USC is a rare but deadly subtype of EC, we conducted a single center retrospective study of 51 patients and found that DM was the independent risk factor of both OS and PFS, the HR were 6.792 and 6.327, respectively.
In our data, about 60% patients were early stage, which differed from previous study[9]. Almost all patients’ complaints were vaginal bleeding or abnormal discharge, which may be the reason for the higher early stage rates of diagnosis.
Only 62.7%(32/51) patients had an accurate pathologic diagnosis before surgery, the rest of patients were mis-diagnosed with endometrioid adenocarcinoma by pre-operation biopsy. According to the famous ‘Mayo Criterion’, for patients of grade 1-2 stage I EC, with tumor size＜2cm and myometrial invasion depth＜1/2，regional lymphadanectomy could be avoided[10]. But for early stage USC, lymphadanectomy is debatable. In our study, Cox regression showed that although the number of lymph nodes removed was not an independent factor, patients with more lymph nodes resected had a better PFS. As for OS(Figure 2), K-M analysis showed patients without lymph node metastasis had a significantly better prognosis, and the OS of patients whose lymph nodes were not removed was poorer, patients with lymph nodes metastasis had the pooerest end. Li’s study enrolled 2853 patients registrated in SEER, the result suggested that patients with ≥12 pelvic lymph nodes (PLNs) removed had significantly better OS than those without (both P < 0.001)[11]. Our results showed the number of lymph nodes removed was not associated with prognosis, we speculated that the small sample size was the reason.
Hence, we think systemic lymph node resection may be recommended to USC patients. Accordingly, the accuracy of pathologic diagnosis before operation was important, cause it directly impacted the decision to ressect lymph nodes or not. If we mis-diagnosed an early stage USC as an endometrioid adenocarcinoma, we may make a wrong surgical decision.
DM has reached epidemic preportions worldwidely, its rate shockingly doubled over the last 3 decades[12]. From an gynecologic cancer prospective, the rise in DM impacts patients’ medical condition across their lifespan. A direct link between DM and type 1 EC is now well appreciated[13, 14]. Hyperglycemia promoted the development of type 1 endometrial cancer and led to poor prognosis. High blood glucose facilitated EC tumor growth by providing carbon sources for diverse metabolic pathways[13]. In vitro experiments exhibited, the proliferation,adhesion and chemo-resistance of tumor cells were promoted when cultured with high glucose condition[15-17]. There are significant differences in molecular phenotypes and hormone receptor expression between type 1 and type 2 EC, thus the prognostic risk factors of the two types may be different. So did DM affect USC patients’ survive time? The answer was positive. Our study revealed for the first time that DM was an independent risk factor for OS and PFS in USC patients. Shou did a retrospective analysis in 139 Chinese non-endometrioid adenocarcinoma patients(including 45 USC), he found that metabolic syndrome(MS), stage and age were independent risk factors for OS of USC patients[18]. MS was a group of diseases including DM, hypertension and hyperlipidemia, while our study was focus on DM only.
Surgery and radiochemotherapy are important in USC, but before or after these oncology treatments, we should pay more attention to the control of co-morbidities to improve outcomes. Metformin is commonly used to treat type 2 DM, it may benefit outcomes of EC in an indirect manner[19]. Perez found among postmenopausal women with EC, taking metformin could decrease overall mortality[20]. Sarfstein’s study showed that metformin decreased expressions of IGF pathway molecures via inhibition of IGF-IR promotor activities in USC cells, finally promoted cell apoptosis, attanuated cell migration and proliferation[21]. On the contrary, Lilia reported that merformin shortened lifespan of C.elegans and human primary cells when provided in late life[22]. But this research studied individuals with healthy metabolic status. As we know, the peak age of USC is later than type 1 EC, therefore, the use of metformin may require more careful selection. Future prospective trials are needed to explore its impact on USC.
Our present study also found that, contrary to previous findings, the prognosis of hypertensive patients seemed to be slightly better than that with normal blood pressure, although the difference was not statistically significant. By increasing the sample size, the differences may be weakened or enlarged.
Limitations of this study are as follows: 1. Single-center retrospective study with low level of evidence, 2. The sample size is small, but USC is a rare disease, and Gynecologic Cancer InterGroup(GCIG) appeals that it should be separately managed and studied[23], 3. For some patients, the follow-up time is less than 2 years, which may lead to bias.
The advantages of this study is that the operation quality is guaranteed in the famous gynecological tumor center in China. It is the first time that medical comorbidities have been found to influence the prognosis of USC, which will guide the treatment of these patients.