|Ahead of print publication
Lymph node yield in colorectal cancer specimens and its impact on pathological staging: Does number matter?
RN Mounika, Anuradha Ananthamurthy
Department of Pathology, St Johns Medical College, Bengaluru, Karnataka, India
|Date of Submission||18-Jun-2021|
|Date of Acceptance||12-Aug-2021|
|Date of Web Publication||27-Apr-2022|
St Johns Medical College, Bengaluru - 560 034, Karnataka
Source of Support: None, Conflict of Interest: None
Introduction: Regional lymph node involvement is an important predictor of outcome in colorectal cancer (CRC). The lymph node yield in resected specimens varies from case to case.
- To assess whether clinicopathologic factors have an impact on the number of lymph nodes harvested from surgical resection specimens of CRCs
- To assess whether the total number of lymph nodes retrieved has a bearing on the positivity of lymph nodes and hence the N category.
Materials and Methods: All resection specimens of treatment naïve CRC received in the department of pathology during a 2 year period (2017–2019) were reviewed. The lymph node yield was correlated with age, sex, type of surgical procedure, length of resected segment, tumor location, histological type and grade, T and N categories. The statistical tests used were Spearman rank, Mann–Whitney U, Kruskal–Wallis, and Chi-square tests.
Results: A total of 51 resections were studied. The mean age was 59.64 years with 72.55% being male. About 76.47% were hemicolectomies and 23.52% were rectosigmoid surgeries. The lymph node yield ranged from 0 to 38, the mean being 12.67. None of the parameters studied had a significant correlation with the lymph node yield except histological grade, specimens with higher-grade tumors yielding more number of nodes (P = 0.0242). There was no significant correlation between node positivity and the average number of lymph nodes (P = 0.0883). There was no significant correlation between total yield in cases with ≥12 lymph nodes and N category (P = 0.180). Furthermore, there was no significant correlation between total yield in node-positive cases with ≥12 lymph nodes and N category (P = 0.216). There was no significant difference in the sizes of the lymph nodes in node-positive and negative cases (P = 0.3930 and 0.2355, respectively).
Conclusion: Among the parameters affecting lymph node yield, the current study found a significant correlation between histological grade and lymph node yield. There was no significant difference in the size of lymph nodes between node-positive and negative cases. The total lymph node yield did not have a bearing on node positivity and this shows that a lower lymph node yield may be accepted as adequate after thorough examination of the specimen.
Keywords: Colorectal cancer, lymph node yield, pathological staging
| > Introduction|| |
Colorectal cancer (CRC) is the third-most common cancer worldwide following cancers of the lung and breast. The oncological resection for CRC involves resection of the intestinal segment with the tumor with adequate margins as well as the removal of the draining regional lymph nodes. The reporting of a case of colorectal neoplasm is not complete without a thorough examination of the regional lymph node status which is a challenging job. This is due to the wide variability in the number of lymph nodes retrieved from the specimens. The current AJCC 8th edition gives a minimum requirement of 12 lymph nodes as a standard quality indicator for CRC resection specimens., The total number of lymph nodes retrieved has prognostic importance for overall survival (OS) in both node-positive and node-negative disease., The aim of the current study is to assess the clinicopathologic factors that may have an impact on the number of lymph nodes harvested from surgical resection specimens of CRCs and to assess whether the lymph node yield has a bearing on the presence or absence of metastasis as well as the number of lymph nodes that show metastasis.
The objectives of this study were to assess clinicopathologic factors that may have an impact on the number of lymph nodes harvested from surgical resection specimens of CRCs and to assess whether the total number of lymph nodes retrieved has a bearing on the positivity of lymph nodes and hence the N category.
| > Materials and Methods|| |
All treatment-naive hemicolectomies, abdominoperineal resections, low anterior resections, and sigmoid colectomy specimens of CRC received during 2017–2019 in the department of Pathology, St Johns Medical College and Hospital were studied and reviewed according to a proforma that incorporated various patient-related and histological parameters. The parameters studied were age, sex, type of procedure, site of tumor, histological type and grade of tumor, T and N categories, number of lymph nodes harvested, number of positive nodes, and the average size of lymph nodes. A total of 51 cases were included in the study. Cases, where the slides were unavailable to review and cases who received neoadjuvant chemotherapy, were excluded from the study. Preliminary analyses used descriptive statistics to summarize the demographic characteristics of patients. All hemicolectomies were grouped together and rectosigmoid surgeries were grouped together, which included low anterior resections, abdominoperineal resections, and sigmoid colectomies. Tumors arising from the cecum, ascending colon, and right two-thirds of the transverse colon were grouped under the right colon. Tumors arising from the left one-third of the transverse colon and descending colon were grouped under the left colon. Rectal and sigmoid colon tumors were grouped together (all adenocarcinomas and mucinous adenocarcinomas were grouped together and other neoplasms, including mixed adenoneuroendocrine carcinoma [MANEC] and low-grade appendiceal mucinous neoplasm [LAMN] were grouped under nonadenocarcinomas).
The correlation of various parameters with lymph node yield was done. The parameters of age and length of the resected segment were correlated with lymph node yield using the Spearman rank test. The T and N categories were correlated with lymph node yield using Kruskal–Wallis test. The rest of the parameters were correlated using Mann–Whitney U-test.
| > Results|| |
A total of 51 cases were included in this study. The age ranged from 28 to 85 years, with a mean of 59.64. There were 37 (72.55%) men and 14 (27.45%) women with a gender ratio of 2.64:1. The 51 cases included 39 (76.47%) hemicolectomies and 12 (23.52%) rectosigmoid surgeries. Length of the resected segment ranged from 9 cm to 99 cm with a mean of 30 cm. The most common tumor location was the right colon (72.55%), followed by rectosigmoid (19.61%) and the least common was the left colon (7.84%). Adenocarcinomas, including mucinous, constituted the majority of the cases (84.31%), while 15.69% of the cases were of MANEC and LAMN. Most of them were moderately or poorly differentiated (72.55%), whereas only 27.45% were well differentiated. Majority of them were categorized as T3 (76.47%), while 23.53% as T4 and 17.65% constituted T1/T2.
As summarized in [Table 1], none of the parameters showed a significant correlation with total lymph node yield with the exception of histological grade, which had a P = 0.0233, higher grade being associated with a higher lymph node number.
|Table 1: Correlation of various clinicopathological parameters with total lymph node yield|
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The total lymph node yield ranged from 0 to 38, with a mean of 12.67. Sixteen cases (61.53%) had a yield ≥12 lymph nodes. One case had zero nodes retrieved. The correlation between the total lymph node yield in node-positive and node-negative cases was done using Mann–Whitney U-test and it yielded a P = 0.0883 as shown in [Table 2]. There was no significant difference between the average lymph node yield in node-positive and negative cases.
|Table 2: Correlation of average lymph node yield between node positive and negative cases (Kruskal-Wallis test)|
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The cases were divided into those that met the cut-off of 12 in number and those that did not. These groups were then correlated with the N category. This again did not yield a significant result [P = 0.180 as depicted in [Table 3]]. Cases with ≥12 lymph nodes did not show an association with higher N category. Even when analyzed in node-positive cases and the total yield divided into <12 and ≥12 lymph nodes, a significant correlation with N category was not seen [P = 0.216 as depicted in [Table 3]].
|Table 3: Correlation between total lymph node yield in all cases and in node-positive cases for ≥12 and <12 lymph nodes; and N category (Chi-square test)|
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The comparison of the average lymph node size between positive and negative cases and a comparison of the largest lymph node size in the positive and average lymph node size in negative cases were also performed which yielded a P = 0.3930 and 0.2355, respectively. There was no significant difference in the sizes of lymph nodes between node-positive and negative cases.
The lymph node ratio (LNR) which is the ratio of positive nodes to total nodes was calculated for the two categories, namely, more than or equal to 12 nodes and <12 nodes. The range was 0.038–0.714 (average = 0.2404) for the >12 nodes category and 0.0909–1 (average = 0.39946) for the <12 nodes category.
| > Discussion|| |
Lymph node retrieval and eventual histopathological examination in resection specimens of any neoplasm holds utmost importance not only for staging but also for the assessment of prognosis and to determine the requirement of adjuvant chemotherapy. It is an established fact that influence on lymph node yield is multifactorial, including a combination of patient-related, tumor associated, surgical, and pathological factors. There have been many studies to determine a minimum number of lymph nodes that are required for adequate staging. The current 8th edition of the American Joint Committee on Cancer (AJCC) staging manual mentions that a minimum of 12 lymph nodes is required for accurate nodal sampling in cases of colorectal carcinomas. This number has been proposed by the Working Party Report to the World Congress of Gastroenterology in Sydney in 1990., The Working Party Report also recognizes that not all specimens will contain this number of lymph nodes.
Multiple studies done previously have shown a significant correlation of many clinicopathologic parameters with the total lymph node yield. A study done by McDonald et al. showed a significant correlation between lymph node yield and parameters such as age, sex, tumor location, T category, N category, and tumor grade. Another study by Orsenigo et al. found that right colon tumors, larger mean size of tumor, length of specimen, pT3-T4 disease, and female sex were found to significantly affect lymph node yield. However, in the current study, we have not found a significant association between any of the parameters studied and the lymph node yield with the exception of histologic grade. Higher the grade, higher was the lymph node yield (P = 0.0233).
The size of the lymph nodes, as studied previously does not always correlate with metastatic involvement. Larger-sized lymph nodes may represent an activated state of the patient's immune system rather than acting as an indicator for the presence of metastasis. As found in previous studies, there was no significant difference in the size of lymph nodes between node-positive and negative cases in our study.,
With regard to the adequacy of total lymph nodes, there have been numerous studies that describe a significant association between higher lymph node yield and increased OS with those having a better survival when the lymph node yield was higher. These studies,, have correlated the lymph node yield with survival and not the rate of positivity. The study by Chi Chung Woo et al. concluded that patients with a higher lymph node yield had a better disease-free and OS. They showed that not only lymph node yield could be a prognostic marker but also stated that the causality between a higher lymph node yield and survival was not proven, much like other similar studies.
Despite numerous studies correlating lymph node yield with survival, studies which compare lymph node yield with the positivity rates are scarce. The current study found that there was no significant difference in the number of lymph nodes between node-positive and node-negative cases. In other words, an increase in lymph node yield did not necessarily translate as a higher N category. Furthermore, no significant correlation was found between cases that met a minimum cut off of 12 lymph nodes with N category (which was also noted for the N categories, N0 to N1, and N1 to N2), i.e., higher lymph node yield which met the recommended number did not show higher rates of positivity. Even in node-positive cases, the total yield in cases that met the said cut-off did not show a significant correlation with N category. Although AJCC recommends at least 12 lymph nodes to be ideally present, finding lesser number of lymph nodes does not preclude the designation as N0 when metastases are absent. Two previous studies that compared lymph node number with positivity rate have findings similar to ours. A population-based study done by Bui et al. found that higher lymph node counts did not correlate with increased node positivity rates. Another study by van Erning et al. found that the node positivity rate did not change despite a steep increase in total lymph node number.
It has been suggested by some authors that the lymph node yield would incidentally be higher in those with a vigorous immune response, therefore having larger and higher number of nodes. A study by Märkl et al. showed that LN size and number is prognostic in node-negative colon cancer. The authors attribute the outcome difference to the activation status of lymph nodes. This shows that the number of lymph nodes may be a consequence of immune response rather than the presence of metastasis. The findings of the present study are significant and challenge the lymph node requirement in CRC according to the current AJCC guidelines. This is also reassuring to the surgeon and the pathologist when the lymph node yield is low, especially in node-negative cases. Although the current study did not correlate lymph node harvest with prognosis, it showed that a lower yield does not influence positivity rate.
Many studies have shown that LNR which is the ratio of positive lymph nodes to total lymph nodes to be an independent prognostic factor in CRC. In the current study, the LNR was higher among the <12 nodes category, reiterating that lesser number of nodes did not affect the positivity ratio.
Apart from clinic pathological factors, surgeon-related factors and surgical techniques can also influence lymph node yield. These factors were not assessed in the current study as it was outside the purview. One of the limitations of the study was the relatively low number of cases.
| > Conclusion|| |
Among the parameters affecting lymph node yield, the current study found a significant correlation between histological grade and lymph node yield. There was no significant difference in the size of lymph nodes between node-positive and negative cases. The total lymph node yield did not have a bearing on node positivity and this shows that a lower lymph node yield may be accepted as adequate after a thorough examination of the specimen.
Acknowledgment (for statistical help)
Mr. John Michael Raj, Lecturer, Department of biostatistics, St Johns Medical College, Bangalore.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Lee CH, Wilkins S, Oliva K, Staples MP, McMurrick PJ. Role of lymph node yield and lymph node ratio in predicting outcomes in non-metastatic colorectal cancer. BJS Open 2019;3:95-105.
Orsenigo E, Gasparini G, Carlucci M. Clinicopathological factors influencing lymph node yield in colorectal cancer: A retrospective study. Gastroenterol Res Pract 2019;2019.
Edge SB, Greene FL, Schilsky RL, Gasper LL, Washington MK, Sullivan DC, et al.
AJCC Cancer Staging Manual. New York : Springer; 2017. p. 254-9.
Ahmadi O, Stringer MD, Black MA, McCall JL. Clinico-pathological factors influencing lymph node yield in colorectal cancer and impact on survival: Analysis of New Zealand cancer registry data. J Surg Oncol 2015;111:451-8.
Ong ML, Schofield JB. Assessment of lymph node involvement in colorectal cancer. World J Gastrointest Surg 2016;8:179-92.
Axon AT. Disinfection and endoscopy: Summary and recommendations. Working party report to the world congresses of gastroenterology, Sydney 1990. J Gastroenterol Hepatol 1991;6:23-4.
McDonald JR, Renehan AG, O'Dwyer ST, Haboubi NY. Lymph node harvest in colon and rectal cancer: Current considerations. World J Gastrointest Surg 2012;4:9-19.
Schrembs P, Martin B, Anthuber M, Schenkirsch G, Märkl B. The prognostic significance of lymph node size in node-positive colon cancer. PLoS One 2018;13:e0201072.
Märkl B, Rößle J, Arnholdt HM, Schaller T, Krammer I, Cacchi C, et al.
The clinical significance of lymph node size in colon cancer. Mod Pathol 2012;25:1413-22.
Foo CC, Ku C, Wei R, Yip J, Tsang J, Chan TY, et al.
How does lymph node yield affect survival outcomes of Stage I and II colon cancer? World J Surg Oncol 2020;18:22.
Bui L, Rempel E, Reeson D, Simunovic M. Lymph node counts, rates of positive lymph nodes, and patient survival for colon cancer surgery in Ontario, Canada: A population-based study. J Surg Oncol 2006;93:439-45.
van Erning FN, Crolla RM, Rutten HJ, Beerepoot LV, van Krieken JH, Lemmens VE. No change in lymph node positivity rate despite increased lymph node yield and improved survival in colon cancer. Eur J Cancer 2014;50:3221-9.
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.
Sinan H, Demirbas S, Ersoz N, Ozerhan IH, Yagci G, Akyol M, et al.
Who is responsible for inadequate lymph node retrieval after colorectal surgery: Surgeon or pathologist? Acta Chir Belg 2012;112:200-8.
[Table 1], [Table 2], [Table 3]