Lymphatic spread patterns in young vs. elderly stage III colon cancer patients

Lymphatic spread patterns in young vs. elderly stage III colon cancer patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Lymphatic spread patterns in young vs. elderly stage III colon cancer patients Song Jihyung, Kozo Kataoka, Manabu Inoue, Takeshi Yamada, Naohito Beppu, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2890434/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: It currently remains unclear whether the anatomical pattern of lymph node (LN) spread differs between young (≤ 45 years, Y) and elderly (≥ 80 years, E) patients with stage III colon cancer (CC). Materials and Methods: Two groups of patients (Y and E) with stage III CC who underwent extensive (D3) lymphadenectomy at Japanese centers were retrospectively analyzed. The primary endpoint was the proportion of positive central LN. The planned sample size was at least 210 (Y) based on an expected value of 9.1% and threshold of 5%, and 230 (E) based on an expected value of 2% and threshold of 5%. Results: Two-hundred and ten Y patients and 348 E patients were identified and compared. The total number of LN harvested and the total number of invaded LN were significantly higher in group Y (median of 31.5 (3-151) vs. 21 (3-116), P < 0.001 and median of 3 (1–21) vs. 2 (1–25), P < 0.001, respectively). The proportion of positive central LN was higher in group Y than the prespecified threshold of 5% (9.52% (95% CI: 6.24–14.2%), p = 0.007); however it was similar to the threshold in group E (4.59% (95% CI:2.84–7.31%), p = 0.351). In multivariate models, central LN invasion was identified as a poor prognostic factor in group Y (HR3.66 (95% CI (1.29–8.87)), but not in group E (HR2.02 (0.95–4.27)). Conclusions: Young stage III colon cancer patients have a higher risk of central LN invasion, suggesting a more aggressive disease biology. The presence of central LN invasion is associated with a worse outcome. central lymph node colon cancer elderly lymph node spreading pattern young Figures Figure 1 Figure 2 Figure 3 1. Introduction Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide, and has the second highest mortality rate [ 1 ]. The incidence of CRC is increasing among young adults, which led to the recommendation of early cancer screening starting at the age of 45 years in the United States and 40 years in Japan[ 2 , 3 ]. On the other hand, due to longer life expectancy, the incidence of CRC in the elderly is also increasing [ 4 ]. Therefore, clinicopathological features of CRC in these two populations need to be clarified. Lymph nodes (LN) involvement is the most important prognostic factor in CRC [ 5 ]. We previously reported the prognostic impact of the anatomical LN spread pattern of colon cancer (CC) in terms of the location of invaded LN (central LN vs. intermediate/paracolic LN), sidedness (right vs. left) and molecular biomarkers (RAS, BRAF, microsatellite instability (MSI)) [ 6 – 8 ]. Additionally, population-based studies suggested age-related variations in the total LN count harvested and invaded in surgically resected CC [ 9 – 11 ]; younger patients were more likely to have a higher total and invaded LN count than elderly patients. However, the relationship between patient age and the anatomical location of lymphatic spread in CC is currently unknown. The presence of metastatic central LNs may be relevant in the decision to perform extensive (D3) lymphadenectomy. It has also been identified as a poor prognostic factor in CC [ 12 – 16 ], however, to the best of our knowledge, it currently remains unclear whether the risk of positive central LN invasion varies with age. Therefore, we investigated the relationship between age and the anatomical pattern of lymphatic spread, and their prognostic impact patients with node positive (stage III) CC. 2. Materials and Methods 2.1. Patient selection Pathological stage III CC patients, treated with curative extensive lymphadenectomy (Japanese D3 dissection) at several Japanese high-volume centers between 1998–2018 were retrospectively analyzed. Rectal cancer patients, and patients treated with neoadjuvant therapy were excluded. This retrospective study was reported in line with the STROCSS criteria [ 17 ] and approved by the Institutional Review Board of Hyogo Medical University, Japan (N0. 3789). 2.2. Surgical treatment/chemotherapy Open or laparoscopic colonic resection with Japanese D3 lymphadenectomy was performed in all patients. When the tumor was right sided, the ileocecal vein and/or right colic vein and/or middle colic vein were divided at its origin and the corresponding mesenteric nodal stations (203, 213, and 223) were removed. High ligation of the inferior mesenteric artery (IMA) was performed for left-sided tumors (sigmoid or rectosigmoid), with the removal of LN at station 253, or the left colic artery was preserved and the superior rectal artery was divided at its origin. In descending colon cancer, the left colic artery was divided at its origin with removal of LN station 253, regardless of preservation of IMA. This technique is theoretically equivalent to complete mesocolic excision (CME) with central venous ligation [ 18 ]. The only difference is that the length of the bowel and area of the mesentery removed are more limited in Japanese D3 lymphadenectomy than in the CME technique [ 19 ]. Adjuvant therapy (5-FU or oxaliplatin-based mFOLFOX6 or CapOX) was administered according to the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines [ 2 ]. 2.3. Definition of the L level and the lymphatic spread pattern According to the Japanese Society for Cancer for the Colon and Rectum (JSCCR) staging system, invaded LN were classified into the following three groups, similar to our previous studies [ 6 – 8 , 20 ]: L1 (paracolic), L2 (intermediate), and L3 (main or central) (Fig. 1 ). The 8th edition of the UICC TNM staging system was used [ 20 ]. The definition of ‘sequential’ and ‘skipped’ LN metastasis was as follows: when a more centrally located LN was positive with all previous LN being invaded, this lymphatic spread pattern was defined as ‘sequential’. On the other hand, when one or two nodal stations (L1 and/or L2) were negative and the more centrally located nodal station (L2 and/or L3) was invaded, the lymphatic spread pattern was defined as ‘skipped’. 2.4. Statistical analysis Previous studies reported an increased risk of LN involvement in younger patients [ 10 , 21 ]. Therefore, we expected LN to be more frequently invaded in the younger patients than in elderly patients. Among LN, central LN metastasis was considered to be a poor prognostic factor and clinically important in CC. According to the largest Japanese nationwide data analysis of 4034 cases of pathological stage III CC, the reported frequency of invaded central LN in patients aged 46–79 was 5.2% [ 6 ]. Therefore, in this retrospective study, the post hoc sample size was calculated to be N = 209 young patients to obtain 75% power, with the hypothesis that the primary endpoint has an expected value of 9.1% and threshold value of 5% with one-sided alfa of 5%. Regarding elderly patients, the sample size was 222 with an expected value of 2% and threshold value of 5% with the same alfa and beta as those in young patients. In consideration of potentially ineligible patients, we aimed to include at least 210 pstage III young CC (group Y) and 230 elderly CC (group E). The chi-squared or Fisher’s exact test was used to evaluate the significance of differences between proportions, and the Student’s t -test or Mann-Whitney U test to assess the significance of differences between means where appropriate. Recurrence-free survival (RFS) and overall survival (OS) were estimated from the date of surgery until recurrence or death from any cause. Unadjusted RFS in the Y and E groups and each L-level were estimated using the Kaplan-Meier method and Log-rank tests were performed to compare survival curves. A Cox proportional hazards model was used to identify the relationships between RFS and several known prognostic factors in CC. Elevated postoperative serum CEA, adjuvant therapy (observation vs. 5-FU/doublet), pT stage (T4 vs. T3/2/1), L level (L3 vs. L1/L2), and lymphatic spread pattern (sequential versus skipped) were included as independent variables. All analyses were performed with JMP Pro 15.2.0. 3. Results In this retrospective analysis, 210 stage III CC patients aged 45 years or younger (group Y) and 349 stage III patients aged 80 year or older (group E) were identified. Clinical and pathological variables in both groups are shown in Table 1 . Table 1 Patients characteristics Variables Group Y (N = 210) Gorup E (N = 349) P Value Sex (M/F) 94/116 165/184 0.60 Age 43 (20–45) 83 (80–96) < 0.001 Tumor size 40 (6-160) 45 (10–150) 0.065 Anatomical location V 2 (0.95%) 0 < 0.001 C 15 (7.1%) 54 (15.3%) A 32 (15.2%) 123 (35.2%) T 26 (12.3%) 44 (12.6%) D 22 (10.5%) 22 (6.3%) S 88 (41.9%) 93 (26.6%) Rs 25 (11.9%) 12 (3.7%) T stage T1 15 (7.1%) 8 (2.3%) 0.02 T2 21 (10.0%) 27 (7.7%) T3 118 (56.1%) 198(56.7%) T4a 44 (21.0%) 100 (28.6%) T4b 12 (5.7%) 16 (4.6%) N stage N1a 63 (30.0%) 146 (41.8%) 0.007 N1b 73 (34.8%) 119 (34.1%) N2a 43 (20.5%) 56 (16.0%) N2b 31 (14.8%) 28 (8.0%) Total number of Lymph nodes (LNs) Harvested 31.5 (3-151) 21 (3-116) < 0.001 positive 3 (1–21) 2 (1–25) < 0.001 Positive anatomical LN level (L group; %) L1 136 (64.8%) 237 (67.9%) 0.27 L2 54 (25.7%) 96 (27.5%) L3 20 (9.52%) 16 (4.6%) Surgery Lap 105 (50%) 143 (41.0%) 0.038 Open 105 (50%) 206 (59.0%) Adjuvant therapy No 38 (18.1%) 288 (82.5%) < 0.001 5-FU 111 (52.9%) 51 (14.6%) Doublet 61 (29.0%) 10 (2.9%) Laparoscopic (or laparo-assisted) surgery was performed more frequently in group Y (50.0% vs. and 41.0%, p = 0.02). Adjuvant therapy was more frequently received by group Y than by group E (P < 0.001): In group Y, only 18.1% of patients chose observation without chemotherapy, while 82.5% of group E chose observation. In Japan, since mFOLFOX6/CapOX regimen was approved in 2009, only 2.0% (2/99) of group Y patients who received surgery in the first 10 year (1998 to 2008) received mFOLFOX6/CapOX, while 47.8% (53/111) of group Y patients in the second 10 year (2009 to 2018) received mFOLFOX6/CapOX. Sigmoid and rectosigmoid cancer was more frequently observed in group Y (p < 0.001). Group Y had more advanced tumors, a more advanced N stage, and a higher number of total LN harvested (median of 31.5 (3-151) vs. 21 (3-116), P < 0.001) and invaded (median of 3 (1–21) vs. 2 (1–25), P < 0.001). In contrast, regarding T factors, group Y had less advanced primary tumors compared to group E, a less advanced T stage, and a smaller primary tumor (median of 40 mm (6-160) vs. 45mm (10–150), p = 0.065). In group Y, the proportion of invaded central LN was higher than the prespecified threshold of 5%, (9.52% (95% CI: 6.24–14.2%), p = 0.007), while in group E, the proportion of invaded central LN was similar to the threshold ((4.59% (95% CI:2.84–7.31%), p = 0.351). The observed lymphatic spread patterns are shown in Table 2 . The proportion of patients with a ‘skipped’ lymphatic spread pattern was similar in both groups (11.0% (Y group) vs. 10.9% (E group)). Table 2 LN spreading patterns in young and elderly groups Group Y (N = 210) Group E (N = 349) Sequential +−− 136 (64.7%) 237 (67.9%) ++− 44 (21.0%) 67 (19.2%) +++ 7 (3.3%) 7 (2.0%) Subtotal 187 (89.0%) 311 (89.1%) Skipped −+− 10 (4.8%) 29 (8.3%) +−+ 9 (4.3%) 3 (0.86%) −−+ 4 (1.7%) 3 (0.86%) −++ 0 (0%) 3 (0.86%) Subtotal 23 (11.0%) 38 (10.9%) Unadjusted 5-year RFS and OS rates were significantly worse in group E than in group Y (57.3% vs. 72.8%; p < 0.001 and 66.7% vs. 87.4%; p < 0.001, respectively) (Fig. 2 ). RFS according to the L status is shown in Fig. 3 . Five-year RFS rates in L3 (central LN positive) were lower compared to that in L1 and L2 in both groups (group Y: L1/L2/L3: 78.5%/64.9%/55.0% (p = 0.031); group E: L1/L2/L3 62.1%/49.0%/40.0% (p = 0.0065), respectively). To examine the prognostic significance of the anatomical pattern of lymphatic spread in each group, a Cox multivariate analysis was performed (Table 3 ). Table 3 Multivariate analysis Group Y (N = 210) Group E (N = 349) HR P value HR P value Elevated postoperative CEA 3.99 (1.85–7.82) 0.0001 1.97 (1.33–2.91) 0.0007 L3 (vs. L1/L2) 3.66 (1.29–8.87) 0.0082 2.02 (0.95–4.27) 0.068 Skipped pattern (vs. sequential) 0.32 (0.10–0.96) 0.049 0.96 (0.55–1.66) 0.87 Adjuvant therapy (obs vs. FU/doublet) 0.69 (0.30–1.60) 0.39 0.62(0.27–1.43) 0.26 T4 (vs. T3/2/1) 2.15 (1.20–3.79) 0.0086 1.47 (1.04–2.07) 0.026 In group Y, elevated postoperative CEA, a skipped LN spread pattern, stage pT4, and the presence of invaded L3 nodes were associated with a poor prognosis. In group E, elevated postoperative CEA and stage pT4 were associated with a poor prognosis. The presence of invaded L3 nodes indicated a slightly worse RFS in group E (HR 2.02 (0.95–4.27) p = 0.068). 4. Discussion Surgery remains the mainstay for curative treatment in resectable CC and lymphadenectomy plays a central role in minimizing the risk of recurrence. Therefore, it is essential to understand the nature of the lymphatic spread pattern. The actual extent of lymphadenectomy may be affected by age; surgeons are more likely to perform radical surgery on young patients. However, limited information is currently available on the relationship between age and lymphatic spread patterns. In this analysis, age-related differences were observed in the lymphatic spread pattern according to patient age: the total number of harvested LN and the number of invaded LN were higher in young CC patients. The frequency of central LN metastases in young CC patients aged 45 years or younger was significantly higher than the prespecified threshold, while that in elderly CC patients aged 80 year or older was similar. The threshold was estimated from a nationwide database from the JSCCR [ 6 ]. Central LN metastasis had a stronger prognostic impact in young CC patients. To the best of our knowledge, this is the first study to report the relationship between age and the anatomical location of invaded LN in stage III CC. In Japan, LN stations are historically mapped according to anatomical location, allowing unique insights in the prognostic significance of spatial and temporal lymphatic spread patterns in CC. The presence of central LN metastasis has been identified as an important prognostic factor in CC [ 12 – 16 ]. In the JSCCR guidelines, central LN metastases are categorized as N3 [ 2 ] (which is different from the eighth edition of the UICC TNM classification [ 20 ]). The present results support this classification: The 5-years RFS rate in the L3 group was poor in both populations (55.0% in the Y group and 40.0% in the E group) and the multivariate analysis identified positive central LN positive as a poor prognostic factor, particularly in the Y group. When the central LN is anticipated to be negative, D2 lymphadenectomy may be sufficient, which may minimize the risk of postoperative complications. However, extended surgery including D3 lymphadenectomy may benefit young CC patients because the frequency of positive central LN is approximately 10%. However, since central LN invasion reflects aggressive disease with a poor prognosis, it is uncertain whether more aggressive surgery can impact survival. It may reduce the risk of local (nodal) recurrence and progression. Furthermore, patients with suspected positive L3 nodes may benefit from neoadjuvant treatment (chemotherapy and/or immune therapy). In the E group, the frequency of central LN positivity was similar to the prespecified threshold. If these patients are fit for surgery, there is also a potential benefit of D3 lymphadenectomy; however, the prognostic impact of radical surgery may be less than in younger patients. Different clinicopathological features were observed between Y and E groups in the present study. Right-sided tumors and advanced primary tumors in size and depth were observed in the E group, whereas the total number of LN harvested and invaded was higher in the Y group. Young CRC patients are more likely to have poorly differentiated and left-sided tumors [ 22 ]. Previous studies reported a correlation between age and the number of LN. Sarli et al. revealed an age-related decrease in the number of LN harvested [ 23 ]. Quan et al. suggested that surgical specimens from young CRC patients yielded a higher number of LN than those from elderly patients [ 24 ]. Furthermore, the host immune response may lead to enlarged LN, and therefore a weaker immune response may lead to smaller LN and fewer LN [ 25 , 26 ]. The present results were consistent with these findings. The differences in tumor size, N stage, and T stage between both groups are consistent with literature findings that early onset CRC is often diagnosed at a later stage. Also, these differences can be due to random variation since p values were not adjusted for multiple comparisons. A detailed molecular profile was not available in our series. Limited information is currently available on the genetic backgrounds of young and elderly CRC patients[ 27 , 28 ]. Further investigation is required to investigate age-specific molecular mechanisms in CC. The existence of a ‘skipped’ LN pattern is clinically important because this pattern may affect the extent of surgery. Two different models of cancer lymphatic spread have been proposed and discussed for decades (Fig. 1 ). The Halsted model assumes that lymphatic spread is a process in which cancer cells migrate in a predictable and stepwise manner from the primary tumor to paracolic LN, and then to intermediate nodes, the central nodes, and eventually to distant organs [ 29 , 30 ]. This model is applicable to head and neck cancer. On the other hand, the Fisher model states that lymphatic progression and hematogenous metastasis occur at random before the previous LN station is breached [ 31 ]. This model reflects the biology of breast cancer, and has led to the abandonment of extensive, mutilating surgery for this cancer type. A high frequency of ‘skipped’ LN metastases supports the possibility that a cancer follows the Fisher model. The incidence of ‘skipped’ metastases in CC varies among studies. A recent systematic review showed an incidence of less than 18% [ 32 ]. Our group suggested differences in the proportion of ‘skipped’ LN metastases depending on the molecular biomarker used and tumor sidedness: this proportion was 9.3% in BRAF mutant vs. 20.0% in BRAF wild type, 4% in MSI-High vs. 10.5% in microsatellite stable, and 13.7% in right-sided CC vs. 9.0% in left-sided CC. The present results showed that the anatomical pattern of LN spread was not affected by age. MSI-H is more frequently detected in young CRC patients [ 33 ]; however, data on molecular biomarkers were not available for the present study. Therefore, further studies that incorporate molecular data and age are warranted. Propensity score matching (PSM) was not used because there is no general agreement on the fact whether PSM is always superior to multivariable regression. Additionally, if PSM was performed in this population, the analyzed population would be quite smaller because common parts between two groups are quite small. Therefore, we have considered Cox regression to be equivalent for the analysis of our data [ 34 ].There were several limitations that need to be addressed. The molecular profile, such as mutations in RAS or BRAF and the mismatch repair status, was not available in the database. Second, since the opposite patient populations were compared using the data collected from a database spanning 20 years, the survival data should be cautiously interpreted. In this study, OS was much worse in group E than in group Y. However, the cause of death was different in the two groups. One hundred and eight out of 186 events of deaths were due to colon cancer in E group, but only 13 out of 35 in Y group. Additionally, the chemotherapy regimen was affected by the year the patients underwent surgery as described in the Results section. Regarding surgery, the concept of D3 extended lymphadenectomy has already been established for more than two decades in Japanese high-volume centers. Since only high-volume centers in which D3 lymphadenectomy is performed as clinical practice since 1998 participated in this present study, the quality of surgery and LN examinations were considered to be high. Another limitation is that the post hoc statistical power to detect the endpoint was only 75%. However, this did likely not affect the results and their clinical significance. In conclusion, differences in the lymphatic spread pattern were observed between young and elderly CC patients. Young CC patients need to undergo extensive D3 lymphadenectomy due to the higher frequency of central LN invasion. When extensive lymphadenectomy is performed on elderly CC patients, a balance between the effects of lymphadenectomy and the fitness of patients’needs to be considered. Surgeons may perform tailored surgery in which the appropriate extent of lymphadenectomy is defined using these data. Abbreviations LN, lymph node; CRC, colorectal cancer; CC, colon cancer; CI, confidence interval; MSI, microsatellite instability; RFS, Relapse-free survival; OS, overall survival; MSS, microsatellite-stable; CME, complete mesocolic excision; HR, Hazard ratio; Declarations Author contributions: We have fifteen authors but all the authors reviewed the manuscript critically, have contributed significantly, and are in agreement with the content of the manuscript. Especially, Kozo Kataoka, and Wim Ceelen mainly contributed to conception and design of this study. Naohito Beppu, Song Jihyung, Takeshi Yamada, Manabu Shiozawa, Yusuke Sakura, Takeshi Suto, Nobuhisa Matsuhashi, Sho Kuriyama, Akiyoshi Kanazawa, Hiroyasu Kagawa mainly contributed to the acquisition of the data. Kozo Kataoka and Wim Ceelen mainly contributed to the statistical analysis. Masataka Ikeda, Yukihide Kanemitsu and Wim Ceelen summarized the interpretation of the results which were discussed among all authors. Kozo Kataoka and Song Jihyung contributed equally to this work as first author. Acknowledgements: This work was supported by JSPS KAKENHI Grant Number 21K15494 Source of Funding: There is no source of funding regarding this work. Disclosure of any commercial interest: The authors have no conflicts of interest to disclose. References Sung H, Ferlay J, Siegel RL et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021; 71: 209-249. Hashiguchi Y, Muro K, Saito Y et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer. Int J Clin Oncol 2020; 25: 1-42. Weinberg BA, Marshall JL, Salem ME. The Growing Challenge of Young Adults With Colorectal Cancer. Oncology (Williston Park) 2017; 31: 381-389. Siegel RL, Miller KD, Fedewa SA et al. Colorectal cancer statistics, 2017. CA Cancer J Clin 2017; 67: 177-193. Ong ML, Schofield JB. 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Are propensity scores really superior to standard multivariable analysis? Contemp Clin Trials 2011; 32: 731-740. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2890434","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":198145029,"identity":"60cacabf-b85f-4dd5-a78a-f3e84b6d72ba","order_by":0,"name":"Song Jihyung","email":"","orcid":"","institution":"Hyogo Medical University","correspondingAuthor":false,"prefix":"","firstName":"Song","middleName":"","lastName":"Jihyung","suffix":""},{"id":198145030,"identity":"3fd42102-2170-4ca8-9965-3c7826162a20","order_by":1,"name":"Kozo Kataoka","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABC0lEQVRIiWNgGAWjYBACCSBmbACxeBgYH4OFmJnBfGYCWgxAWpiNGUAMZkbitbBJg7VAbcUJJNvbHz6cUfNHnp/n8LPqgoo/0fztQC0/KhjYzXFokeY5kGy44ZiB4czeNrPbM84Y5M44zNjA2HOGgdkSh2VyEgnHJB+wGTBuOM9gdpu3zSC3AaiFmbGNgdngAC4tiW2SD/4Z2G84z/6tGKRlPiEt0hLJbJIb2wwSN5ztMWMGadlASItkzzFmw5l9xskze84US/OcMc7dCNRysOeMBE6/SBwHhljPNznbfp70jZ95KuRy550/fPDBjwqbZFwhhh0AnSSRbECSFhCwI13LKBgFo2AUDFMAALryWKaENNVoAAAAAElFTkSuQmCC","orcid":"","institution":"Hyogo Medical University","correspondingAuthor":true,"prefix":"","firstName":"Kozo","middleName":"","lastName":"Kataoka","suffix":""},{"id":198145031,"identity":"a9741e1d-6f27-4864-a4a8-2ec28653867b","order_by":2,"name":"Manabu Inoue","email":"","orcid":"","institution":"National Cancer Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Manabu","middleName":"","lastName":"Inoue","suffix":""},{"id":198145032,"identity":"012b7068-d758-44ea-b890-8e61ed937a33","order_by":3,"name":"Takeshi Yamada","email":"","orcid":"","institution":"Nippon medical school","correspondingAuthor":false,"prefix":"","firstName":"Takeshi","middleName":"","lastName":"Yamada","suffix":""},{"id":198145033,"identity":"e4bb4cee-230c-4f72-be5e-0ee37f545efe","order_by":4,"name":"Naohito Beppu","email":"","orcid":"","institution":"Hyogo Medical University","correspondingAuthor":false,"prefix":"","firstName":"Naohito","middleName":"","lastName":"Beppu","suffix":""},{"id":198145034,"identity":"8d2c888a-a6cb-46b0-a3c9-1af426528f50","order_by":5,"name":"Sho Kuriyama","email":"","orcid":"","institution":"Nippon medical school","correspondingAuthor":false,"prefix":"","firstName":"Sho","middleName":"","lastName":"Kuriyama","suffix":""},{"id":198145035,"identity":"ff5c5c0f-cdcd-480e-b9bf-7781dddf0da1","order_by":6,"name":"Takeshi Suto","email":"","orcid":"","institution":"Yamagata Prefectural Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Takeshi","middleName":"","lastName":"Suto","suffix":""},{"id":198145036,"identity":"7c39e45a-38d1-4d74-8182-4165014adb2f","order_by":7,"name":"Nobuhisa Matsuhashi","email":"","orcid":"","institution":"Gifu University","correspondingAuthor":false,"prefix":"","firstName":"Nobuhisa","middleName":"","lastName":"Matsuhashi","suffix":""},{"id":198145037,"identity":"0addf682-12a1-4433-9cf0-1fd2d3d70577","order_by":8,"name":"Yusuke Sakura","email":"","orcid":"","institution":"Shimane Prefectural Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yusuke","middleName":"","lastName":"Sakura","suffix":""},{"id":198145038,"identity":"5cc85967-251b-48e5-9860-1d86a274cb71","order_by":9,"name":"Akiyoshi Kanazawa","email":"","orcid":"","institution":"Shimane Prefectural Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Akiyoshi","middleName":"","lastName":"Kanazawa","suffix":""},{"id":198145039,"identity":"a078f42b-bd6f-48b1-9fc1-8f8ba5a327a3","order_by":10,"name":"Hiroyasu Kagawa","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Hiroyasu","middleName":"","lastName":"Kagawa","suffix":""},{"id":198145040,"identity":"ed4e1080-7dd1-4798-b83e-a27a167a26e6","order_by":11,"name":"Yukihide Kanemitsu","email":"","orcid":"","institution":"National Cancer Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yukihide","middleName":"","lastName":"Kanemitsu","suffix":""},{"id":198145041,"identity":"c6a81132-d015-44b8-9df4-e0a0e778b59c","order_by":12,"name":"Wim Ceelen","email":"","orcid":"","institution":"Ghent University Hospital, Ghent University","correspondingAuthor":false,"prefix":"","firstName":"Wim","middleName":"","lastName":"Ceelen","suffix":""},{"id":198145042,"identity":"27d4b1cd-5f5b-4a5a-9866-bb2f3290da9c","order_by":13,"name":"Masataka Ikeda","email":"","orcid":"","institution":"Hyogo Medical University","correspondingAuthor":false,"prefix":"","firstName":"Masataka","middleName":"","lastName":"Ikeda","suffix":""}],"badges":[],"createdAt":"2023-05-03 14:44:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2890434/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2890434/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":36792884,"identity":"0274f0ca-d865-40b3-bbcf-eace90e3452e","added_by":"auto","created_at":"2023-05-10 21:59:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1976987,"visible":true,"origin":"","legend":"\u003cp\u003eA, Anatomical LN mapping in the Japanese Society for Cancer of the Colon and Rectum (JSCCR). B, Definition of the L level. When central LN was invaded, patients were categorized as L3. When intermediate LN was positive, they were categorized as L2. Blue arrows indicate the flow of lymphatic tumor spread (L1→L2→L3) following the Halsted model. On the other hand, in the Fisher model, spread of metastatic tumor cells occurs to distant LN and metastatic sites occurred in parallel. T, primary tumor;\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-2890434/v1/f97a57a88f6f27825851aaf5.png"},{"id":36791953,"identity":"5f16c7ec-2c2d-496b-a5af-dc49b5fae0e4","added_by":"auto","created_at":"2023-05-10 21:51:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":406787,"visible":true,"origin":"","legend":"\u003cp\u003eUnadjusted RFS and OS according to ages in stage III colon cancer. Young group (aged 45 or younger) = blue, Elderly group (aged 80 or older) = red.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-2890434/v1/be905e8ff1894dbb0e6cf71a.png"},{"id":36791955,"identity":"0b183256-7c40-4515-a1e1-32ced63b28f0","added_by":"auto","created_at":"2023-05-10 21:51:01","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":471163,"visible":true,"origin":"","legend":"\u003cp\u003eRFS in young and elderly groups according to the L status. L1=red, L2=green, L3=blue\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-2890434/v1/27e82ca94dcc8cc991534a3f.png"},{"id":42901530,"identity":"81873fdc-8fa3-4ba6-985e-c8da4eca621b","added_by":"auto","created_at":"2023-09-10 16:07:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1152333,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2890434/v1/5f09435e-1af8-4cc5-929d-2327c4874240.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Lymphatic spread patterns in young vs. elderly stage III colon cancer patients","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eColorectal cancer (CRC) is the third most common cancer diagnosed worldwide, and has the second highest mortality rate [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The incidence of CRC is increasing among young adults, which led to the recommendation of early cancer screening starting at the age of 45 years in the United States and 40 years in Japan[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. On the other hand, due to longer life expectancy, the incidence of CRC in the elderly is also increasing [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Therefore, clinicopathological features of CRC in these two populations need to be clarified.\u003c/p\u003e \u003cp\u003eLymph nodes (LN) involvement is the most important prognostic factor in CRC [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. We previously reported the prognostic impact of the anatomical LN spread pattern of colon cancer (CC) in terms of the location of invaded LN (central LN vs. intermediate/paracolic LN), sidedness (right vs. left) and molecular biomarkers (RAS, BRAF, microsatellite instability (MSI)) [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Additionally, population-based studies suggested age-related variations in the total LN count harvested and invaded in surgically resected CC [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]; younger patients were more likely to have a higher total and invaded LN count than elderly patients. However, the relationship between patient age and the anatomical location of lymphatic spread in CC is currently unknown. The presence of metastatic central LNs may be relevant in the decision to perform extensive (D3) lymphadenectomy. It has also been identified as a poor prognostic factor in CC [\u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], however, to the best of our knowledge, it currently remains unclear whether the risk of positive central LN invasion varies with age.\u003c/p\u003e \u003cp\u003eTherefore, we investigated the relationship between age and the anatomical pattern of lymphatic spread, and their prognostic impact patients with node positive (stage III) CC.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Patient selection\u003c/h2\u003e \u003cp\u003ePathological stage III CC patients, treated with curative extensive lymphadenectomy (Japanese D3 dissection) at several Japanese high-volume centers between 1998\u0026ndash;2018 were retrospectively analyzed. Rectal cancer patients, and patients treated with neoadjuvant therapy were excluded. This retrospective study was reported in line with the STROCSS criteria [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and approved by the Institutional Review Board of Hyogo Medical University, Japan (N0. 3789).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Surgical treatment/chemotherapy\u003c/h2\u003e \u003cp\u003eOpen or laparoscopic colonic resection with Japanese D3 lymphadenectomy was performed in all patients. When the tumor was right sided, the ileocecal vein and/or right colic vein and/or middle colic vein were divided at its origin and the corresponding mesenteric nodal stations (203, 213, and 223) were removed. High ligation of the inferior mesenteric artery (IMA) was performed for left-sided tumors (sigmoid or rectosigmoid), with the removal of LN at station 253, or the left colic artery was preserved and the superior rectal artery was divided at its origin. In descending colon cancer, the left colic artery was divided at its origin with removal of LN station 253, regardless of preservation of IMA. This technique is theoretically equivalent to complete mesocolic excision (CME) with central venous ligation [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The only difference is that the length of the bowel and area of the mesentery removed are more limited in Japanese D3 lymphadenectomy than in the CME technique [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Adjuvant therapy (5-FU or oxaliplatin-based mFOLFOX6 or CapOX) was administered according to the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Definition of the L level and the lymphatic spread pattern\u003c/h2\u003e \u003cp\u003eAccording to the Japanese Society for Cancer for the Colon and Rectum (JSCCR) staging system, invaded LN were classified into the following three groups, similar to our previous studies [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]: L1 (paracolic), L2 (intermediate), and L3 (main or central) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The 8th edition of the UICC TNM staging system was used [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The definition of \u0026lsquo;sequential\u0026rsquo; and \u0026lsquo;skipped\u0026rsquo; LN metastasis was as follows: when a more centrally located LN was positive with all previous LN being invaded, this lymphatic spread pattern was defined as \u0026lsquo;sequential\u0026rsquo;. On the other hand, when one or two nodal stations (L1 and/or L2) were negative and the more centrally located nodal station (L2 and/or L3) was invaded, the lymphatic spread pattern was defined as \u0026lsquo;skipped\u0026rsquo;.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Statistical analysis\u003c/h2\u003e \u003cp\u003ePrevious studies reported an increased risk of LN involvement in younger patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Therefore, we expected LN to be more frequently invaded in the younger patients than in elderly patients. Among LN, central LN metastasis was considered to be a poor prognostic factor and clinically important in CC. According to the largest Japanese nationwide data analysis of 4034 cases of pathological stage III CC, the reported frequency of invaded central LN in patients aged 46\u0026ndash;79 was 5.2% [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Therefore, in this retrospective study, the post hoc sample size was calculated to be N\u0026thinsp;=\u0026thinsp;209 young patients to obtain 75% power, with the hypothesis that the primary endpoint has an expected value of 9.1% and threshold value of 5% with one-sided alfa of 5%. Regarding elderly patients, the sample size was 222 with an expected value of 2% and threshold value of 5% with the same alfa and beta as those in young patients. In consideration of potentially ineligible patients, we aimed to include at least 210 pstage III young CC (group Y) and 230 elderly CC (group E). The chi-squared or Fisher\u0026rsquo;s exact test was used to evaluate the significance of differences between proportions, and the Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test or Mann-Whitney U test to assess the significance of differences between means where appropriate.\u003c/p\u003e \u003cp\u003eRecurrence-free survival (RFS) and overall survival (OS) were estimated from the date of surgery until recurrence or death from any cause. Unadjusted RFS in the Y and E groups and each L-level were estimated using the Kaplan-Meier method and Log-rank tests were performed to compare survival curves. A Cox proportional hazards model was used to identify the relationships between RFS and several known prognostic factors in CC. Elevated postoperative serum CEA, adjuvant therapy (observation vs. 5-FU/doublet), pT stage (T4 vs. T3/2/1), L level (L3 vs. L1/L2), and lymphatic spread pattern (sequential versus skipped) were included as independent variables. All analyses were performed with JMP Pro 15.2.0.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eIn this retrospective analysis, 210 stage III CC patients aged 45 years or younger (group Y) and 349 stage III patients aged 80 year or older (group E) were identified. Clinical and pathological variables in both groups are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatients characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup Y (N\u0026thinsp;=\u0026thinsp;210)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGorup E (N\u0026thinsp;=\u0026thinsp;349)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (M/F)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94/116\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e165/184\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43 (20\u0026ndash;45)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83 (80\u0026ndash;96)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor size\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e40 (6-160)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e45 (10\u0026ndash;150)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.065\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"6\" rowspan=\"7\"\u003e \u003cp\u003e\u003cb\u003eAnatomical location\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eV\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e2 (0.95%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"6\" rowspan=\"7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eC\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e15 (7.1%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e54 (15.3%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e32 (15.2%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e123 (35.2%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e26 (12.3%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e44 (12.6%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e22 (10.5%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e22 (6.3%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e88 (41.9%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e93 (26.6%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eRs\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e25 (11.9%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e12 (3.7%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e\u003cb\u003eT stage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eT1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e15 (7.1%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e8 (2.3%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eT2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e21 (10.0%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e27 (7.7%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eT3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e118 (56.1%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e198(56.7%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eT4a\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e44 (21.0%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e100 (28.6%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eT4b\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e12 (5.7%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e16 (4.6%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003eN stage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eN1a\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e63 (30.0%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e146 (41.8%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003e0.007\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eN1b\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e73 (34.8%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e119 (34.1%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eN2a\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e43 (20.5%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e56 (16.0%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eN2b\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e31 (14.8%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e28 (8.0%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eTotal number of Lymph nodes (LNs)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eHarvested\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e31.5 (3-151)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e21 (3-116)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003epositive\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e3 (1\u0026ndash;21)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e2 (1\u0026ndash;25)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003ePositive anatomical LN level (L group; %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eL1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e136 (64.8%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e237 (67.9%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003e0.27\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eL2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e54 (25.7%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e96 (27.5%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eL3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e20 (9.52%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e16 (4.6%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eSurgery\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eLap\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e105 (50%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e143 (41.0%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e0.038\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eOpen\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e105 (50%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e206 (59.0%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eAdjuvant therapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e38 (18.1%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e288 (82.5%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e5-FU\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e111 (52.9%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e51 (14.6%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eDoublet\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e61 (29.0%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e10 (2.9%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eLaparoscopic (or laparo-assisted) surgery was performed more frequently in group Y (50.0% vs. and 41.0%, p\u0026thinsp;=\u0026thinsp;0.02). Adjuvant therapy was more frequently received by group Y than by group E (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001): In group Y, only 18.1% of patients chose observation without chemotherapy, while 82.5% of group E chose observation. In Japan, since mFOLFOX6/CapOX regimen was approved in 2009, only 2.0% (2/99) of group Y patients who received surgery in the first 10 year (1998 to 2008) received mFOLFOX6/CapOX, while 47.8% (53/111) of group Y patients in the second 10 year (2009 to 2018) received mFOLFOX6/CapOX. Sigmoid and rectosigmoid cancer was more frequently observed in group Y (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Group Y had more advanced tumors, a more advanced N stage, and a higher number of total LN harvested (median of 31.5 (3-151) vs. 21 (3-116), P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and invaded (median of 3 (1\u0026ndash;21) vs. 2 (1\u0026ndash;25), P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In contrast, regarding T factors, group Y had less advanced primary tumors compared to group E, a less advanced T stage, and a smaller primary tumor (median of 40 mm (6-160) vs. 45mm (10\u0026ndash;150), p\u0026thinsp;=\u0026thinsp;0.065).\u003c/p\u003e \u003cp\u003eIn group Y, the proportion of invaded central LN was higher than the prespecified threshold of 5%, (9.52% (95% CI: 6.24\u0026ndash;14.2%), p\u0026thinsp;=\u0026thinsp;0.007), while in group E, the proportion of invaded central LN was similar to the threshold ((4.59% (95% CI:2.84\u0026ndash;7.31%), p\u0026thinsp;=\u0026thinsp;0.351).\u003c/p\u003e \u003cp\u003eThe observed lymphatic spread patterns are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The proportion of patients with a \u0026lsquo;skipped\u0026rsquo; lymphatic spread pattern was similar in both groups (11.0% (Y group) vs. 10.9% (E group)).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLN spreading patterns in young and elderly groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup Y (N\u0026thinsp;=\u0026thinsp;210)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup E (N\u0026thinsp;=\u0026thinsp;349)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eSequential\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e+\u0026minus;\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e136 (64.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e237 (67.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e++\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (21.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67 (19.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e+++\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (3.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (2.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubtotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e187 (89.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e311 (89.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSkipped\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026minus;+\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (4.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e+\u0026minus;+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (4.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (0.86%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026minus;\u0026minus;+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (1.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (0.86%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026minus;++\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (0.86%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubtotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (11.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (10.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eUnadjusted 5-year RFS and OS rates were significantly worse in group E than in group Y (57.3% vs. 72.8%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and 66.7% vs. 87.4%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, respectively) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). RFS according to the L status is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Five-year RFS rates in L3 (central LN positive) were lower compared to that in L1 and L2 in both groups (group Y: L1/L2/L3: 78.5%/64.9%/55.0% (p\u0026thinsp;=\u0026thinsp;0.031); group E: L1/L2/L3 62.1%/49.0%/40.0% (p\u0026thinsp;=\u0026thinsp;0.0065), respectively).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo examine the prognostic significance of the anatomical pattern of lymphatic spread in each group, a Cox multivariate analysis was performed (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eGroup Y (N\u0026thinsp;=\u0026thinsp;210)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eGroup E (N\u0026thinsp;=\u0026thinsp;349)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eElevated postoperative\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eCEA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e3.99 (1.85\u0026ndash;7.82)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e1.97 (1.33\u0026ndash;2.91)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.0007\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eL3 (vs. L1/L2)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e3.66 (1.29\u0026ndash;8.87)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.0082\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.02 (0.95\u0026ndash;4.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.068\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSkipped pattern (vs. sequential)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.32 (0.10\u0026ndash;0.96)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.049\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.96 (0.55\u0026ndash;1.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAdjuvant therapy\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(obs vs. FU/doublet)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.69 (0.30\u0026ndash;1.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.62(0.27\u0026ndash;1.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eT4 (vs. T3/2/1)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e2.15 (1.20\u0026ndash;3.79)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.0086\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e1.47 (1.04\u0026ndash;2.07)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.026\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn group Y, elevated postoperative CEA, a skipped LN spread pattern, stage pT4, and the presence of invaded L3 nodes were associated with a poor prognosis. In group E, elevated postoperative CEA and stage pT4 were associated with a poor prognosis. The presence of invaded L3 nodes indicated a slightly worse RFS in group E (HR 2.02 (0.95\u0026ndash;4.27) p\u0026thinsp;=\u0026thinsp;0.068).\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eSurgery remains the mainstay for curative treatment in resectable CC and lymphadenectomy plays a central role in minimizing the risk of recurrence. Therefore, it is essential to understand the nature of the lymphatic spread pattern. The actual extent of lymphadenectomy may be affected by age; surgeons are more likely to perform radical surgery on young patients. However, limited information is currently available on the relationship between age and lymphatic spread patterns.\u003c/p\u003e \u003cp\u003eIn this analysis, age-related differences were observed in the lymphatic spread pattern according to patient age: the total number of harvested LN and the number of invaded LN were higher in young CC patients. The frequency of central LN metastases in young CC patients aged 45 years or younger was significantly higher than the prespecified threshold, while that in elderly CC patients aged 80 year or older was similar. The threshold was estimated from a nationwide database from the JSCCR [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Central LN metastasis had a stronger prognostic impact in young CC patients. To the best of our knowledge, this is the first study to report the relationship between age and the anatomical location of invaded LN in stage III CC.\u003c/p\u003e \u003cp\u003eIn Japan, LN stations are historically mapped according to anatomical location, allowing unique insights in the prognostic significance of spatial and temporal lymphatic spread patterns in CC. The presence of central LN metastasis has been identified as an important prognostic factor in CC [\u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In the JSCCR guidelines, central LN metastases are categorized as N3 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] (which is different from the eighth edition of the UICC TNM classification [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]). The present results support this classification: The 5-years RFS rate in the L3 group was poor in both populations (55.0% in the Y group and 40.0% in the E group) and the multivariate analysis identified positive central LN positive as a poor prognostic factor, particularly in the Y group. When the central LN is anticipated to be negative, D2 lymphadenectomy may be sufficient, which may minimize the risk of postoperative complications. However, extended surgery including D3 lymphadenectomy may benefit young CC patients because the frequency of positive central LN is approximately 10%. However, since central LN invasion reflects aggressive disease with a poor prognosis, it is uncertain whether more aggressive surgery can impact survival. It may reduce the risk of local (nodal) recurrence and progression. Furthermore, patients with suspected positive L3 nodes may benefit from neoadjuvant treatment (chemotherapy and/or immune therapy). In the E group, the frequency of central LN positivity was similar to the prespecified threshold. If these patients are fit for surgery, there is also a potential benefit of D3 lymphadenectomy; however, the prognostic impact of radical surgery may be less than in younger patients.\u003c/p\u003e \u003cp\u003eDifferent clinicopathological features were observed between Y and E groups in the present study. Right-sided tumors and advanced primary tumors in size and depth were observed in the E group, whereas the total number of LN harvested and invaded was higher in the Y group. Young CRC patients are more likely to have poorly differentiated and left-sided tumors [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Previous studies reported a correlation between age and the number of LN. Sarli et al. revealed an age-related decrease in the number of LN harvested [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Quan et al. suggested that surgical specimens from young CRC patients yielded a higher number of LN than those from elderly patients [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Furthermore, the host immune response may lead to enlarged LN, and therefore a weaker immune response may lead to smaller LN and fewer LN [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The present results were consistent with these findings. The differences in tumor size, N stage, and T stage between both groups are consistent with literature findings that early onset CRC is often diagnosed at a later stage. Also, these differences can be due to random variation since p values were not adjusted for multiple comparisons. A detailed molecular profile was not available in our series. Limited information is currently available on the genetic backgrounds of young and elderly CRC patients[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Further investigation is required to investigate age-specific molecular mechanisms in CC.\u003c/p\u003e \u003cp\u003eThe existence of a \u0026lsquo;skipped\u0026rsquo; LN pattern is clinically important because this pattern may affect the extent of surgery. Two different models of cancer lymphatic spread have been proposed and discussed for decades (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The Halsted model assumes that lymphatic spread is a process in which cancer cells migrate in a predictable and stepwise manner from the primary tumor to paracolic LN, and then to intermediate nodes, the central nodes, and eventually to distant organs [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. This model is applicable to head and neck cancer. On the other hand, the Fisher model states that lymphatic progression and hematogenous metastasis occur at random before the previous LN station is breached [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. This model reflects the biology of breast cancer, and has led to the abandonment of extensive, mutilating surgery for this cancer type. A high frequency of \u0026lsquo;skipped\u0026rsquo; LN metastases supports the possibility that a cancer follows the Fisher model.\u003c/p\u003e \u003cp\u003eThe incidence of \u0026lsquo;skipped\u0026rsquo; metastases in CC varies among studies. A recent systematic review showed an incidence of less than 18% [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Our group suggested differences in the proportion of \u0026lsquo;skipped\u0026rsquo; LN metastases depending on the molecular biomarker used and tumor sidedness: this proportion was 9.3% in BRAF mutant vs. 20.0% in BRAF wild type, 4% in MSI-High vs. 10.5% in microsatellite stable, and 13.7% in right-sided CC vs. 9.0% in left-sided CC. The present results showed that the anatomical pattern of LN spread was not affected by age. MSI-H is more frequently detected in young CRC patients [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]; however, data on molecular biomarkers were not available for the present study. Therefore, further studies that incorporate molecular data and age are warranted.\u003c/p\u003e \u003cp\u003ePropensity score matching (PSM) was not used because there is no general agreement on the fact whether PSM is always superior to multivariable regression. Additionally, if PSM was performed in this population, the analyzed population would be quite smaller because common parts between two groups are quite small. Therefore, we have considered Cox regression to be equivalent for the analysis of our data [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].There were several limitations that need to be addressed. The molecular profile, such as mutations in RAS or BRAF and the mismatch repair status, was not available in the database. Second, since the opposite patient populations were compared using the data collected from a database spanning 20 years, the survival data should be cautiously interpreted. In this study, OS was much worse in group E than in group Y. However, the cause of death was different in the two groups. One hundred and eight out of 186 events of deaths were due to colon cancer in E group, but only 13 out of 35 in Y group. Additionally, the chemotherapy regimen was affected by the year the patients underwent surgery as described in the \u003cspan refid=\"Sec7\" class=\"InternalRef\"\u003eResults\u003c/span\u003e section. Regarding surgery, the concept of D3 extended lymphadenectomy has already been established for more than two decades in Japanese high-volume centers. Since only high-volume centers in which D3 lymphadenectomy is performed as clinical practice since 1998 participated in this present study, the quality of surgery and LN examinations were considered to be high. Another limitation is that the post hoc statistical power to detect the endpoint was only 75%. However, this did likely not affect the results and their clinical significance.\u003c/p\u003e \u003cp\u003eIn conclusion, differences in the lymphatic spread pattern were observed between young and elderly CC patients. Young CC patients need to undergo extensive D3 lymphadenectomy due to the higher frequency of central LN invasion. When extensive lymphadenectomy is performed on elderly CC patients, a balance between the effects of lymphadenectomy and the fitness of patients\u0026rsquo;needs to be considered. Surgeons may perform tailored surgery in which the appropriate extent of lymphadenectomy is defined using these data.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eLN, lymph node; CRC, colorectal cancer; CC, colon cancer; CI, confidence interval; MSI, microsatellite instability; RFS, Relapse-free survival; OS, overall survival; MSS, microsatellite-stable; CME, complete mesocolic excision; HR, Hazard ratio;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003eWe have fifteen authors but all the authors reviewed the manuscript critically, have contributed significantly, and are in agreement with the content of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEspecially, Kozo Kataoka, and Wim Ceelen \nmainly contributed to conception and design of this study. Naohito Beppu, Song Jihyung, Takeshi Yamada, Manabu Shiozawa, Yusuke Sakura, Takeshi Suto, Nobuhisa Matsuhashi, Sho Kuriyama, Akiyoshi Kanazawa, Hiroyasu Kagawa mainly contributed to the acquisition of the data. Kozo Kataoka and Wim Ceelen mainly contributed to the statistical analysis. Masataka Ikeda, Yukihide Kanemitsu and Wim Ceelen summarized the interpretation of the results which were discussed among all authors. Kozo Kataoka and Song Jihyung contributed equally to this work as first author.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eThis work was supported by JSPS KAKENHI Grant Number 21K15494\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSource of Funding:\u0026nbsp;\u003c/strong\u003eThere is no source of funding regarding this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of any commercial interest:\u0026nbsp;\u003c/strong\u003eThe authors have no conflicts of interest to disclose.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSung H, Ferlay J, Siegel RL et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021; 71: 209-249.\u003c/li\u003e\n\u003cli\u003eHashiguchi Y, Muro K, Saito Y et al. 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Prognostic significance of number versus location of positive mesenteric nodes in stage iii colon cancer. Eur J Surg Oncol 2019; 45: 1862-1869.\u003c/li\u003e\n\u003cli\u003eSong J, Kataoka K, Yamada T et al. The impact of molecular profile on the lymphatic spread pattern in stage III colon cancer. Cancer Sci 2021; 112: 1545-1555.\u003c/li\u003e\n\u003cli\u003eMeyer JE, Cohen SJ, Ruth KJ et al. Young Age Increases Risk of Lymph Node Positivity in Early-Stage Rectal Cancer. J Natl Cancer Inst 2016; 108.\u003c/li\u003e\n\u003cli\u003eXie X, Yin J, Zhou Z et al. Young age increases the risk for lymph node metastasis in patients with early Colon Cancer. BMC Cancer 2019; 19: 803.\u003c/li\u003e\n\u003cli\u003eAlexander MS, Lin J, Shriver CD et al. Age and Lymph Node Positivity in Patients With Colon and Rectal Cancer in the US Military Health System. Dis Colon Rectum 2020; 63: 346-356.\u003c/li\u003e\n\u003cli\u003eAng CW, Tweedle EM, Campbell F, Rooney PS. Apical node metastasis independently predicts poor survival in Dukes C colorectal cancer. Colorectal Dis 2011; 13: 526-531.\u003c/li\u003e\n\u003cli\u003eKanemitsu 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: 609-615.\u003c/li\u003e\n\u003cli\u003eChin CC, Yeh CY, Tang R et al. 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: 783-788.\u003c/li\u003e\n\u003cli\u003eTaflampas P, Christodoulakis M, DeBree E. Prognostic impact of inferior mesenteric artery lymph node metastasis in colorectal cancer. Ann Surg Oncol 2011; 18 Suppl 3: S235; author reply S236.\u003c/li\u003e\n\u003cli\u003eHida J, Okuno K, Yasutomi M et al. Number versus distribution in classifying regional lymph node metastases from colon cancer. 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Cancer 1998; 83: 666-672.\u003c/li\u003e\n\u003cli\u003eOgino S, Nosho K, Kirkner GJ et al. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut 2009; 58: 90-96.\u003c/li\u003e\n\u003cli\u003eBarault L, Charon-Barra C, Jooste V et al. Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases. Cancer Res 2008; 68: 8541-8546.\u003c/li\u003e\n\u003cli\u003eHALSTED WS. The Results of Operations for the Cure of Cancer of the Breast Performed at the Johns Hopkins Hospital from June, 1889, to January, 1894. Ann Surg 1894; 20 (5): 497-555.\u003c/li\u003e\n\u003cli\u003eKlein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer 2009; 9: 302-312.\u003c/li\u003e\n\u003cli\u003eFisher B. Biological research in the evolution of cancer surgery: a personal perspective. Cancer Res 2008; 68: 10007-10020.\u003c/li\u003e\n\u003cli\u003eBertelsen CA, Kirkegaard-Klitbo A, Nielsen M et al. Pattern of Colon Cancer Lymph Node Metastases in Patients Undergoing Central Mesocolic Lymph Node Excision: A Systematic Review. Dis Colon Rectum 2016; 59: 1209-1221.\u003c/li\u003e\n\u003cli\u003eAparicio T, Schischmanoff O, Poupardin C et al. Deficient mismatch repair phenotype is a prognostic factor for colorectal cancer in elderly patients. Dig Liver Dis 2013; 45: 245-250.\u003c/li\u003e\n\u003cli\u003eBiondi-Zoccai G, Romagnoli E, Agostoni P et al. Are propensity scores really superior to standard multivariable analysis? Contemp Clin Trials 2011; 32: 731-740.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"central lymph node, colon cancer, elderly, lymph node spreading pattern, young","lastPublishedDoi":"10.21203/rs.3.rs-2890434/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2890434/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIt currently remains unclear whether the anatomical pattern of lymph node (LN) spread differs between young (\u0026le;\u0026thinsp;45 years, Y) and elderly (\u0026ge;\u0026thinsp;80 years, E) patients with stage III colon cancer (CC).\u003c/p\u003e\u003cp\u003e\u003cb\u003eMaterials and Methods:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTwo groups of patients (Y and E) with stage III CC who underwent extensive (D3) lymphadenectomy at Japanese centers were retrospectively analyzed. The primary endpoint was the proportion of positive central LN. The planned sample size was at least 210 (Y) based on an expected value of 9.1% and threshold of 5%, and 230 (E) based on an expected value of 2% and threshold of 5%.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTwo-hundred and ten Y patients and 348 E patients were identified and compared. The total number of LN harvested and the total number of invaded LN were significantly higher in group Y (median of 31.5 (3-151) vs. 21 (3-116), P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and median of 3 (1\u0026ndash;21) vs. 2 (1\u0026ndash;25), P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, respectively). The proportion of positive central LN was higher in group Y than the prespecified threshold of 5% (9.52% (95% CI: 6.24\u0026ndash;14.2%), p\u0026thinsp;=\u0026thinsp;0.007); however it was similar to the threshold in group E (4.59% (95% CI:2.84\u0026ndash;7.31%), p\u0026thinsp;=\u0026thinsp;0.351). In multivariate models, central LN invasion was identified as a poor prognostic factor in group Y (HR3.66 (95% CI (1.29\u0026ndash;8.87)), but not in group E (HR2.02 (0.95\u0026ndash;4.27)).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eYoung stage III colon cancer patients have a higher risk of central LN invasion, suggesting a more aggressive disease biology. The presence of central LN invasion is associated with a worse outcome.\u003c/p\u003e","manuscriptTitle":"Lymphatic spread patterns in young vs. elderly stage III colon cancer patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-05-10 21:50:55","doi":"10.21203/rs.3.rs-2890434/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c6f61a74-4546-46cb-b627-3ecbd341385d","owner":[],"postedDate":"May 10th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-09-10T15:59:18+00:00","versionOfRecord":[],"versionCreatedAt":"2023-05-10 21:50:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2890434","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2890434","identity":"rs-2890434","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}