Cancer histological types in the LNs of CRC patients
We first defined whether cancer cells formed different histological types. Adenocarcinomas form various hollow cavities, including slender hollow tubular cavities and round hollows. Histological types were categorized into four groups: tubular (TubLN), poorly differentiated (PorLN), mucinous (MucLN), and cribriform (CriLN). TubLN types were composed of an elongated hollow cavity-like tube and cancer cell polarity (Fig. 1A, 2A, 2B), CriLN types had small empty cavities in the tumor mass and no cancer cell polarity (Fig. 1B, 2C, 2D), PorLN types formed no hollow cavities in the tumor and no cancer cell polarity (Fig. 1C, 2E, 2F), and MucLN types contained mucin in the cavity (Fig. 1D). Based on histological type in the metastatic lymph nodes, patients with LNM were assigned to one of four groups: the node-positive group with TubLN in all LNMs (Stage III or IV tub), the node-positive group with CriLN in at least one LNM (Stage III or IV cri), the node-positive group with MucLN in all LNMs (Stage III or IV muc), and the node-positive group with PorLN in at least one LNM (Stage III or IV por). Of the paraffin-embedded, hematoxylin and eosin-stained LNM tumor tissue sections from the 87 stage III patients, 53 (60.9%) were the stage III tub group, 29 (33.3%) were the stage III cri group, 3 (3.4%) were the stage III muc group, 2 (2.3%) were the stage III por group. Of the 32 node-positive stage IV tumor sections, 8 (25%) were the stage IV tub group, 20 (62.5%) were the stage IV cri group, 4 (12.5%) were the stage IV por group. There was no stage IV muc patient.
Lnm Histology Differs From That Of The Primary Lesion
Various cancer cell clones are thought to exist in primary tumors. Assuming a single cancer cell clone metastasizes and grows in each LN, these clones can present with different histologies. To determine whether the cancer cells in each LN formed different histological types, we compared the histological type of the primary tumor with that in the LN (Table 1).
Table 1
Changes in histological type in the primary lesion and lymph nodes of node-positive patients with colorectal cancer
Primary lesion | Lymph node | No. of cases (%) |
Wel | T | 5 (4.2%) |
| C | 1 (0.8%) |
| T་C | 2 (1.7%) |
Mod | T | 53 (44.5%) |
| C | 27 (22.7%) |
| T+C | 18 (15.1%) |
| P | 4 (3.4%) |
Por | P | 1 (0.8%) |
Muc | M | 3 (2.5%) |
| T | 2 (1.7%) |
| C | 1 (0.8%) |
Pap | T | 1(0.8%) |
AS | P | 1 (0.8%) |
Abbreviations: Wel, well differentiated adenocarcinoma; Mod; moderately differentiated adenocarcinoma; Por, poorly differentiated adenocarcinoma; Muc, mucinous adenocarcinoma; Pap, papillary adenocarcinoma; AS, adenosquamous carcinoma; T, tubular type; C, cribriform type; P, poorly differentiated type; M, mucinous type; No., Number. |
Comparison of survival times among histological type in node-positive patients including those with stage III and IV
To assess the impact of histological type in LN on OS in node-positive patients regardless of stage III or IV, the group tub, cri, muc or por were compared. The prognosis was good in order of muc, tub, cri, and por in node-positive CRC patients. Kaplan-Meier analysis of OS showed that the cri group had significantly shorter OS (p<0.0001) than tub group (Fig. 3). Although there were few cases of patients with PorLN and MucLN, the comparative analyses showed that the por group had significantly shorter OS (p=0.0007) than the cri group (Fig. 3), whereas, the muc group were alive after 5 years (Fig. 3).
Comparison of OS times between stage II and III tub groups
We have already shown that stage III tub group had longer RFS and OS times than stage III cri group. In this study, the survival times between stage II and stage III tub group were compared. The Kaplan-Meier curve of RFS showed that stage III tub group had significantly shorter RFS than stage II patients (p=0.0475; Fig. 4A). Kaplan-Meier analysis of OS showed that stage II and stage III tub groups did not have significantly different OS times (p=7069; Fig. 4B).
Comparison of survival times between stage IV tub, IV cri, and IV por groups
Kaplan-Meier analysis of OS showed that stage IV tub group had significantly longer OS than stage IV cri group (p=0.0011; Fig. 5A). There was also significant difference between stage IV cri and stage IV por groups (p=0.0013; Fig. 5A).
Comparison of survival times between stage IV tub and IV cri, and stage III cri and III tub groups
There was no significant different between stage IV tub group and stage III cri group (p=0.1567; Fig. 5B), whereas, there was a significant difference between stage IV tub group and stage III tub group (p=0.0168; Fig. 5C).
Tubular-type carcinoma in all LNMs predicts OS, clinical complete response, and possible metastasectomy in node-positive stage IV CRC patients
Of all parameters, tumor site and all tubular-type in LNMs were prognostic factors for OS in the univariate analyses (Table 2). Multivariate analyses with these two parameters revealed that TubLN in all LNMs was independent prognostic factor for OS (HR: 0.137, 95% CI: 0.031–0.606; p=0.0088) (Table 2). Of all parameters, tumor site and tubular-type in all LNMs were predictive factors for clinical complete response in the univariate analyses (Table 3). Multivariate analyses with these two parameters revealed that all TubLN in all LNMs was an independent predictive factor for clinical complete response (HR: 56.81, 95% CI: 5.060–1994; p=0.0005) (Table 3). Of all parameters, only tubular-type in all LNMs was predictive factors for possible liver or lung resection in the univariate analyses (Table 4). Multivariate analyses with all parameters revealed that TubLN in all LNMs was independent predictive factor for possible liver or lung resection (HR: 8.386, 95% CI: 1.087–90.11; p=0.0413) (Table 4).
Table 2
Univariate and multivariate analyses for overall survival of node-positive stage IV patients with colorectal cancer
Variable | Univariate analysis | Multivariate analysis |
HR | 95% CI | p-value | HR | 95% CI | p-value |
Sex (men) | 1.390 | 0.612-3.158 | 0.4315 | | | |
Tumor site (rectum) | 0.324 | 0.137-0.766 | 0.0103 | 0.426 | 0.178-1.019 | 0.0551 |
Lymphatic permeation (presence) | 3.003 | 0.403-22.35 | 0.2831 | | | |
Venous permeation (presence) | 0.561 | 0.247-1.275 | 0.1678 | | | |
Tubular-type carcinoma in all LNMs | 0.114 | 0.026-0.499 | 0.0039 | 0.137 | 0.031-0.606 | 0.0088 |
Abbreviations: HR, hazard ratio; CI, confidence interval; LNM, lymph node metastasis. |
Table 3
Univariate and multivariate analyses for clinical complete regression of node-positive stage IV patients with colorectal cancer
Variable | Univariate analysis | Multivariate analysis |
HR | 95% CI | p-value | HR | 95% CI | p-value |
Sex (female) | 1.333 | 0.221-7.438 | 0.7419 | | | |
Tumor site (colon) | 0.078 | 0.004-0.562 | 0.0092 | 0.106 | 0.003-1.651 | 0.1100 |
Lymphatic permeation (absence) | 4 | 0.144-111.7 | 0.3641 | | | |
Venous permeation (absence) | 0.296 | 0.014-2.134 | 0.2476 | | | |
Tubular-type carcinoma in all LNMs | 69 | 7.439-1756 | <0.0001 | 56.81 | 5.060-1994 | 0.0005 |
Abbreviations: HR, hazard ratio; CI, confidence interval; LNM, lymph node metastasis. |
Table 4
Univariate and multivariate analyses for resection of liver or lung metastasis of node-positive stage IV patients with colorectal cancer
Variable | Univariate analysis | Multivariate analysis |
HR | 95% CI | p-value | HR | 95% CI | p-value |
Sex (female) | 1.889 | 0.296–12.17 | 0.4882 | | | |
Tumor site (colon) | 0.313 | 0.038–1.909 | 0.2094 | | | |
Lymphatic permeation (absence) | 5 | 0.178–141.9 | 0.2990 | | | |
Venous permeation (absence) | 0.378 | 0.018–2.843 | 0.3708 | | | |
Tubular-type carcinoma in all LNMs | 11 | 1.618–102.9 | 0.0141 | 8.386 | 1.087–90.11 | 0.0413 |
Abbreviations: HR, hazard ratio; CI, confidence interval; LNM, lymph node metastasis. |