Risk Factors for Metastasis to No.253 Lymph Node for Colorectal Cancer Patients

Background: No.253 lymph nodes metastasis is related to poor prognosis of colorectal cancer, while the role of No.253 lymph nodes dissection in colorectal cancer is still controversial. Methods: A total of 157 patients who were received laparoscopic radical resection of colorectal cancer with preservation of the left colon artery + D3 lymph node dissection (low ligation + high dissection) in our hospital were enrolled. No.253 lymph nodes of each patients were dissected and sent for examination. Clinicaopathological factors correlated with No.253 lymph nodes metastasis, including gender, age, tumor location, tumor size, length of tumor from the anus, whether lymphovascular invasion, whether perineural invasion, tumor markers CEA, CA125 and CA199, tumor T stage, whether it is distant metastasis, the total number of lymph nodes harvested, tumor type, and histologic grade were respectively analyzed. Results: A total of 2286 lymph nodes were sent for examination, of which 557 No.253 lymph nodes were sent for examination. Among them, 5 patients had a total of 27 No.253 lymph node metastases. Preoperative CA125 level (X 2 =4.736, p=0.030), whether perineural invasion (X 2 =8.086, p<0.01), whether lymphovascular invasion (X 2 = 7.053, p<0.01), tumor type (X 2 =21.019, p<0.01), histologic grade (X 2 =15.315, p<0.01) were signicantly correlated with positive No.253 lymph nodes metastasis. A multivariate logistic regression analysis showed that none of risk factor from above are independent risk factors for No.253 lymph node metastasis(P>0.05). Conclusion: Preoperative CA125 level, whether perineural invasion, whether lymphovascular invasion, tumor type, histologic grade were risk factors of the No.253 lymph nodes metastasis. Multivariate


Background
Colorectal cancer is one of the common malignant tumors, with the third highest incidence rate and the fourth highest mortality rate worldwide (1).According to data from the National Cancer Center of China, the incidence and mortality of colorectal cancer in our country are gradually increasing (2).Although in recent years, breakthroughs have been made in the treatment of colorectal cancer, radical surgery is still the rst choice for improving survival and quality of life of patients with resectable and resectable colorectal cancer after neoadjuvant therapy. In 1982, Heald et al. proposed total mesorectal excision (TME) for rectal cancer (3).In 2009, Hohenberger et al. proposed complete mesocolic excision (CME) to remove the tumor and perform regional lymph node dissection without destroying the integrity of the colonic membrane (4). Advances in surgical concepts and equipment have improved the surgical treatment of colorectal cancer, but there are still controversies about the scope of regional lymph node dissection during surgical operations.
According to the Japanese Classi cation of Colorectal Carcinoma, the lymph nodes at the root of the inferior mesenteric artery (IMA) are named No. 253 lymph nodes. The JSCCR guidelines recommend routine D3 lymph node dissection (including 253 groups of lymph nodes), and D2 dissection is only used for patients with T1 and some T2 stage colorectal cancer (5).The NCCN guidelines recommend routine low-position ligation and D2 dissection, and at least 12 lymph nodes are obtained during the operation for pathological evaluation. Unless suspected metastatic lymph nodes are found in preoperative imaging, extended dissection is not allowed (6).
Metastasis of No.253 lymph nodes is suggested to be related to poor prognosis of colorectal cancer, but the value of dissection still needs further evaluation and discussion (7)(8)(9). Selective lymph node dissection in 253 groups may be bene cial to the prognosis of some patients. Therefore, further analysis of the risk factors of No.253 lymph node metastasis has important reference value for the selection of surgical methods and the scope of dissection. At present, there are few studies on the risk factors of lymph node metastasis in group 253. Related studies have found that age, tumor size, T stage, degree of differentiation, and preoperative tumor marker levels are important factors affecting lymph node metastasis at the root of mesenteric vessel (10)(11)(12). However, these studies have small samples and limited risk factors. Therefore, this study adopts a retrospective analysis method to assess the risk factors of 253 lymph node metastasis, to provide individualized basis for the scope of lymph node dissection during radical resection of colorectal cancer in different patients, and to improve the surgical bene t of patients.

Patients
In this study, 187 colorectal cancer patients were selected for radical resection of colorectal cancer at the Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from October 2018 to June 2020. Eligibility criteria of this study included: (1)pathologically proven colorectal carcinoma; (2)Laparoscopic radical resection of colorectal cancer with preservation of the left colon artery + D3 lymph node dissection (low ligation + high dissection;

Clinicopathological statistics
The No.253 lymph node is located at the root of the inferior mesenteric artery. To study the risk factors of No.253 lymph node metastasis, the clinicopathological statistics in this study include: gender, age, tumor location, tumor size, length of tumor from the anus, whether lymphovascular invasion, whether perineural invasion, tumor markers CEA, CA125 and CA199, tumor T stage, whether it is distant metastasis, the total number of lymph node harvested, tumor type, and histologic grade.
Statistical analysis SPSS 23.0 software was used for data processing and analysis, and p < 0.05 was considered statistically signi cant. Taking No.253 lymph node metastasis as the dependent variable and the clinicopathological statistics from above as the independent variable, the relationship between the above factors and No.253 lymph node metastasis was explored through Chi-square test. The single factor of p < 0.05 was included into the multivariate logistic regression model for analysis to discuss the independent risk factors of lymph node metastasis in 253 groups.

Patients characteristics
A total of 157 patients underwent laparoscopic radical resection of colorectal cancer with preservation of the left colon artery + D3 lymph node dissection (low ligation + high dissection) in the Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from October 2018 to June 2020, included 105 males(66.9%) and 52 females(33.1%). The age ranges from 32 to 85 years old (60.47 ± 10.35). There were 98 patients' tumor distance from the anus > 10 cm (62.4%), 59 patients' tumor distance from the anus < = 10 cm (37.6%). Preoperative tumor marker examination showed 40 patients' CEA > 5U/mL(25.5%) and 117 patients' CEA < = 5U/mL(74.5%) ; 5 patients' CA125 > 35U/mL(3.2%), 152 patients' CA125 < = 35U/mL(96.8%) ; 12 patients' CA199 > 37U/mL(7.6%), 145 patients' CA125 < = 37U/mL(92.4%). Pathological examination results showed tumor type: 150 patients with adenocarcinoma(95.5%), 7 patients with mucinous adenocarcinoma/signet ring cell carcinoma(4.5%) ; degree of differentiation: 20 patients with poorly differentiated and moderately differentiated (including special types)(12.7%), 137 patients with moderately differentiated and well differentiated(83.3%) ; whether perineural invasion: 40 patients with perineural invasion(25.5%), 117 patients without perineural invasion(74.5%) ; whether lymphovascular invasion: 26 patients with lymphovascular invasion(16.6%), 131 patients without lymphovascular invasion(83.4%) ; the maximum tumor diameter: 32 patients' maximum tumor diameter > = 5 cm(20.4%), 125 patients' maximum tumor diameter < 5 cm(79.6%) ;whether it is distant metastasis: 8 patients with distant metastasis(5.1%), 139 patients without distant metastasis(94.9%) ; number of lymph nodes harvested: 94 patients' number of lymph node harvested > = 12(59.9%), 63 patients' number of lymph node harvested < 12(40.1%) ; T stage: T1-2 60 patients with T1-2 (38.2%), 97 patients with T3-4 (61.8%) ; tumor location: 124 patients in rectal(79.0%) while 33 patients in sigmoid colon and others(21.0%). As shown in Table 1.  A multivariate logistic regression analysis was performed on the above 5 statistically signi cant No.253 lymph node positive risk factors to assess whether the above 5 factors are independent risk factors for No.253 lymph node metastasis, the appeal parameter was set as an independent variable, and No.253 lymph node metastasis was set as the cause variables were included in the binary logistic regression model. The results showed that preoperative CA125 levels, whether nerve invasion, whether vascular invasion, tumor type, and degree of differentiation are not independent risk factors for No.253 lymph node metastasis(P > 0.05). As shown in Table 3. In this study, 105 male patients and 52 female patients were enrolled, and all 5 patients with positive No.253 lymph node were male. The rate of No.253 lymph node metastasis in men was higher than that in women. There was no signi cant difference in lymph node metastasis (χ 2 = 2.558, p = 0.110). It can be considered that gender has no related with No.253 lymph node metastasis. There is controversy about the correlation between age and lymph node metastasis. A study involving 1205 patients (10) showed that the rate of lymph node metastasis in the No.253 group of people less than 65 years old was higher, and the difference was statistically signi cant (p = 0.028), which may be related to the low degree of tumor differentiation in the low-age group. More studies have shown that lymph node metastasis in the No.253 group has no correlation with age (8,12). In our study, the rate of lymph node metastasis in group No.253 in the age ≤ 60 years group was higher than that in the group over 60 years old (5.5% vs 1.2%), and the difference was not statistically signi cant, suggesting that age has no correlation with No.253 lymph node metastasis.
Preoperative tumor markers CEA, CA125, CA199 are the most commonly used clinical indicators for diagnosis, monitoring the progress of gastrointestinal tumors and treatment effects, and their application value in colorectal tumors has been widely recognized (20,21). According to research reports, the level of preoperative tumor markers is related to lymph node metastasis. Sun (22) et al. showed that the preoperative increase in CEA level was positively correlated with No.253 lymph node metastasis and led to a poor prognosis. In this study, the lymph node metastasis rate in the No.253 group with elevated levels of tumor markers CEA, CA125, and CA199 was higher than that in the normal group. The preoperative CA125 level increased (20.0% vs 2.6%, χ 2 = 4.736, p = 0.030) while compared with the normal group, the difference is statistically signi cant. Through our study and previous study, we thought that higher level of preoperative tumor markers suggested higher risk of No.253 lymph node metastasis. Therefore, it is believed that the preoperative CA125 level is a risk factor for No.253 lymph node metastasis.
Studies have reported that tumor size is related to No.253 lymph node metastasis. Yi (12)  There are some shortcomings in this study. As it is a single-center retrospective study, which has limitations and small sample size, leading to potential risk factors such as T staging, CEA, CA199, tumor size, etc. with no statistical signi cant difference. The follow-up study will continue to expand the sample size, and further con rm the risk factors related to No.253 lymph node metastasis. And we also look forward to conducting multi-center, large sample, prospective research to provide more evidence for the scope of 253 lymph node.

Conclusion
The scope of lymph node dissection during colorectal surgery is still controversial. Although the rate of No.253 lymph nodes metastasis is low, the prognosis of patients with No.253 lymph node metastasis is poorer. Through our retrospective study, we found that preoperative CA125 level, whether perineural invasion, whether lymphovascular invasion, tumor type, histologic grade were risk factors of the No.253 lymph nodes metastasis. Therefore, we believe that patients with colorectal cancer who have the above risk factors require routine No.253 lymph nodes dissection.