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The impact of lymph node ratio on overall survival in patients with colorectal cancer

1 Departments of Medical Oncology, University of Health Sciences, Dışkapı Yıldırım Beyazıt Research and Training Hospital, Ankara, Turkey
2 Department of Medical Oncology, Baskent University, Ankara, Turkey
3 Department of Medical Oncology, University of Health Sciences, Dışkapı Yıldırım Beyazıt Research and Training Hospital, Ankara, Turkey

Correspondence Address:
Goksen İnanğ İmamoğlu,
Department of Medical Oncology, University of Health Sciences, Diskapi Yildirim Beyazit Research and Training Hospital, Ankara
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_11_19

 > Abstract 

Background: Lymph node metastasis is a predominant prognostic indicator in colorectal cancer. Number of lymph nodes removed surgically was demonstrated to correlate with staging accuracy and oncological outcomes. However, number of lymph nodes removed depends on uncontrolled variables. Therefore, a more reliable prognostic indicator is needed. Calculation of ratio of positive lymph nodes to total number of removed lymph nodes may be an appealing solution.
Materials and Methods: We retrospectively analyzed data of 156 Stage III colorectal cancer patients whom underwent surgery between 2008 and 2015. Patients' demographic characteristics, tumor grade, location, vascular-perineural invasion status, number of removed lymph nodes, and ratio of positive lymph nodes to number of removed lymph nodes were recorded. Spearman correlation analysis was used to determine the correlation coefficient while Kaplan–Meier method and Cox proportional hazard regression model were performed for the prediction of survival and multivariate analysis, respectively.
Number of removed lymph nodes did not correlate with survival, but it was inversely correlated with number of positive lymph nodes. Multivariate analysis showed that ratio of removed positive lymph nodes to the total number of lymph nodes was a significant prognostic factor for survival for a ratio equal or above 0.31 was a poor prognostic indicator (108 months vs. 34 months, hazard ratio: 4.24 [95% confidence interval: 2.15–8.34]; P < 0.019). Tumor characteristics failed to demonstrate any prognostic value.
This study showed that positive lymph node ratio (PLNR) is an important prognostic factor for Stage III colorectal cancer. Although 0.31 can be taken as threshold for “PLNR,” prospective trials including larger patient groups are needed to validate its role as a prognostic indicator.

Keywords: Colorectal cancer, lymph node, prognosis, ratio, survival

How to cite this URL:
İmamoğlu G&, Oğuz A, Cimen S, Eren T, Karacin C, Colak D, Altşbaş M, Türker S, Yazılıta D. The impact of lymph node ratio on overall survival in patients with colorectal cancer. J Can Res Ther [Epub ahead of print] [cited 2021 Jul 25]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=275132

 > Introduction Top

The most important determinant of prognosis in colorectal cancer patients is lymph node involvement. Lymph node involvement decreases the 5-year survival rates from 80% to 30%–60%.[1],[2] In addition, the number of lymph nodes removed with the surgical specimen affects both staging accuracy and oncological outcomes. However, the number of removed lymph nodes is affected by many variables such as patient age, body mass index, tumor location, and the extent of surgical resection.[2],[3],[4],[5] In order to prevent downstaging due to inadequate sampling, College of American Pathologists (CAP) and the American Joint Committee on Cancer (AJCC) staging system recommended removal of a minimum of 10–14 lymph nodes per specimen.[6],[7],[8] Despite this recommendation, a population-based study showed that only 37% of colon cancer patients had adequate lymph node sampling and assessment.

The nodal staging methodology of the AJCC staging system is based on the number of positive lymph nodes. However, this methodology, which focuses on the numbers only, may pave the way for staging errors and/or under-staging, especially when a suboptimal number of lymph nodes are removed. Since under-staging may lead to under treatment, another parameter which has the potential to decrease the risk of under-staging during lymph node specimen assessment is needed. In this study, we sought to determine if the ratio of positive lymph nodes to total number of lymph nodes removed (i.e., positive lymph node ratio [PLNR]) could take this role and provide reliable and clinically relevant prognostic information during the nodal assessment of colorectal cancer.

 > Materials and Methods Top

Between January 2008 and 2015, 414 patients were diagnosed with colorectal cancer in Ankara Diskapi Research and Training Hospital. Among these patients, 166 were found to have Stage III disease and underwent radical surgery. After the approval of the ethics committee, patients were evaluated. Exclusion criteria were the presence of familial adenomatous polyposis (FAP), multiple primary colorectal cancers, history of neoadjuvant chemotherapy or radiotherapy, early recurrence or death within 3 months' postsurgery. Patients who were lost to follow-up were also excluded. Files of these patients were reviewed retrospectively. Variables such as age, gender, family history, and chief complaint at presentation were all recorded. Histopathological data, including tumor location, grade, vascular-perineural invasion status, number of total lymph nodes extracted, and positive lymph nodes, were obtained from pathological assessment reports, all of which were signed by two experienced colorectal pathologists.

The PLNR was defined as the ratio of positive lymph nodes to the total number of removed lymph nodes. This parameter was calculated for each patient with the guidance of the pathology reports. Survival was calculated for each patient based on the time of diagnosis and the time of death or the last date of follow-up.

SPSS Statistics 20.0 (IBM-SPSS Inc., Chicago, IL, USA) software was used for statistical analysis. Shapiro–Wilk's test was used; histograms and q-p plots were plotted to assess the data normality. Values were expressed as frequencies and percentages or median and 25th–75th percentiles. Spearman's nonparametric test was used for correlation analysis. Survival probabilities were predicted by Kaplan–Meier method and group comparisons were performed by log-rank test. Univariate and multivariate Cox regression analysis was used to determine the most significant risk factors. Significant variables on univariate analysis were taken into multivariate model, and backward stepwise selection was performed using Wald statistic at P < 0.10 stringency level. Hazard ratios (HRs) were also given with 95% confidence intervals (CIs). P < 0.05 was considered as statistically significant. Receiver operating characteristic (ROC) curve analysis was used for determining the cutoff value for q/p ratio.

After the surgery, patients were followed up every 3 months for 2 years, then every 6 months for 3 years and every year thereafter. The follow-up assessments included detailed history, physical examination, complete blood count, liver function tests, carcinoembryonic antigen (CEA) level, chest X-ray, abdominal ultrasound, and colonoscopy. Thoracoabdominal computed tomography scans and abdominal magnetic resonance imaging were performed as needed.

 > Results Top

After application of the exclusion criteria, 156 patients were included in this study. Among 156 Stage III colorectal patients, 80 (51.3%) were male and 76 (48.7%) were female. The mean age of all patients was 59.1 ± 13.7 years. A family history of malignancy (other than FAP) was found in 26 cases (16.7%). The most common main complaints at the time of diagnosis were abdominal pain (n = 50), rectal bleeding (n = 44), constipation (n = 23), and weight loss (n = 3). Curative surgery was performed in all patients and of those 8 were emergent cases [Table 1].
Table 1: The patients' characteristics

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Rectum was the most common tumor location (n = 49, 31.4%). It was followed by the sigmoid colon (n = 42, 26.9%), ascending colon (n = 28, 17.9%), caecum (n = 13, 8.3%), descending colon (n = 12, 7.7%), and transverse colon (n = 12, 7.7%). The median follow-up time was 31.6 months. Median overall survival for entire group was 100.73 ± 37.6 months. There was no relation between tumor location and overall survival (P > 0.05).

Tumor grades had been reported in 118 of all pathology reports. These tumor grades varied from well-differentiated adenocarcinoma in 26 cases (22%) to moderately differentiated in 78 cases (66.1%) and poorly differentiated in 14 cases (11.9%). There was no correlation between the survival rate and tumor grades (P > 0.05). Vascular and perineural invasion were also evaluated in the pathology reports; 55 (56.1%) patients were found to have vascular invasion, whereas perineural invasion was detected in 41 (48.2%) patients. Vascular and perineural invasion did not have a correlation with patient survival.

Among 156 Stage III colorectal cancer patients, the mean number of total lymph nodes removed was 14.15 ± 10. The mean number of positive lymph nodes was 4.05 ± 4.71. The total number of lymph nodes evaluated did not correlate with patient survival (P > 0.05). However, the number of positive lymph nodes was inversely correlated with survival. In the ROC analysis for the number of positive lymph nodes, the cutoff value was found 4. There was statistically significant difference in overall survival between the patients above and below this value (108 vs. 38 months, HR: 2.12 [95% CI: 1.12–4.00], P = 0.020).

In the Kaplan–Meier analysis, The patients who have N2 stage have significantly longer overall survival compared to N1 group (108 vs. 43 months, HR: 1.97 [95% CI: 1.04–3.69], P < 0.036 for N2 vs. N1 group), this OS difference was also present in PLNR ≥0.31 group compared to <0.31 group (108 vs. 34 months, HR: 8.98 [95% CI 1.43–56.25]; P < 0.001) [Figure 1]. This relation was not detected between tumor grade and overall survival (P > 0.05). In multivariate analysis, significant correlation with overall survival was detected solely for PLNR value (HR: 4.24 [95% CI: 2.15–8.34]; P < 0.019) [Table 2]. The ROC curve analysis showed that PLNR ratio of 0.31 was the cutoff value for predicting survival (area under the curve: 0.704; with a sensitivity 65%, specificity 65%; P < 0.001) [Figure 2].
Figure 1: The overall survival according to cutoff value (0.31) positive to negative lymph node ratio

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Table 2: Univariate and multivariate Cox regression analysis for overall survival

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Figure 2: The receiver operating characteristic curve for positive to total lymph node ratio

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 > Discussion Top

Colorectal cancer is one of the most common malignancies; nearly 600,000 cases are diagnosed annually worldwide.[6],[7],[8] During the past decades, the 5-year survival rate improved from 33% in 1970s to 55.3% in 1990s and 60% more recently.

The variables associated with survival in the setting of colorectal cancer are continuously being studied.[8],[9],[10] These variables include age at the onset of disease, gender, stage at diagnosis, lymph node status, presence of distant metastasis, tumor grade, location, lymphatic and vascular invasion, preoperative CEA level, and liver function tests. Among these parameters, lymph node status is considered to be the most important prognostic factor.

In 1932, Dukes recognized the importance of lymph node status for the first time and formed a staging system for rectal cancer.[10] A few years later, Simpson and Mayo applied this system to colon cancer patients.[11] Today, tumor-node-metastasis (TNM) staging system is widely used. According to the current TNM staging system, N category is determined by the number of positive lymph nodes. The breakpoints for defining patients as N1 (a/b/c) or N2 (a/b) is solely based on the number of positive lymph nodes. Therefore, this system disregards the total number of lymph nodes examined in each specimen. Ignorance of the number of removed lymph nodes and PLNR has the potential to lead to “under staging” given that number of removed lymph nodes depends on many factors which can often cause inadequate lymph node sampling [Table 3]. These factors may be patient, tumor, pathologist or surgeon-related. However, regardless of the cause, it may cause under-staging and under treatment. The CAP and AJCC Stating System recommended having a minimum of 10–14 lymph nodes per specimen.[7],[8],[12] In alignment with these recommendations, the mean number of lymph nodes examined in our patient series was 14.15 ± 10.
Table 3: The factors are causes of inadequate lymph node sampling

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Our study showed that the total number of lymph nodes evaluated did not correlate with patient survival (P > 0.05); however, the number of positive lymph nodes was inversely correlated with survival. In the ROC analysis, for the number of positive lymph nodes, the cutoff value was found 4. There was statistically significant difference in overall survival between the patients above and below this value (108 vs. 38 months, HR; 2.12, [95% CI: 1.12–4.00], P = 0.020). This finding is also supported by the study of Le Voyer et al.[2]

Since inadequate lymph node sampling may lead to downstaging and significant changes in treatment planning, solutions were sought to improve lymph node sampling and histological assessment. The utilization of PLNR may diminish the possible stage migration. As a potential prognostic indicator, PLNR has been studied in different types of solid tumors including breast, stomach, and esophagus cancers with promising results.

Hatoum et al. analyzed the data of nonmetastatic breast cancer patients and concluded that axillary PLNR was a significant predictor of overall survival.[13] In multivariate analysis, PLNR ≥0.25 has been determined as a stronger independent predictor of survival than the number of positive surgically removed lymph nodes. In 536 esophageal cancer patients, Mariette et al. found that the presence of more than 4 positive lymph nodes and a PLNR of >0.2 were the only predictors of poor prognosis (P < 0.001 for both).[14]

As per our knowledge, four independent study groups reported evidence favoring PLNR as a prognostic indicator in the setting of colorectal cancer.[15],[16],[17],[18] However, these series included a relatively small number of patients with positive lymph nodes. Our study is unique to reflect the Turkish population with sufficient power to detect differences and produce a ROC curve.

The ROC curve plot analysis performed in our study showed the cutoff value of 0.31 to be a significant predictor for survival in patients with Stage III Colorectal Cancer. Elias et al. followed a similar methodology and divided the patients into two groups as per PLNR in their retrospective analysis.[15] They analyzed the data of 164 Stage III colon cancer patients and compared the survival rates based on PLNR. They concluded that 1, 5, and 10 years' survival rates were 94.1%, 77.3%, and 60.6%, respectively, for patients with PLNR of ≤0.4 while they were 86.2%, 40.6%, and 0%, respectively, for patients with PLNR higher than 0.4 (P = 0.02).[19] The same PLNR threshold level of 0.4 was also tested by De Ridder et al. in Stage III colon cancer patients and these authors found that PLNR >0.4 was a strong independent prognostic risk factor (P < 0.0001).[16] Different PLNR cutoff levels such as 0.18 and 0.25 were reported in Stage III colon cancer patients for predicting survival by different study groups.[17],[18]

In addition to PLNR, patient and tumor characteristics have also been studied as potential prognostic indicators in the setting of colorectal cancer.[19],[20],[21],[22],[23],[24],[25],[26] Patients' age of >75 years at the time of diagnosis was associated with poor prognosis while patient age of <69 indicated a better prognosis.[20],[21] Factors related to old age such as presence of comorbidities, performance of a “less aggressive” surgery, and discontinuation of adjuvant treatment has been implicated.[20],[22] On the other hand, Hemminki et al. showed that female gender was a favorable prognostic factor (HR: 0. 55 [95% CI: 0. 46–0. 67]).[26] In our study, we did not find any correlation between survival and patients' gender or age.

Several studies have demonstrated that the presence of perineural invasion is associated with a significantly worse prognosis.[27],[28],[29] A retrospective analysis of 269 colorectal cancer patients found a 4-fold greater 5-year survival in patients without perineural invasion compared to patients with perineural invasion.[27] The analysis of patients with Stages II and III colorectal cancer has shown that patients with perineural invasion have a significantly worse 5-year disease-free survival versus the ones without.[28],[29] In our study, the presence of perineural invasion and vascular invasion was not significantly correlated with survival. However, it must be considered that we analyzed 3-year survival rates in contrast to these studies which reviewed 5-year survival.

The relation between the number of surgically removed lymph nodes and survival has been studied previously. Le Voyer et al. analyzed the association of survival with the number of removed lymph nodes in Stages II and III colon cancer patients who were recruited to the Intergroup Trial INT-0089.[2] They revealed that the number of lymph nodes removed is a significant variable that affects survival in both node negative and node positive patients, regardless of the number of positive nodes. They also postulated that patients with a higher number of lymph nodes identified in their pathologic specimen had probably undergone both a more complete resection of their cancer and a more thorough pathological staging process.

 > Conclusion Top

Our study demonstrated that PLNR – but not the total number of removed lymph nodes – can provide reliable prognostic information and a ratio above 0.31 was found to be a poor prognostic indicator in the setting of surgically treated Stage III colorectal cancer. Despite the fact that this finding supports the utilization of PLNR as a prognostic marker, it must be considered that our study is a retrospective analysis which bears all potential disadvantages of a retrospective type study. However, we strongly believe that prospective trials involving larger patient groups will validate the role of PLNR as a prognostic indicator during the management of Stage III colorectal cancer patients.

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There are no conflicts of interest.

 > References Top

Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011;61:212-36.  Back to cited text no. 1
Le Voyer TE, Sigurdson ER, Hanlon AL, Mayer RJ, Macdonald JS, Catalano PJ, et al. Colon cancer survival is associated with increasing number of lymph nodes analyzed: A secondary survey of intergroup trial INT-0089. J Clin Oncol 2003;21:2912-9.  Back to cited text no. 2
Bilimoria KY, Palis B, Stewart AK, Bentrem DJ, Freel AC, Sigurdson ER, et al. Impact of tumor location on nodal evaluation for colon cancer. Dis Colon Rectum 2008;51:154-61.  Back to cited text no. 3
Wong SL, Ji H, Hollenbeck BK, Morris AM, Baser O, Birkmeyer JD, et al. Hospital lymph node examination rates and survival after resection for colon cancer. JAMA 2007;298:2149-54.  Back to cited text no. 4
Jass JR, O'Brien MJ, Riddell RH, Snover DC; Association of Directors of Anatomic and Surgical Pathology (ADASP). Recommendations for the reporting of surgically resected specimens of colorectal carcinoma. Virchows Arch 2007;450:1-3.  Back to cited text no. 5
Tepper JE, O'Connell MJ, Niedzwiecki D, Hollis D, Compton C, Benson AB 3rd, et al. Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 2001;19:157-63.  Back to cited text no. 6
Washington MK, Berlin J, Branton P, Burgart LJ, Carter DK, Fitzgibbons PL, et al. Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum. Arch Pathol Lab Med 2009;133:1539-51.  Back to cited text no. 7
Edge SB, Compton CC. The American Joint Committee on Cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010;17:1471-4.  Back to cited text no. 8
Swanson RS, Compton CC, Stewart AK, Bland KI. The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol 2003;10:65-71.  Back to cited text no. 9
Dukes CE. The classification of cancer of the rectum. J Pathol Bacteriol 1932;35:323-32.  Back to cited text no. 10
Simpson WC, Mayo CW. The mural penetration of the carcinoma cell in the colon: Anatomic and clinical study. Surg Gynecol Obstet 1939;68:872-7.  Back to cited text no. 11
Moertel CG. Chemotherapy for colorectal cancer. N Engl J Med 1994;330:1136-42.  Back to cited text no. 12
Hatoum HA, Jamali FR, El-Saghir NS, Musallam KM, Seoud M, Dimassi H, et al. Ratio between positive lymph nodes and total excised axillary lymph nodes as an independent prognostic factor for overall survival in patients with nonmetastatic lymph node-positive breast cancer. Indian J Surg Oncol 2010;1:305-12.  Back to cited text no. 13
Mariette C, Piessen G, Briez N, Triboulet JP. The number of metastatic lymph nodes and the ratio between metastatic and examined lymph nodes are independent prognostic factors in esophageal cancer regardless of neoadjuvant chemoradiation or lymphadenectomy extent. Ann Surg 2008;247:365-71.  Back to cited text no. 14
Elias E, Mukherji D, Faraj W, Khalife M, Dimassi H, Eloubeidi M, et al. Lymph-node ratio is an independent prognostic factor in patients with stage III colorectal cancer: A retrospective study from the Middle East. World J Surg Oncol 2012;10:63.  Back to cited text no. 15
De Ridder M, Vinh-Hung V, Van Nieuwenhove Y, Hoorens A, Sermeus A, Storme G. Prognostic value of the lymph node ratio in node positive colon cancer. Gut 2006;55:1681.  Back to cited text no. 16
Schumacher P, Dineen S, Barnett C Jr., Fleming J, Anthony T. The metastatic lymph node ratio predicts survival in colon cancer. Am J Surg 2007;194:827-31.  Back to cited text no. 17
Vaccaro CA, Im V, Rossi GL, Quintana GO, Benati ML, Perez de Arenaza D, et al. Lymph node ratio as prognosis factor for colon cancer treated by colorectal surgeons. Dis Colon Rectum 2009;52:1244-50.  Back to cited text no. 18
Holch JW, Ricard I, Stintzing S, Modest DP, Heinemann V. The relevance of primary tumour location in patients with metastatic colorectal cancer: A meta-analysis of first-line clinical trials. Eur J Cancer 2017;70:87-98.  Back to cited text no. 19
Quaglia A, Tavilla A, Shack L, Brenner H, Janssen-Heijnen M, Allemani C, et al. The cancer survival gap between elderly and middle-aged patients in Europe is widening. Eur J Cancer 2009;45:1006-16.  Back to cited text no. 20
Angell-Andersen E, Tretli S, Coleman MP, Langmark F, Grotmol T. Colorectal cancer survival trends in Norway 1958-1997. Eur J Cancer 2004;40:734-42.  Back to cited text no. 21
Vulto AJ, Lemmens VE, Louwman MW, Janssen-Heijnen ML, Poortmans PH, Lybeert ML, et al. The influence of age and comorbidity on receiving radiotherapy as part of primary treatment for cancer in South Netherlands, 1995 to 2002. Cancer 2006;106:2734-42.  Back to cited text no. 22
Lincourt AE, Sing RF, Kercher KW, Stewart A, Demeter BL, Hope WW, et al. Association of demographic and treatment variables in long-term colon cancer survival. Surg Innov 2008;15:17-25.  Back to cited text no. 23
O'Connell JB, Maggard MA, Liu JH, Etzioni DA, Livingston EH, Ko CY, et al. Do young colon cancer patients have worse outcomes? World J Surg 2004;28:558-62.  Back to cited text no. 24
Adams J, Audisio RA, White M, Forman D. Age-related variations in progression of cancer at diagnosis and completeness of cancer registry data. Surg Oncol 2004;13:175-9.  Back to cited text no. 25
Hemminki K, Santi I, Weires M, Thomsen H, Sundquist J, Bermejo JL. Tumor location and patient characteristics of colon and rectal adenocarcinomas in relation to survival and TNM classes. BMC Cancer 2010;10:688.  Back to cited text no. 26
Liebig C, Ayala G, Wilks J, Verstovsek G, Liu H, Agarwal N, et al. Perineural invasion is an independent predictor of outcome in colorectal cancer. J Clin Oncol 2009;27:5131-7.  Back to cited text no. 27
Quah HM, Chou JF, Gonen M, Shia J, Schrag D, Landmann RG, et al. Identification of patients with high-risk stage II colon cancer for adjuvant therapy. Dis Colon Rectum 2008;51:503-7.  Back to cited text no. 28
Fujita S, Shimoda T, Yoshimura K, Yamamoto S, Akasu T, Moriya Y. Prospective evaluation of prognostic factors in patients with colorectal cancer undergoing curative resection. J Surg Oncol 2003;84:127-31.  Back to cited text no. 29


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