

1.4 Myometrial Infiltration

Myometrial invasion of more than 50% of the endometrium reduces survival in stage I cancers significantly (HR 2.0). The extend of myometrial invasion is a significant prognostic factor regarding recurrent disease in early-stage endometrial cancer [4].

1.5 Lymphatic Space Involvement (LVSI)

Presence of malignant cells in the lymphatic space crucially influences survival due to increased risk of pelvic and paraaortic lymph node metastasis. Particularly for patients in early stage the detection of LVSI is an important risk factor. It results in a more than twofold increase in risk of recurrent disease [5]. Especially in early-stage endometrial cancer a single institutional study confirmed that lymphatic space involvement is an independent prognostic factor for poor recurrence-free and overall survival (HR, 2.8 for both) [6]. In an intraoperative risk assessment for surgical management of endometrial cancer all patients except for those in the low-risk group underwent lymphonodectomy (LNE) . In multivariate analysis LNE did not sustain as a significant factor for survival [7].

1.6 Age

Generally, elderly women have an adverse outcome and a reduced disease-specific 5-year survival compared to younger women. Incidence of endometrial cancer increases with age . The mean age of manifestation is 61 years [8]. About 90% of cases occur after the age of 50. Incidence is highest between 75 and 80 years with around 90 cases per 100,000 in western countries [9]. Age at diagnosis remains an independent prognostic factor. According to a SEER database analysis, women older than 40 years of age are more likely to present with more advanced stage of disease, higher tumor grades and histologically more aggressive tumors [10]. Additionally age is associated with recurrent disease in early stage.

1.7 Race

The lifetime risk of developing endometrial cancer among all women is lowest for Native Americans. It shows increasing incidence in Asian Pacific Islanders, Hispanics, African-Americans, and is highest in US white population [11]. Nevertheless, the likelihood of dying of endometrial cancer is doubled in the subpopulation of African-American women. Although this subgroup showed a 12% decrease in disease rate, the death rate among these women had an 86% increase. African-American women seem to be more likely to present with type-II tumors, displaying more aggressive subtypes and higher tumor grades [12]. On the basis of molecular analysis it was revealed that African-American women more often show tumors with p53 mutations which are associated with poorer prognosis [13].

2 Molecular Risk Factors

In the last decade our knowledge about endometrial cancer has been substantially expanded by the identification of an increasing number of molecules that influence tumor growth and disease spreading . It is desirable to improve the understanding of molecular changes within malignomas to be able to identify patients with a higher risk at an early stage of disease to tailor management after primary surgery.

2.1 Hormone Receptors

The identification of estrogen (ER) and progesterone receptors (PR) as independent prognostic factors on recurrence-free survival in early-stage endometrial cancer were among the first molecular markers evaluated more than three decades ago. Presence of both of these steroid molecules improves disease-free survival significantly especially in stages I and II [14]. They further serve as targets for hormonal therapy especially in young women with early-stage disease. Treatment with progestins for instance, presents an option in young women with the desire of fertility preservation.

2.2 TP53 Status

Mutation of the p53-tumor-suppressor gene is one of the most common genetic alterations found in type-II carcinomas. Mutation is found in 18.5–46% of endometrial carcinomas [15]. The p53 alterations are more frequently found in non-endometrioid histologic types, are associated with higher-grade tumors and do less likely express progesterone receptors. When p53 is mutated survival is significantly reduced [16]. In three out of four cases of precursor lesions (endometrial intraepithelial carcinoma, EIC) a loss of function heterozygosity for chromosome 17p (region of p53) can be detected indicating that alteration occurs early in carcinogenesis [17].

2.3 HER2/neu Status

HER2/neu is a transmembrane glycoprotein, which belongs to the human EGFR tyrosine kinase family. The overexpression that is caused by gene amplification of this molecule increases cell proliferation, differentiation, and cell survival [18]. Highest HER2 gene amplification rates have been identified in serous endometrial carcinomas [19]. In type-II endometrial carcinomas (of non-endometrial histology) HER2 expression was found in up to 40% of cases [18, 20].

2.4 PTEN Mutation

This tumor suppressor gene regulates the cell cycle arrest and thereby controls apoptosis. The loss-of-function PTEN mutation is among the most frequent genetic alterations in endometrial carcinomas and can be found in 40–83% of type-I cancers [21, 22]. PTEN mutation is an early event to occur during carcinogenesis and can also be present in precursor lesions like complex atypical endometrial hyperplasia [23, 24].

2.5 PI3Kinase Mutation

Phosphatidylinositol 3-kinase pathway is a downstream signal from receptor tyrosine kinases (RTK) that is frequently found activated in endometrial cancer. Mutated PI3Kinase and PI3K pathway aberrations are found in up to 36% and 80% of ECs, respectively [25, 26]. PTEN loss can be a potential activator of the pathway but also somatic mutations or fibroblast growth factor receptor mutations interfere with the RTK signaling [27]. Apart from diagnostic purpose PI3Kinase can also serve as a therapeutic target, as dual PI3Kinase/mTOR inhibitors are under clinical investigation [28].

2.6 Microsatellite Instability (MSI)

Microsatellite instability is caused by a failure of the DNA mismatch repair system leading to formation of novel microsatellite fragments, which are repetitive short DNA segments. Affected DNA mismatch repair genes, for instance, MLH1, MSH2, MSH6, and PMS2, are responsible for Lynch syndrome. This condition increases the risk of multiple malignancies, including endometrial cancer. Women carrying the disease have a 40–60% lifetime risk for developing endometrial cancer [29]. MSI positive tumors are more commonly found in white women and more frequently seen in early stages [30].

2.7 Somatic Copy Numbers (SCN)

Data from the Cancer Genome Atlas project on the analysis of endometrial cancers on a molecular level were obtained to further characterize the disease. When analyzing different histologic subtypes it was observed that endometrioid subtypes were similar on a molecular level, frequently displaying PTEN and KRAS mutations, seldom p53 mutations, and low somatic copy number alterations (SCNA) . Serous and other subtypes often showed p53 mutations and high SCNA. Tumors that had high CN molecularly resembled serous ovarian carcinomas and the clinical behavior and survival was much akin to that of serous ovarian cancer [31].

2.8 POLE Proofreading Mutation

Germline mutation in the exonuclease domain of DNA polymerase POLE predisposes to endometrial cancer . In POLE-mutated cancers polymerase proofreading is impaired leading to an increase of base substitution mutations by a defect in the correction of impaired bases. Sporadic POLE mutations are present in around 7% of EC [32]. POLE-mutant tumors were shown to have a lower risk of recurrent disease although there is a strong correlation with high-grade tumors. POLE proofreading mutation was shown to be of independent prognostic significance predicting favorable prognosis especially in grade 3 endometrial tumors [33].

2.9 HE4

Human epididymis protein (HE) 4 is a potential preoperative biomarker for endometrial cancer especially in early stage [34]. It was shown that high levels of HE4 correlated with aggressive biological behavior of endometrial cancer. Hence it was concluded that HE4 may be an independent prognostic predictor for poorly differentiated carcinomas [35]. Furthermore HE4 was preoperatively evaluated in combination with CA125 levels in early-stage endometrial carcinomas. HE4 was an independent prognostic marker for overall survival, (HR 2.4, p = 0.017). The combination of HE4 and CA125 even increased the hazard ratio on overall survival (HR 4.0, p = 0.023). Especially in the subgroup of endometrioid differentiated ECs HE4 was of significant prognostic value [36].

2.10 L1CAM (CD171)

L1CAM is a 200–220 kDA transmembrane glycoprotein that belongs to the Ig superfamily. It is expressed on the cell surface of different human carcinomas but also found in blood and ascites by its shed form, the soluble L1–32 [37, 38]. L1CAM was evaluated in endometrial carcinoma. In all detected cases of cancer, L1CAM was associated with a poor prognosis and adverse outcome [39]. In a large multicenter study L1CAM was evaluated in early-stage endometrioid uterine cancer. Usually this subgroup of patients has a favorable prognosis and very low recurrence rates. About 18% of patients were L1CAM positive and had a significantly reduced disease-free and overall survival with a hazard ratio of 15.8 and 13.6, respectively. L1CAM-negative patients had an excellent prognosis regardless of tumor grade, stage, or risk. However, as soon as L1CAM was present in malignant tissue, disease-free survival decreased significantly with increasing tumor grade, FIGO stage and in high risk patients (see Fig. 14.1) [40]. As a future perspective use of L1CAM as a target itself for antibody therapy seems to be another promising approach. A fully humanized anti-L1CAM antibody has already been successfully synthesized and tested [41].

Fig. 14.1
figure 1

Univariate disease-free survival analyses for FIGO stage , grading and risk assessment according to the L1CAM status [40]

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3 Additional Risk Factors

A variety of other prognostic parameters have been investigated but influence on survival remains controversial.

3.1 Tumor Size

Chattopadhyay et al. investigated tumor size in endometrioid-type stage-I cancers with a cut-off value of 3.75 cm as a prognostic factor. Tumor size proved to be the only independent significant factor for distant metastasis and disease specific survival in this subset of patients [42]. In a recently published study a 2 cm tumor diameter was used as a cut-off value. Tumors greater than 2 cm were significantly associated with pelvic nodal disease. Additionally the impact of location of uterine mass was assessed. Cases of high-grade endometrial carcinomas located in the lower uterine segment showed a significant correlation with pelvic and paraaortic nodal involvement [43].

3.2 DNA Ploidy

Malignant tissue often displays aneuploidy , which predisposes to a more aggressive histologic behavior and a poor prognosis. On evaluation of stage-I endometrioid uterine tumors ploidy proved to be a significantly independent marker for recurrence-free survival , with a hazard ratio of 4.5 (CI 1.3–15.3). In the subgroup analyses of patients regarded as low risk there was still a significant difference in recurrence-free survival in favor for patients with euploid tumors [44].

3.3 Positive Peritoneal Cytology

Since the revision of the FIGO classification in 2009, peritoneal cytology is no longer a stage-defining variable as it used to be in the 1988 classification. However, a large retrospective study of 14,704 patients with uterine stage-I cancer showed a significantly reduced disease-specific survival for patients with positive peritoneal cytology (PPC). The hazard ratio was 4.7 for patients with positive cytology compared to negative peritoneal cytology in stage IA over all subtypes. When stratified for histologic subtype, the HR even increased to 5.8 in endometrioid/mucinous subtype and was an independent significant prognostic factor for survival [45].

4 Summary

Given all these factors the question of practicability in routine diagnostics remains. The use of molecular factors beyond established classic risk factors can give us a better picture of the individual patient’s disease and can help us tailor treatments. This may help to reduce overtreatment in some cases while still permitting to identify high-risk patients at an early stage.

In conclusion, this range of novel molecules used as prognostic markers will provide new therapeutic opportunities for targeted therapies. Anti-HER2 therapies are already state of the art in breast cancer therapy and could potentially be used in EC in selected cases as an additional treatment option. Also anti-L1CAM antibodies are currently under testing. Clinical trials will be needed to evaluate these new approaches. In future, new options will hopefully enable physicians to perform a more “personalized” medicine and get away from the “one size fits all” model.