3. ENDOMETRIAL CANCER
3.5. PROGNOSTIC FACTORS
A prognostic factor is a situation, condition, or a characteristic of a patient, that can be used to estimate the likely outcome of an illness (i.e., chance of recovery from a disease or the chance of the disease recurring).
The prognosis of EC depends on several factors, mainly on the FIGO stage, differentiation grade, histological type, lymphovascular space invasion, tumor size and age.
3.5.1. FIGO stage
The 2009 International Federation of Gynecology and Obstetrics (FIGO) staging is the most widely used classification. It takes into account the extent of the tumor, and whether the cancer has spread to lymph nodes or distant sites. This staging system classifies EC cases into four stages 119, which are described and pictured in Figure 6. Overall 5-year survival rates significantly decrease in the higher stages 120.
3.5.2. Differentiation grade
While all NEECs are considered high grade by definition, EEC cases present different histological grades (Figure 7). The most widely used system for grading is the FIGO system, which is primarily based on the architectural grade of the tumor, and secondarily modified based on the nuclear grade.
• The architectural grade is based on three grades according to the proportion of solid areas of tumor cells (Table 5) 97,121.
• The nuclear grade is based on the presence of significant nuclear atypia. This is characterized by large, pleomorphic nuclei, irregular chromatin clumping, large irregular nucleoli, and loss of cellular polarity. The tumor is upgraded from grade 1 to 2, or from grade 2 to 3 in cases showing striking nuclear atypia 76,122. Nuclear grading takes precedence over architectural grading in mixed types, which are considered grade 3 in cases where ≥ 10% is serous, clear cell or undifferentiated histology.
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Figure 6. FIGO staging of EC. Adapted from Pecorelli et al. 2009 119 and Lewin et al. 2010 120. Image adapted from http://teachmeobgyn.com/.
However, FIGO grading of EEC tumors requires evaluation of histological features that can be difficult to assess and reproduce. Reported interobserver agreement varies between 63%
and 81% 123, being the reproducibility associated with the identification of grade 2 tumors particularly low. Moreover, the outcome of patients with grade 1 and 2 has been reported to be very similar (overall 5-year survival rates of 97% and 94% respectively), while grade 3 tumors are associated with a lower 5-year survival rate of 76% 123. Consequently, several
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studies have suggested several modifications and the conversion of this 3-tiered grading system into a binary system 124,125. Grade 3 versus combined grades 1 and 2 still proves to be of independent prognostic significance 123,126 with higher reproducibility 126,127.
Table 5. FIGO histological grades. Adapted from Oncoguía SEGO 2016 97.
3.5.3. Histological type
ECs should be typed according to the 2014 WHO classification 128, since the diverse histological types present a very different overall prognosis.
The type I or EEC adenocarcinoma is characterized by the endometrioid histology, a gland-forming growth pattern of varying differentiation grade (Figure 7) 129. Several subtypes or variants have been described by the WHO: adenocarcinoma with squamous differentiation (the most common variant), villoglandular carcinoma, and secretory carcinoma. Mucinous adenocarcinomas can be also included as type I.
The most frequent NEEC carcinomas are serous and clear cell carcinomas 130 (Figure 7).
These histological types are highly invasive and aggressive, associated with a poor prognosis. Other subtypes are the neuroendocrine tumors, the undifferentiated carcinomas and the dedifferentiated carcinomas. Mixed adenocarcinomas are also common. These are a mixture of two or more different histological types. At least one of the subtypes must be a type II tumor and the minor type must account for at least 5% of the total tumor volume. Mixed adenocarcinomas with a type II tumor fraction of 25% or more have a poor prognosis. In addition, carcinosarcomas (also called malignant mixed Müllerian tumors) are mixed epithelial and mesenchymal tumors and they are treated in the same way as aggressive type II carcinomas 128.
3.5.4. Others
Other independent prognostic factors, related to the tumor spread and reflected in the FIGO staging, are myometrial invasion, cervical invasion, and lymph node metastasis. Deep myometrial invasion is associated with increased lymphovascular invasion, lymph node affectation and a decrease in the 5-year survival 131. In addition, patients without lymph node
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metastasis have a 5 year disease-free survival of 90%, that goes down to 60-70% in patients with pelvic lymph node metastasis and to 30-40% in those with para-aortic lymph node metastasis 69,132. Another important prognostic factor is the lymphovascular space invasion. The presence of tumor cells within vascular spaces is considered an early step in the metastatic process even for patients with tumors that seem to be confined to the uterus, and a strong predictor of nodal metastasis, recurrence and cancer-specific death 133,134. In addition, the age of the patient at the time of diagnosis is one the most widely reported prognostic factors 135. Advanced age negatively affects survival in EC. Younger women tend to have better-differentiated lesions, while NEEC with worse prognosis typically affects older women.
Figure 7. Histology of three common types of epithelial EC. Adapted from Murali et al. 2014 84.
3.5.5. Risk stratification systems
Risk stratification systems combine prognostic factors to define groups of patients with similar outcomes (low, intermediate, or high-risk of recurrence). These stratification systems are used worldwide to determine the most appropriate treatment for each group. Although the core variables of the different risk stratification systems are very similar, the combination of these variables changes. Results of a study comparing the five major risk stratification
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systems suggested that the European Society for Medical Oncology (ESMO) modified system was the most accurate in the prediction of lymph node status and survival 136. In 2016, a consensus between ESMO, the European Society for Radiotherapy & Oncology (ESTRO) and the European Society of Gynaecological Oncology (ESGO) introduced a few changes in this classification 33, which is detailed in Table 6. However, none of these systems show high accuracy in stratifying the risk of recurrence or nodal metastasis, particularly in patients with early-stage EC. It has been suggested that the incorporation of molecular and genetic characteristics would be useful to improve the accuracy of these risk stratification systems 84. According to the TCGA classification (described in section 3.3.2, page 16), EC cases showing POLE mutations have an excellent prognosis, and patients could be spared unnecessary adjuvant treatment. Other novel candidate prognostic markers, such as stathmin or L1 cell adhesion molecule (L1CAM) have been identified.
Stathmin has been described as a predictive biomarker for resistance to paclitaxel 137. L1CAM has been reported to be a strong predictor of poor outcome in early-stage and advanced-stage EECs, but not NEECs, in several large multicenter studies 138,139. L1CAM expression in EECs cancers indicates the need for adjuvant treatment.