Prognostic significance of lymphovascular invasion in colorectal mucinous adenocarcinoma after curative resection: a nationwide multi-center retrospective cohort study

Introduction

Colorectal cancer (CRC) is the third most prevalent cancer and the second leading contributor to cancer-related mortality worldwide (1,2). Among the histological subtypes of CRC, adenocarcinoma is the most frequently diagnosed, whereas mucinous adenocarcinoma (MAC) constitutes a distinct variant characterized by mucinous components exceeding 50% of the tumor volume (3). Compared with conventional adenocarcinoma, MAC has distinct clinicopathological and molecular characteristics, treatment responses, and prognostic patterns (4). Recent cohort studies further suggest that survival differences are especially evident in stage III disease and that MAC may show reduced sensitivity to conventional adjuvant chemotherapy (5,6). These findings support the need for MAC-specific postoperative risk stratification.

In addition, treatment options are usually determined on the basis of histopathological features (7). Therefore, pathological markers that refine recurrence risk may help guide postoperative management. Lymphovascular invasion (LVI) represents a critical step in lymph node metastasis and systemic dissemination of cancer cells, and is associated with an increased risk of micrometastasis in localized carcinoma (8,9). The detection of cancer cells in peritumoral or intratumoral vessels is a sign of the initiation of the metastatic process, and it is generally considered an indicator of poor prognosis (10). Some investigators have reported that LVI-positive CRC patients have a worse prognosis than LVI-negative patients (11,12), and LVI has been reported as an independent adverse prognostic factor in patients with CRC. Recent evidence supports the role of LVI as a risk-stratification marker in CRC. LVI predicts lymph node metastasis in early CRC, and a recent meta-analysis of T2 CRC reported a strong association between LVI and lymph node metastasis (13,14). The 2022 American Society of Clinical Oncology (ASCO) guideline update for stage II colon cancer also lists LVI among high-risk pathological features that may inform adjuvant chemotherapy decisions (15). However, clinical implementation of LVI remains complicated by variability in pathological assessment, because central review and ancillary staining can change LVI detection and improve diagnostic reliability (16,17).

Despite these data, the prognostic significance of LVI in colorectal MAC remains insufficiently defined. Most previous studies evaluated all CRC histologies together, focused on early-stage lesions, or examined lymph node metastasis rather than long-term survival. Because MAC has distinct biology and heterogeneous outcomes, the independent effect of LVI in this subtype warrants dedicated evaluation.

This nationwide multicenter retrospective cohort study evaluated the association of LVI with clinicopathological features, overall survival (OS), and disease-free survival (DFS) in patients with stage I–III MAC after curative resection. The study aimed to clarify the prognostic value of LVI and inform more targeted postoperative risk stratification and postoperative risk stratification. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0275/rc).

Methods

Study design and population

This multicenter retrospective cohort study used clinicopathological and follow-up data from 21 hospitals in China. Records were screened for patients with pathologically diagnosed MAC or colorectal adenocarcinoma with a mucinous component who underwent curative resection between January 2016 and December 2021. Among 6,933 screened records, 2,391 patients met the eligibility criteria and were included in the final cohort. Eligible patients were adults with pathological MAC, defined as a mucinous component of at least 50%. Patients were excluded if they were younger than 18 years or older than 80 years, had multiple primary tumors, synchronous multiple CRCs, stage IV, a mucinous component below 50%, or insufficient clinical, pathological, or follow-up information. Because this was a retrospective cohort of all eligible patients during the study period, no a priori sample-size calculation was performed.

Data collection and definitions

Clinical and pathological variables were abstracted from medical records and pathology reports. The collected variables included sex, age, tumor size, tumor location, histological differentiation, LVI status, T category, N category, and tumor-node-metastasis (TNM) stage. Tumor location was categorized as right-sided colon, left-sided colon, or rectum. Age was grouped as <60 or ≥60 years, and tumor size was grouped as <5 or ≥5 cm.

LVI was defined by the presence of tumor cells within the endothelial-lined space or the destruction of a lymphovascular wall by tumor cells. We divided patients into two groups according to pathological findings: (I) the LVI-positive group, in which metastasis was found in the microvessels and/or lymphatic vessels surrounding the tumor; and (II) the LVI-negative group, in which no metastasis was found in the microvessels and/or lymphatic vessels surrounding the tumor. According to pathology records, patients were classified as LVI-positive when tumor cells were identified in microvessels and/or lymphatic vessels around the tumor, and as LVI-negative otherwise.

Follow-up method

Patients underwent postoperative surveillance at outpatient clinics every 3 months for 2 years, followed by every 6 months for up to 5 years. Surveillance included physical examination, tumor marker measurement, computed tomography (CT), and colonoscopy. CT was repeated every 6 months for 5 years, and colonoscopy at 1 to 3 years. For survival analysis, follow-up was defined as the interval from surgery to death, recurrence, progression, loss to follow-up, or last contact, as appropriate for each endpoint.

Study endpoint

The follow-up interval for survival analyses started on the date of surgery and ended at death, recurrence or progression, loss to follow-up, or the last clinical contact. OS was defined as the time from surgery to death from any cause. DFS was defined as the time from surgery to recurrence or death from any cause. Patients without an event were censored at the last follow-up. Patients with incomplete survival time or event status were excluded from survival model fitting.

Statistical analysis

To determine the associations between LVI status and various clinicopathological variables, the chi-square test was used as appropriate. OS and DFS were estimated using the Kaplan-Meier method, and survival curves were compared using the log-rank test.

Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). LVI was prespecified as the primary exposure and retained in all multivariable models. Multicollinearity was assessed using the variance inflation factor (VIF). Variables with VIF ≥5 were not included in the same adjusted model. Eligible variables were then incorporated into a multivariable Cox proportional hazards model. All tests were two-sided, with P<0.05 considered statistically significant.

Primary analyses used IBM SPSS Statistics version 25.0 (IBM Corp., Armonk, NY, USA). Cox model specification and collinearity screening were conducted using R version 4.1.3.

Ethical statement

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of The First Affiliated Hospital of Shandong First Medical University & Shandong Qianfoshan Hospital [No. YXLL-KY-2024(116)]. Informed consent was waived in this retrospective study. All participating hospitals were informed of and agreed to the study.

Results

Associations between LVI status and clinicopathological features

The clinical data of 6,933 patients who were pathologically diagnosed with MAC or adenocarcinoma complicated with a mucinous component were reviewed. A final cohort of 2,391 patients who satisfied the eligibility criteria was included in this study (Figure 1). The clinical and pathological characteristics of these patients are presented below: 1,397 were males (58.4%) and 994 were females (41.6%); 1,266 were 60 years of age or older (52.9%) and 1,125 were younger than 60 years old (47.1%); 986 patients (41.2%) had a primary tumor in the right-sided colon, 514 patients (21.5%) had a tumor in the left-sided colon, and 891 patients (37.3%) had a tumor in the rectum; and 137 patients (5.7%) had stage I disease, 1,023 patients (42.8%) had stage II disease, and 1,231 patients (51.5%) had stage III disease (Table 1).

Figure 1 Flow chart showing the patient selection process. CRC, colorectal cancer; LVI, lymphovascular invasion.

Patients were categorized according to their LVI status, with 541 patients (22.6%) in the LVI-positive group and 1,850 patients (77.4%) in the LVI-negative group. In the LVI-positive group, 209 (41.2%) patients had tumors located in the right-sided colon, 116 (21.5%) had tumors located in the left-sided colon, and 216 (37.3%) had tumors located in the rectum (Table 1). Patients in the LVI-positive group were more likely to have poorly differentiated tumors than those in the LVI-negative group (P<0.001) (Table 1). In addition, the LVI-positive group was more likely to have advanced T stage (P<0.001), N stage (P<0.001), and TNM stage (P<0.001) (Table 1). These results suggest that LVI-positive patients have distinct clinicopathological characteristics and that LVI is correlated with advanced stages of MAC.

Association of LVI status with prognosis

To determine the effect of LVI on prognosis, survival was compared between the LVI-positive group and the LVI-negative group. The OS rates of patients in the LVI-positive group and the LVI-negative group were 74.2% and 86.5%, respectively (P<0.001) (Figure 2A). The DFS rates of patients in the LVI-positive group and the LVI-negative group were 73.8% and 86.3%, respectively (P<0.001) (Figure 2B).

Figure 2 Kaplan-Meier curves for all the patients according to LVI status, 3-year overall survival (A) and 3-year disease-free survival (B). LVI, lymphovascular invasion.

To further understand the prognostic effect of LVI in MAC, subgroup analysis was conducted. For colonic MAC patients, the OS and DFS rates of LVI-positive patients were significantly lower than those of LVI-negative patients (OS: 77.1% vs. 87.7%, P=0.002; DFS: 76.8% vs. 87.6%, P=0.001) (Figure 3A,3B). For rectum MAC patients, the OS and DFS rates of LVI-positive patients were significantly lower than those of LVI-negative patients (OS: 69.1% vs. 84.3%, P=0.003; DFS: 68.8% vs. 84.0%, P=0.002) (Figure 3C,3D). Furthermore, there was no significant difference in the OS or DFS rates between LVI-positive patients and LVI-negative patients when the tumor was located in the right-sided colon (OS: 81.1% vs. 87.5%, P=0.13; DFS: 80.7% vs. 87.4%, P=0.12) (Figure 4A,4B). However, the OS and DFS rates of LVI-positive patients were much poorer than those of LVI-negative patients when the tumor was located in the left-sided colon (OS: 70.4% vs. 88.9%, P<0.001; DFS: 70.1% vs. 88.0%, P=0.001) (Figure 4C,4D). Consistently, LVI-positive patients with rectal MAC had poorer OS and DFS than LVI-negative patients (Figure 4E,4F). In terms of TNM stage, the DFS (93.4% vs. 91.6%, P=0.69) and OS (93.4% vs. 91.7%, P=0.66) rates were similar in patients with TNM stage II disease (Figure 5A,5B). However, patients with TNM stage III disease showed significant differences in OS and DFS rates between LVI-positive and LVI-negative groups (OS: 69.9% vs. 77.1%, P=0.01; DFS: 66.2% vs. 76.4%, P=0.01) (Figure 5C,5D). In addition, among patients with T2 stage disease, the OS and DFS rates were similar between the LVI-positive and LVI-negative groups (OS: 90.0% vs. 97.7%, P=0.18; DFS: 90.0% vs. 97.6%, P=0.18) (Figure 6A,6B). In patients with T3 stage disease, the LVI-positive group had significantly lower OS and DFS rates than the LVI-negative group (OS: 74.0% vs. 87.1%, P<0.001; DFS: 73.6% vs. 87.0%, P<0.001) (Figure 6C,6D). However, among patients with T4 stage disease, the OS and DFS rates were similar between the two groups (OS: 71.9% vs. 79.6%, P=0.16; DFS: 71.5% vs. 79.2%, P=0.15) (Figure 6E,6F). Finally, both the OS and DFS rates were significantly different between patients in the LVI-positive and LVI-negative groups with lymph node metastasis (OS: 66.9% vs. 77.0%, P=0.01; DFS: 66.2% vs. 76.4%, P=0.01) (Figure 7A,7B), although they were similar in lymph node-negative patients (OS: 92.8% vs. 94.0%, P=0.74; DFS: 92.7% vs. 94.0%, P=0.76) (Figure 7C,7D). These results indicate that LVI is correlated with poor survival in certain subgroups of MAC patients and that LVI-positive patients with tumors located in the left-sided colon, with T3 stage disease, with lymph node metastasis, and with TNM stage III disease should receive more attention during follow-up.

Figure 3 Kaplan-Meier survival curves of patients with MAC in different locations. (A) Overall survival of patients with MAC in the colon. (B) Disease-free survival of patients with MAC in the colon. (C) Overall survival of patients with MAC in the rectum. (D) Disease-free survival of patients with MAC in the rectum. MAC, mucinous adenocarcinoma.

Figure 4 Prognostic significance of LVI for 3-year overall survival and 3-year disease-free survival according to the location of the tumor. (A) Overall survival of patients with MAC in the right-sided colon. (B) Disease-free survival of patients with MAC in the right-sided colon. (C) Overall survival of patients with MAC in the left-sided colon. (D) Disease-free survival of patients with MAC in the left-sided colon. (E) Overall survival of patients with MAC in the rectum. (F) Disease-free survival of patients with MAC in the rectum. LVI, lymphovascular invasion; MAC, mucinous adenocarcinoma.

Figure 5 Prognostic significance of LVI for 3-year overall survival and 3-year disease-free survival according to TNM stage. (A) Overall survival of patients with TNM stage II disease. (B) Disease-free survival of patients with TNM stage II disease. (C) Overall survival of patients with TNM stage III disease. (D) Disease-free survival of patients with TNM stage III disease. LVI, lymphovascular invasion; TNM, tumor-node-metastasis.

Figure 6 Prognostic significance of LVI for 3-year overall survival and 3-year disease-free survival according to T stage. (A) Overall survival of patients with T2 stage disease. (B) Disease-free survival of patients with T2 stage disease. (C) Overall survival of patients with T3 stage disease. (D) Disease-free survival of patients with T3 stage disease. (E) Overall survival of patients with T4 stage disease. (F) Disease-free survival of patients with T4 stage disease. LVI, lymphovascular invasion; T, tumor.

Figure 7 Prognostic significance of LVI for 3-year overall survival and 3-year disease-free survival according to the degree of lymph node metastasis. (A) Overall survival of patients with lymph node metastasis. (B) Disease-free survival of patients with lymph node metastasis. (C) Overall survival of patients without lymph node metastasis. (D) Disease-free survival of patients without lymph node metastasis. LVI, lymphovascular invasion.

Factors affecting the prognosis of MAC

Furthermore, univariate and multivariable Cox regression analyses were conducted to evaluate prognostic factors for MAC. Univariate analysis revealed that age (HR =1.930; 95% CI: 1.401–2.658, P<0.001), LVI status (HR =2.041; 95% CI: 1.463–2.847, P<0.001), T stage (HR =6.460; 95% CI: 2.063–20.229, P<0.001) and N stage (P<0.001) were significant risk factors for poor OS (Table 2). To assess the adjusted prognostic effect of LVI, LVI was fixed in the multivariable Cox model. Variables with a VIF<5, including age, sex, differentiation, tumor location, tumor size, and T stage, were included in the adjusted model (Figure S1). In this model, LVI (HR =1.855; 95% CI: 1.319–2.607, P<0.001) positivity remained independently associated with poorer OS, together with age ≥60 years (HR =2.018; 95% CI: 1.463–2.784, P<0.001) and T3–4 stage (HR =6.904; 95% CI: 2.180–21.867, P=0.001) (Table 2). For DFS, univariate analysis showed that age, LVI status, T stage, and N stage were also significant prognostic factors (Table 3). In the fixed-LVI multivariable model, LVI (HR =1.923; 95% CI: 1.366–2.706, P<0.001) positivity was independently associated with poorer DFS. Age ≥60 years (HR =2.016; 95% CI: 1.462–2.781, P<0.001), rectum tumor location (HR =1.529; 95% CI: 1.079–2.168, P=0.02), and T3–4 stage (HR =7.041; 95% CI: 2.223–22.303, P<0.001) were also associated with poorer DFS (Table 3). N category and TNM stage were not included in the primary multivariable Cox models because of their conceptual overlap with disease stage and the potential risk of overadjusting the LVI–survival association. Nevertheless, LVI positivity remained independently associated with poorer OS and DFS in patients with MAC. These findings showed that LVI positivity was an independent prognostic risk factor for poorer OS and DFS in patients with MAC.

Discussion

Accumulating evidence has revealed the prognostic importance of LVI in CRC and adverse histopathological features (18-20). Numerous studies have shown that LVI is an independent predictor of recurrence and survival in patients with CRC (21-23). However, the clinical significance of LVI in MAC remains insufficiently studied. The present study revealed that the LVI-positive rate was 22.6% in MAC patients. LVI-positive MAC patients were more likely to have higher histological grades and advanced T, N, and TNM stages. They also had significantly poorer OS and DFS than LVI-negative patients. After adjustment in fixed-LVI Cox models, LVI remained independently associated with poorer OS (HR =1.855; 95% CI: 1.319–2.607, P<0.001) and DFS (HR =1.923; 95% CI: 1.366–2.706, P<0.001). These findings indicate that LVI is an independent adverse prognostic marker in MAC after curative resection.

Previous studies have reported inconsistent conclusions regarding whether LVI predicts prognosis after adjustment for other clinicopathological factors (24-28). Recent evidence and clinical guidance further support the value of LVI as a clinically meaningful risk-stratification marker in CRC. The 2022 ASCO guideline update lists LVI as a high-risk feature in stage II colon cancer (15). This feature may inform individualized discussions about adjuvant chemotherapy. Huang et al. reported that LVI was independently associated with poorer survival and shorter DFS after curative resection in stage I CRC (29). Gao et al. found that LVI independently predicted prognosis in stage II CRC. They also showed improved prognostic discrimination when LVI was added to TNM-based staging (30). In rectal MAC, Sun et al. found that LVI was associated with poorer post-recurrence survival among patients who experienced recurrence (31). Collectively, these findings support the interpretation that LVI reflects biologically aggressive disease and adds prognostic information beyond conventional clinicopathological staging.

In subgroup analysis, the prognosis of patients with MAC in different tumor locations and of TNM stages was analyzed. Our study showed that LVI status was correlated with prognosis in patients with tumors in the left-sided colon and rectum, TNM stage III disease, T3 stage disease, and lymph node metastasis. These results suggest that LVI predicts poor OS and DFS in MAC patients. Barresi et al. (8) have found that 63.4% of LVI-positive patients had lymph node metastasis. In our study, we found that 80.8% of the 541 LVI-positive patients had lymph node metastasis, which was much higher than that of LVI-negative patients (42.9%). LVI represents an early indicator of lymph node metastasis and is associated with an increased risk of micrometastasis in patients with localized CRC. These findings suggest that LVI may help refine postoperative risk assessment.

This study has several limitations. First, several essential clinicopathological features, including CEA levels, tumor budding, MSI/MMR status, or treatment-related factors such as adjuvant therapy, were not available or were incompletely reported in the database, and thus, they could not be considered in the analysis. The omission of these key covariates limits the reliability of the multivariable model and raises concerns about potential residual confounding, which may have biased the estimated independent prognostic effect of LVI. Second, LVI assessment relied on pathology reports from multiple participating institutions, and detailed staining protocols were not standardized. This may have introduced diagnostic heterogeneity. A recent systematic review showed that ancillary staining can improve LVI detection and interobserver agreement compared with hematoxylin and eosin staining alone (17). Finally, some data were excluded because of a lack of recurrence and metastasis time, which may affect the calculation of DFS.

Conclusions

In summary, LVI was associated with advanced pathological features in patients with MAC after curative resection. LVI also independently predicted poorer OS and DFS. Incorporating LVI status into postoperative risk stratification may help identify patients at increased recurrence and mortality risk after curative resection.

Acknowledgments

The authors acknowledge the following 21 participating hospitals for providing data for this study: The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital; Qilu Hospital of Shandong University; Second Hospital of Shandong University; Shandong First Medical University Affiliated Provincial Hospital; Affiliated Cancer Hospital of Shandong First Medical University; Jinan Central Hospital; Yantai Yuhuangding Hospital; The Second Affiliated Hospital of Shandong First Medical University; Cancer Hospital, Chinese Academy of Medical Sciences; Renji Hospital, Shanghai Jiao Tong University School of Medicine; The First Affiliated Hospital of Nanjing Medical University; Union Hospital Affiliated to Huazhong University of Science and Technology; Affiliated Hospital of Xuzhou Medical University; The First Affiliated Hospital of Xi’an Jiaotong University; Liaoning Cancer Hospital and Institute; Ningxia Medical University General Hospital; Zhongnan Hospital of Wuhan University; Hebei People’s Hospital; Affiliated Hospital of Hebei University; The First Affiliated Hospital of Nanchang University; and Tianjin People’s Hospital.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0275/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0275/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0275/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0275/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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by The Institutional Review Board of the First Affiliated Hospital of Shandong First Medical University & Shandong Qianfoshan Hospital [No. YXLL-KY-2024(116)]. Informed consent was waived in this retrospective study. All participating hospitals were informed of and agreed to the study.

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/.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. Siegel RL, Miller KD, Fuchs HE, et al. Cancer Statistics, 2021. CA Cancer J Clin 2021;71:7-33. [Crossref] [PubMed]
3. Hugen N, Brown G, Glynne-Jones R, et al. Advances in the care of patients with mucinous colorectal cancer. Nat Rev Clin Oncol 2016;13:361-9. [Crossref] [PubMed]
4. Huang A, Yang Y, Shi JY, et al. Mucinous adenocarcinoma: A unique clinicopathological subtype in colorectal cancer. World J Gastrointest Surg 2021;13:1567-83. [Crossref] [PubMed]
5. Bong JW, Gim JA, Ju Y, et al. Prognosis and Sensitivity of Adjuvant Chemotherapy in Mucinous Colorectal Adenocarcinoma without Distant Metastasis. Cancers (Basel) 2022;14:1297. [Crossref] [PubMed]
6. Kim S, Huh JW, Lee WY, et al. Prognostic Impact of Mucinous Adenocarcinoma in Stage II and III Colon Cancer. Dis Colon Rectum 2023;66:1473-80. [Crossref] [PubMed]
7. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010;17:1471-4.
8. Barresi V, Reggiani Bonetti L, Vitarelli E, et al. Immunohistochemical assessment of lymphovascular invasion in stage I colorectal carcinoma: prognostic relevance and correlation with nodal micrometastases. Am J Surg Pathol 2012;36:66-72. [Crossref] [PubMed]
9. Nathanson SD, Kwon D, Kapke A, et al. The role of lymph node metastasis in the systemic dissemination of breast cancer. Ann Surg Oncol 2009;16:3396-405. [Crossref] [PubMed]
10. Huh JW, Lee JH, Kim HR, et al. Prognostic significance of lymphovascular or perineural invasion in patients with locally advanced colorectal cancer. Am J Surg 2013;206:758-63. [Crossref] [PubMed]
11. Wang X, Cao Y, Ding M, et al. Oncological and prognostic impact of lymphovascular invasion in Colorectal Cancer patients. Int J Med Sci 2021;18:1721-9. [Crossref] [PubMed]
12. Zhang K, Ren Y, Xu S, et al. A clinical-radiomics model incorporating T2-weighted and diffusion-weighted magnetic resonance images predicts the existence of lymphovascular invasion / perineural invasion in patients with colorectal cancer. Med Phys 2021;48:4872-82. [Crossref] [PubMed]
13. Rönnow CF, Arthursson V, Toth E, et al. Lymphovascular Infiltration, Not Depth of Invasion, is the Critical Risk Factor of Metastases in Early Colorectal Cancer: Retrospective Population-based Cohort Study on Prospectively Collected Data, Including Validation. Ann Surg 2022;275:e148-54. [Crossref] [PubMed]
14. Watanabe J, Ichimasa K, Kudo SE, et al. Risk factors for lymph node metastasis in T2 colorectal cancer: a systematic review and meta-analysis. Int J Clin Oncol 2024;29:921-31. [Crossref] [PubMed]
15. Baxter NN, Kennedy EB, Bergsland E, et al. Adjuvant Therapy for Stage II Colon Cancer: ASCO Guideline Update. J Clin Oncol 2022;40:892-910. [Crossref] [PubMed]
16. Lee H, Yoo SY, Park IJ, et al. The Prognostic Reliability of Lymphovascular Invasion for Patients with T3N0 Colorectal Cancer in Adjuvant Chemotherapy Decision Making. Cancers (Basel) 2022;14:2833. [Crossref] [PubMed]
17. Watanabe J, Ichimasa K, Kataoka Y, et al. Additional staining for lymphovascular invasion is associated with increased estimation of lymph node metastasis in patients with T1 colorectal cancer: Systematic review and meta-analysis. Dig Endosc 2024;36:533-45. [Crossref] [PubMed]
18. Lugli A, Karamitopoulou E, Zlobec I. Tumour budding: a promising parameter in colorectal cancer. Br J Cancer 2012;106:1713-7. [Crossref] [PubMed]
19. Karamitopoulou E, Zlobec I, Born D, et al. Tumour budding is a strong and independent prognostic factor in pancreatic cancer. Eur J Cancer 2013;49:1032-9. [Crossref] [PubMed]
20. Koelzer VH, Langer R, Zlobec I, et al. Tumor budding in upper gastrointestinal carcinomas. Front Oncol 2014;4:216. [Crossref] [PubMed]
21. Zhong JW, Yang SX, Chen RP, et al. Prognostic Value of Lymphovascular Invasion in Patients with Stage III Colorectal Cancer: A Retrospective Study. Med Sci Monit 2019;25:6043-50. [Crossref] [PubMed]
22. Harris EI, Lewin DN, Wang HL, et al. Lymphovascular invasion in colorectal cancer: an interobserver variability study. Am J Surg Pathol 2008;32:1816-21. [Crossref] [PubMed]
23. Jiang HH, Zhang ZY, Wang XY, et al. Prognostic significance of lymphovascular invasion in colorectal cancer and its association with genomic alterations. World J Gastroenterol 2019;25:2489-502. [Crossref] [PubMed]
24. Al-Sukhni E, Attwood K, Gabriel EM, et al. Lymphovascular and perineural invasion are associated with poor prognostic features and outcomes in colorectal cancer: A retrospective cohort study. Int J Surg 2017;37:42-9. [Crossref] [PubMed]
25. Lim SB, Yu CS, Jang SJ, et al. Prognostic significance of lymphovascular invasion in sporadic colorectal cancer. Dis Colon Rectum 2010;53:377-84. [Crossref] [PubMed]
26. Kang YJ, Kim HS, Jang WS, et al. Impact of lymphovascular invasion on lymph node metastasis for patients undergoing radical prostatectomy with negative resection margin. BMC Cancer 2017;17:321. [Crossref] [PubMed]
27. Wang X, Wang H, He H, et al. Clinicopathological and prognostic features of colorectal mucinous adenocarcinomas: a systematic review and meta-analysis. BMC Cancer 2024;24:1161. [Crossref] [PubMed]
28. Yan C, Yang H, Chen L, et al. Clinical significance of mucinous component in colorectal adenocarcinoma: a propensity score-matched study. BMC Cancer 2021;21:1286. [Crossref] [PubMed]
29. Huang L, Luo S, Lai S, et al. Survival after curative resection for stage I colorectal mucinous adenocarcinoma. BMC Gastroenterol 2022;22:192. [Crossref] [PubMed]
30. Gao Z, Cao H, Xu X, et al. Prognostic value of lymphovascular invasion in stage II colorectal cancer patients with an inadequate examination of lymph nodes. World J Surg Oncol 2021;19:125. [Crossref] [PubMed]
31. Sun Y, Deng Y, Xu M, et al. A refined prediction of early recurrence combining tumor deposits in patients with resected rectal mucinous adenocarcinoma. Surg Today 2023;53:762-72. [Crossref] [PubMed]