Research ArticleClinical Studies

Impact of Inferior Mesenteric Artery Lymph Node Metastasis on the Prognosis of Left-sided Colorectal Cancer

KAZUYA TAKABATAKE, TOMOHIRO ARITA, MASAYOSHI NAKANISHI, YOSHIAKI KURIU, YASUTOSHI MURAYAMA, HIROKI SHIMIZU, MICHIHIRO KUDOU, JUN KIUCHI, TOSHIYUKI KOSUGA, HIROTAKA KONISHI, RYO MORIMURA, ATSUSHI SHIOZAKI, HISASHI IKOMA, TAKESHI KUBOTA, HITOSHI FUJIWARA, KAZUMA OKAMOTO and EIGO OTSUJI
Anticancer Research May 2021, 41 (5) 2533-2542; DOI: https://doi.org/10.21873/anticanres.15031

Abstract

Background/Aim: This study aimed to investigate the impact of the inferior mesenteric artery (IMA) lymph node metastasis [IMALN (+)] on prognosis in left-sided colorectal cancer (LCRC). Patients and Methods: A total of 285 patients with stage III LCRC and 118 patients with stage IV LCRC who underwent resection of primary tumor between 2005 and 2016 were included. Results: IMALN (+) patients (n=10) had worse overall survival (OS) than patients without IMA lymph node metastasis [IMALN (–); n=275] in stage III LCRC (p=0.007). Multivariate analysis revealed that IMALN (+) was a prognostic factor in stage III LCRC (OS, HR=3.09, p=0.043). Conversely, there was no difference between the OS of IMALN (+) and stage IV LCRC with distant lymph node metastasis only [stage IV LCRC (LYM); n=21; p=0.434]. Conclusion: The prognosis of IMALN (+) was worse than that of IMALN (–); it was similar to that of stage IV LCRC (LYM).

Key Words:

Lymph node metastasis is one of the strongest prognostic factors in colorectal cancer. An increased number of cases of lymph node metastasis have been reported to be associated with poor prognosis in colorectal cancer (1-3); thus, according to the 8th edition of the Union for International Cancer Control (UICC) TNM Classification of Malignant Tumors, the N stage is determined according to the number of metastatic lymph nodes (4). Conversely, in the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma, the N stage is defined based on the location of lymph node metastasis as well as the number of metastatic lymph nodes (5).

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 defined as the regional lymph nodes and the main lymph nodes in left-sided colorectal cancer (LCRC) (4, 5). A previous study reported that stage III LCRC patients with IMA lymph node metastasis [IMALN (+)] had worse prognoses than those without IMA lymph node metastasis [IMALN (–)] (6). Other studies have suggested that IMALN (+) can be an independent predictor of poor prognosis (7, 8); thus, IMA lymph nodes may as well be regarded as distant lymph nodes rather than regional lymph nodes (7). However, direct evidence has not been provided, since there are no studies comparing the prognosis between IMALN (+) and distant lymph node metastasis.

In addition, lateral pelvic lymph node metastasis [LPLN (+)] has been reported as an independent risk factor for poor overall survival (OS) and local recurrence in rectal cancer (9-11); thus, LPLN (+) is generally considered to be a distant lymph node metastasis (12, 13). Conversely, the Japanese classification of colorectal cancer defines lateral pelvic lymph nodes as regional lymph nodes, N3, similar to IMA lymph nodes (5). Though both IMA lymph nodes and lateral pelvic lymph nodes are classified as regional lymph nodes using this classification, no studies have compared the prognosis between these two types of lymph node metastasis. Therefore, the prognostic importance of IMALN (+) is still unclear.

In the present study, we compared the prognosis of stage III IMALN (+) patients with that of stage III IMALN (–) patients and stage IV LCRC with distant lymph node metastasis only [stage IV LCRC (LYM)] patients to evaluate the prognostic impact of IMALN (+). Furthermore, we compared the prognostic impact of IMALN (+) with LPLN (+) and with other distant lymph node metastases.

Patients and Methods

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 IV LCRC located in the descending colon, sigmoid colon, or rectum were enrolled in this study. The IMA lymph node was defined as the presence of the lymph node from the origin of the inferior mesenteric artery to the origin of the left colic artery, the lateral pelvic lymph node as the internal iliac, obturator, common iliac, external iliac, and sacral lymph node, and the para-aortic lymph node as lymph nodes along the aorta (5). The regional lymph node in LCRC was the mesenteric lymph node; the inferior mesenteric, left colic, sigmoid, superior, middle, and inferior rectal lymph node (4). The distant lymph node was defined as the lateral pelvic lymph node, para-aortic lymph node, and lymph node at other sites. The internal iliac and sacral lymph node are included in the regional lymph node according to UICC TNM classification; however, they were excluded from the regional one in this study because the lateral lymph node dissection was performed according to the Japanese classification and because it is difficult to accurately diagnose whether it is an internal iliac or an obturator lymph node before and during operation. The lateral lymph node dissection was performed for deep tumor above cT3 with distal end lower than abdominal reflection and/or clinical LPLN (+) or mesenteric lymph node metastasis and curative resection was possible, and the para-aortic lymph node dissection was performed when there was no other distant involvement and curative resection was possible according to the Japanese Society for Cancer of the Colon and Rectum guidelines (14). Patients were divided into three groups, according to the presence or absence of IMA lymph node metastasis and distant lymph node metastasis pathologically. Moreover, patients with only distant lymph node metastasis were divided into two groups, according to the presence of LPLN (+) and para-aortic lymph node metastasis [PALN (+)].

Information about patients and their clinical course was retrospectively collected from medical, operative, and pathology reports. Macroscopic and microscopic classifications of tumors were based on the UICC TNM staging system and the 8th edition of the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma. Follow-ups 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 continued periodically for up to 5 years. The median follow-up in 403 patients was 48 months.

Informed consent was obtained from all participants included in the study. All procedures performed in this study 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. The 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 log-rank test. Multivariate analyses were carried out by the Cox regression analysis. Relationships between host and tumor factors were evaluated using Fisher’s exact test or the chi-square test. In all analyses, p<0.05 was considered significant.

Results

In-patient setting. Among 1,566 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 IV LCRC located in the descending colon, sigmoid colon, and rectum were enrolled in this study (Figure 1). A total of 10 stage III LCRC patients had IMA lymph node metastasis (2.4%), 275 patients had no IMA lymph node metastasis, and 118 patients had stage IV LCRC. Table I shows the details of patients with IMALN (+). Among 118 patients, 21 patients had distant lymph node metastasis only and 97 patients had other distant metastasis. Of these 21 patients, 7 had lateral lymph node metastasis, 12 had para-aortic lymph node metastasis, and two had both

Figure 1.
Figure 1.

A total of 403 patients with stage III or stage IV left-sided colorectal cancer, who underwent resection of the primary tumor were involved in this study. The patients were grouped according to the UICC TNM staging system and IMA or distant lymph node metastasis status. IMA: Inferior mesenteric artery.

View this table:
Table I.

Detailed clinical information of stage III IMALN (+) patients.

Tumor factors in patients with stage III IMALN (+), IMALN (–), or stage IV LCRC (LYM). First, tumor factors of patients in the three groups were investigated. Four or more lymph node metastasis (p=0.001), poorly differentiated type (p=0.038), and high serum CA19-9 (p=0.034) were more frequently observed in stage III IMALN (+) patients than in IMALN (–) patients (Table II). Bleeding during operation (p=0.021), rectal cancer (p=0.020), and deeper tumor (p=0.021) were more frequently observed in stage IV LCRC (LYM) patients than in IMALN (+) patients (Table III).

View this table:
Table II.

Tumor factors of stage III IMALN (–) and stage III IMALN (+) LCRC patients.

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Table III.

Tumor factors of stage III IMALN (+) and stage IV (LYM) LCRC patients.

Long-term prognosis in patients with stage III IMALN (+), IMALN (–), and stage IV LCRC (LYM). Further, we analyzed the long-term prognosis of the patients. The 5-year OS rates of stage III IMALN (+) and IMALN (–) patients were 50.0% and 78.5%, respectively (p=0.007; Figure 2A). The 5-year cancer-specific survival (CSS) rates were 50.0% and 84.4%, respectively (p<0.001; Figure 2B). The 5-year disease-free survival (DFS) rates were 40.0% and 67.1%, respectively (p=0.010). Multivariate analysis revealed that IMALN (+) was an independent prognostic factor (OS, HR=3.09, p=0.043; Table IV) along with tumor venous invasion, serum CEA levels, and adjuvant chemotherapy status in stage III LCRC. Conversely, the 5-year OS and CSS rates of stage IV LCRC (LYM) patients were 33.3% and 36.3%, respectively, and the prognosis of stage IV LCRC (LYM) patients was not significantly different from that of stage III IMALN (+) patients (OS, p=0.434; CSS, p=0.546; Figure 2A and B).

Figure 2.
Figure 2.

Survival analysis based on the status of IMA lymph node metastasis and distant lymph node metastasis. (A) OS and (B) CSS, based on the status of IMA lymph node metastasis and distant lymph node metastasis. Log-rank test showed that patients with IMALN (+) had worse OS and CSS than those with IMALN (–) (OS, p=0.007; CSS, p<0.001), and there was no difference between patients with IMALN (+) and stage IV (LYM) in OS and CSS (OS, p=0.434; CSS, p=0.546). CSS: Cancer-specific survival; IMA: inferior mesenteric artery; IMALN (+): presence of inferior mesenteric artery lymph node metastasis; IMALN (–): absence of inferior mesenteric artery lymph node metastasis; OS: overall survival; Stage IV (LYM): stage IV patients with distant lymph node metastasis only.

View this table:
Table IV.

Multivariate analysis for prognostic factors in stage III LCRC.

Comparison of prognosis in patients with stage III IMLN (+) and patients with LPLN (+) or PALN (+). Fourteen patients with PALN (+), including two patients who also had LPLN (+), and seven patients with LPLN (+) only, were observed in stage IV LCRC (LYM). The prognosis of stage III IMALN (+) patients was not significantly different from that of patients with PALN (+) or LPLN (+) only (OS, p=0.676; CSS, p=0.816; Figure 3A and B). In patients with IMALN (+) and LPLN (+), the 5-year disease-free survival (DFS) rates were 40.0% and 42.8%, respectively (p=0.844).

Figure 3.
Figure 3.

Survival compared among patients with IMALN (+), LPLN (+) and PALN (+). (A) OS and (B) CSS, compared among patients with IMALN (+), LPLN (+) and PALN (+). Log-rank test showed no difference among those three groups (OS, p=0.676; CSS, p=0.816). CSS: Cancer-specific survival; IMALN (+): presence of inferior mesenteric artery lymph node metastasis; LPLN (+): presence of lateral pelvic lymph node metastasis only; OS: overall survival; PALN (+): presence of para-aortic lymph node metastasis.

Moreover, we compared the prognosis by the location of the tumor. In rectal cancer, there was no significant prognostic difference among the three groups [IMALN (+), LPLN (+), and PALN (+)] (OS, p=0.956; CSS, p=0.999; Figure 4). Additionally, in sigmoid and descending colon cancer, there was no significant prognostic difference between IMALN (+) and PALN (+) (OS, p=0.496; CSS, p=0.496; Figure 5).

Figure 4.
Figure 4.

Survival compared among patients with IMALN (+), LPLN (+) and PALN (+) in rectal cancer. (A) OS and (B) CSS, compared among patients with IMALN (+), LPLN (+) and PALN (+) in rectal cancer. Log-rank test showed no difference among those the three groups (OS, p= 0.956; CSS, p=0.999). CSS: Cancer-specific survival; IMALN (+): presence of inferior mesenteric artery lymph node metastasis; LPLN (+): presence of lateral pelvic lymph node metastasis only; OS: overall survival; PALN (+): presence of para-aortic lymph node metastasis.

Figure 5.
Figure 5.

Survival compared among patients with IMALN (+) and PALN (+) in descending and sigmoid colon cancer. (A) OS and (B) CSS, compared between patients with IMALN (+) and PALN (+) in descending and sigmoid colon cancer. Log-rank test showed no difference between those two groups (OS, p=0.496; CSS, p=0.496). CSS: Cancer-specific survival; IMALN (+): presence of inferior mesenteric artery lymph node metastasis; OS: overall survival; PALN (+): presence of para-aortic lymph node metastasis.

Discussion

In the present study, we have shown that stage III IMALN (+) patients had worse prognosis than stage III IMALN (–) patients. Conversely, no significant prognostic differences were observed between stage III IMALN (+) patients and stage IV LCRC (LYM) patients. Moreover, the prognosis of IMALN (+) was as poor as that of PALN (+) or LPLN (+). These findings may indicate that IMALN (+) is not regarded as a regional lymph node metastasis.

Our results regarding the worse prognosis of stage III IMALN (+) patients compared to that of stage III IMALN (–) patients are consistent with those of previous studies, which further revealed that stage III IMALN (+) was a significant prognostic factor in stage III LCRC (6-8). In this study, multivariate analysis revealed that IMALN (+) was an independent prognostic factor as well as tumor venous invasion, serum CEA levels, and adjuvant chemotherapy status, but not the number of lymph node metastasis in stage III LCRC. This might be due to the restriction to stage III LCRC patients, all of whom had lymph node metastasis. This bias may weaken the effect of the number of lymph node metastasis. IMA lymph nodes are located at the root of IMA, and they can be regarded as apical lymph nodes in LCRC. Some studies reported that apical node metastasis is one of the poor prognostic factors in LCRC (15, 16); thus, this suggests that IMA lymph node involvement has a strong impact on prognosis in stage III LCRC.

In the present study, the prognosis of stage III IMALN (+) patients was as poor as that of stage IV LCRC (LYM) patients. We defined LPLN (+), and not regional lymph nodes metastasis, as involvement of distant lymph nodes, and LPLN (+) and PALN (+) were observed in stage IV (LYM) in this study. Several studies have reported that LPLN (+) is a poor prognostic factor (9-11); thus, LPLN (+) generally has a distant disease status in western countries and adjuvant chemoradiation therapy was recommended (12, 13, 17). In fact, in this study, patients with LPLN (+) had worse prognoses than those with IMALN (–): The 5-year OS rates of patients with LPLN (+) and stage III IMALN (–) patients were 40.0% and 78.5%, respectively (p=0.002). PALN (+) is also reported to be a poor prognostic factor (18-20). Thus, PALN (+) has a distant disease status in both the UICC TNM and Japanese colorectal classification owing to its malignancy. In addition, Newland et al. have reported that apical lymph node involvement would implicate a spread to lymph node metastasis beyond the range of dissection (21). Recently, Zhao et al. also reported that IMALN (+) had a higher risk of postoperative recurrence, especially liver and lung metastasis, because of the apical lymph node metastasis (22). Therefore, these findings suggest that IMALN (+) can be regarded with a distant disease status.

In this study, we defined descending colon, sigmoid colon, and rectal cancers as LCRC and revealed the malignancy potential of IMALN (+) in stage III LCRC. However, the descending colon, sigmoid colon, and rectal cancers generally have varying biological features since they involve different lymphatic and blood vessels. Therefore, we compared the prognosis according to the location of the tumor and revealed that the prognostic impact of IMALN (+) was as poor as that of LPLN (+) and PALN (+), regardless of tumor site. Kang et al. reported that there was no significant difference in the systemic recurrence pattern between the sigmoid colon and rectal cancers (6). Altogether, these findings suggest that IMA lymph nodes may be classified as systemic lymph nodes regardless of left-sided colon or rectum.

To improve the prognosis of IMALN (+) patients, the indications of postoperative adjuvant chemotherapy are important; for stage III patients who have undergone R0 resection, 5-Fluorouracil (5-FU)-based chemotherapy is recommended (14). Kim et al. have reported that adjuvant chemotherapy was an independent prognostic factor in IMALN (+) patients (7). In our study, seven of the ten stage III IMALN (+) patients received adjuvant chemotherapy. The 5-year OS rate of patients who received adjuvant chemotherapy was 57.1%, and the rate of patients who did not receive adjuvant chemotherapy was 33.3%. However, no significant difference was observed between these two groups (p=0.229). The combination of 5-FU and oxaliplatin (L-OHP) is more effective for stage III CRC patients as adjuvant chemotherapy than mono-chemotherapy (23), whereas the combination of 5-FU and CPT-11 or 5-FU and molecular target drugs has not been proven superior (24-27); thus, currently, L-OHP combination chemotherapy may be more recommended for IMALN (+) patients owing to their poor prognosis.

The present study had some limitations. It is a retrospective study in a single institute, with a small number of patients. In particular, the number of patients with IMALN (+) was small because IMALN (+) is relatively rare (7, 28). However, regardless of the small number, our results may have meaningful implications on tumor stage classification, showed stage III IMALN (+) had worse prognosis than stage III IMALN (–), and showed no significant difference between stage III IMALN (+) and stage IV LCRC (LYM). Therefore, a large, prospective, randomized study is needed in the future to verify our findings.

In conclusion, the present study suggests that IMALN (+) can be a poor prognostic factor for 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 IMALN (+).

Acknowledgements

The Authors would like to thank Editage (www.editage.com) for English language editing.

Footnotes

  • Authors’ Contributions

    All Authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by KT and TA. The first draft of the manuscript was written by KT and TA. All Authors commented on previous versions of the manuscript and read and approved the final manuscript.

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest in relation to this study.

  • Received March 27, 2021.
  • Revision received April 15, 2021.
  • Accepted April 16, 2021.

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