A multicenter cohort study on mapping of lymph node metastasis for splenic flexural colon cancer

Abstract Aim There have been no reports of searching for metastases to lymph nodes along the accessory middle colic artery (aMCA). The aim of this study was to investigate the metastasis rate of the aMCA for splenic flexural colon cancer. Methods Patients with histologically proven colon carcinoma located in the splenic flexure, clinically diagnosed as stage I‐III were eligible for this study. Patients were retrospectively and prospectively enrolled. The primary endpoint was frequency of lymph node metastasis to the aMCA (station 222‐acc and 223‐acc). The secondary endpoint was the frequency of lymph node metastasis to the middle colic artery (MCA) (station 222‐lt and 223) and left colic artery (LCA) (station 232 and 253). Results Between January 2013 and February 2021, a total of 153 consecutive patients were enrolled. The location of the tumor was 58% in the transverse colon and 42% in the descending colon. Lymph node metastases were observed in 49 cases (32%). The presence of aMCA rate was 41.8% (64 cases). The metastasis rates of stations 221, 222‐lt, and 223 were 20.0%, 1.6%, and 0%, and stations 231, 232, and 253 were 21.4%, 1.0%, and 0%, respectively. The metastasis rates of stations 222‐acc and 223‐acc were 6.3% (95% confidence interval: 1.7%‐15.2%) and 3.7% (95% confidence interval: 0.1%‐19%), respectively. Conclusions This study identified the distribution of lymph node metastases from splenic flexural colon cancer. If the aMCA is present, this vessel should be targeted for dissection, taking into account the frequency of lymph node metastasis.

where the aMCA is present. 10,11 Their findings suggested that the lymphatic channels along the aMCA might be important pathways for the drainage of splenic flexural colon cancer, and dissection of the lymph nodes along the aMCA may result in improved oncological outcomes. 11 However, there have been no reports investigating metastases to lymph nodes along the aMCA. How often lymph node metastases occur in the lymph nodes along the aMCA is thus unclear.
Therefore, the Japanese Society for Cancer of the Colon and Rectum (JSCCR), mainly composed of colorectal surgeons, conducted a multicenter cohort study to investigate the metastasis rate of the aMCA and to determine the optimal extent of lymph node dissection for splenic flexural colon cancer.

| Patients
This study was a multicenter, retrospective, prospective cohort study in Japan. The study protocol was approved by the Ethics Advisory Committee of Yokohama City University and the institutional review board of each participating hospital before the study was initiated and registered in the UMIN Clinical Trials Registry as UMIN-CTR000037195 (http://www.umin.ac.jp/ctr/index.htm). Patients were recruited from 12 institutions of the JSCCR between January 2013 and February 2021. The patients encountered up to July 2019 were retrospectively accumulated, and those encountered from August 2019 were prospectively enrolled. For patients in the retrospective phase, we used the opt-out approach to disclose the study information. For patients in the prospective phase, before enrolling in this study, all patients provided their written informed consent.
The eligibility criteria were as follows: (1) patients who were more than 20 years old; (2) patients with histologically proven colon carcinoma; (3) a tumor located within 10 cm from the splenic flexure; (4) a clinical diagnosis of Union for International Cancer Control (UICC) TMN classification (8th edition) stage I-III. 12 ; and (5) curative resection planned and scheduled for undergo lymph node dissection of ≥D2.

Conclusions:
This study identified the distribution of lymph node metastases from splenic flexural colon cancer. If the aMCA is present, this vessel should be targeted for dissection, taking into account the frequency of lymph node metastasis.

K E Y W O R D S
accessory middle colic artery, colorectal cancer, complete mesocolic excision, lymph node metastasis, splenic flexure

| Definition of lymph node station number
The definition of the lymph node station number is shown in Figure 1.
Station numbers for the middle and left colic arterial regions followed the JCCRC. 9 Since the station number of the aMCA was not defined in the JCCRC, the intermediate lymph node of the aMCA was defined as station 222-acc, and the main lymph node was station 223-acc. The aMCA was defined as the artery running from the SMA to the splenic flexure branching from the SMA on the central side of the root of the MCA. Clinically, it was defined as the artery that crossed the anterior surface of the inferior mesenteric vein and ran along the lower edge of the pancreas and toward the splenic flexure ( Figure 2).

| Mapping of dissected lymph nodes
The surgeons identified lymph nodes from specimens after surgery and mapped them onto the schematic board, assigned numbers, and

| Endpoints
The primary endpoint was the frequency of lymph node metastasis to the aMCA (station 222-acc and 223-acc). The secondary endpoint was the frequency of lymph node metastasis to the MCA (station 222-lt and 223) and LCA (station 232 and 253).

| Statistical analyses
The expected lymph node metastasis frequency to station 222-acc of splenic flexural colon cancer was set to 5%, and the threshold lymph node metastasis frequency was set to 1%. A total of 139 patients would be required at a significance level of 0.05 and power of 0.80.
The data are presented as the median and interquartile range (IQR). We estimated metastasis rates and 95% confidence intervals  Table 4.

| DISCUSS ION
This is the first study conducted by the JSCCR to investigate the site and frequency of lymph node metastasis of splenic flexural colon cancer, taking into account the presence of the aMCA.
Blood supply to the splenic flexure has been shown to be variable. In 89% of cases, blood is supplied primarily by the IMA via the LCA, and in 11% of cases, it is supplied by the SMA via the MCA. 13 The LCA and lt-MCA are considered feeding arteries and the focus of lymph node dissection. This idea is also adopted in the Japanese guidelines, and the lymph nodes along the MCA are assigned station numbers in the 220s, while those along the LCA are assigned station numbers in the 230s. 9 The aMCA was first reported by Steward et al in 1933. 14 It has since been evaluated by dissecting cadavers [14][15][16][17][18][19] and based on intra-operative findings. 11 Although the detection rate of the aMCA was low before 1989 (8%-21%), the rate has increased since 1990 (38.7%-49.2%). 20 In this study, the aMCA  (0.7%), right hepatic artery (0.7%), and the gastroduodenal artery (0.6%). 23 In this study, we did not find any aMCAs exhibiting these aberrant branches. However, when ligating the aMCA at the root, we need to be aware that these aberrant branches may be present.
There are some limitations associated with this study. First, this study included patients collected in both a retrospective and a prospective phase. Second, this study was conducted to investigate the frequency of lymph node metastases and did not investigate longterm outcomes. Third, the frequency of lymph node metastases along the aMCA that is given in this study has a wide CI because of the combination of a small number of patients with lymph node metastases and a small number of patients with aMCA.
In conclusion, this was the first study to investigate the frequency of lymph node metastases along the aMCA for splenic flexural colon cancer. If the aMCA is present, this vessel should be targeted for dissection, taking into account the frequency of lymph node metastasis.

D I SCLOS U R E S
Funding: None.