Introduction

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality and morbidity worldwide. Its tumor microenvironment is composed of a complex interplay of various monocytes, dendritic cells, macrophages and T-cells. Among them, there are various subtypes of T-cells, each of which plays a very important role and has been reported to be associated with prognosis in various cancers. In CRC, there are many reports on the association between CD8+ T-cells and Foxp3+ T-cells and prognosis. However, these are all reports mainly focused on advanced cancers. No studies on T-cells focused on early-stage CRC have been reported to date. Among early-stage CRC, submucosal deep invasive (T1b) CRC has a lymph node metastasis rate of about 10%. Although submucosal invasion depth, vascular invasion, histologic grade, or budding grade are known to be pathological risk factors of lymph node metastasis, there have been no reports evaluating the relationship between tumor microenvironment and lymph node metastasis. Therefore, in this study, we aimed to investigate the characteristics of T-cells according to the degree of CRC invasion and the association between T-cells and the risk of lymph node metastasis in T1b CRC.

Aims & Methods

Initially, 60 patients with colorectal neoplasia [20 with intramucosal neoplasia (IM group); 20 with submucosal invasive CRC (SM group); and 20 with advanced cancer (AD group)] treated at Hiroshima University Hospital from January 2011 to December 2015 were randomly selected. We examined changes in T-cells with tumor invasion. Next, 84 patients with T1b CRC who underwent initial surgical resection with lymph node dissection or additional surgical resection with lymph node dissection after endoscopic resection at Hiroshima University Hospital from March 2013 to July 2019 were selected. We examined the relationship between T-cells and lymph node metastasis in T1b CRC. For all specimens, the phenotype and number of T-cells were evaluated using the triple immunofluorescence method of CD4 (helper T-cell marker), CD8 (killer T-cell marker), and Foxp3 (regulatory T-cell marker). We counted T-cells by subtype in the center (CT) and the invasive front (IF) of the tumor and examined their association with lymph node metastasis.

Results

In the IM group, there was no significant difference in the number of any subtype between CT and IF, while in the SM and AD groups, all subtypes were more numerous in IF than CT. They were also predominantly more numerous as the degree of tumor invasion with IM, SM, and AD. The high number of Foxp3 in IF and the high ratio of Foxp3/CD4 and Foxp3/CD8 were positively correlated with lymph node metastasis.

Conclusion

High Foxp3 counts and high Foxp3/CD4 and high Foxp3/CD8 ratios in IF of T1b CRC may help predict lymph node metastasis.

Disclosure

The authors have no conflicts of interest or financial ties to disclose.

Introduction

There are insufficient data to guide clinical decision-making regarding the implementation of additional surgery following endoscopic therapy in patients with deep submucosal invasive colorectal cancer (T1b CRC) and no additional risk factors for lymph node metastasis (LNM). This investigation sought to identify factors associated with LNM in cases of T1b CRC without other risk factors.

Aims & Methods

Consecutive cases with pathologically proven T1b CRC were retrospectively collected from 2014 to 2023 at a single tertiary hospital in Korea. These patients received either surgical or endoscopic treatment. In patients who received endoscopic treatment alone, no LNM was deemed to exist if there was no recurrence after at least 3 years of follow-up. Excluded were cases with other risk factors, including poor differentiation, lymphovascular invasion, perineural invasion. The cases were compared based on the presence of LNM.

Results

A total of 305 cases were enrolled and LNM was observed in 28 cases (9.18%). In univariate analysis, differentiation, sm3 invasion, tumor growth pattern, and peri-tumoral white spots were related with LNM. Multivariate analysis identified presence of non-polypoid growth parts (odd ratio [OR] 6.39; 95% CI 2.76-14.79), and peri-tumoral white spots (OR 2.85; 95% CI 1.22-6.64) as significant predictive factors for LNM.

Table. Multivariate analysis

Conclusion

Endoscopic findings including presence of non-polypoid growth and peri-tumoral white spots were related with increased risk of LNM in T1b CRC in the absence of other pathologic risk factors. These findings may be useful in determining further treatment strategy for patients with Tb1 CRC received endoscopic resection.

References

Liselotte W. Zwager,1,2,3 Barbara A. J. Bastiaansen, et al.
Deep Submucosal Invasion Is Not an Independent Risk
Factor for Lymph Node Metastasis in T1 Colorectal Cancer:
A Meta-Analysis. Gut 2022;163:174-189

Chihiro Yasue, Akiko Chino, et al.
Pathological risk factors and predictive endoscopic factors
for lymph node metastasis of T1 colorectal cancer: a single-center
study of 846 lesions. J Gastroenterol(2019) 54: 708-717

Introduction

Accurate prediction of lymph node metastasis (LNM) in submucosal invasive (T1) colorectal cancer (CRC) is essential for determining the need for additional surgery following endoscopic resection. Conventional histopathological assessments, however, are limited by interobserver variability. This study aimed to develop and externally validate a stacking-based artificial intelligence (AI) model integrating histopathological whole slide images (WSIs) and clinical parameters to predict the risk of LNM in T1 CRC.

Aims & Methods

This retrospective study included 1,056 patients with histologically confirmed T1 CRC treated at Showa Medical University Northern Yokohama Hospital. Of these, 593 cases were used for model training and 100 for internal testing. External validation was conducted on 25 cases from two independent institutions.
The proposed stacking ensemble model incorporated the Multiple Instance Self-Training (MIST) score derived from WSIs, patient sex, and tumor location (colon vs. rectum). Base learners included logistic regression, XGBoost, and random forest, with a meta-learner synthesizing their outputs to generate the final LNM prediction. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) in both internal and external cohorts.

Results

LNM was observed in 69 (11.6%) training cases, 15 (15.0%) test cases, and 2 (8.0%) external validation cases. The model achieved an AUC of 0.6965 in the internal test cohort and 0.7500 in the external validation cohort, demonstrating stable and generalizable predictive performance.
A representative case involved a 64-year-old man with a 16-mm type 0-Is lesion in the sigmoid colon resected via endoscopic mucosal resection (EMR). Histopathology showed well-differentiated tubular adenocarcinoma (tub1 > tub2), submucosal invasion depth of 3,300 µm (T1b), tumor budding grade BD1, Ly0, V1a, and negative resection margins (HM0, VM0). Despite guideline-based recommendations prompting additional surgical resection, no LNM was found (N0, 0/16), and the patient remained recurrence-free five years postoperatively—consistent with the AI model’s prediction.

Conclusion

The stacking-based AI model exhibited robust and generalizable performance in predicting LNM in T1 CRC, both internally and across external institutions. This approach offers a complementary tool to conventional pathology and may enhance individualized decision-making regarding the necessity of additional surgical intervention.

Introduction

Several guidelines, including those from the US, Europe, and Japan, recognize "tumor differentiation" as a risk factor for lymph node metastasis (LNM) in T1 colorectal cancer. Surgical resection with lymph node dissection is recommended if poorly differentiated adenocarcinoma, signet-ring cell carcinoma, or mucinous carcinoma are observed in histological findings from endoscopically resected specimens. Recent reports suggest that moderately differentiated adenocarcinoma (tub2) may also be a risk factor for LNM.

Aims & Methods

This study aims to investigate whether tub2 is a risk factor for LNM. We initially evaluated 1,742 patients with T1 colorectal cancer who underwent surgical resection with lymph node dissection at our institution from April 2001 to April 2024. Lesions were assessed based on the worst grade of differentiation. Exclusions were made for patients with (a) metachronous or synchronous advanced cancer, (b) invasion deeper than the muscularis propria, (c) Lynch syndrome, familial adenomatous polyposis, or ulcerative colitis, (d) preoperative chemotherapy or radiotherapy, (e) missing data, or (f) lesions without surgical resection. In addition, after excluding 177 patients with poorly differentiated, mucinous, or signet-ring cell adenocarcinoma, 881 patients were enrolled for analysis. We investigated the sensitivity, specificity, and area under the receiver operating characteristics (ROC) curve of tub2 for predicting LNM, alongside correlations between pathological factors and LNM using multivariate analysis.

Results

LNM was detected in 9.9% (87/881) of patients. The sensitivity, specificity, and area under the ROC curve for tub2 were 78.2%, 42.2%, and 0.60, respectively. In the univariate analysis, tub2 was associated with LNM (p<0.001). Multivariate analysis identified lymphatic invasion, vascular invasion, and tub2 as significant risk factors for LNM, with odds ratios of 7.49, 1.97, and 1.95 (p < 0.01, < 0.01, and = 0.02, respectively).

Conclusion

Moderately differentiated adenocarcinoma (tub2) is a risk factor for LNM in T1 colorectal cancer.

Disclosure

Conflicts of interest:None

Introduction

Tumor budding is a significant prognostic value in the management of colorectal cancer (CRC). There are grades of tumor budding: 0-4 buds as low, 5-9 buds as intermediate, and more than 10 buds as high. However, the specific prognosis difference between cases with 0 buds and those with 1-4 buds, is not well-established due to a lack of comparative studies.

Aims & Methods

The aim of this study is to examine and compare the rate of lymph node (LN) metastasis and prognosis by distinguishing between 0 buds and 1-4 buds within the low-grade category (0-4 buds) of tumor budding in T1 and T2 CRC. This study retrospectively identified a total of 224 cases of T1 and T2 CRC from 2015 to 2018 across three medical institutions using medical records. The pathology, including the assessment of tumor budding, was subsequently reconfirmed, and the recurrence and survival of patients were evaluated up to December 2023.

Results

Patients in the BD1 group exhibited a higher T stage compared to BD0, accompanied by significantly increased rates of lymphovascular invasion and perineural invasion. The prevalence of LN metastasis was 14.8%. No significant difference in LN metastasis was observed between BD0 and BD1. In a multivariate analysis exploring factors associated with LN metastasis, relevant factors included lymphatic invasion, perineural invasion, and 5 buds or more. (Table 1) There were no significant distinctions in 5-year survival and progression free survival rate between the BD0 and BD1 groups (P=0.971).
Table 1. Univariate and multivariate analysis for risk factor of lymph node metastasis

Conclusion

The study confirmed that there was no significant difference in LN metastasis and prognosis between BD0 and BD1.

References

1. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA: A Cancer Journal for Clinicians 2023;73(1):17-48.
2. Lugli A, Kirsch R, Ajioka Y, Bosman F, Cathomas G, Dawson H, et al. Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol 2017;30(9):1299-311.

Introduction

The risk factors for synchronous lymph node metastasis (LNM) in pT1 colorectal cancer (CRC) are submucosal invasion depth (≥1000µm), lymphovascular involvement (LVI), poorly differentiated components (por), and tumor budding (BD). On the other hand, in pedunculated lesions with invasion confined to the head of the polyp, the incidence of LNM and recurrence have been reported to be very low (0-2.4% and 0%, respectively).^1,2 However, the robust evidence has been limited.

Aims & Methods

This retrospective study aimed to compare the incidence of LNM and recurrence between the head and stalk invasion groups, based on submucosal invasion assessment using Haggitt Level 2 (HL2; the junction line between normal and neoplastic epithelium), and to evaluate the impact of LNM/recurrence risk factors in pedunculated pT1 CRC.
Patients with pedunculated pT1 CRC treated by endoscopic or surgical resection in our hospital between January 2010 and December 2021 were included. Those with multiple invasive CRCs, synchronous advanced cancer in other organs, and familial adenomatous polyposis were excluded. The submucosal invasion was classified into two groups, head invasion (above HL2) and stalk invasion (beyond HL2). Clinicopathological characteristics, incidence of LMN, and recurrence rate were analyzed between patients with head and stalk invasion.

Results

The study included 66 patients with 66 lesions. The median age was 67 years, and 52 patients (78.8%) were male. The median tumor size was 20mm, and the location was as follows: 4 lesions (6.1%) in the right colon and 62 lesions (93.9%) in the left colon. There were 40 head invasion and 26 stalk invasion lesions. There were no significant differences between the two groups for LVI (17.5% vs 26.9%), por (2.5% vs 7.5%), and BD (5.0% vs 7.7%). Surgical resection was performed more frequently in the stalk invasion group (20% vs 77%, P < 0.01). Synchronous LNM was observed in 2 patients in the head invasion group (5.0%, 95% confidence interval [CI] 0.6-16.9), and 1 patient in the stalk invasion group (3.8%, 95%CI 0.1-19.6) (P = 1). Recurrence was observed in 1 patient in the head invasion group (2.5%, 95%CI 0.1-13.2), and 1 patient in the stalk invasion group (3.8%, 95%CI 0.1-19.6) (P = 1), both of them were distant metastasis. In patients without LVI, por, nor BD, there was no LMN in either group, but recurrence was observed in 1/32 patients in the head invasion group (3.1%, 95%CI 0-17.1), and 1/16 patients in the stalk invasion group (6.3%, 95%CI 0-30.3) (P = 0.61). The patient with recurrence in the head invasion group without LVI/por/BD revealed multiple liver metastases one year after endoscopic resection, and he received chemotherapy but died of colon cancer one and a half years after recurrence.

Conclusion

In pedunculated pT1 CRC, synchronous LNM and recurrence were observed in the head invasion group, with no significant difference from the stalk invasion group. Among cases without LVI/por/BD, there was no LNM but recurrence was observed in both of head and stalk invasion groups. Contrary to the previous reports, head invasion was not a completely LNM/recurrence-free condition, so endoscopic resection alone cannot be considered curative.

References

1. Matsuda T, et al. Risk of lymph node metastasis in patients with pedunculated type early invasive colorectal cancer: A retrospective multicenter study, Cancer Sci. 2022;102:1693-1697.
2. Asayama N, et al. Long-term outcomes after treatment for pedunculated-type T1 colorectal carcinoma: a multicenter retrospective cohort study, J Gastroenterol. 2016;51:702-710.