Colorectal cancer is one of the most common cancers and the second leading cause of cancer-related deaths in the United States [
TNM classification is widely used to evaluate cancer staging and make treatment decisions [
The presence of lymph node metastasis and the number of metastatic lymph nodes are useful prognostic factors for colorectal adenocarcinoma [
This study investigated the prognostic significance of ENTE in colorectal cancer with lymph node metastasis. We retrospectively reviewed a consecutive series of 419 patients with colorectal adenocarcinoma who underwent curative resection for primary cancer and evaluated the correlation between ENTE and clinicopathologic factors and investigated survival rates in homogeneous pN staging groups.
From an institutional database, 419 patients who had undergone curative resection for primary colorectal adenocarcinoma from January 2005 to December 2010 at the Department of Surgery, Hanyang University Hospital, were selected. Excluded were patients who had received neoadjuvant or adjuvant chemotherapy or radiotherapy or those with recurrent colorectal cancer or fewer than 12 lymph nodes. Medical records were reviewed to define clinical characteristics including age, gender, date of surgery, date of last follow-up, date of first local recurrence, and date of first distant metastasis. This study was approved by the Institutional Review Board of the Hanyang University Hospital (HYUH 2015-05-023). Two surgical pathologists (Hyunsung Kim and Seung Sam Paik) reviewed all hematoxylin and eosin stained slides and pathology reports to confirm diagnoses and define clinicopathologic characteristics. TNM staging and other pathologic parameters were determined according to a protocol for examining specimens from patients with primary carcinoma of the colon and rectum [
Representative microphotos of lymph node metastasis without extranodal tumor extension (a) and with extranodal tumor extension (b) (hematoxylin and eosin, ×20).
Statistical analysis was performed using SPSS software version 21 (IBM Corp., Armonk, NY, USA). Mann-Whitney
Selected were 419 patients who underwent curative resection for primary colorectal cancer between January 2005 and December 2010. Their clinicopathologic information is in Table
Baseline patient characteristics (
Factors | Value (%) |
---|---|
Number of patients | 419 (100%) |
Mean age at surgery (years) | 63.4 (±11.4) |
Sex | |
Male | 257 (61.3%) |
Female | 162 (38.7%) |
Histologic grade | |
Grade 1 | 31 (7.4%) |
Grade 2 | 196 (46.8%) |
Grade 3 | 168 (40.1%) |
Grade 4 | 24 (5.7%) |
Pathologic characteristics | |
pT | |
1 | 35 (8.4%) |
2 | 42 (10.0%) |
3 | 263 (62.8%) |
4a | 52 (12.4%) |
4b | 27 (6.4%) |
pN | |
0 | 180 (43.0%) |
1a | 48 (11.5%) |
1b | 55 (13.1%) |
1c | 9 (2.1%) |
2a | 62 (14.8%) |
2b | 65 (15.5%) |
M | |
0 | 390 (93.0%) |
1a | 25 (6.0%) |
1b | 4 (1.0%) |
Mean number of removed LNs | 29.2 (±15.78) |
Mean number of metastatic LNs | 3.6 (±6.83) |
LNs: lymph nodes.
Of the 419 patients, 230 (54.9%) showed lymph node metastasis with 108 (47.0%) with ENTE in metastatic lymph node(s). Correlation among ENTE and clinicopathologic parameters of colorectal adenocarcinoma is in Table
Correlations between ENTE and clinicopathologic factors in colorectal adenocarcinoma with regional lymph node metastasis (
Factors |
|
ENTE |
|
|
---|---|---|---|---|
Negative (%) | Positive (%) | |||
( |
( | |||
Age (year) | 0.476† | |||
Mean (±SD) | 230 | 62.66 (±10.30) | 63.43 (±12.82) | |
Gender | 0.857‡ | |||
Male | 137 | 72 (52.6%) | 32 (47.4%) | |
Female | 93 | 50 (53.8%) | 43 (46.2%) | |
Tumor size | 0.477† | |||
Mean (±SD) | 230 | 5.13 (±2.06) | 5.33 (±2.12) | |
Gross type | 0.026‡ | |||
UI | 127 | 59 (46.5%) | 68 (53.5%) | |
UF & P | 103 | 63 (61.2%) | 40 (38.8%) | |
Location | 0.275‡ | |||
Colon | 134 | 67 (50.0%) | 67 (50.0%) | |
Rectum | 96 | 55 (57.3%) | 41 (42.7%) | |
Histologic grade | 0.012‡ | |||
Low grade | 101 | 63 (62.4%) | 38 (37.6%) | |
High grade | 129 | 59 (45.7%) | 70 (54.3%) | |
Tumor budding | 0.003‡ | |||
Low grade | 111 | 70 (63.1%) | 41 (36.9%) | |
High grade | 119 | 52 (43.7%) | 67 (56.3%) | |
Vascular invasion | <0.001‡ | |||
Absent | 158 | 96 (60.8%) | 62 (39.2%) | |
Present | 72 | 26 (36.1%) | 46 (63.9%) | |
Perineural invasion | 0.015‡ | |||
Absent | 69 | 45 (65.2%) | 24 (34.8%) | |
Present | 161 | 77 (47.8%) | 84 (52.2%) | |
Tumor deposit | <0.001‡ | |||
Absent | 158 | 101 (63.9%) | 57 (36.1%) | |
Present | 72 | 21 (29.2%) | 51 (70.8%) | |
MLN/TLN | <0.001† | |||
Mean ratio (%) | 230 | 15.30 (±14.43) | 31.81 (±25.46) | |
T stage | 0.211‡ | |||
T1 | 2 | 1 (50.0%) | 1 (50.0%) | |
T2 | 15 | 11 (73.3%) | 4 (26.7%) | |
T3 | 148 | 81 (54.7%) | 67 (45.3%) | |
T4 | 65 | 29 (44.6%) | 36 (55.4%) | |
N stage | <0.001‡ | |||
N1 | 103 | 75 (72.8%) | 28 (27.2%) | |
N2 | 127 | 47 (37.0%) | 80 (63.0%) | |
Distant metastasis | 0.741‡ | |||
Absent | 204 | 109 (53.4%) | 95 (46.6%) | |
Present | 26 | 13 (50.0%) | 13 (50.0%) |
SD: standard deviation; †Mann-Whitney test; ‡chi-square test; UI: ulceroinfiltrative; UF: ulcerofungating; P: polypoid; MLN/TLN: metastatic lymph nodes/total lymph nodes.
The 5-year survival rate was 74% in the ENTE (−) group and 52% in the ENTE (+) group with a significant difference between the ENTE (−) and ENTE (+) groups in both overall and disease-free survival (
Univariable and multivariable analyses in colorectal adenocarcinoma with regional lymph node metastasis (
Variable | Univariable analysis | Multivariable analysis | ||
---|---|---|---|---|
HR (95% CI) |
|
HR (95% CI) |
|
|
Overall survival | ||||
ENTE (absent versus present) | 2.484 (1.603–3.848) | <0.001 | 1.676 (1.065–2.637) | 0.026 |
Vascular invasion | 3.095 (2.034–4.710) | <0.001 | 2.469 (1.595–3.822) | <0.001 |
Perineural invasion | 1.806 (1.086–3.002) | 0.023 | 1.078 (0.631–1.841) | 0.785 |
Tumor deposit | 3.778 (2.477–5.763) | <0.001 | 2.850 (1.839–4.416) | <0.001 |
Tumor budding (low grade versus high grade) | 1.990 (1.284–3.084) | 0.002 | 1.704 (1.087–2.672) | 0.020 |
Disease-free survival | ||||
ENTE (absent versus present) | 1.866 (1.171–2.973) | 0.009 | 1.357 (0.821–2.244) | 0.234 |
Vascular invasion | 2.967 (1.858–4.738) | <0.001 | 1.211 (0.722–2.029) | 0.468 |
Perineural invasion | 1.410 (0.834–2.384) | 0.200 | 1.154 (0.651–2.042) | 0.624 |
Tumor deposit | 2.205 (1.373–3.542) | <0.001 | 0.937 (0.556–1.580) | 0.807 |
Tumor budding (low grade versus high grade) | 1.244 (0.769–2.012) | 0.375 | 0.888 (0.524–1.503) | 0.658 |
HR: hazard ratio; CI: confidence interval; ENTE: extranodal tumor extension.
Significant difference between ENTE (−) and ENTE (+) groups in overall survival (a) and disease-free survival (b) (
To analyze the effect of ENTE in homogeneous pN groups, we grouped the patients with lymph node metastasis into N1 and N2 according to the 6th AJCC staging system and further subdivided them without ENTE and with ENTE. A significant difference was seen in overall survival between the ENTE (−) and ENTE (+) groups in both the N1 (
In N1 and N2 homogeneous group analyses, a significant difference was seen between ENTE (−) and ENTE (+) groups in overall survival (a and b). In N1a and N1b homogeneous group analyses, a significant difference was seen in overall survival (c) and disease-free survival (d) by N1a staging group between ENTE (−) and ENTE (+) groups. In N2a and N2b homogeneous group analyses, a significant difference was seen in overall survival (e) of N2b staging group between ENTE (−) and ENTE (+) groups. No significant difference was seen in disease-free survival (f) (Kaplan-Meier method with log-rank test).
ENTE in metastatic lymph nodes is widely regarded as a poor prognostic factor in many malignancies including gastric cancer [
A few studies have investigated the prognostic value of ENTE in colorectal cancer [
We found that ENTE was more frequent in cancers with well-known adverse histopathologic features such as higher histologic grade, high grade tumor budding, vascular invasion, perineural invasion, tumor deposit, and pT and pN stages. These results suggested that ENTE was closely associated with aggressive clinical behavior of colorectal adenocarcinoma with lymph node metastasis. In survival analyses, Kaplan-Meier survival curves revealed a significant difference between ENTE (−) and ENTE (+) patients in both overall survival and disease-free survival. These results suggested that ENTE is a poor prognostic factor for colorectal adenocarcinoma with lymph node metastasis.
The prognostic impact of ENTE in homogeneous pN staging groups of colorectal cancer has not been reported. In subgroup analyses by homogeneous pN staging groups, significant differences were seen in overall survival between ENTE (−) and ENTE (+) groups in both N1 and N2 staging groups and overall and disease-free survival in the N1a staging group with and without ENTE. In the N2b homogeneous group, overall survival was significantly different between the ENTE (−) and ENTE (+) groups. These results suggested that ENTE is an important prognostic factor in homogeneous pN staging groups. Therefore, careful pathological examination should be done to detect ENTE in metastatic lymph nodes and pathology reports should specify the presence of ENTE in colorectal adenocarcinoma with lymph node metastasis.
Our study had several limitations in patient selection and definite criteria for ENTE. Neoadjuvant treatment is a well-known effective therapy for colorectal adenocarcinoma that is essential for some patients. However, we could not determine the clinicopathologic correlations between neoadjuvant treatment and ENTE and excluded all patients who received neoadjuvant or adjuvant chemotherapy or radiotherapy. We defined ENTE as perforation of the nodal capsule by tumor tissue with extranodal growth and evaluated ENTE as present or absent. However, this definition cannot be applied in all cases. For example, some lymph nodes have no fibrous tissue covering the lymphoid tissue. Komuta et al. also graded the amount of ENTE by the number of tumor cells in the extranodal space [
In conclusion, our study demonstrated that the presence of ENTE was an important prognostic factor in homogeneous pN staging groups. The prognostic effect of ENTE as number of metastatic lymph nodes with ENTE or thickness of ENTE in metastatic lymph nodes should be validated in further studies. We recommend that the number of metastatic lymph nodes and the presence of ENTE be considered in determining the pN stage of colorectal cancer.
The authors declare that they have no competing interests.