Abstract
Background
An inadequate surgical margin is the major reason for disease recurrence; however, tumor recurrence sometimes even occurs in patients with pathologically negative surgical margins. The aim of this study is to determine the ideal surgical margin in radical colorectal cancer (CRC) surgery using panoramic pathology coupled with a molecular surgical margin (MSM) analysis.
Methods
The surgical specimens and clinical data of 194 CRC patients at the Guangxi Medical University Cancer Hospital from January 2016 to December 2019 were collected. Specifically, whole pathological sections of intact primary lesions of CRC were collected. Carcinoembryonic antigen (CEA) and methylation detection were used to analyze the molecular changes and protein expression patterns of different regions.
Results
A total of 194 patients with high-quality sections and complete clinical data were included in this study. Different tumor cells and different regions of the primary focus of CRC had different protein expression patterns, and some cells expressed multiple proteins. The submucosal interstitial space of the tumor margin (i.e., the extension area) and the submucosal space near the cancer area was obvious. The positive rate of CEA in the normal mucosal tissues of distant cancer was 19.15%.
Conclusions
A tumor is a disease caused by molecular regulation failure and internal environment disorder at the high molecular level of the body. “Cell-cell” interactions may play an important role. In tumor surgery, the cutting edge may not always need to be as extensive as possible, especially when function preservation is important, which affects the quality of life of patients and ultimately affects the actual treatment outcomes. Further high-powered randomized trials need to be conducted to confirm the results of this study.
Keywords: Primary colorectal cancer (primary CRC), whole pathological sections, histomorphology, molecular and protein expression
Highlight box.
Key findings
• In tumor surgery, the cutting edge may not always need to be as extensive as possible, especially when function preservation is important.
What is known and what is new?
• Generally, it is thought that the larger the cutting edge, the lower the recurrence rate; however, in some cases, such as sphincter-preserving surgery, extending the surgery results in organ destruction.
• In our study, we found that 2-cm cutting edge in the colorectal surgery ensured the oncology safety of the distal margin.
What is the implication, and what should change now?
• In tumor surgery, the cutting edge may not always need to be as extensive as possible, especially when function preservation is important, which affects the quality of life of patients and ultimately affects the actual treatment outcomes.
Introduction
Colorectal cancer (CRC) is a common malignancy. It is the third most commonly diagnosed cancer and third most common cause of cancer-related death among men and women in the United States (1). CRC also represents a significant health burden in China (2). In China, a majority of CRC patients present at an advanced or late stage (3). Disease recurrence is a major factor affecting patient outcomes (4).
Research has revealed that suboptimal resection margins, decreased pre-surgical prognostic nutritional index levels, increased serum carcinoembryonic antigen (CEA) levels, increased cancer antigen 19-9 (CA 19-9) levels, the presence of lymph node involvement, and increased operative blood loss are significantly correlated with an increased risk of postoperative tumor recurrence (5,6). Postoperative margin status serves as a predictive indicator for assessing the likelihood of neoplasm reappearance (6). An uninvolved margin, without malignant cellular infiltration, indicates a decreased risk of disease re-occurrence, while a positive or infiltrative margin, with cancerous elements, indicates an increased risk of recurrence. Conventionally, a gross surgical border of at least 2 cm is recommended for malignancies; however, this substantially decreases the pool of candidates eligible for sphincter-sparing procedures (7). Recurrence has been recurrently documented among individuals with ostensibly negative margins (8).
Molecular surgical margin (MSM) analysis via tissue imprinting is an ultra-sensitive and expeditious technique for assessing the surgical margins of excised tissues (9). For example, following the surgical removal of a pancreatic head carcinoma, the extracted sample commonly features an extensive margin zone that includes the anterior serosal layers, posterior connective structures, and the groove around the portal vein (10). In such cases, the use of nitrocellulose membranes for tissue imprinting has been shown to be better at capturing minuscule cells from intricate margin surfaces than conventional margin tissue sampling methods.
Currently, pathological diagnosis commonly employs a punctual sampling approach; however, this approach does not provide a dynamic and coherent examination protocol. Conversely, large-scale histopathological sectioning is a novel diagnostic modality that has recently gained traction, as it enables the observation of sequential alterations in tissue slices. This study sought to examine the medical records of patients who underwent anus-sparing surgery for CRC to describe the spatial patterns of tumor cell dispersion and histomorphological alterations across distinct zones of expansive pathological sections. This analysis also sought to examine the interplay between recurrence rates and various clinicopathological features in CRC.
The surgical cutting margin in colorectal surgery is inconsistent. In American surgical literature, a “left partial colectomy” for descending colon tumors involves excising portions of the transverse colon and the sigmoid colon until midway through each, as well as nearly all of the sigmoid arteries bar the terminal one. Under this protocol, the colonic resection margin ideally extends approximately 20 cm (potentially more in certain circumstances) from either end of the primary lesion, albeit without precise quantification (11). The American Society of Colon and Rectal Surgeons (ASCRS) recommends a minimum resection margin of 5–7 cm on both the proximal and distal ends of the colon to ensure complete eradication of pericolonic lymph nodes susceptible to metastases (12). Further, a previous study reported pronounced variations in the length of bowel resected worldwide during CRC surgeries. For example, when complete mesocolic excision was applied at a prominent German facility, the median length of the large intestine specimen removed for left-sided neoplasms measured 38 [32–43] cm. However, in Japanese establishments using D3 lymphadenectomy, the corresponding figure was only 15 [13–20] cm (13). The present study conducted a cross-sectional analysis to determine the ideal surgical margin in radical CRC surgery using panoramic pathology coupled with a MSM analysis. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1146/rc).
Methods
Data collection
This study was approved by the Ethics Committee of the Guangxi Medical University Cancer Hospital (KY2025–040). Informed consent was obtained from all patients or their families. Data privacy and confidentiality were maintained according to the Declaration of Helsinki and its subsequent amendments. A total of 194 CRC patients with high-quality sections who underwent surgical treatment at the Guangxi Medical University Cancer Hospital from January 2016 to December 2019 were included in the study. For the large pathological continuous sections, the surgical specimens of patients were prepared in large pathological wax blocks. Additionally, pathological wax blocks of the upper and lower incisal margins of some patients were collected. The sections underwent hematoxylin and eosin (HE) staining and immunohistochemical staining.
To be eligible for inclusion in the study, the patients had to meet the following inclusion criteria: (I) have a pathological diagnosis of primary CRC without other tumors; (II) have complete clinical data and pathological specimens obtained by surgical excision after admission; (III) have no other intestinal diseases; and (IV) have provided informed consent. Patients were excluded from the study if they met any of the following exclusion criteria: (I) had other tumors or other intestinal diseases; and/or (II) had incomplete pathological and clinical data.
Pathological specimen preparation
The complete CRC surgically resected specimens were quickly rinsed in sterile, pre-cooled phosphate buffered saline or saline solution to remove residual blood and debris. The bowel was cut lengthwise using surgical scissors (avoiding the tumor area as much as possible to maintain tumor integrity) and flattened onto a 7.5-cm by 10 cm foam plate. Next, the edge of the intestinal tube was fixed on the flat foam board with a push pin to prevent the intestinal tube from shrinking and sliding. The fixed intestinal tube was completely immersed in a specimen bag containing 10% neutral formalin solution according to the regulations, and sent to the Pathology Department for embedding and continuous sections with a large pathological microtome (5–10 pieces for each specimen). The upper and lower edge specimens were made by routine sampling in the Pathology Department.
Review and analysis of the film
To analyze the film, the following steps were employed:
The pathological sections were reviewed independently by two senior pathologists. Tissue FAXS panoramic scanning or EVOS auto intelligent automatic fluorescence microscopic imaging system software was used to scan the immunohistochemical sections to obtain 200-fold images, which were output and saved.
According to the above definition of the extended area, the start and end points of the extended area were marked in each large pathological section. The starting point was the boundary between the peripheral region and the extended region; while the ending point was the farthest point of the distribution of tumor cells along the submucosal trend. The length measured by the horizontal axis of the mucosal substratum was the length of the extension area (measured separately by two senior pathologists).
CEA detection methods and immunohistochemical interpretation were carried out as previously descried.
The HE immunohistochemistry (IHC) of the conventional pathological wax blocks was assessed by HE staining; IHC staining was performed on three single targets, and multiplex immunohistochemistry (mIHC) staining was performed on the same three target sections. The conventional pathological sections stained by IHC and mIHC were analyzed by panoramic pathological scans on the TissueGnostics platform, and the results were matched and compared to verify the synchronization and reliability of the scanning analysis results of the mIHC and IHC staining platform with a single target stics. The mIHC staining and HE staining were performed on the large pathological wax blocks and the associated metastatic wax blocks. The panoramic pathological scan analysis was conducted using the TissueGnostics platform. The scoring of immunostaining was evaluated based on staining intensity and percentages of three randomly positive stained areas by two pathologists in a double-blinded manner. To score the expression of Survivin, we used a three-level scale: 1= weakly positive; 2= moderately positive; 3= strongly positive, ranging from: 1: 0–30%; 2: 30–60%; 3: 60–100%.
P16 methylation was evaluated by methylation assays in 24 patients in tumor, paracancer 1 cm, paracancer 2 cm of the primary tumor of CRC, and five different CpG sites were evaluated. The methylation levels of the 5 CpG sites of the P16 gene in different regions of the primary lesion were calculated, and the mean ± standard deviation (SD) methylation percentage of each CpG site in different regions of the tumor tissue was analyzed.
Statistical analysis
The statistical analysis was performed using IBM SPSS Statistics 23.0. The measurement data are presented as the mean ± SD (). The unpaired bilateral t-test was used for comparisons between two groups, the Chi-squared test was used for comparisons of differences between the counting data, and a one-way analysis of variance was used for comparisons of means among multiple groups. Kaplan-Meier survival curves and log-rank tests were used to analyze the overall survival (OS) of the patients with incision margin status. A P value <0.05 was considered statistically significant.
Results
A total of 194 CRC patients with large primary lesions were enrolled in this study (Table 1). The distribution and histomorphological changes of the primary tumor cells of CRC followed common rules. According to the characteristics of tumor histopathologic structure, a tumor can be roughly divided into the following four different areas from the center to the two sides: the primary tumor; the peripheral area; the extended area; and the normal tissue area (Figure 1). The main area comprises the most concentrated part of the neoplastic tissue and structure under low magnification microscopy. A large number of tumor cells and cancer nests are densely distributed, squeezed together and piled on top of each other, and the structure of the diseased glands is chaotic and destroyed. The peripheral area refers to the continuous extension of the tumor tissue and structure in the main lesion area under low magnification microscopy. The extension area refers to the area of scattered and discontinuous distribution of tumor tissues and cells outside the extension terminal of tumor tissue and structural continuity. The normal tissue area is completely free of tumor cells and tissue (Figure 1). A distinct quadripartite pattern of eminent, ulcerated, and invasive CRC was observed in the primary lesions.
Table 1. Clinical data of 194 patients with colorectal cancer.
| Clinical features | Statistical interpretation |
|---|---|
| Gender | |
| Male | 122 (62.9) |
| Female | 72 (37.1) |
| Age (years) | |
| <60 | 93 (47.9) |
| ≥60 | 101 (52.1) |
| T stage | |
| T1–T2 | 37 (19.1) |
| T3–T4 | 148 (76.3) |
| Unknown | 9 (4.6) |
| TNM stage | |
| Stage I | 28 (14.4) |
| Stage II | 50 (25.8) |
| Stage III | 65 (33.5) |
| Stage IV | 44 (22.7) |
| Unknown | 7 (3.6) |
| Tumor differentiation | |
| Medium-low differentiation | 164 (84.5) |
| High differentiation | 15 (7.7) |
| Unknown | 15 (7.7) |
| Tumor classification | |
| Protruding type | 71 (36.6) |
| Ulceration type | 102 (52.6) |
| Infiltrating type | 9 (4.6) |
| Unknown | 12 (6.2) |
| Tumor site | |
| Rectum | 87 (44.8) |
| Colon | 106 (54.6) |
| Unknown | 1 (0.5) |
| Maximum tumor diameter (cm) | |
| <5 | 93 (47.9) |
| ≥5 | 96 (49.5) |
| Unknown | 5 (2.6) |
| Lymphatic metastasis | |
| Yes | 94 (48.5) |
| No | 92 (47.4) |
| Unknown | 8 (4.1) |
| Distant metastasis | |
| Yes | 50 (25.8) |
| No | 142 (73.2) |
| Unknown | 2 (1.0) |
| Vascular tumor thrombus | |
| Yes | 42 (21.6) |
| No | 144 (74.2) |
| Unknown | 8 (4.1) |
| Perineural invasion | |
| Yes | 94 (48.5) |
| No | 93 (47.9) |
| Unknown | 7 (3.6) |
Data are presented as n (%). TNM, tumor-node-metastasis.
Figure 1.
The distribution of four zones on a large pathological section of primary colon cancer.
A total of 128 patients with high-quality sections of large primary CRC lesions were selected for the sectional evaluation of T staging in different sections of the sections. The primary tumor was staged as T4 in 10 patients, T3 in 89 patients, T2 in 27 patients, and T1 in 2 patients in the main area; 16 patients had T3 stage, 71 had T2 stage, and 41 had T1 stage in the peripheral area. In the extended area, 1 patient had stage T3, 18 patients had stage T2, 102 patients had stage T1, and 7 patients had stage T0. Further, 128 patients had normal tissue stage T0 (Table 2). The depth of tumor invasion decreased gradually during the process of extension from the main tumor area to the periphery.
Table 2. Comparison of T staging of different regions on large pathological slices of primary lesions.
| Areas | T0 | T1 | T2 | T3 | T4 |
|---|---|---|---|---|---|
| The main area | 0 | 2 | 27 | 89 | 10 |
| The peripheral area | 0 | 41 | 71 | 16 | 0 |
| Extended area | 7 | 102 | 18 | 1 | 0 |
| Normal tissue area | 128 | 0 | 0 | 0 | 0 |
T, tumor.
Analysis of the extended area of primary CRC
To evaluate the longest transverse extension of the tumor cells along the submucosa, we selected 100 high-quality whole pathological sections with four clearly visible zones, and measured the length of the extension area of these 100 whole pathological sections. The shortest length of the extension area was 0.1 mm, the longest length of the extension area was 15 mm, and the median length of the extension area was 10 mm. An extension area length ≤5 mm accounted for 95%, and an extension area length ≤10 mm accounted for 99%.
Gender, age, the maximum depth of invasion, TNM stage, the degree of differentiation, the tumor type, the tumor site, the tumor size, lymph node metastasis, distant metastasis, vascular cancer thrombus, and nerve invasion were not significantly correlated with the length of the extended area.
CEA protein expression in different regions of the primary tumor
A total of 104 high-quality, large slices of CRC with four clearly visible zones were selected to evaluate the immunohistochemical expression of the CEA protein in different zones of the primary lesion. Immunohistochemical staining of the whole pathological section of the primary lesions of 104 patients showed that the CEA protein was mainly expressed in the cytoplasm of the primary lesions of the patients with CRC (Figure 2A,2B). The expression rates of the CEA protein in main area, peripheral area, extended area, normal tissue area (<1 cm), and far normal tissue area (≥1 cm) of the primary lesion were 93.27%, 92.31%, 91.35%, 68.27%, 56.73%, respectively (Table 3). While the expression intensity in main area, peripheral area, extended area, normal tissue area (<1 cm), and far normal, tissue area (≥1 cm) of the primary lesion were 7.26±1.90,7.24±1.92, 7.16±1.94, 5.83±2.67, and 5.12±2.63, respectively (Table 4). The difference in the CEA protein expression levels was statistically significant (P<0.05).
Figure 2.
Carcinoembryonic antigen protein expression in the primary tumors of patients with colorectal cancer (×100) (A: negative expression; B: positive expression). The mIHC staining and HE staining were performed on the large pathological wax blocks and the associated metastatic wax blocks. The panoramic pathological scan analysis was conducted using the TissueGnostics platform. The scoring of immunostaining was evaluated based on staining intensity and percentages of 3 randomly positive stained areas by 2 pathologists in a double-blinded manner. To score the expression of Survivin, we used a three-level scale: 1= weakly positive; 2= moderately positive; 3= strongly positive, ranging from: 1: 0–30%; 2: 30–60%; 3: 60–100%. HE, hematoxylin and eosin; mIHC, multiplex immunohistochemistry.
Table 3. The positive rate of CEA protein among different regions of the primary lesion (n=104).
| Areas | The main area | The peripheral area | Extended area | Normal tissue area (<1 cm) | Far normal tissue area (≥1 cm) |
|---|---|---|---|---|---|
| No. of positive cases (positive rate) | 97 (93.27%) | 96 (92.31%) | 95 (91.35%) | 71 (68.27%) | 59 (56.73%) |
CEA, carcinoembryonic antigen.
Table 4. Expression analysis of CEA protein in different regions of the primary tumor (n=104).
| Areas | The main area | The peripheral area | Extended area | Normal tissue area | F | P | |
|---|---|---|---|---|---|---|---|
| <1 cm | ≥1 cm | ||||||
| Expression strength | 7.26±1.90 | 7.24±1.92 | 7.16±1.94 | 5.83±2.67 | 5.12±2.63 | 20.36 | <0.05 |
Data of the main area, the peripheral area, extended area, normal tissue area were presented as mean ± standard deviation. CEA, carcinoembryonic antigen.
The upper and lower incisors of 46 cases were randomly selected for synchronous analysis. The positive expression rates of the CEA protein in the main tumor area, peripheral tumor area, extended tumor area, normal tissue area (<1 cm), far normal tissue area (≥1 cm), and upper and lower incisor margins were 95.74% (45/47), 93.62% (44/47), 91.49% (43/47) 68.09% (32/47), 59.57% (28/47) and 19.15% (9/47), respectively.
Methylation assays were conducted on 24 CRC specimens, and they were successfully detected. The percentage of methylation in the main area of the primary tumor of CRC was 7%, 14%, 19%, 6%, and 9%; the methylation percentage in the 1 cm tissue of the primary tumor of CRC was 6%, 8%, 11%, 5%, and 5%, respectively; and the percentage of methylation in the 2 cm tissue of the primary tumor of CRC was 3%, 6%, 6%, 3% and 4%, respectively. The average methylation level in the main body of the primary lesion was 6.51±3.65, that in the adjacent 1-cm tissue was 5.85±2.71, and that in the adjacent 2-cm tissue was 7.53±3.75. There was no significant correlation between the methylation levels of the P16 promoter in the three regions (P>0.05).
Prognosis
The follow-up begin in January 2016, and ended in December 2024. In total, 19 patients (9.8%) were lost follow-up. Among these patients, 9 (5.1%) developed liver metastasis, 3 (1.7%) developed lung metastasis, and 2 (1.1%) developed bone metastasis. Additionally, 16 patients (9.1%) developed multiple systemic metastases, while none developed local recurrence.
The positive expression rates of CEA protein in the upper and lower incisor margins were defined as MSM positive. In total, the MSM status of 46 patients was determined. In terms of the postoperative prognostic outcomes, 9 patients were MSM positive and 37 patients were MSM negative (Figure 3). There were no significant differences between the MSM-negative and MSM-positive groups in terms of OS.
Figure 3.
Overall survival between the molecular surgical margin-negative and molecular surgical margin-positive groups (0, molecular surgical margin-negative expression group; 1, molecular surgical margin-positive expression group).
Discussion
Surgery remains the gold standard in the treatment of CRC (14,15). In CRC surgery, generally, it is thought that the larger the cutting edge, the lower the recurrence rate; however, in some cases, such as sphincter-preserving surgery, extending the surgery results in organ destruction (16). In this study, no local recurrence was observed in the 194 CRC patients; thus, the 2-cm cutting edge in the colorectal surgery ensured the oncology safety of the distal margin.
We examined large pathological sections of 194 patients with primary CRC, and we found that rapid cell division and proliferation in the tumor structure was common, but not all areas of the tumor structure displayed rapid cell proliferation histopathologic changes. In the large pathological sections of the vast majority of the primary CRC lesions, the histomorphological changes of tumor cell aggregation, division, and proliferation mainly appeared in the central region of the tumor (i.e., the main region), where there was basically no normal tissue structure and morphology. There were also obvious differences in the size and morphology of the tumor cells, and the morphological characteristics formed by the rapid proliferation of the cells were relatively obvious. However, in the tumor extension area, the tumor cells were often isolated and scattered, and incoherent with each other.
In recent years, many studies have found that both cells with multidirectional differentiation ability and mature cells can be directionally induced to differentiate into cells with different biological characteristics under certain biological environmental conditions (17,18), and can be induced to change when co-cultured with other cells (19). These cells can obtain morphological characteristics similar to those of adjacent cells. This is a very typical “biological induction” phenomenon. Ombrato et al. found that normal lung epithelial cells acquired cancer-associated parenchymatocytoid phenotypes when co-cultured with metastatic breast cancer cells and supported their growth characteristics (20), which suggests that normal cells can be modified by targeted induction with tumor cells.
The traditional view is that the resection margin should be as far away from the tumor as possible, but determining an “appropriate” margin is a difficult problem that requires accuracy. According to the guidelines for CRC, low rectal cancer (distance from the anus <5 cm), when the safe margin of resection is at least 1 cm away from the tumor (21), and the margin of resection is <1 cm due to anal preservation, it is recommended that an intraoperative frozen pathological examination be conducted to prove that the margin of resection is negative. The relevant analysis in this group suggested that the length of the extended area of CRC was mostly <0.5 cm. Thus, in theory, when the margin of resection is >0.5 cm, about 95% of the patients reach the margin without tumor cells, and when the margin of resection is >1.0 cm, about 99% of patients reach the margin without tumor cells, which is consistent with previous reports.
Based on advances in research on the biological mechanisms and behavior of tumors, we are of the view that in tumor surgery, the cutting edge does not always need to be as extensive as possible, especially where function preservation is important, which affects the quality of life of patients and ultimately affects the actual treatment outcomes.
Study has shown that regardless of whether or not patients have received neoadjuvant chemoradiotherapy, a margin of <1 cm is sufficient to ensure the radical resection of rectal cancer (22). A study of 415 patients who underwent pre-resection for rectal cancer reported that there was no significant difference in the local recurrence rate, distant metastasis rate, and OS rate between the group with the margin of >1 cm and the group with the margin of ≤1 cm (23). The results of this study provide an objective basis for controlling the distance of the incisal edge when necessary. A large number of previous clinical studies have also shown that the detection of a safe incisal margin can ensure the complete removal of tumor tissue in the lesion area, avoid damage to anal function, minimize the scope of resection, reduce surgical complications, and improve patient prognosis and quality of life (24-26).
As tumor-related research has advanced, it has shown that a tumor is not a disease at the cellular, tissue, and organ level; rather, it is a disease caused by molecular regulation failure and internal environment disorder at the high molecular level of the body. Surgery cannot solve problems related to molecular level disorder. The ultimate solution to the tumor etiology problem is to restore the patient’s self-regulation and repair ability. Thus, it is particularly important that the patient’s organs and the whole body state are protected in the course of tumor treatment.
In this study, CEA and other related markers of primary CRC were detected and observed in different regions. CEA is the most common tumor marker for CRC (27). The level of CEA in the serum increases, such that the higher the level of CEA in the blood, the more advanced the disease and the higher the degree of malignancy (28). Consistent with previous study (29), this study found that CEA protein was highly expressed in the primary tumor. However, CEA was also observed to be positively expressed in cells with normal tissue morphology at the margin of 1–2 cm. We found that the CEA protein had a positive expression rate of 19.17% in the upper and lower margins of CRC. Unlike previous studies (8), in this study, no significant differences were found between the MSM-negative and MSM-positive groups in terms of OS; however, this might be due to the small sample size of the study (46 cases) and biases might have been introduced into the study.
The findings of this research group and other related studies suggest that morphologically normal mucosal cells far from the tumor area display corresponding biological and molecular changes to varying degrees (30-33). Thus, in this regard, in addition to showing that the tumor environment affects the so-called “normal” cells, we found that the blind, unlimited expansion of the scope of resection does not address the environment disorder issue in the body of patients with oncologic diseases; rather, it harms the effective recovery of the body after treatment, thus providing an opportunity for the recurrence and metastasis of the tumor.
However, we acknowledged several potential limitations in the current study. First, this retrospective designed study was conducted in a single-center, there is potential for data missing and incompleteness. Second, the small sample size limited the power of this study. Additionally, due to limited funding, CEA expression and methylation assays could not be conducted in all CRC tissue samples. We hope that future research will carefully consider these factors.
Conclusions
A tumor is a disease caused by molecular regulation failure and internal environment disorder at the high molecular level of the body. “Cell-cell” interactions may play an important role. In tumor surgery, the cutting edge may not always need to be as extensive as possible, especially when function preservation is important, which affects the quality of life of patients and ultimately affects the actual treatment outcomes. Additional high-powered randomized-controlled trials need to be conducted to confirm the results of this study.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
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. This study was approved by the Ethics Committee of the Guangxi Medical University Cancer Hospital (KY2025–040). Informed consent was obtained from all patients or their families.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1146/rc
Funding: This study was funded by the Guangxi Science and Technology Department Project (#GuikeAB18221086).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1146/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1146/dss
References
- 1.Siegel RL, Wagle NS, Cercek A, et al. Colorectal cancer statistics, 2023. CA Cancer J Clin 2023;73:233-54. 10.3322/caac.21772 [DOI] [PubMed] [Google Scholar]
- 2.Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin 2016;66:115-32. 10.3322/caac.21338 [DOI] [PubMed] [Google Scholar]
- 3.Ma S, Sun B, Li M, et al. High-precision detection and navigation surgery of colorectal cancer micrometastases. J Nanobiotechnology 2023;21:403. 10.1186/s12951-023-02171-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Okumura T, Hayashi T, Kudo SE, et al. Endoscopic submucosal dissection for colorectal neoplasms: Risk factors for local recurrence and long-term surveillance. DEN Open 2024;4:e269. 10.1002/deo2.269 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Cheun JH, Kim HK, Lee HB, et al. Residual Risk of Ipsilateral Tumor Recurrence in Patients Who Achieved Clear Lumpectomy Margins After Repeated Resection. J Breast Cancer 2023;26:558-71. 10.4048/jbc.2023.26.e46 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Nitta T, Nakamura T, Mitsuhashi T, et al. The impact of margin status determined by the one-millimeter rule on tumor recurrence and survival following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. Surg Today 2017;47:490-7. 10.1007/s00595-016-1420-7 [DOI] [PubMed] [Google Scholar]
- 7.Basta AV, Fritz CD, Chiang YJ, et al. The Impact of Surgical Margin in Wide Local Excision of Pediatric Melanoma - An Argument for a More Conservative Approach. J Pediatr Surg 2025;60:161897. 10.1016/j.jpedsurg.2024.161897 [DOI] [PubMed] [Google Scholar]
- 8.Sunagawa Y, Hayashi M, Yamada S, et al. Impact of molecular surgical margin analysis on the prediction of pancreatic cancer recurrences after pancreaticoduodenectomy. Clin Epigenetics 2021;13:172. 10.1186/s13148-021-01165-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Hayashi M, Wu G, Roh JL, et al. Correlation of gene methylation in surgical margin imprints with locoregional recurrence in head and neck squamous cell carcinoma. Cancer 2015;121:1957-65. 10.1002/cncr.29303 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Sina N, Olkhov-Mitsel E, Chen L, et al. Utility of intraoperative pathology consultations of whipple resection specimens and their impact on final margin status. Heliyon 2023;9:e20238. 10.1016/j.heliyon.2023.e20238 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Takehara Y, Yamashita K, Morimoto S, et al. Clinical usefulness of hybrid endoscopic submucosal dissection for T1b colorectal carcinomas ≤20 mm to ensure adequate vertical margins. DEN Open 2025;5:e70030. 10.1002/deo2.70030 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Carmichael JC, Keller DS, Baldini G, et al. Clinical practice guideline for enhanced recovery after colon and rectal surgery from the American Society of Colon and Rectal Surgeons (ASCRS) and Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Surg Endosc 2017;31:3412-36. 10.1007/s00464-017-5722-7 [DOI] [PubMed] [Google Scholar]
- 13.Aghayeva A, Seker ME, Bayrakceken S, et al. Comparison of Postoperative Outcomes and Long-Term Survival Rates between Patients Who Underwent Robotic and Laparoscopic Complete Mesocolic Excision for Right-Sided Colon Cancer. J Laparoendosc Adv Surg Tech A 2024;34:890-7. 10.1089/lap.2024.0144 [DOI] [PubMed] [Google Scholar]
- 14.Lee KY, Lee J, Park YY, et al. The effect of circular stapler size on anastomotic stricture formation in colorectal surgery: A propensity score matched study. PLoS One 2023;18:e0287595. 10.1371/journal.pone.0287595 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Luo Z, Bi X. Surgical treatment of colorectal cancer liver metastases: individualized comprehensive treatment makes a difference. Hepatobiliary Surg Nutr 2021;10:899-901. 10.21037/hbsn-2021-23 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Tang J, Yang J, Yang JS, et al. Stoma-site approach single-port laparoscopic versus conventional multi-port laparoscopic Miles's procedure for low rectal cancer: A prospective, randomized controlled trial. Asian J Surg 2023;46:4317-22. 10.1016/j.asjsur.2023.06.021 [DOI] [PubMed] [Google Scholar]
- 17.Wang W, Sun J, Aarabi G, et al. Effect of tetracycline hydrochloride application on dental pulp stem cell metabolism-booster or obstacle for tissue engineering? Front Pharmacol 2023;14:1277075. 10.3389/fphar.2023.1277075 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Zhou J. Curcumin-loaded porous scaffold: an anti-angiogenic approach to inhibit endochondral ossification. J Biomater Sci Polym Ed 2023;34:2255-73. 10.1080/09205063.2023.2231663 [DOI] [PubMed] [Google Scholar]
- 19.Li RF, Nan GX, Wang D, et al. BMP9 Can Induce Schwann Cells Expressing Simian Virus 40 T Antigen to Differentiate into Fat and Bone In Vivo and In Vitro. Cell Reprogram 2021;23:108-16. 10.1089/cell.2020.0069 [DOI] [PubMed] [Google Scholar]
- 20.Ombrato L, Nolan E, Kurelac I, et al. Metastatic-niche labelling reveals parenchymal cells with stem features. Nature 2019;572:603-8. 10.1038/s41586-019-1487-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Calvo FA, Rivas F, Sole CV, et al. Post-chemoradiation anastomotic recurrence in locally advanced rectal cancer: no increased risk associated with distal margin. Clin Transl Oncol 2014;16:573-80. 10.1007/s12094-013-1119-9 [DOI] [PubMed] [Google Scholar]
- 22.Zhang C, Cui M, Xing J, et al. Oncological results in rectal cancer patients with a subcentimetre distal margin after laparoscopic-assisted sphincter-preserving surgery. ANZ J Surg 2022;92:1454-60. 10.1111/ans.17503 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Kang DW, Kwak HD, Sung NS, et al. Oncologic outcomes in rectal cancer patients with a ≤1-cm distal resection margin. Int J Colorectal Dis 2017;32:325-32. 10.1007/s00384-016-2708-1 [DOI] [PubMed] [Google Scholar]
- 24.Guedj N, Maggiori L, Poté N, et al. Distal intramural and tumor spread in the mesorectum after neoadjuvant radiochemotherapy in rectal cancer: about 124 consecutive patients. Hum Pathol 2016;52:164-72. 10.1016/j.humpath.2016.01.017 [DOI] [PubMed] [Google Scholar]
- 25.Manegold P, Taukert J, Neeff H, et al. The minimum distal resection margin in rectal cancer surgery and its impact on local recurrence - A retrospective cohort analysis. Int J Surg 2019;69:77-83. 10.1016/j.ijsu.2019.07.029 [DOI] [PubMed] [Google Scholar]
- 26.Sun G, Ye X, Zheng K, et al. Measurement of distal intramural spread and the optimal distal resection by naked eyes after neoadjuvant radiation for rectal cancers. World J Surg Oncol 2022;20:296. 10.1186/s12957-022-02756-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Lozada-Martinez ID, Bolaño-Romero MP, Lambis-Anaya L, et al. CEA-delta could be a biomarker of tumor phenotype, clinical stage, and chemotherapeutic response in rectal cancer with OCT4-positive cancer stem cells. Front Oncol 2023;13:1258863. 10.3389/fonc.2023.1258863 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Zhao J, Zhao H, Jia T, et al. Combination of Changes in CEA and CA199 Concentration After Neoadjuvant Chemoradiotherapy Could Predict the Prognosis of Stage II/III Rectal Cancer Patients Receiving Neoadjuvant Chemoradiotherapy Followed by Total Mesorectal Excision. Cancer Manag Res 2022;14:2933-44. 10.2147/CMAR.S377784 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Paku M, Uemura M, Kitakaze M, et al. Clinical Significance of Preoperative and Postoperative Serum CEA and Carbohydrate Antigen 19-9 Levels in Patients Undergoing Curative Resection of Locally Recurrent Rectal Cancer. Dis Colon Rectum 2023;66:392-400. 10.1097/DCR.0000000000002655 [DOI] [PubMed] [Google Scholar]
- 30.Alorda-Clara M, Torrens-Mas M, Hernández-López R, et al. Inflammation- and Metastasis-Related Proteins Expression Changes in Early Stages in Tumor and Non-Tumor Adjacent Tissues of Colorectal Cancer Samples. Cancers (Basel) 2022;14:4487. 10.3390/cancers14184487 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Galati L, Gupta P, Tufaro A, et al. Evaluation of human papillomavirus DNA in colorectal cancer and adjacent mucosal tissue samples. Infect Agent Cancer 2023;18:71. 10.1186/s13027-023-00552-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Ito Y, Osakabe M, Niinuma T, et al. Genome-wide analysis of mRNA and microRNA expression in colorectal cancer and adjacent normal mucosa. J Pathol Clin Res 2022;8:313-26. 10.1002/cjp2.268 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Xi HQ, Zhang KC, Li JY, et al. Expression and clinicopathologic significance of TUFM and p53 for the normal-adenoma-carcinoma sequence in colorectal epithelia. World J Surg Oncol 2017;15:90. 10.1186/s12957-017-1111-x [DOI] [PMC free article] [PubMed] [Google Scholar]