Ramifications of lymph node metastasis in patients with pT1 colorectal cancer

Introduction

Colorectal cancer (CRC) is the most common cause of cancer-related deaths (1), although tumors confined to submucosa (T1) are generally considered early-stage malignancies potentially curable by complete removal (2). Still, appropriate treatment for early-stage CRC remains controversial. Non-invasive techniques, such as endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) (3), are typically reserved for T1 CRC without lymph node metastasis (LNM−). In the presence of lymph node metastasis (LNM+), one of the most viable means to postoperatively stage T1 CRC becomes radical surgical resection (4).

The tumor-nodes-metastasis (TNM) classification system is the current gold standard for clinical staging of cancer worldwide (1,5). Patient prognosis is generally inclined to worsen along with advancing stage, although pathologic staging of tumors within various organs is inconsistent. Both the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system and the Japanese systems categorize T1–2N1 esophageal cancer correspondingly as IIB (6), whereas T1N1 and T2N1 subsets of gastric cancer are designated IB and IIA (7), respectively. Moreover, CRC with positive lymph nodes is stage III disease by definition, with subdivisions of IIIA (T1–2N1, ≤3 positive nodes), IIIB (T3–4aN+), or IIIC (T4bN+) (8), based on level of nodal involvement. Hence, pT1N+ CRC is seemingly more advanced than pT1N+ gastric or esophageal cancer under the present staging hierarchy, which is rarely contested (9).

In a previous study of ours, we found that relapse-free survival (RFS) alone is impacted by LNM positivity in patients with pT2 CRC. Cancer-specific survival (CSS) and overall survival (OS) rates are otherwise unaffected (10). The purpose of this study was to investigate LNM status and its clinical relevance in patients with pT1 CRC and to explore the possibility of downstaging pT1N+ tumors. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2611/rc).

Methods

Between April 2007 and December 2021, a total of 6,273 patients with CRC underwent radical resections at Saitama Medical University International Medical Center in Japan. Among them, 775 had confirmed pT1 CRC (Figure 1). In some candidates (n=52), recurrence or multiple cancers (n=20), non-radical resection (n=11), preoperative radio- or chemotherapy (n=9) and incomplete data (n=12) were excluded from the study. The remainder (n=723) were grouped according to LNM status (LNM+ vs. LNM−) (Figure 2). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The Institution’s Ethics Committee of Saitama Medical University International Medical Center approved this study (No. 19-006), and informed consent was obtained from all qualifying participants.

Figure 1 Pathologic characteristics of patients with T1 colorectal cancer (hematoxylin-eosin staining, magnification 4×10). Dotted white line is muscularis mucosae. Ca, carcinoma; M, mucosa; MM, muscularis mucosae; MP, muscularis propria; SM, submucosa.

Figure 2 Schematic of patient allocation/study design. CRC, colorectal cancer; LNM−, lymph node metastasis negative; LNM+, lymph node metastasis positive.

Prior to propensity score matching (PSM), we first analyzed clinicopathologic patient data to assess group differences in prognosis (LNM+ vs. LNM−), including RFS and CSS. Cox logistic regression then served to identify independent risk factors. PSM variables were largely clinical or surgical in nature, namely sex, age, tumor location, surgical approach, American Society of Anesthesiologists (ASA) health score, preoperative carcinoembryonic antigen (CEA) level, body mass index (BMI), surgical approach, lymph node dissection level, operative time, postoperative complications, and hospital stay (days). Subjects were also matched by pathologic features, such as tumor size, histotype, lymphatic or venous invasion, and harvested lymph nodes. After matching, Cox logistic regression was repeated.

In terms of postoperative pathological data collection, we fully adhered to General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and Anus, issued by the Japanese Society for Cancer of the Colon and Rectum (JSCCR). Tumor staging relied on clinical parameters, using UICC TNM classification standards cited in the AJCC Cancer Staging Manual (8^th edition).

Statistical analysis

All statistical computations took place in a Mac environment (Apple Inc., Cupertino, CA, USA) powered by standard software (SPSS v22; IBM Corp, Armonk, NY, USA). Chi-squared and Fisher’s exact tests were used to address differing categorical variables, with RFS and CSS estimates generated through Kaplan-Meier method. Significance was set at P<0.05.

Results

A total of 775 patients had confirmed as pT1 CRC. Qualifying patients (n=723) were grouped as LNM+ (96/723, 13.3%) or LNM− (627/723, 86.7%) (Table 1). Of 96 LNM+ patients, 92 patients (95.83%) were N1 and only 4 (4.17%) patients were N2. A total of 80 (83.3%) CRC patients received adjuvant chemotherapy with capecitabine plus oxaliplatin (CAPOX) for 3 months or capecitabine orally for 6 months according to the Japanese guidelines for the treatment of colorectal cancer. The routine recommendation is a 3-month CAPOX regimen, and oral capecitabine chemotherapy can be selected if the patient is older or inconvenient to come to the hospital for intravenous chemotherapy. The remaining 16 patients did not receive adjuvant chemotherapy because of their advanced age or serious cardiopulmonary underlying diseases.

In univariate analyses, there were no significant group-wise differences with respect to sex, age, family tumor history, tumor location, surgical approach, ASA score, preoperative CEA level, BMI, lymph node dissection level, operative time, postoperative complications, postoperative blood loss, or day of first food intake. Patients of the LNM+ (vs. LNM−) group more often had rectal cancers (50.0% vs. 36.4%; P=0.01) (Table 1). Likewise, mean operative time (204.7±76.2 vs. 187.9±67.9; P=0.02) and hospital stay (10.47±9.449 vs. 8.32±7.029; P=0.03) proved to be lengthier; and tumors were much bulkier (≥3 cm: 25.0% vs. 15.8%; P=0.03), with greater propensity for lymphatic (41.7% vs. 25.2%; P<0.001) or vascular (55.2% vs. 30.1%; P=0.004) invasion. Other parameters, including tumor histotype, perineural invasion, harvested lymph nodes, and lengths of proximal/distal resection margins, did not differ significantly by group (Table 2).

Although 5-year RFS was significantly worse for the LNM+ (vs. LNM−) group (90.5% vs. 97.4%; P=0.004) (Figure 3A), 5-year CSS rates of both groups were similar (98.5% vs. 99.0%; P=0.67) (Figure 3B).

Figure 3 Survival outcomes in patients with pT1 CRC, without (LNM−) or with (LNM+) LNM, analyzed before and after PSM: (A) RFS before matching; (B) CSS before matching; (C) RFS after matching; and (D) CSS after matching. CRC, colorectal cancer; CSS, cancer-specific survival; LNM, lymph node metastasis; PSM, propensity score matching; RFS, relapse-free survival.

To accurately gauge the influence of each variable on patient prognosis, we performed Cox regression analysis before matching. LNM+ status [hazard ratio (HR) =2.82, 95% confidence interval (CI): 0.103–22.77; P=0.01] and tumor size (HR =0.337, 95% CI: 0.128–0.886; P=0.02) emerged as independent risk factors for RFS (Table 3). However, there were no independent risk factors for CSS (Table 4), not even LNM+ status (HR =1.692, 95% CI: 0.063–7.562; P=0.76).

PSM was carried out at a 1:1 ratio, ensuring 79 patients in each group for univariate analysis. The matched groups did not differ significantly in clinicopathologic characteristics (Tables 1,2), and the 5-year RFS did not differ (LNM+, 90.2%; LNM−, 94.8%; P=0.33) (Figure 3C) as it had before matching. The 5-year CSS rates were similar (LNM+, 98.7%; LNM−, 100%; P=0.23) (Figure 3D). There were no independent risk factors associated with CSS after PSM (Table 4). Independent risk factors for RFS were tumor differentiation (HR =4.998, 95% CI: 1.205–20.733; P=0.02) and preoperative CEA level (HR =1.175, 95% CI: 1.029–1.342; P=0.01).

Our final analysis examined recurrence distributions of the two groups. Before matching, overall recurrences were significantly more frequent in the LNM+ (vs. LNM−) group (7.3% vs. 1.8%; P=0.001), with significantly more LNM (2.1% vs. 0.5%; P=0.03). After matching, overall recurrences in the LNM+ (vs. LNM−) group no longer differed significantly (8.8% vs. 5.1%; P=0.51) (Table 5).

Discussion

The incidence of CRC in Japan has grown in recent years (11), and alongside cancer screening and diagnostic technology advances, detection of early-stage tumors (confined to submucosa) is increasing (12). Kikuchi et al. have subdivided these early lesions by invasive depth, involving upper third (SM1), middle third (SM2), or lower third (SM3) (13) of submucosa. There have also been many attempts at developing models to predict LNM in patients with early CRC (through invasive depth or histotype), hoping to define circumstances where further surgical resection is needed (14-18). Results of this study indicate that in matched patients with pT1 CRC, lymph node positivity has no impact on CSS or RFS, despite a significantly worse RFS shown for the LNM+ (vs. LNM−) group before PSM.

Present guidelines advise radical surgical resection of CRC in the setting of positive endoscopically resected margins, submucosal infiltration ≥1,000 microns, lymphatic/vascular infiltration, poor histologic grade (i.e., poorly differentiated or mucinous adenocarcinoma), or tumor budding (grade 2/3) (1,11). Yet, the extent of surgical intervention is still subject to much debate. There is some evidence to suggest that highly differentiated forms of early-stage CRC call for dissection of paracolic lymph nodes, whereas poorly differentiated variants require intermediate lymph node dissection. On this basis, JSCCR Guidelines for the Treatment of Colorectal Cancer have put forth more detailed recommendations. If LNM+ status is suspected preoperatively, then D3 lymph node dissection (sweeping to the root of tumor blood vessels) is advocated, anticipating a lower chance of postoperative recurrence. Despite some lingering differences in technical aspects and scopes of enterectomy practices throughout Europe, the United States, and Japan, the long-term prognosis after complete mesocolon excision is good (19-21).

The aggregate of lymph node metastases derived from pathologic staging is an important prognostic determinant of patient prognosis and survival (22,23). A 6-month regimen of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) is advised as adjuvant chemotherapy for stage III CRC, administering CAPOX for 3 months in low-risk stage III groups, such as pT1–2N+ CRC (11). However, adjuvant use of platinum preparations and fluorouracil are not without side effects, making chemotherapeutic optimization our future direction of research. Given present findings, the 5-year CSS of even patients with pT1N1 CRC (stage IIIA) is apt to exceed 98.5%, which is not significantly different from that expected for pT1N0 CRC (stage I) (8). Also, patients with early gastric cancer (T1N1) do not routinely receive adjuvant chemotherapy after surgery (24). It is therefore quite reasonable to propose downstaging of all patients with pT1N1 CRC, eliminating postoperative adjuvant chemotherapy.

The existing classification of colorectal, appendiceal, and anal cancers in Japan currently places 5-year OS for patients with CRC at 93% for stage I, 88.2% for stage II, and 92.5% for stage IIIA, falling sharply to 81.0% for stage IIIB (11). In an earlier investigation, we found a higher postoperative recurrence rate for patients with LNM+ (vs. LNM−) pT2 CRC, regardless of background; whereas RFS in matched patients with pT1 CRC did not differ significantly by lymph node status (LNM+ vs. LNM−) (10). These outcomes truly underscore a fundamental prognostic disparity between patients with T1N1 and T2N1CRC, one that may well merit downstaging of pT1N1CRC to IIA or IB.

As we known that with the deepening of tumor invasion, the risk of LNM increases. Our study showed that even when LNM occurred in pT1 CRC, 95.83% were N1. In other words, pT1 CRC has relatively mild biological metastasis characteristics, Therefore, it may be possible to try to downstage T1N1 CRC appropriately to dispense with adjuvant chemotherapy. A prospective comparative study of adjuvant chemotherapy and unadjuvanted chemotherapy in patients with T1N1 CRC may be the direction of future research.

A retrospective, non-randomized, and single-center study of this sort has inherent limitations, especially the issue of confounding variables. In addition, this time we studied rectal cancer together with colon cancer patients. If there were enough pT1 N1CRC cases, colon and rectal cancer could be further studied separately, and more accurate results may be obtained. We did adjust for baseline patient differences through PSM, but prospective clinical trials addressing larger patient populations are needed to validate and extrapolate our observations.

Conclusions

LNM does not affect the long-term survival of patients with pT1N1CRC after radical resection. Appropriate downstaging from stage IIIA may be a reasonable prospect for pT1N1CRC with a low recurrence factor.

Acknowledgments

We would like to thank Dr. Jian Guan from the Department of Pathology at the Shenzhen Hospital of the Chinese Academy of Medical Sciences Cancer Hospital for her professional support and assistance in pathological analysis.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2611/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2611/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2611/prf

Funding: This study was supported by the Shenzhen High-level Hospital Construction Fund.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2611/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The institution’s Ethics Committee of Saitama Medical University International Medical Center approved our investigation (No. 19-006), and informed consent was obtained from all qualifying participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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