Impact of Inferior Mesenteric Artery Lymph Node Metastasis on the Prognosis of Patients With Left-sided Colorectal Cancer: A Case Control Study


 Background:

The clinical significance of metastasis in inferior mesenteric artery (IMA) lymph node in patients with left-sided colorectal cancer (LCRC) is unclear. The aim of this study was to investigate the impact of IMA lymph node metastasis (IMA-LN (+)) on the prognosis of patients with LCRC.
Methods:

A total of 292 patients with stage III LCRC and 111 patients with stage IV LCRC who underwent radical resection of the primary tumor between 2005 and 2016 were included. The clinicopathological features and prognosis, which were retrospectively obtained from medical records, were compared regarding IMA-LN (+).
Results:

IMA-LN (+) was observed in 10 patients with stage III LCRC (2.3%). Moreover. ≥4 metastatic lymph nodes (p = 0.001) and poorly differentiated type (p = 0.049) were more frequently observed in patients with IMA-LN (+) than in patients without IMA lymph node metastasis (IMA-LN (-)) in stage III; IMA-LN (+) patients had significantly worse overall survival (OS) than IMA-LN (-) patients in stage III (p = 0.015). Conversely, there was no significant difference between the OS of stage III IMA-LN (+) and stage IV patients (p = 0.192). Likewise, there was no significant difference between the OS of stage III IMA-LN (+) and stage IV patients with distant metastatic lymph nodes only (n = 12) (p = 0.294).
Conclusion:

The prognosis of IMA-LN (+) patients was worse than that of IMA-LN (-) patients in stage III LCRC; moreover, it was similar to that of patients with stage IV LCRC.


Conclusion:
The prognosis of IMA-LN (+) patients was worse than that of IMA-LN (-) patients in stage III LCRC; moreover, it was similar to that of patients with stage IV LCRC.

Background
Lymph node metastasis is one of the strongest prognostic factors in colorectal carcinoma. An increased number of cases of lymph node metastasis have been reported to be associated with poor prognosis in colorectal carcinoma [1,2]; thus, according to the 8th edition of the TNM Classi cation of Malignant Tumors, the N stage is determined according to the number of metastatic lymph nodes [3]. Conversely, in the Japanese Classi cation of Colorectal, Appendiceal and Anal Carcinoma, the N stage is determined based on the main lymph node metastasis as well as the number of metastatic lymph nodes [4].
The inferior mesenteric artery (IMA) lymph nodes, which lie along the IMA from the origin of the IMA to the origin of the left colic artery, are de ned as the regional lymph nodes and the main lymph nodes in left-sided colorectal cancer (LCRC) [3,4]. A previous study has reported that stage III LCRC patients with IMA lymph node metastasis (IMA-LN (+)) had worse prognosis than those without it (IMA-LN (-)) [5]. Other studies have suggested that IMA-LN (+) can be an independent predictor of poor prognosis [6,7]; thus, IMA lymph nodes could be included in not so much the regional lymph nodes as distant lymph nodes [6].
However, direct evidence is not provided, since there are no studies comparing the prognosis between stage III IMA-LN (+) and stage IV LCRC patients. Thus, the prognostic importance of IMA-LN (+) is still unclear.
In the present study, we aimed to evaluate the prognostic impact of IMA-LN (+) in stage III. Furthermore, we compared the prognosis of stage III IMA-LN (+) patients with that of stage IV LCRC patients.

Patients and Data Collection
Between 2005 and 2016, 1,566 consecutive patients underwent resection of the primary tumor for colorectal cancer at the Kyoto Prefectural University of Medicine. Among them, 403 patients with stage III or stage IV LCRC located in the descending colon, sigmoid colon, and rectum were involved in this study. The IMA lymph node was de ned as the presence of lymph node from the origin of the inferior mesenteric artery to the origin of the left colic artery [4]. Patients were divided into three groups, according to the presence of IMA lymph node metastasis and the Union for International Cancer Control/American Joint Committee on Cancer Tumour, Node, Metastasis system version 8, and the Union for International Cancer Control (UICC). Moreover, stage IV patients were divided into two groups, according to the distant metastasis status.
Information about patients and their clinical course was collected from medical, operative, and pathology reports. Macroscopic and microscopic classi cations of tumors were based on the UICC TNM staging system and the 8th edition of the Japanese Classi cation of Colorectal, Appendiceal, and Anal Carcinoma. Follow-up consisted of blood tests, gastrointestinal tract radiographies, endoscopic procedures, computed tomography, and ultrasonography. Follow-up procedures were performed every 3 months for at least 2 years and were continued periodically for up to 5 years. The median follow-up in 403 patients was 42 months.
Informed consent was obtained from all individual participants included in the study. All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was reviewed and approved by the Kyoto Prefectural University of Medicine Independent Ethics Committee (ERB-C-1178-1).

Statistical Analysis
Statistical analysis was performed using JMP version 14 (ASA Institute, Cary, NC, USA). Survival curves were calculated according to the Kaplan-Meier method. Differences between survival curves were examined by the Wilcoxon signed-rank test. Relationships between host and tumor factors were evaluated using Fisher's exact test of independence. In all analyses, p < 0.05 values were considered signi cant.

In-Patient Setting
Among 1566 patients undergoing resection of the primary tumor for colorectal cancer at our institution, 964 patients with stage 0, I, or II colorectal carcinoma, 187 patients with right-sided or transverse colon cancer, and 12 patients with other malignant diseases within 5 years were excluded. Eventually, 403 patients with stage III or stage IV LCRC located in the descending colon, sigmoid colon, and rectum were enrolled in this study. A total of 10 stage III LCRC patients had IMA lymph node metastasis (2.3%), 282 patients had no IMA lymph node metastasis, and 111 patients were diagnosed with stage IV LCRC. Among 111 patients, 12 patients had distant lymph node metastasis only ( Fig. 1).  (Table 1). Conversely, no signi cant differences were observed between stage III IMA-LN (+) and stage IV LCRC patients in each tumor factor ( Table 2).

Discussion
In the present study, we have shown that stage III IMA-LN (+) patients had worse prognosis than stage III IMA-LN (-) patients. Conversely, no signi cant prognostic differences were observed between stage III IMA-LN (+) patients and stage IV LCRC patients, especially with distant lymph node metastasis only. These ndings may indicate that IMA-LN (+) is not regarded as regional lymph node metastasis.
Our results regarding the poor prognosis of stage III IMA-LN (+) patients are consistent with those of previous studies.  Table 1), consistent with the previous report. Therefore, IMA-LN (+) may have a strong impact on prognosis regardless of the number of metastatic lymph nodes.
In the present study, the prognosis of stage III IMA-LN (+) patients was as poor as that of stage IV (LYM) LCRC patients. Newland et al. have reported that the apical lymph node involvement would implicate a spread to lymph node metastasis beyond the range of dissection [8]; Kang et al. have shown the high distant lymph node recurrence rate and signi cant association with para-aortic lymph node recurrence in stage III IMA-LN (+) patients [5]. Moreover, IMA-LN (+) was reported to be an independent prognostic factor in tumor factors including T, N, and M categories [6]. These ndings, including our results, suggest that the IMA lymph nodes might be classi ed as systemic lymph nodes.
To improve the prognosis of IMA-LN (+) patients, the indications of postoperative adjuvant chemotherapy are important; for stage III patients who have undergone R0 resection, 5-FU-based chemotherapy is recommended [9]. Kim et al. have reported that adjuvant chemotherapy was an independent prognostic factor in IMA-LN (+) patients [6]. In our study, 7 among 10 stage III IMA-LN (+) patients received adjuvant chemotherapy. The 5-year OS rate of patients with adjuvant chemotherapy was 57.1% and that of those without adjuvant chemotherapy was 33.3%. However, no signi cant difference was observed between the two groups (data not shown). The combination of 5-FU plus L-OHP is more effective for stage III CRC patients as adjuvant chemotherapy than mono-chemotherapy [10], whereas the combination of 5-FU plus CPT-11 or 5-FU plus molecular target drugs has not proven superior [11][12][13][14]; thus, currently, L-OHP combination chemotherapy may be more recommended for IMA-LN (+) patients, due to poor prognosis.
In the present study, seven IMA-LN (+) patients had sigmoid colon cancer, while three of them had rectal cancer. In general, descending/sigmoid colon and rectal cancers have different biological features because they have different lymphatic and blood vessels. However, neither signi cant prognostic nor recurrent rate difference was observed between the two groups (data not shown). Kang et al. have also reported that there was no signi cant difference in the systemic recurrence pattern between the sigmoid colon and rectal cancers [5]. These data may suggest that IMA lymph node metastasis is a signi cant prognostic factor, regardless of tumor location.
The present study has some limitations. It is a retrospective study in a single institute, with a small number of patients. In particular, the number of patients with IMA-LN (+) was small, because IMA-LN (+) is relatively rare [6,15]. However, regardless of the small number, our results may have meaningful suggestion on tumor stage classi cation that stage III IMA-LN (+) had worse prognosis than stage III IMA-LN (-), and there was no signi cant difference between stage III IMA-LN (+) and stage IV LCRC. Therefore, we wish to perform large size, prospective and randomized study.

Conclusion
In conclusion, the present study suggests that IMA-LN (+) can be a poor prognostic factor in stage III LCRC and cannot be regarded as an indicator of regional lymph node metastasis. Therefore, intensive adjuvant chemotherapy may be necessary to improve the poor prognosis in patients with stage III IMA-LN

Consent for publication
Written consent for their personal or clinical details along with any identifying images to be published in this study was also obtained from all individual participants.

Availability of data and materials
The datasets and/or analyzed during the current study available fromthe corresponding author on reasonable request.
The authors declare that they have no con ict of interest.

Funding
There is no funding supports for this paper.
Authors' Contribution TA contributed to the study conception and design. Material preparation, data collection and analysis were performed by KT. The rst draft of the manuscript was written by KT and all authors commented on previous versions of the manuscript. All authors approved the nal manuscript and have agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any partof the work are appropriately investigated, resolved, and the resolution documented in the literature. Tables   Table 1. Tumor factors of stage III IMA-LN (-) and stage III IMA-LN (+) patients      Supplementary Files