This paper builds a new predictive model and compares it with the predictive power of CT. The establishment of predictive models makes these risk factors more intuitive and more visible. The high AUC value of the nomogram and the good calibration performance shown by the calibration curve both demonstrate the better predictive power of the nomogram than the CT. These results give us greater certainty that predictive models can better inform clinicians about treatment decisions.
Our findings suggested that T stage, total bilirubin, Laurent classification, vascular invasion, blood sugar, tumor size, and γ-GT were independent risk factors for LNM. Mu et al.(23) constructed a predictive model for LNM based on clinical patient data and found that tumor size, vascular invasion, degree of differentiation, and invasion depth were considered high-risk factors for LNM through univariate and multivariate analysis. While the authors emphasize that vascular invasion plays a crucial role in the assessment of LNM as it accounts for a large proportion of the nomogram score, which is consistent with our findings. Previous studies have also reported that vascular invasion is one of the important steps in lymph node metastasis(24), which also explains the high risk of vascular invasion. Therefore, the inclusion of vascular infiltration in the model can greatly improve the prediction accuracy, making the model more consistent with the actual situation.
As a reliable classification method for gastric cancer, the Lauren classification has been used in clinical treatment guidelines, which categorize gastric cancer into intestinal type, diffuse type, and mixed type(25). In general, compared with the diffuse type, the intestinal type has a lower risk of LN metastasis and is more suitable for ER. The multivariate results of this article show that the diffuse type has a higher odd ratio, but it is not statistically significant. The mixed type not only has a higher risk of LN metastasis than the intestinal type but also has a significant statistical significance. Pyo et al.(26) included 5309 EGC patients in the study, of whom 495 (9.3%) had LN metastases. The positive rate of mixed type (15.4%) was significantly higher than that of intestinal type (7.2%) and diffuse type (10.6%). This may be because mixed tumors are commonly found in the upper third of the stomach, are larger, and are prone to submucosal infiltration. Therefore, in the assessment of LNM metastasis, more attention should be paid to mixed gastric cancer.
Moreover, T stage and tumor size have also been considered by many studies as risk factors for LN metastasis in EGC,(23, 27, 28). Poorer T stage and larger tumor size make it easier for lesions to invade the submucosa, resulting in a higher risk of LN metastasis. It is also the reason why the prediction model of this article is included in the T stage.
Laboratory examinations of patients with EGC were also considered, and TB and γ-GT were incorporated into the prediction model. In this article, patients with TB ≥ 7.85 µmol/L (OR = 0.526, 95%CI 0.339–0.816, P = 0.004) and patients with γ-GT ≥ 11.5 U/L (OR = 0.516, 95%CI 0.300-0.888, P = 0.017) had a lower probability of LN metastasis. To find out the relationship between TB and LNM, we found that serum bilirubin had anticancer activity through related experiments and clinical research(29–31). It has been reported that oxidative stress is associated with the development and prognosis of cancer(32). As an antioxidant, bilirubin is likely to prevent the development of cancer(33). which explained our research conclusion to a certain extent. Wei et al.(34) found that total bilirubin levels, as well as direct and indirect bilirubin, were significantly reduced in gastric cancer patients. Another study constructed a survival-related nomogram by including variables such as total bilirubin and albumin in 778 gastric cancer patients and found that patients with lower total bilirubin and albumin had a shorter five-year overall survival rate (P < 0.01)(35). As for γ-GT, according to a multivariate analysis of a clinical study(36), high levels of γ-GT (> 14U/L, HR = 1.004, 95%CI 1.002–1.007, P = 0.001) was associated with lower overall survival in advanced gastric cancer. This is inconsistent with our conclusions, most likely because of heterogeneity of data from different institute.
Finally, our results found that blood sugar was also a risk factor for LN metastasis in EGC patients. The study by Deng et al.(37) found that Glucose-derived AGEs (Advanced glycation end products) were highly expressed in tumor tissue and blood of GC patients. The depth of tumor invasion and lymph node metastasis were associated with AGEs. This also explains why hyperglycemic EGC patients have a higher risk of LN metastasis.
Of course, this study has certain limitations. First, this is a single-center retrospective study, and to improve the accuracy of the nomogram, we should validate it with more diverse populations. Second, this paper does not incorporate genetic information such as P53, HER-2, and molecular factors of the tumor microenvironment associated with LNM, which may make the nomogram more accurate.