Lymph node metastasis is the most common metastatic model of gastric and colon cancers. With the development of surgery in the management of these cancers, laparoscopic surgery, by virtue of its short-term minimally invasive advantages and long-term safety, has been confirmed as an early alternative for gastric and colon cancers by several clinical randomized controlled trials and meta-analyses [9, 10]. However, in the case of advanced tumors, the use of laparoscopy is still controversial [11]. In addition, MAGIC, FNCLCC, and FFCD studies 12,13 report that preoperative chemotherapy can not only play a role in reducing the period, but also prolong survival. Therefore, preoperative evaluation of lymph node metastasis is crucial in improving the surgical outcomes and reducing the extent of damage caused to patients.
Currently, clinical laparoscopy and pathological biopsy are the gold standards for treatment, however, the degree of trauma caused by these procedures render them less desirable. Therefore, non-invasive diagnosis models have a good scope for further exploration. CT and MRI are the most common techniques used to predict lymph node metastases. However, the sensitivity of CT and MRI was only 50% in the determination of metastasis of lymph nodes that were 5 mm or smaller [5]. While Pet-CT can assess the involvement of lymph nodes and distant organs in tumor patients [14], its high cost outweighs its popularity. Therefore, there is an urgent need to develop a more effective method for the preoperative diagnosis of lymph node metastasis in patients with gastric and colon cancers.
Preoperative serum markers are commonly used in predicting lymph node metastasis of gastrointestinal tumors. In the current treatment scenario, serum tumor markers are most commonly used, but they have not been widely adopted owing to their low sensitivity and specificity. Some researchers [7] use a combination of several markers to improve the sensitivity of diagnoses (96.3%) and specificities (69.8%), however, there are only few such clinical studies that are relevant. In addition, increasing attention has been paid to the relationship between a tumor and the body’s inflammatory response [15].Chronic inflammatory response induces lymphocyte to infiltrate into the tumor, and consequently, into the surrounding tissues, thus increasing the chances of metastases. Studies have shown that PLR and NLR contribute to the diagnoses and prognoses of malignant tumors [16]. In our study, CA125 (OR = 2.660, P = 0.032) and PLR (OR = 3.896, P = 0.008) were independent risk factors for lymph node metastasis in patients with colon cancer, but not for gastric cancer. Apparently, these variables could not be used exclusively in predicting lymph node metastasis in all patients.
With the development and use of immunohistochemistry, it is possible to predict the metastasis of lymph node tumors more accurately. Li found that the metastasis rate was higher in patients with T4 stage gastric cancer, with a lower degree of differentiation, and Borrmann type Ⅲ + Ⅳ [17]. In addition, a study [18] found that the gross type, pathological grade, and invasion depth were risk factors for lymph node metastasis in colon cancer. These clinicopathological features can be confirmed by preoperative endoscopic examinations. Therefore, we attempted to analyze the relationship between clinicopathologic features and lymph node metastasis in gastric and colon cancers.
Scartozzi [19] studied 734 patients with gastric cancer and showed that a positive rate of nerve infiltration (NI) and vascular infiltration (VI) was 26%, which is associated with lymph node metastasis. In our study, the values for NI and VI were 35.43% and 39.76%, respectively. We used HE and S100, D2-40, and CD31 protein immunohistochemical staining to improve the accuracy of NI and VI. The effect of VI on gastric cancer and colon cancer has been studied [20, 21]. But the effect of NI presented different sounds. Although the relationship between NI and prognosis has been evaluated by meta-analysis of colon cancer studies [22],this relationship remains controversial. A meta-analysis [23] included a total of 30590 patients with gastric cancer in 24 studies and found that the NI positive rate was 6.8–75.6%, with an average positive rate of 40.9%. The difference in NI positive rate in each study is large, which is mainly due to the difference in the definition of NI in each study. Currently, there is still no unified standard for the definition of NI. Tanaka reports [24] that NI has a prognostic value in patients with a T2 grade gastric tumor, but not in patients with grade T3/4 tumor. Another study [25]reports that NI has no statistical significance in cardiac cancers. Our study too, found that NI was not an independent risk factor for gastric cancer.
Ren [26] reports that tumor invasion depth is an independent risk factor for lymph node metastasis in gastric cancers. A study by Bravo[27] indicates that the risk of lymph node metastasis by tumor infiltration into the submucosa is 3.103 times higher than that of the tumor confined to the mucosa. We obtained similar results in our study, with the only difference being the type of cancer evaluated. These findings can be attributed to the abundant lymphatic vascular network in the gastric submucosa and the higher concentration of lymphatic reflux channels in the serosal layer. In addition, it is seen in Kodera’s study[28] that the lymph node metastasis rate for patients with well-differentiated gastric cancer is 6.9%, whereas this value for patients with poorly-differentiated gastric cancer is 13.0%. This difference between groups is statistically significant (P < 0.05). The relationship between the degree of differentiation and lymph node metastasis in colon cancer is still unclear, which is consistent with our study. There are few studies exploring the relationship between pathological types and lymph node metastasis. Wang [29] found no correlation between pathological types and lymph node metastasis in the study of 103 cases of early gastric cancer. In our research, we found that the pathological nature of the tumor was an independent risk factor for lymph node metastasis in gastric and colon cancer patients (P = 0.021), however, the subdivision into gastric and colon cancer patients was not statistically significant. It is considered that the number of early cancer cases in our study is relatively small, and the determination of the type of pathology is mostly dependent on the subjective judgment of endoscopists and surgeons. In some cases, the pathological type is inconsistent with that observed after postoperative pathology, which may be attributed to the experience of clinicians and their judgment of intraoperative lesions.
Based on these differences, we attempted to identify independent risk factors for lymph node metastasis in patients with gastric and colon cancers. In order to increase the accuracy of predicting lymph node metastasis preoperatively, multivariate logistic regression analyses were performed by combining serum characteristics and clinicopathological characteristics. These parameters have rarely been considered in previous studies. We determined that CA125, hemoglobin, albumin, tumor size, pathological type, nerve invasion, and vascular invasion were independent risk factors for lymph node metastasis in gastric and colon cancers. Finally, the preoperative scores, including the above independent risk factors was established. Subsequently, ROC analyses were performed to verify the diagnostic accuracy of the preoperative scores. As expected, the AUC values of Score in lymph node metastasis of gastric and colon cancers were 0.923 and 0.870, respectively. Its sensitivity was 92.2%, specificity was 78.9% and 60.2%, respectively, thereby significantly improving the accuracy. Therefore, we believe that the preoperative scores has potential diagnostic value for lymph node metastasis in gastric and colon cancers.
We used the ROC curve to further determine the cutoff value of Score for lymph node metastasis in gastric and colon cancers, and established it to be 287. Accordingly, patients were divided into a high Score group (≥ 287) and a low Score group (< 287). Further studies revealed that Score was firmly related to several tumor characteristics. A higher Score was associated with a larger tumor size, a certain pathological type, increased differentiation, a deeper degree of invasion, and a more severe lymph node metastasis. Therefore, we believe that the cutoff value of 287 for Score is ideal for the preoperative prediction of lymph node metastasis in gastric and colon cancers. This preoperative scores includes serum indicators and clinicopathological features to make it more comprehensive and accurate. In addition, all involved indicators can be confirmed by preoperative blood tests and preoperative endoscopic examination, which are convenient, inexpensive, and suitable for all patients. Combined with clinical practicality and accuracy, the preoperative scores can be used as a reliable indicator for the development of preoperative surgical plans and comprehensive treatment regimens.
Our study still has some limitations that should not be neglected. Since this was a retrospective study, tumor-characteristic parameters such as invasion depth, lymphatic invasion, and pathological type were obtained postoperatively. These parameters can be obtained preoperatively by endoscopy, however, the results may be inaccurate. Furthermore, because of the incomplete data and a partial loss of our follow-up data, we did not add the analysis of prognosis in our study. Moreover, all patients analyzed in our study were from a single hospital. Therefore, our findings still require validation using extensive prospective multicenter studies. Most importantly, the sensitivity of our model was not sufficiently high to diagnose lymph node metastasis. Therefore, it can only be used as an auxiliary tool.