Compared with FIGO 2009, FIGO 2018 is related to more prognostic factors
The total number of early surgically treated cervical cancer patients was 5544, of which 64 (1.15%) were SCNEC. The mean age of SCNEC patients was 44.48 ± 10.63 years (median, 43.50 years; range, 22–76 years). The total 5-year OS was 67.9%. The main symptom was abnormal vaginal bleeding (71.9%), and other complaints included abnormal physical examination (14.1%) and abnormal vaginal discharge (10.9%). Approximately half of the patients who underwent an HPV test were HPV18-positive (56.7%); only 3.3% were HPV16-positive, and 33.3% were not classified. The remaining 6.7% patients were HPV-negative. These results indicated that more than 90% of SCNEC patients were HPV-positive, and most were HPV18-positive. However, before surgery, the rate of pathological diagnosis for SCNEC was only 48.3% because some SCNEC cases were mixed type.
Other clinicopathological parameters are detailed in Supplementary Table 1, and were compared between the two staging systems. Because FIGO 2009 is a clinical staging system, it is not accurate in determining vaginal involvement, parametrial infiltration, and tumor size. Therefore, it was observed that a small number of stage I patients had pathological indications of vaginal involvement, and a small number of stage IIA patients had parametrial infiltration, while some tumor sizes did not match the stage standard. However, the FIGO 2009 staging system is also related to LNM (P=0.023), parametrial infiltration (P<0.001) and lower uterine involvement (P=0.014), which may be related to prognosis [12, 13] suggesting that the FIGO 2009 staging system also has a role in predicting prognosis. Compared with the old system, FIGO 2018 staging based on pathological staging is more accurate regarding pathological parameters such as vaginal involvement, parametrial involvement, tumor size, and LNM, and is related to more prognostic factors (two medium risk factors in Sedlis standard: tumor invasion depth and LVSI). Therefore, it can be theoretically inferred that the FIGO 2018 staging system is more accurate for prognosis.
FIGO stage (2009/2018) and the degree of lymph node metastasis were significantly related to patient prognosis
There was no difference in the 5-year OS between IB1 and IB2 (78.2% vs 80%, P=0.723), as well as between IIA1 and IIA2 (20.0% vs 25.0%, P=0.463) of FIGO 2009. The same was true in stage I and stage II groups of FIGO 2018 (Table 1). We conducted univariate analysis by not subdividing substage; the results are shown in Table 2 together with other parameters. Five variables with P-values of less than 0.01 (involvement of the lower uterine segment, LNM, parametrial involvement, and FIGO stage (2009 and 2018)) and another four clinically important variables (depth of tumor invasion, LVSI, tumor size, and surgical margin) were included in the multivariate Cox regression analysis. The results showed that only FIGO 2009 stage (P<0.001) had statistical significance, and the other variables with P<0.10 were LNM (P=0.058) and FIGO 2018 (P=0.062). This result was consistent with most other studies, where stage (FIGO 2009) was the most important prognostic factor .
It has been reported that the ratio of LNM is more helpful than the presence of LNM in determining prognosis . Therefore, we calculated the rate of LNM; the mean was 0.201 ± 0.156. According to the receiver operating characteristic curve (ROC), we confirmed that rate of LNM was more effective than the presence LNM to predict survival (AUC 0.631 vs 0.604), and calculated the optimal threshold value of 0.20 (Fig 1A). According to this threshold value, patients were divided into different degrees of LNM: non LNM group (ratio = 0), low LNM group (ratio ≤0.20), and high LNM group (ratio >0.20). After the status of LNM was replaced by the degree of LNM, multivariate Cox regression analysis showed that FIGO 2009 stage (HR 1.85, 95%CI 1.34–2.56, P<0.001), FIGO 2018 stage (HR 1.63, 95%CI 0.92–2.87, P=0.015) and the degree of LNM (HR 2.52, 95%CI 1.36–4.67, P=0.003) were independent prognostic factors.
The optimized staging system (FIGO 2018) can predict the prognosis of patients more accurately
Furthermore, we compared the prognosis of the two staging systems. The 5-year OS of patients at stage I and II (FIGO 2009) was 78.5% and 22.2%, respectively (Fig 1B). There was also no difference in 5-year OS between FIGO 2018 stage I and II (P=0.761), and the 5-year OS for FIGO 2018 stage I/II, IIIC1, and IIIC2 was 74.1%, 60.2%, and 0%, respectively (P=0.003; Fig 1C). However, in FIGO 2018 staging, as long as there is LNM, it will be classified as stage IIIC, which ignores an important prognostic factor, tumor local invasion . Therefore, we further divided stage IIIC into IIICT1, IIICT2, and IIICT3 according to pathological findings (T1, limited to the cervix and vagina, and no parametrial infiltration; T2, parametrial involvement; and T3, pelvic and abdominal cavity involvement). The 5-year OS of IIICT1, IIICT2, and IIICT3 was 83.3%, 30.0%, and 0%, respectively (P=0.010; Fig 1D). Another interesting finding was that when IIIC was divided into IIICN1a, IIICN1b, and IIICN1c according to the degree and location of LNM (N1a, limited to the pelvic cavity with a metastasis rate ≤0.20; N1b, limited to the pelvic cavity with a metastasis rate >0.20; N1c, metastasis to the para-aortic LNs), the 5-year OS was 80.0%, 26.7%, and 0%, respectively (P=0.016; Fig1E).
Taken together, the prognosis of stage II (FIGO 2009) was underestimated, and stage IIIC (FIGO 2018) was ambiguous. Therefore, the combination of the FIGO 2018 staging system and tumor local invasion factors can more individualize and accurately evaluate the prognosis of SCNEC patients. It is also a reasonable method to combine the FIGO 2018 staging system with the factors of LNM for SCNEC.