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. 2023 Jun 15;14:100190. doi: 10.1016/j.sipas.2023.100190

Lymph node harvest as a predictor of survival for colon cancer: A systematic review and meta-analysis

Simarpreet Ichhpuniani a,†, Tyler McKechnie b,†, Jay Lee a, Jeremy Biro a, Yung Lee b, Lily Park b, Aristithes Doumouras b,c, Dennis Hong b,c, Cagla Eskicioglu b,c,$,⁎
PMCID: PMC11750021  PMID: 39845856

Highlights

  • •

    A lymph node harvest cut-off of 12 can predict five-year overall survival.

  • •

    Lymph node harvest cut-offs as low as 7 can predict five-year overall survival.

  • •

    Lymph node harvest cut-offs other than 12 have not been as rigorously studied.

  • •

    Further prospective study evaluating cut-offs other than 12 are warranted.

Keywords: Colon cancer, Lymph nodes, Lymph node harvest, Lymphadenectomy, Survival, Colorectal Surgery

Abstract

Background and Objectives

The number of lymph nodes found harboring metastasis can be impacted by the extent of harvest. Guidelines recommend 12 lymph nodes for adequate lymphadenectomy to predict long-term oncologic outcomes, yet different cut-offs remain unevaluated. The aim of this review was to determine cut-offs that may predict survival outcomes.

Methods

Medline, Embase, and CENTRAL were systematically searched. Articles were included if they compared overall survival (OS) or disease-free survival (DFS) above and below a lymph node harvest cut-off. Studies solely examining rectal cancer or stage-IV disease were excluded. Pairwise meta-analyses using inverse variance random effects were performed.

Results

From 2587 citations, 20 studies with 854,359 patients (51.9% female, mean age: 68.9) were included, with 19 studies included in quantitative synthesis. A lymph node harvest cut-off of 12 predicted improved five-year OS (7 studies; OR 1.11, 95% CI 1.08–1.14, p<0.00001). A cut-off as low as 7 was associated with improved five-year OS (2 studies; OR 1.16, 95% CI 1.08–1.25, p<0.0001) and DFS (3 studies; OR 1.66, 95% CI 1.32–2.10, p<0.00001). All cut-offs greater than 12 demonstrated improved survival.

Conclusions

A lymph node cut-off of 12 distinguishes differences in five-year oncologic outcomes. Contrarily, lymph node harvests other than 12 have not been rigorously studied and thus lack the statistical power to derive meaningful conclusions compared to the 12-lymph node cut-off. Nonetheless, it is possible that a lymph node harvest cut-offs less than 12 may be adequate in predicting long-term survival. Further prospective study evaluating cut-offs below 12 are warranted.

1. Introduction

Effectively treating and prognosticating colon cancer is dependent on the extent of its spread [1]. Colon cancer originates in the lamina propria and advances deeper into the colonic wall and will eventually metastasize to other organs if left untreated [2]. Regional lymph nodes and the lymphatic system are the main pathway through which colon cancer disseminates. Retrieval and pathological examination of regional lymph nodes can thus effectively predict oncologic outcome [3]. Examination of lymph nodes at surgical resection partially defines staging of colorectal cancer as per the american joint committee on cancer (AJCC) tumor, node, metastasis (TNM) classification [1]. Treatment decisions, such as the initiation of adjuvant chemotherapy, as well as prognosis, are predicated on lymph node positivity [2]. National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) data have demonstrated a five-year survival of colon cancer of 90.2% when there is no lymphatic metastases, compared to 71.8% with spread to regional lymph nodes [4].

With treatment decisions and prognosis hinging on staging, adequate lymph node harvest during colonic resection is essential [2]. Current AJCC and National Comprehensive Cancer Network (NCCN) guidelines recommend a minimum of 12 lymph nodes harvested at the time of oncologic resection [1,5]. This is based on evidence demonstrating that lower lymph node yields are associated with worse long-term survival [6], [7], [8]. Several early observational studies have shown survival improvements at various thresholds of lymph node harvesting [7,6,9,10]. A systematic review in 2007 by Chang et al. supported the improvements in survival with increased harvest [11]. However, this study noted heterogeneity in lymph node harvest cut-offs used by the included studies, and was unable to provide definitive harvesting cut-offs to follow in clinical practice [11]. Moreover, the reason for the improved survival with greater lymph node harvest has not been fully elucidated. Increased accuracy in staging with greater harvest is potentially a factor [11]. A nationwide survey of Japanese institutions by Ueno et al. demonstrated that under-staging can be avoided by adequate lymphadenectomy [12]. Furthermore, Song et al. analyzed Survival, Epidemiology, and End Result Program (SEER) data and found worse survival in Stage II patients with inadequate lymphadenectomy compared to Stage III patients with adequate lymphadenectomy [13]. While currently adequate lymphadenectomy is defined as 12 or more lymph nodes, there are available data evaluating different cut-off values with similar results.

A systematic review and meta-analysis in 2020 by Tan et al. evaluated the prognostic impact of the 12-lymph node cut-off in a rectal cancer patient population receiving neoadjuvant therapy. This demonstrated improved overall survival (OS) and disease-free survival (DFS) above the 12 node cut-off [14]. Similar analysis of various lymph node harvest cut-offs, including but not limited to 12, have yet to be systematically reviewed and meta-analyzed in colon cancer patients. There are numerous observational studies examining various lymph node harvest cut-offs for patients undergoing oncologic resection for colon cancer [7,15,16]. As such, the aim of this study is to evaluate the impact on long-term survival of the number of lymph nodes analysed, at various cut-offs, during curative oncologic colonic resection for colon cancer.

2. Materials and methods

2.1. Search strategy

The following databases covering the period from database inception through to April 2021 were searched: Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). Search terms included “colorectal cancer”, “lymphadenectomy”, “survival”, and more (complete search strategy available in Appendix 1). References of published studies and gray literature were manually searched to ensure that all relevant articles were included. This systematic review and meta-analysis is reported in accordance with Preferred Reporting items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE). The study protocol was registered on the PROSPERO International Prospective Register for Systematic Reviews a priori (ID: CRD42022339047).

2.2. Study selection

Articles were eligible for inclusion if they compared either five-year OS or DFS between groups solely differentiated by the lymph node harvest following surgical resection for colon cancer. Studies that solely evaluated patients with rectal cancer were excluded. A study including patients with both colon and rectal cancer was excluded if more than 50% of the included patients had rectal primaries. Studies including less than 10 patients were excluded. Data from large, population level databases were carefully inspected. Significant chronologic overlap in data between studies was an indication for exclusion if one or more of the studies evaluated the same database. Studies including stage IV patients and patients undergoing emergent resection for obstructive symptoms or perforation were excluded. Studies not in English were excluded. Studies were not discriminated based on operative approach (laparoscopic, open). Abstracts, posters, opinions, case reports, reviews, meta-analyses, letters to editors and editorials were excluded.

2.3. Outcomes assessed

The primary outcome was long term survival, reported as five-year OS. Five-year was specified as the primary outcome as it the most common reported survival interval following colon cancer treatment. Additionally, five-year survival serves as the benchmark for long-term survival in colon cancer [17].

Secondary outcomes included five-year DFS and number of lymph node harvest cut-offs reported in the literature. DFS is often reported in addition to OS in the literature. The number of lymph node harvest cut-offs reported somewhat indicate the extent of research conducted per cut-off thus far.

2.4. Data extraction

Three reviewers independently screened the systematically searched titles and abstracts using a standardized, pilot-tested form. Discrepancies that occurred at the title and abstract screening phases were resolved by inclusion of the study. At the full-text screening stage, discrepancies were resolved by consensus between the three reviewers. If the disagreement persisted, a fourth reviewer was consulted. Three reviewers extracted data into a data collection form designed a priori. The extracted data included study characteristics (e.g., author, year of publication, study design), patient demographics (e.g., age, gender, operation type, cancer histology, cancer location, cancer stage), lymph node harvesting data (e.g., defined groups by number of lymph nodes harvested), and oncologic outcome (i.e., OS, DFS).

2.5. Risk of bias assessment

Risk of bias for each of the included observational study was assessed using the Methodological Index for Non-Randomized Studies (MINORS) tool [18]. Two reviewers assessed study quality for each study. Discrepancies were discussed amongst the reviewers until consensus was reached.

2.6. Statistical analysis

All statistical analyses and meta-analyses were performed on STATA version 14 (StataCorp, College, TX) and Cochrane Review Manager 5.3 (London, United Kingdom). The threshold for statistical significance was set a priori at a p of <0.05. A pairwise meta-analysis was performed using an inverse variance random effects model for all meta-analyzed outcomes. Studies were meta-analyzed according to their reported lymph node harvest cut-offs. For example, all studies reporting five-year OS or DFS for patients above and below a lymph node harvest cut-off of 12 were included in the same meta-analysis, all studies reporting five-year OS or DFS for patients above and below a lymph node harvest cut-off of 11 were included in the same meta-analysis, and so on. Pooled effect estimates were obtained by calculating the odds ratios (OR) along with their respective 95% confidence intervals (CI) to confirm the effect size estimation. Mean and standard deviation (SD) was estimated for studies that only reported median and interquartile range using the method described by Wan et al. [19]. Assessment of heterogeneity was completed using the inconsistency (I2) statistic. An I2 greater than 50% was considered to represent considerable heterogeneity [20]. Bias in meta-analyzed outcomes was assessed with funnel plots when data from more than 10 studies were included in the analysis. Meta-analyses were performed for all lymph node harvest cut-offs that were reported in two or more studies [21].

3. Results

3.1. Study characteristics

From, 2587 citations, 20 studies (3 prospective cohorts, 17 retrospective cohorts) conducted between 2002 and 2019 were included, with 19 studies included for quantitative synthesis [7,9,[15], [16],[22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35]]. A PRISMA flow diagram of the study selection process is illustrated in Fig. 1. In total, the included studies had 854,359 patients (51.9% female, mean age: 68.9). The most commonly studied cut-off value was 12 lymph nodes (11 studies); followed by a lymph node cut off of 10 (3 studies), 9 (3 studies), 6–7 (3 studies); followed by a lymph node cut off of 11 (2 studies). Detailed study characteristics are reported in Table 1. Studies meeting inclusion criteria include 6 studies from individual sites [22,25,27,31,32,35], with the remaining 14 studies featuring large population level databases or multiple hospitals/sites (Table 1) [7,9,[15], [16],22,23,26,27,29,31,32,34,[36], [37], [38]].

Fig. 1.

Fig 1

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PRISMA Diagram – Transparent reporting of systematic reviews and meta-analysis flow diagram outlining the search strategy results from initial search to included studies.

Table 1.

Study characteristics of included studies.

Study Location Study Period Type of Study Database/Site Studied N Mean Age (SD) % Female LN Cut-Off(s)
Cianchi, 2002 Italy 1988–1995 Retrospective University of Florence, School of Medicine 140 65.0 (9.6) 41.4 9
Prandi, 2002 Italy 1992–1999 Retrospective INTACC 3491 61.1 (9.6) 44.0 7, 13, 18
Le Voyer, 2003 USA 1988–1992 Prospective INT-0089 3411 58.1 (10.5) 45.8 11, 21, 36, 41
Edler, 2007 Sweden 1991–1997 Retrospective Sweden 50 hospitals, Denmark 2 hospitals 1025 – 43.5 12
Morris, 2007 UK 1995–2003 Retrospective NYCRIS 5556 – 45.5 12
Murphy, 2007 Ireland – Retrospective St. Mark's Hospital 269 – – 10
Bilimoria, 2008 USA 1998–2004 Retrospective NCDB 142,009 – 52.4 12
Tsikitis, 2009 USA 1996–2001 Prospective Division of Colorectal Surgery, Mayo Clinic 329 70.0 (12.8) 51.7 13
Wang, 2009 Argentina 1988–2003 Retrospective SEER 24,477 69.2 (13.1) 53.8 12
Fretwell, 2010 UK 1999–2003 Retrospective Royal Liverpool and Broadgreen hospitals 351 64.5 (6.86) 42.5 9, 10
Moore, 2010 USA 1994–1998 Retrospective SEER 11,399 77.8 (7.6) 56.4 7, 12
Shimomura, 2011 Japan 1991–2008 Retrospective Department of Surgery, Hiroshima University 266 61.0 (12.0) 34.2 12
Kotake, 2012 Japan 1985–1994 Retrospective JSCCR Registration System 16,865 – 42.4 10, 17, 27
Sugimoto, 2013 Japan 1992–2005 Retrospective Juntendo University Faculty of Medicine 311 62.5 (10.4) 42.1 12
Becerra, 2016 USA 2003–2012 Retrospective NCDB 360,846 70.7 (12.1) 52.5 12
Guan, 2016 China 2004–2012 Retrospective SEER 17,058 – 64.1 9, 12
Hoshino, 2016 Japan 1997–2003 Retrospective JFUP-CRC 2100 62.3 (11.21) 40.4 6
Guan, 2018 China 2004–2013 Retrospective SEER 2360 +Neoadjuvant – 56.7, 5.9
-Neoadjuvant – 65.0, 14.8		 39.8 22
Li Destri, 2019 Italy 2001–2016 Retrospective Department of Medical and Surgical Sciences and Advanced Technology, University of Catania 463 66.3(-) 44.2 12
Trepanier, 2019 USA 2010–2014 Retrospective NCDB 261,423 68.0 (13.7) 50.8 12, 24
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(N, number of participants; LNH, Lymph node harvest; INTACC, National Intergroup for Adjuvant Therapy on Colon Cancer; INT-0089, Intergroup 0089; NYCRIS, Northern and Yorkshire Cancer Registry and Information Service; NCDB, National Cancer Database; SEER, Surveillance Epidemiology and End Results; JSCCR, Japanese Society for Cancer of the Colon and Rectum; JFUP-CRC, Japanese Study Group for Postoperative Follow-up of Colorectal Cancer.

3.2. Disease characteristics

Tumors were most commonly located in the right colon (n = 466,402, 55.5%). Of the remaining lesions, 187,849 (22.3%) were located in the left colon and 9674 (1.2%) were located in the rectum. The median cancer stage was III (range: I-III).

Treatment details were variably reported and are included in Table 2 for each individual study. Four studies reported operation details [9,16,39,40]. The majority of patients underwent partial colectomies (n = 508,004). Operations were performed laparoscopically in 118,893 (45.4%) of cases in the 1 study reporting operative approach [16]. Overall, 37 (0.01%) patients underwent neoadjuvant therapy, and 129,290 (28.8%) patients underwent adjuvant therapy. 12 studies reported neoadjuvant therapy details, 15 studies reported adjuvant therapy details (Table 2).

Table 2.

Tumor- and treatment-related data for included studies.

Study N Operation (N,%) Operative Approach (N,%) Tumor Location (N,%) Cancer Stage (N,%) Cancer Differentiation (N,%) Neoadjuvant and Adjuvant Treatment (N,%)
Cianchi, 2002 140 – – Right colon: 39 (27.8)
Left colon: 54 (38.6)
Rectum: 54 (38.6)		 II: 140 (100) G1: 17 (14.9)
G2: 93 (81.6)
G3: 4 (3.5)		 Neoadjuvant: -
Adjuvant: -
Prandi, 2002 3491 – – Right colon: 1080 (30.9)
Left colon: 788 (22.6)
Sigmoid colon: 1654 (47.4)		 II: 1816 (52.0)
III: 1675 (48.0)		 G1: 349 (1.0)
G2: 2794 (80.0)
G3: 505 (14.5)		 Neoadjuvant: 0 (0)
Adjuvant: 3491 (100)
Le Voyer, 2003 3411 Right hemicolectomy: 1475 (43.2)
Left hemicolectomy: 481 (14.1)
Anterior resection: 415 (12.2)
Segmental resection: 717 (21.0)
Subtotal Colectomy: 124 (3.6)
Total Colectomy: 84 (2.5)
Other: 152 (4.5)		 – Right colon: 1392 (40.8)
Transverse colon: 259 (7.6)
Splenic flexure: 178 (5.2)
Left colon: 215 (6.3)
Sigmoid colon: 1276 (37.4)		 II-III – Neoadjuvant: 0 (0)
Adjuvant: 3411 (100)
Edler, 2007 1025 – – Right colon: 326 (31.8)
Transverse colon: 53 (5.2)
Left colon: 66 (64.4)
Sigmoid colon: 264 (25.8)
Colon unspecified: 18 (1.8)
Rectum: 298 (29.1)		 II: 498 (48.6)
III: 527 (51.4)		 G1: 203 (19.8)
G2: 718 (70.0)
G3: 75 (7.3)
 Randomized to neoadjuvant or adjuvant, unknown values
Neoadjuvant: -
Adjuvant: -
Morris, 2007 5556 – – Colon: 5326 (75.4)
Rectum: 1736 (24.6)		 I: 1131 (16.0)
II: 3030 (42.9)
III: 2732 (38.7)
Unknown: 169 (2.4)		 – Neoadjuvant: -
Adjuvant: 0(0)
Murphy, 2007 269 – – – II: 269 (100) – Neoadjuvant: 0 (0)
Adjuvant: 0 (0)
Bilimoria, 2008 142,009 – – Right colon: 79,444 (55.9)
Left colon: 62,565 (44.1)		 T1: 2578 (1.8)
T2: 32,477 (22.9)
T3: 73,890 (52.0)
T4: 7275 (5.1)		 G1-G2: 117,722 (82.9)
G3: 17,399 (12.3)		 Neoadjuvant: 0 (0)
Adjuvant: 20,839 (14.7)
Tsikitis, 2009 329 – – Cecum: 81 (24.7)
Right colon: 67 (20.5)
Hepatic flexure: 19 (5.7)
Transverse: 36 (10.8)
Splenic: 13 (3.9)
Left + Sigmoid Colon: 105 (32.0)		 III: 329 (100) – Neoadjuvant: 0 (0)
Adjuvant: 212 (64.0)
Wang, 2009 24,477 – – Cecum: 6780 (27.7)
Right colon: 4283 (17.5)
Hepatic flexure: 1420 (5.8)
Transverse colon: 2252 (9.2)
Splenic flexure: 1077 (4.4)
Left colon: 1444 (5.9)
Sigmoid: 7196 (29.4)		 III: 24, 477 (100) G1: 17,767 (68.5)
G3: 6486 (26.5)
Unknown: 1224 (5.0)		 Neoadjuvant: -
Adjuvant: -
Fretwell, 2010 351 – – Colon: 236 (67.2)
Rectum: 115 (32.8)		 II: 183 (52.1)
III: 168 (47.9)		 G1: 4 (1.1)
G2: 325 (92.6)
G3: 22 (6.3)		 Neoadjuvant: 37 (10.5)
Adjuvant: 98 (27.9)
Moore, 2010 11,399 Partial colectomy, Hemicolectomy – – I: 2206 (19.4)
II: 5436 (47.7)
III: 3757 (33.0)		 – Neoadjuvant: 0 (0)
Adjuvant: 3306 (29.0)
Shimomura, 2011 266 – – Right colon: 61 (22.9)
Left colon: 103 (38.7)
Rectal: 102 (383.)		 III: 266 (100) G1: 81 (30.5)
G2: 155 (58.3)
G3: 10 (3.8)
Other: 20 (7.5)		 Neoadjuvant: 0 (0)
Adjuvant: 199 (76.5)
Kotake, 2012 16,865 – – Right colon: 4817 (28.6)
Left colon: 5281 (31.3)
Rectum: 6767 (40.1)		 II: 9143 (54.2)
III: 7722 (45.8)		 G1: 8415 (49.9)
G2: 7143 (42.4)
G3: 1307 (7.7)		 Neoadjuvant: 0 (0)
Adjuvant: 10,995 (65.2)
Sugimoto, 2013 311 – – Proximal colon: 204 (33.4)
Distal colon: 207 (66.6)		 T1–3: 200 (64.3)
T4: 111 (35.7)
N1: 234 (75.2)
N2: 77 (24.8)		 Low grade: 292 (93.4)
High grade: 19 (6.1)		 Neoadjuvant: -
Adjuvant: 225 (72.3)
Becerra, 2016 360,846 Right colon: 222,711 (61.7)
Left colon: 33,460 (9.3)
Sigmoid: 89,764 (24.9)
Total: 9098 (2.5)
Proctocolectomy: 1813 (0.5)
Colectomy: 2817 (0.8)		 – Right colon: 222,711 (61.7)
Left colon: 33,460 (9.3)
Sigmoid: 89,764 (24.9)		 I-III G1: 12,682 (13.8)
G2: 65,167 (70.9)
G3: 13,087 (14.2)
G4: 985 (1.1)		 Neoadjuvant: -
Adjuvant: -
Guan, 2016 17,058 – – Right colon: 15,085 (88.4)
Left colon: 1973 (11.6)		 I: 3961 (23.2)
II: 7535 (44.2)
III: 5562 (32.6)		 G1: 1373 (8.0)
G2: 10,997 (64.5)
G3: 3846 (22.6)		 Neoadjuvant: -
Adjuvant: -
Hoshino, 2016 2100 Hemi/Total colectomy: 504 (24.0)
Partial colectomy: 758 (36.1)
Rectal: 835 (39.8)		 – Right colon: 659 (31.4)
Left colon: 977 (46.5)
Rectum: 464 (22.1)		 II: 2100 (100) G1+G2: 1966 (93.6) Neoadjuvant: -
Adjuvant: 0 (0)
Guan, 2018 2360 Partial colectomy: 917 (38.9)
Hemicolectomy: 1443 (61.1)		 – Right colon: 1145 (48.5)
Left colon: 1215 (51.5)		 I: 293 (12.4)
II: 823 (34.9)
III: 1244 (52.7)		 G1: 146 (6.2)
G2: 1622 (68.7)
G3: 517 (21.9)
G4: 75 (3.2)		 Neoadjuvant: 0 (0)
Adjuvant: -
Li Destri, 2019 463 – – Colon: 311 (67.1)
Rectum: 138 (29.9)
Synchronous: 14 (3.0)		 II: 232 (50.1)
III: 200 (43.2)		 – Neoadjuvant: -
Adjuvant: 185 (40.0)
Trepanier, 2019 261,423 Partial colectomy: 248, 995 (95.25)
Total colectomy: 7133 (2.73)
Total Proctocolectomy: 1629 (0.62)
Unknown: 3666 (1.40)		 Open: 126,995 (48.58)
Laparoscopic: 118,848 (45.5)		 Right colon: 126,993 (48.6)
Transverse: 24,656 (9.4)
Left: 79,396 (30.8)
Rectosigmoid: 23,639 (9.04)
Other: 6729 (2.6)		 I: 61,779 (27.0)
II: 73,125 (32.0)
III: 93,748 (41.0)		 G1+G2: 197,170 (75.4)
G3: 46,049 (17.61)
Unknown: 1820 (7.0)		 Neoadjuvant: 0 (0)
Adjuvant: 86,329 (33.6)
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(N, number of participants; G1, well differentiated; G2, moderately differentiated; G3, poorly differentiated; -, no data reported; T1–4, TNM primary tumor staging; N0–2, TNM lymph node staging).

3.3. Long-Term oncologic outcomes

Of the 12 studies examining a cut-off of 12, 7 reported OS and 4 reported DFS (Table 3). Patients with 12 or more lymph nodes harvested at the time of oncologic resection had significantly greater five-year OS (7 studies, OR 1.11, 95%CI 1.08–1.14, p<0.0001, I2=97%), but not five-year DFS (4 studies, OR 1.09, 95%CI 0.96–1.23, p = 0.18, I2=76%) (Fig. 2A and 2B).

Table 3.

Five-year survival outcomes for included studies.

Study Cut-Off(s) N 5-y OS (%) 5-y DFS (%)
Cianchi, 2002 <9 55 54.9 –
≥9 85 79.9 –
Prandi, 2002 ≤7 777 69.0 56.0
≥8, <13 986 69.0 60.0
≥13, <18 666 76.0 64.0
≥18 819 76.0 67.0
Le Voyer, 2003 N0 <11 309 73.0 72.0
N0 ≥11, <21 220 80.0 79.0
N0 ≥21 119 87.0 83.0
N1 <11 1020 67.0 65.0
N1 ≥11, <41 807 74.0 70.0
N1 ≥41 30 90.0 93.0
N2 <36 864 51.0 48.0
N2 ≥36 42 71.0 69.0
Edler, 2007 <12 895 64.0 –
≥12 130 77.0 –
Morris, 2007 <12 3239 53.4 –
≥12 2316 58.8 –
Murphy, 2007 <10 94 69.4 –
≥10 175 87.6 –
Karl, 2008 <12 81,825 60.4 –
≥12 60,794 64.9 –
Tsikitis, 2009 <13 160 – 59.9
≥13 169 – 59.5
Wang, 2009 <12 12,381 45.0 –
≥12 12,096 51.0 –
Fretwell, 2010 <9 31 45.2 –
≥9 152 68.4 –
<10 39 25.6 –
≥10 129 48.8 –
Moore, 2010 <7 3328 50.8 –
≥7, <12 3419 54.3 –
≥12 4652 57.9 –
Shimomura, 2011 <12 91 – 63.0
≥12 175 – 60.0
Kotake, 2012 II <10 2294 81.0 –
II ≥10, <17 2333 84.3 –
II ≥17, <27 2290 84.6 –
II ≥27 2226 87.4 –
III <10 1758 64.2 –
III ≥10, <17 1949 68.1 –
III ≥17, <27 1969 68.8 –
III ≥27 2046 73.0 –
Sugimoto, 2013 <12 74 – 62.9
≥12 237 – 67.4
Becerra, 2016 <12 91,921 64.0 –
≥12 268,925 73.0 –
Guan, 2016 <9 2343 – –
≥9 1923 – –
≥9, <12 14,715 – –
≥12 12,792 – –
Hoshino, 2016 <6 83 – 63.8
≥6 2017 – 83.0
Guan, 2018 <22 1179 – –
≥22 1181 – –
Li Destri, 2019 <12 163 – 63.0
≥12 269 – 72.0
Trepanier, 2019 <12 36,877 62.8 –
≥12, <24 139,523 66.9 –
≥24 85,023 71.7 –
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(N, number of participants; y, years; OS, overall survival; DFS, disease free survival).

Fig. 2.

Fig 2

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12 Lymph Nodes Harvested Survival - Random effect meta-analysis comparing between <12 and ≥12 lymph nodes harvested. A) Overall survival, B) Disease free survival.

For cut-off values below 12, meta-analyses were possible for 7, 9, 10, and 11. Cut-off values of 7 (OS: 2 studies, OR 1.16, 95%CI 1.08–1.25, p<0.0001, I2=0%; DFS: 3 studies, OR 1.66, 95%CI 1.32–2.10, p<0.0001, I2=79%) (Fig. 3A and 3B), 9 (OS: 2 studies, OR 1.48, 95%CI 1.18–1.85, p = 0.0006, I2=0%), and 11 (OS: 2 studies, OR 2.03, 95%CI 1.02–4.06, p = 0.05, I2=79%) were predictive of five-year OS and DFS. A cut-off value of 10 was not a significant predictor of five-year OS (2 studies, OR 1.69, 95%CI 0.82–3.50, p = 0.16, I2=72%).

Fig. 3.

Fig 3

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7 Lymph Nodes Harvested Survival –Random effect meta-analysis comparing survival between <7 and ≥7 lymph nodes harvested. A) Overall survival, B) Disease free survival.

For cut-off values above 12, a meta-analysis was only possible for five-year DFS at a cut-off of 13 and five-year OS at a cut-off of 17. Both a cut-off value of 13 (DFS: 2 studies, OR 1.23, 95%CI 1.02–1.49, p = 0.03, I2=20%) and 17 (OS: 2 studies, OR 1.23, 95%CI 1.15–1.32, p<0.0001, I2=0%) were able to distinguish between patients above and below the cut-offs.

Table 4 reports the results of all pair-wise meta-analyses performed for the various lymph node harvest cut-offs.

Table 4.

Summary of pairwise meta-analyzed outcomes.

Outcome LNH Comparison Sample size Number of studies Pairwise Meta-Analysis
OR 95% CI P I[2]
5y-OS <7 vs. >7 15,019 2 1.16 1.08, 1.25 <0.0001 0
<9 vs. >9 303 2 1.48 1.18, 1.85 0.0006 0
<10 vs. >10 17,033 2 1.69 0.82, 3.50 0.16 72
<11 vs. >11 2816 2 2.03 1.02, 4.06 0.05 79
<12 vs. >12 807,073 7 1.11 1.08, 1.14 <0.00001 97
<17 vs. >17 20,113 2 1.23 1.15, 1.32 <0.00001 0
5y-DFS <7 vs. >7 17,119 3 1.66 1.32, 2.10 <0.0001 79
<12 vs. >12 18,492 4 1.09 0.96, 1.23 0.18 76
<13 vs. >13 4243 2 1.23 1.02, 1.49 0.03 20
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(y, year; OS, overall survival; DFS, disease free survival; LNH, lymph node harvest; OR, odds ratio; CI, confidence interval).

A subset analysis of long-term survival for each lymph node cut-off, differentiated by stage was not possible due to limited number of studies per cut-off, per stage. No cut-off had two or more studies included reporting long-term oncologic outcomes per stage.

3.4. Risk of bias

Table 5 presents the risk of bias analysis according to the MINORS tool for each of the included studies. The mean MINORS score was 15.33 (±0.96). All of the included studies stated the aim of their study appropriately in the manuscript, included consecutive patients, reported appropriate end points, had adequate follow up periods, had adequate statistical models (i.e., Kaplan Meier curves), and had adequate control groups. Only one of the included studies evaluated prospectively collected data. None of the included studies calculated an a priori sample size, nor did any of the included studies report having blinded data outcome accrual and statistical analysis.

Table 5.

Methodological Index for Non-Randomized Studies (MINORS) for the included full-text studies.

Study MINORS Criteria
Stated Aim Consecutive Patients Prospective Data Collection Appropriate End Points Unbiased End Point Assessment Follow-up Period Loss to Follow-up Calculation of Sample Size Adequate Control Group Contemporary Groups Baseline Equivalence Adequate Stats Total (/24)
Cianchi, 2002 2 2 0 2 0 2 0 0 2 2 1 2 15
Prandi, 2002 2 2 1 2 0 2 0 1 2 2 0 2 16
Le Voyer, 2003 2 2 1 2 1 2 0 0 2 2 0 2 16
Edler, 2007 2 2 2 2 0 2 0 0 2 2 1 2 17
Morris, 2007 2 2 0 2 1 2 0 0 2 2 2 2 17
Murphy, 2007 2 2 0 2 0 2 0 0 2 2 0 2 14
Karl, 2008 2 2 0 2 0 2 0 0 2 2 1 2 15
Tsikitis, 2009 2 2 1 2 0 2 0 0 2 2 0 2 15
Wang, 2009 2 2 1 2 0 2 0 0 2 2 0 2 15
Fretwell, 2010 2 2 0 2 0 2 0 0 2 2 2 2 16
Moore. 2010 2 2 0 2 0 2 0 0 2 2 1 2 15
Shimomura, 2011 2 2 0 2 0 2 0 0 2 2 0 2 14
Kotake, 2012 2 2 0 2 0 2 0 0 2 2 2 2 16
Sugimoto, 2013 2 2 0 2 0 2 0 0 2 2 1 2 15
Becerra, 2016 2 2 0 2 0 2 0 0 2 2 2 2 16
Guan, 2016 2 2 0 2 0 2 0 0 2 2 2 2 16
Hoshino, 2016 2 2 0 2 0 2 0 0 2 2 0 2 14
Guan, 2018 2 2 0 2 0 2 0 0 2 2 0 2 14
Li Destri, 2019 2 2 1 2 0 2 1 0 2 2 0 2 16
Trepanier, 2019 2 2 0 2 0 2 0 0 2 2 2 2 16
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MINORS tool score for individual studies: red (0) = not reported, yellow (1) = reported but not adequate, green (2) = reported and adequate. Maximum possible score of 24 for each included study.

4. Discussion

Adequate lymph node harvest during colonic resection allows for sufficient pathological examination for metastases, therefore allowing accurate staging. While current AJCC and NCCN guidelines recommend a 12 lymph node harvest at time of index oncologic resection, other cut-offs may be adequate in predicting long-term survival [1,5]. This systematic review and meta-analysis collected data from 20 studies comparing various lymph node harvest cut-offs in terms of long-term oncologic outcomes. A lymph node harvest of greater than 12 was a significant predictor of five-year OS (7 studies; OR 1.11, 95% CI 1.08–1.14, p<0.00001, I2=97%) and was the most extensively studied cut-off value. The only lymph node harvest cut-off values above 12 included in this meta-analysis were 13 and 17, and both were significant predictors of five-year survival. When considering cut-offs less than 12, a lymph node harvest as low as 7 was able to distinguish five-year OS (2 studies, OR 1.16, 95%CI 1.08–1.25, p<0.0001, I2=0%) and DFS (3 studies, OR 1.66, 95%CI 1.32–2.10, p<0.0001, I2=79%). A lymph node cut-off of 10 was not predictive of five-year OS (2 studies, OR 1.69, 95%CI 0.82–3.50, p = 0.16, I2=72%).

The present study uniquely considered various lymph node harvest cut-offs of 12, above 12, and below 12. Previous studies show support for increased lymph node harvest being associated with improved long-term survival in colon cancer patients, including a systematic review by Chang et al. [11]. To support its conclusion, the study by Chang et al. considered studies from nested cohorts like intergroup 0089 [9], population registries such as the Surveillance Epidemiology and End Results program (SEER), and various single institution studies. Across various methodologies and lymph node harvest cut-offs, the survival benefit of increased harvest was repeatedly demonstrated. However various lymph node harvesting cut-offs and their association to long term survival remained unexplored through a meta-analysis. A previous systematic review and meta-analysis in rectal cancer patients by Tan et al. supported improved survival at the 12 lymph node harvest cut-off [14]. In particular, Tan et al. showed a favourable pooled hazard ratio for a ≥ 12 lymph node harvest in rectal cancer patients with previous neoadjuvant chemotherapy. Tan et al. indicated this benefit may extend to other cut-offs, with a brief literature summary of relevant studies considering different lymph node harvests. However, cut-offs above and below 12 and their association with five-year DFS and OS in colon cancer patients remained to be meta-analysed.

Inadequate lymphadenectomy, currently defined as a lymph node harvest of 12 or less, occurs in 20–50% of colonic oncologic resections [7,41]. The underlying cause for inadequate lymphadenectomy is likely multifactorial; including surgeon, pathologist, and patient factors. Surgeon factors identified in a SEER-database analysis by Nathan et al. that increased the likelihood of a nodal harvest of greater than 12 included speciality training in colorectal surgery (OR 1.21, 95% CI 1.08–1.35, p = 0.001) and high surgeon colorectal volume (OR 1.10, 95% CI 1.00–1.19, p = 0.039) [41]. Moreover, a retrospective analysis by Douaiher et al. demonstrated that a minimally invasive surgical approach is significantly more likely to result in adequate lymphadenectomy as compared to open surgery (Laparoscopic: OR 1.74, 95% CI 1.49–2.04; Robotic: OR 1.48, 95% CI 1.20–1.84) [42]. For pathologists, studies by Da Costa et al. and Hsu et al. demonstrate that individual pathologists can have significant differences in achieving adequate lymph node harvest [43,44]. Burlet et al., illustrate a relationship between time spent by a pathologist on a sample to increased lymph node harvest [45]. Lastly, numerous patient factors have been identified as being associated with increased lymph node harvest, including younger age, greater clinical T stage, poor tumor differentiation, lack of neoadjuvant radiation, and right-sided colon cancer [41,46,47].

Since the present study demonstrated mixed results and low power with cut-offs under 12, further research is warranted to determine whether lower cut-offs can distinguish survival, and if AJCC and NCCN guidelines for minimum lymphadenectomy can be loosened [1,5]. As for cut-offs greater than 12, this study demonstrated that all included lymph node harvest cut-offs greater than 12 (i.e., 13, 17) were able to significantly distinguish between five-year OS and DFS. Thereby supporting previous research that greater lymph node harvest continues to predict long-term survival even beyond a harvest of 12 [11]. Potential reasons behind this survival benefit include greater accuracy of staging with greater lymph node harvest and greater tumor clearance. A nationwide survey of institutions in Japan by Ueno et al. demonstrated that under-staging from stage III to stage II can be avoided by obtaining an adequate lymphadenectomy of 12, with a higher lymph node harvest aiding in more accurate staging [12]. Song et al. identified through a SEER dataset analysis that Stage II T4N0 patients with between 0 and 10 lymph nodes harvested had worse OS compared to Stage III T3N2 patients (HR 1.211, 95% CI 1.005–1.459, p<0.05).

The strengths of this study includes rigorous methodology, comprehensive risk of bias assessment, homogenous outcome data, inclusion of a wide variety of lymph node harvest cut-offs, and a large number of patients (n = 854,359) in the included studies. The strength of this study's approach of analyzing each lymph node harvest cut-off separately allowed for a nuanced understanding of the impact of the extent of lymph node harvest on survival that has not been previously explored. The study limitations include a small number of studies reporting data for cut-offs other than 12, a number of studies that collected data from over 30 years ago, a small number of studies with controlled prospective data, and heterogeneity in methodologies between the included studies. Given the variety in cut-offs, cut-offs other than 12 were less vigorously studied. In particular, five-year overall survival was less reliably predicted by cut-offs below 12, potentially as a result of lack of pooling of data. The presented data is heterogenous in regard to colon cancer location, as well as patient age. While this impacts the specificity of the findings, it makes the findings generalizable. Furthermore, current NCCN guidelines for the treatment of colon cancer do not differentiate by cancer location in the colon or patient age [5]. Lastly, statistical heterogeneity I2 values were greater than 50% for multiple lymph node harvest cut-offs. Thus highlighting potential inconsistencies in methodologies between studies, and warranting interpretation of data with this in mind [20].

5. Conclusion

This systematic review and meta-analysis demonstrates that a lymph node harvest cut-off of 12 is able to effectively predict survival for five-year OS in colon cancer. Contrarily, lymph node harvests other than 12 have not been rigorously studied and thus lack the statistical power to derive meaningful conclusions compared to the 12-lymph node cut-off. Further prospective study evaluating cut-offs other than 12, in particular cut-offs below 12, are warranted to ascertain whether current guidelines regarding adequate lymphadenectomy may allow for a lesser lymph node harvest while still providing adequate survival predictions.

Ethics approval and consent to participate

Not Applicable.

Consent for publication

Not applicable.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors’ contributions

Conception and design of the study – All authors.

Acquisition of data – Ichhpuniani, McKechnie, Lee, Biro.

Analysis and interpretation of data – All authors.

Drafting and revision of the manuscript – All authors.

Approval of the final version of the manuscript – All authors.

Agreement to be accountable for all aspects of the work – All authors.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

None.

Appendix 1. Complete Search Strategy

  • 1

    exp Colorectal Neoplasms/

  • 2

    colorectal carcinoma.mp.

  • 3

    colorectal cancer.mp.

  • 4

    colorectal tumo*.mp.

  • 5

    colon cancer.mp.

  • 6

    colon carcinoma.mp.

  • 7

    colon tumo*.mp.

  • 8

    rectal cancer.mp.

  • 9

    rectal carcinoma.mp.

  • 10

    rectal tumo*.mp.

  • 11

    large bowel cancer.mp.

  • 12

    lymph node dissection.mp.

  • 13

    lymph node removal.mp.

  • 14

    lymph node resection.mp.

  • 15

    exp Lymph Node Excision/

  • 16

    lymphadenectomy.mp.

  • 17

    lymph node analy*.mp.

  • 18

    lymph node harvest.mp.

  • 19

    lymph node basin removal.mp.

  • 20

    exp Prognosis/

  • 21

    exp Survival/

  • 22

    exp Survival Rate/

  • 23

    exp Neoplasm Staging/

  • 24

    overall survival.mp.

  • 25

    cancer specific survival.mp.

  • 26

    exp Disease-Free Survival/

  • 27

    exp Neoplasm Recurrence, Local/

  • 28

    distant recurrence.mp.

  • 29

    cancer staging.mp.

  • 30

    exp mortality/

  • 31

    1 or 2 or 3 or 4 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11

  • 32

    12 or 13 or 14 or 15 or 16 or 17 or 18 or 19

  • 33

    20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30

  • 34

    31 and 32 and 33

  • 35

    limit 34 to humans

  • 36

    limit 35 to (adaptive clinical trial or clinical conference or clinical study or clinical trial, all or clinical trial, phase i or clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or clinical trial protocol or clinical trial or comparative study or controlled clinical trial or dataset or equivalence trial or evaluation study or journal article or observational study or pragmatic clinical trial or randomized controlled trial or technical report or validation study) [Limit not valid in Embase; records were retained]

  • 37

    remove duplicates from 36

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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