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Abstract Background: It is unclear whether the number or distribution of lymph node metastases can provide a more accurate prognosis. The aim of this study was to evaluate the prognostic impact of inferior mesenteric artery (IMA) lymph node metastasis (LNM) in sigmoid colon and rectal cancer. Methods: We included 188 patients who underwent curative resection for stage III sigmoid colon and rectal cancer between January 2001 and December 2012. Patients were divided into two groups based on the presence of IMA LNM (LNM-positive vs. LNM-negative group). Clinicopathological characteristics, 3-year recurrence-free survival and 5-year overall survival rates, and recurrence patterns were compared between the two groups. Results: Of 188 patients, nine patients (4.79%) were in the LNM-positive group. After curative resection, 3-year recurrence-free survival and 5-year overall survival rates were significantly lower in the LNM-positive group compared to the LNM-negative group (44.44% vs. 69.98%, p = 0.016 for 3-year recurrence-free survival and 48.61% vs. 81.73%, p = 0.018 for 5-year overall survival). Multivariate analysis revealed that the presence of IMA LNM (p = 0.04), not the number of LNMs (p = 0.153), was an independent prognostic factor for recurrence-free survival. The paraaortic lymph node metastasis rate was significantly higher in the LNM-positive group (p = 0.0078). Conclusions: IMA LNM is an independent predictor of survival for stage III sigmoid colon and rectal cancer patients. Evaluation of IMA LNM enables accurate estimation of patient prognosis and enhances appropriate postoperative therapy. Keywords: Lymph node metastasis・Inferior mesenteric artery・Prognostic factor・ Colorectal cancer. Introduction The presence of regional lymph node metastasis is an important prognostic factor after curative resection for colorectal cancer. This factor defines the tumor stage and determines the postoperative therapy. According to the guidelines of the TNM Committee of the International Union Against Cancer (UICC, seventh edition), only the number of lymph node metastases defines N classification; the distribution of lymph node metastasis is not taken into consideration.1,2 This TNM staging system has the advantage of simplicity and has been adopted as a standard worldwide. A recent study revealed that the anatomical location of lymph node metastasis is also an important factor for accurate diagnosis.3-6 Kang et al. demonstrated that inferior mesenteric artery (IMA) lymph node metastasis is associated with a high incidence of systemic recurrence and poor prognosis after curative resection of colorectal cancer.7 Moreover, Huh et al. showed that the distribution of lymph node metastasis is an independent predictor of survival for patients with colorectal cancer.8 They stated that evaluating the distribution of regional lymph node metastases may be helpful for accurate prognostic stratification and appropriate postoperative therapy. By contrast, however, Suzuki et al. and others demonstrated that the number, not location, of lymph node metastases better predicts prognosis for colon cancer.9-11 Thus, whether the distribution of regional lymph node metastases provides a more accurate prognosis is subject to debate. Moreover, few studies have focused on IMA lymph node metastasis, because dissecting the IMA lymph node generally requires complicated surgery and because the incidence of IMA lymph node metastasis is very low. Therefore, the purpose of this study was to investigate the prognostic significance of IMA lymph node metastasis for patients with stage III sigmoid colon and rectal cancer after curative resection. Materials and Methods Patients and Study design From January 2001 to December 2012, data from 953 consecutive patients who underwent surgical resection for carcinoma of the sigmoid colon or rectum at our institute were reviewed. Of these, only patients who underwent curative resection and had been diagnosed with pathologically curative stage III carcinoma of the sigmoid colon or rectum were included in this study. Patients were excluded if they had had preoperative chemotherapy or radiotherapy. Consequently, a total of 188 patients were included in this study. We defined IMA lymph nodes as a regional lymph node that lies along the IMA, from the origin of the IMA to the bifurcation of the left colic artery. Patients were divided into two groups based on the presence of IMA lymph node metastasis: positive IMA lymph node metastasis (LNM-positive group) and negative IMA lymph node metastasis (LNM-negative group). Clinicopathological characteristics, 3-year recurrence-free survival and 5-year overall survival rates, and recurrence patterns were compared between the two groups. All patients provided written informed consent, in accordance with guidelines approved by the Institutional Review Board of Ethics at our institute, in accordance with the Declaration of Helsinki. Surgical Technique All patients who were included in this study underwent curative resection for their primary tumors, according to surgical oncological principles, and total mesorectal excision was performed by experienced surgical experts who are board certified surgeons in gastroenterology by The Japanese Society of Gastroenterological Surgery. All regional lymph nodes were dissected, including IMA lymph nodes. The inferior mesenteric vein was ligated and divided. Distal surgical margins of >5 cm were achieved for tumors located above the peritoneal reflection, and surgical margins were >2 cm for tumors located below the peritoneal reflection. Lateral pelvic lymph node dissection was not performed routinely in the surgical procedure. The primary tumor and all dissected lymph node specimens were stained with hematoxylin and eosin and evaluated by experienced pathologists. Pathological stages were determined according to the seventh edition of the UICC TNM Classification of Malignant Tumors.2 Following curative resection of the tumor, patients underwent blood tests including tumor marker CEA and CA19-9 every 3 months, chest-abdominal computed tomography every 6 months, and colonoscopy annually. Statistical Analysis Statistical analyses were performed using the JMP10 program (SAS Institute, Cary, NC, USA) and GraphPad Prism version 6.00 for Windows (GraphPad Software, San Diego CA, USA). Factors between the two groups were compared using chi-square test and Fisher’s exact test, and continuous variables were compared with Student’s t-test. Survival rates were calculated using the Kaplan–Meier method. After univariate analysis of the potential predictive factors affecting recurrence-free survival and overall survival, only the significant variables were used in the multivariate analysis, which used the Cox proportional hazard model and the log-rank test to calculate hazard ratios (HR) and 95% confidence intervals (CI). Analysis data are expressed as mean ± standard deviations, and two-tailed p values < 0.05 were considered statistically significant. Results Clinicopathological Characteristics Clinicopathological characteristics between the two groups are shown in Table 1. IMA lymph node metastasis (LNM-positive group) was observed in nine patients (4.79%), whereas 179 patients (95.21%) had no IMA lymph node metastasis (LNM-negative group). Although the number of retrieved lymph nodes was not significantly different between the two groups, the number of metastatic lymph nodes was significantly higher in the LNM-positive group than in the LNM-negative group (p < 0.001). No significant differences were found in sex, age, preoperative carcinoembryonic antigen (CEA) levels, tumor size, tumor location, tumor invasion, histological grade, nor postoperative adjuvant chemotherapy. The patients in each group received exactly the same adjuvant chemotherapy. In LNM-positive group, 7 out of 9 patients (77.8%) received 5fluorouracil (5-FU) based adjuvant chemotherapy. Among these 7 patients, 2 patients (28.6%) received 5-FU plus oxaliplatin based adjuvant chemotherapy. In the LNMnegative group, 137 out of 179 patients (76.5%) received 5-FU based adjuvant chemotherapy. Within these 137 patients, 13 patients (9.5%) received 5-FU plus oxaliplatin based adjuvant chemotherapy. Importantly, the ratio of the patients who received 5-FU based adjuvant chemotherapy in each group was statistically the same (p = 1.00, analyzed by Fisher's exact test). However, 44 patients did not receive adjuvant treatment due to poor performance status or patient refusal. Survival Analysis With a median follow-up period of 981 days, the 3-year recurrence-free survival rate was significantly lower in the LNM-positive group than in the LNM-negative group (44.44% vs 69.98%, respectively; p = 0.016) (Fig. 1). Moreover, with a median followup period of 1499 days, the 5-year overall survival rate was also significantly lower in the LNM-positive group than in the LNM-negative group (48.61% vs 81.73%, respectively; p = 0.018) (Fig. 2). Clinicopathological Factors Associated with Poor Prognosis Univariate analysis indicated that the clinicopathological factors associated with poor recurrence-free survival were tumor size (p = 0.002), tumor invasion (p = 0.0003), and IMA lymph node metastasis (p = 0.046). Multivariate analysis revealed that IMA lymph node metastasis was an independent prognostic factor (p = 0.04), in addition to tumor size (p = 0.035) and tumor invasion (p = 0.006) (Table 2). However, the number of metastatic lymph nodes was not associated with poor prognosis in this patient population (p = 0.153). For overall survival, the preoperative CEA level was the only factor associated with poor prognosis (p = 0.027) (Table 3). Primary Recurrence Pattern Among the various primary recurrence patterns, the paraaortic lymph node metastasis rate was significantly higher in the LNM-positive group than in the LNM-negative group (33.3% vs 3.91%, respectively; p = 0.0078) (Table 4). The median interval of paraaortic lymph node recurrence was 480 days after curative resection. In other primary recurrence patterns, no significant differences were found between the two groups. Discussion The present study revealed that the survival rate was significantly lower in the LNMpositive group than in the LNM-negative group. The reasons for this poorer prognosis could be the larger number of metastatic lymph nodes and the higher rate of paraaortic recurrence in the LNM-positive group. Moreover, IMA lymph node metastasis was an independent poor prognostic factor for patients with stage III sigmoid colon and rectal cancer. Multivariate analysis indicated that the number of metastatic lymph nodes was not an independent prognostic factor in this study. These results support the concept that the distribution, rather than the number of lymph node metastases, is a valuable and a reliable prognostic factor for patients with colorectal cancer.8,12,13 Furthermore, the present study yielded a reasonable average number of retrieved lymph nodes: 21.94 per patient. Indeed, the American Joint Committee on Cancer and other reports have recommended that 12 or more lymph nodes should be retrieved in patients with colorectal cancer who undergo curative intent surgery.1,14,15 A recent prospective study by Leibold et al. suggested that the current TNM staging system, based on the number of metastatic lymph nodes alone, may not provide an accurate assessment, especially after preoperative chemoradiotherapy.16 Because the number of involved lymph nodes decreases after preoperative treatment, the authors stated that the staging system should incorporate the distribution as well as the number of metastatic lymph nodes. Moreover, Kang et al. reported that the 5-year disease-free survival rate was lower in the positive IMA lymph node metastasis group than in the negative IMA lymph node metastasis group (31.9% vs 69.4%, respectively; p < 0.001).7 They demonstrated that IMA lymph node metastasis was associated with a high incidence of systemic recurrence, and that it was an independent prognostic factor after curative resection of stage III sigmoid or rectal cancer patients. Consequently, in this context, the current Japanese Classification of Colorectal Carcinoma (eighth edition) is based on both the presence of IMA lymph node metastasis and the absolute number of metastatic lymph nodes.17 Although several reports have suggested the prognostic significance of IMA lymph node metastasis in colorectal cancer, the appropriate region of elective lymph node dissection has not been established. According to our results, IMA lymph node metastasis was significantly associated with paraaortic lymph node recurrence, because they are anatomically close and connected through lymphatic vessels. Furthermore, a previous study demonstrated the high incidence of systemic recurrence in patients with IMA lymph node metastasis.7 These findings may support the survival benefits of removal of IMA lymph nodes by high ligation.18 In addition, Kanemitsu et al. evaluated 1188 consecutive patients who underwent resection for sigmoid colon or rectal cancer, with high ligation of the IMA.19 They demonstrated that high ligation of the IMA allowed curative resection and long-term survival. By contrast, recent systematic reviews reported that there is no survival benefit to removal of IMA lymph nodes by high ligation.20 This surgical procedure decreases perfusion and innervation of the proximal limb, increasing the risk of anastomotic leakage.21 Moreover, the incidence of IMA lymph node metastasis was 4.79% in our study and was reported in previous studies to be low, ranging from 0.3% to 8.6%.16,20,22,23 This low incidence could also be one of the reasons that we and others could not demonstrate a survival benefit. Taken together, there is no conclusive evidence to support a survival benefit among patients who undergo removal of IMA lymph node by high ligation.24-26 However, our results suggest that pathological evaluation after dissection of the IMA lymph node is necessary for appropriate tumor staging and accurate estimation of patient prognosis. Moreover, these results would be beneficial in determining appropriate postoperative treatment strategy. The patients with positive IMA lymph node metastasis should be carefully followed up with tumor biomarkers as well as imaging modalities, and should be highly recommended to receive 5-FU plus oxaliplatin based adjuvant chemotherapy intensively. There are several limitations to this study. First, the number of patients who had IMA lymph node metastasis was relatively small in this study, which is similar to other studies. Second, patients with either sigmoid colon cancer or rectal cancer were included in this study, although these two cancers have generally different biological behaviors, especially different drainage basins of the lymph nodes. However, there was no significant difference in tumor location between the two groups and multivariate analysis revealed that IMA lymph node metastasis was prognostically significant, regardless of the tumor location. Third, advances and changes in chemotherapy since 2001 could have some impact on patient survival in this study. However, the baseline ratio of patients who received 5-FU based adjuvant chemotherapy in each group was statistically the same, and thus enabled us to perform fair comparisons between the two groups. Further studies are needed to evaluate the impact of IMA lymph node metastasis on survival in order to yield the best outcomes for patients with colorectal cancer. In conclusion, our study revealed that IMA lymph node metastasis is an independent poor prognostic factor for patients with stage III sigmoid colon and rectal cancer after curative resection. Pathological evaluation of IMA lymph node metastasis enables accurate estimation of patient prognosis and enhances appropriate postoperative therapy. Conflict of Interest All authors have no potential conflicts of interest to disclose. References 1. Nelson H, Petrelli N, Carlin A, Couture J, Fleshman J, Guillem J et al. Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst 2001;93(8):583-596 2. Sobin LH, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumours, 7th Edition: Wiley-Blackwell; 2009. 3. Kim JS, Sohn DK, Park JW, Kim DY, Chang HJ, Choi HS et al. Prognostic significance of distribution of lymph node metastasis in advanced mid or low rectal cancer. J Surg Oncol 2011;104(5):486-492 4. Wang XJ, Chi P, Lin HM, Lu XR, Huang Y, Xu ZB et al. A scoring system to predict inferior mesenteric artery lymph node metastasis and prognostic value of its involvement in rectal cancer. Int J Colorectal Dis 2014;29(3):293-300 5. Peng J, Wu H, Li X, Sheng W, Huang D, Guan Z et al. Prognostic significance of apical lymph node metastasis in patients with node-positive rectal cancer. Colorectal Dis 2013;15(1):e13-20 6. Kim JC, Lee KH, Yu CS, Kim HC, Kim JR, Chang HM et al. The clinicopathological significance of inferior mesenteric lymph node metastasis in colorectal cancer. Eur J Surg Oncol 2004;30(3):271-279 7. Kang J, Hur H, Min BS, Kim NK, Lee KY. Prognostic impact of inferior mesenteric artery lymph node metastasis in colorectal cancer. Ann Surg Oncol 2011;18(3):704-710 8. Huh JW, Kim YJ, Kim HR. Distribution of lymph node metastases is an independent predictor of survival for sigmoid colon and rectal cancer. Ann Surg 2012;255(1):70-78 9. Suzuki O, Sekishita Y, Shiono T, Ono K, Fujimori M, Kondo S. Number of lymph node metastases is better predictor of prognosis than level of lymph node metastasis in patients with node-positive colon cancer. J Am Coll Surg 2006;202(5):732-736 10. Homma Y, Hamano T, Otsuki Y, Shimizu S, Kobayashi Y. Total number of lymph node metastases is a more significant risk factor for poor prognosis than positive lateral lymph node metastasis. Surg Today 2015;45(2):168-174 11. Sabbagh C, Mauvais F, Cosse C, Rebibo L, Joly JP, Dromer D et al. A lymph node ratio of 10% is predictive of survival in stage III colon cancer: a French regional study. Int Surg 2014;99(4):344-353 12. Kobayashi H, Ueno H, Hashiguchi Y, Mochizuki H. Distribution of lymph node metastasis is a prognostic index in patients with stage III colon cancer. Surgery 2006;139(4):516-522 13. Hida J, Okuno K, Yasutomi M, Yoshifuji T, Matsuzaki T, Uchida T et al. Number versus distribution in classifying regional lymph node metastases from colon cancer. J Am Coll Surg 2005;201(2):217-222 14. Park IJ, Choi GS, Jun SH. Nodal stage of stage III colon cancer: the impact of metastatic lymph node ratio. J Surg Oncol 2009;100(3):240-243 15. La Torre M, Lorenzon L, Pilozzi E, Barucca V, Cavallini M, Ziparo V et al. Number of harvested lymph nodes is the main prognostic factor in Stage IIa colorectal cancer patients. J Surg Oncol 2012;106(4):469-474 16. Leibold T, Shia J, Ruo L, Minsky BD, Akhurst T, Gollub MJ et al. Prognostic implications of the distribution of lymph node metastases in rectal cancer after neoadjuvant chemoradiotherapy. J Clin Oncol 2008;26(13):2106-2111 17. Watanabe T, Itabashi M, Shimada Y, Tanaka S, Ito Y, Ajioka Y et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines 2014 for treatment of colorectal cancer. Int J Clin Oncol 2015;20(2):207-239 18. Chin CC, Yeh CY, Tang R, Changchien CR, Huang WS, Wang JY. The oncologic benefit of high ligation of the inferior mesenteric artery in the surgical treatment of rectal or sigmoid colon cancer. Int J Colorectal Dis 2008;23(8):783- 788 19. Kanemitsu Y, Hirai T, Komori K, Kato T. Survival benefit of high ligation of the inferior mesenteric artery in sigmoid colon or rectal cancer surgery. Br J Surg 2006;93(5):609-615 20. Lange MM, Buunen M, van de Velde CJ, Lange JF. Level of arterial ligation in rectal cancer surgery: low tie preferred over high tie. A review. Dis Colon Rectum 2008;51(7):1139-1145 21. Beppu N, Matsubara N, Noda M, Kimura F, Yamanaka N, Yanagi H et al. A'high tie'confers an increased risk of anastomotic leakage for lower rectal cancer surgery in patients treated with preoperative radiotherapy. Surg Today 2015;45(5):600-605 22. Hida J, Yasutomi M, Maruyama T, Fujimoto K, Nakajima A, Uchida T et al. Indication for using high ligation of the inferior mesenteric artery in rectal cancer surgery. Examination of nodal metastases by the clearing method. Dis Colon Rectum 1998;41(8):984-987; discussion 987-991 23. Uehara K, Yamamoto S, Fujita S, Akasu T, Moriya Y. Impact of upward lymph node dissection on survival rates in advanced lower rectal carcinoma. Dig Surg 2007;24(5):375-381 24. Hida J, Okuno K. High ligation of the inferior mesenteric artery in rectal cancer surgery. Surg Today 2013;43(1):8-19 25. Titu LV, Tweedle E, Rooney PS. High tie of the inferior mesenteric artery in curative surgery for left colonic and rectal cancers: a systematic review. Dig Surg 2008;25(2):148-157 26. Cirocchi R, Trastulli S, Farinella E, Desiderio J, Vettoretto N, Parisi A et al. High tie versus low tie of the inferior mesenteric artery in colorectal cancer: a RCT is needed. Surg Oncol 2012;21(3):e111-123 Figure Legends Figure 1. Kaplan–Meier recurrence-free survival in LNM-positive and LNM-negative groups. The 3-year recurrence-free survival rates of the LNM-positive group and the LNM-negative group were 44.44% and 69.98%, respectively (p = 0.016). Figure 2. Kaplan–Meier overall survival in LNM-positive and LNM-negative groups. The 5-year overall survival rates of the LNM-positive group and the LNM-negative group were 48.61% and 81.73%, respectively (p = 0.018). Table 1. Clinicopathological characteristics SD, standard deviation; RS, rectosigmoid; Ra, above peritoneal reflection; Rb, below peritoneal reflection; No, number; well, well differentiated; mod, moderately differentiated. Table 2. Univariate and multivariate analyses for recurrence-free survival RR, relative risk; CEA, carcinoembryonic antigen; LN, lymph node; IMA, inferior mesenteric artery; well, well differentiated; mod, moderately differentiated. Table 3. Univariate and multivariate analyses for overall survival RR, relative risk; CEA, carcinoembryonic antigen; LN, lymph node; IMA, inferior mesenteric artery; well, well differentiated; mod, moderately differentiated. Table 4. Primary recurrence patterns LN, lymph node.