INTRODUCTION
Gastric cancer remains a significant public health concern in South Korea, despite a gradual decline in its overall prevalence. According to the 2021 National Cancer Registry, it accounted for approximately 10.6% of all cancer cases, ranking fourth among all malignancies [1]. Improvements in nationwide screening programs and surgical advancements have led to a substantial increase in the 5-year survival rate, from 43.9% in 1993–1995 to 78.4% in 2018–2022 [2].
The standard curative treatment for gastric cancer is surgical resection, with the primary goal of achieving an R0 resection, meaning no cancer cells remain at the margin. A positive margin (R1) is associated with higher local recurrence and lower survival and intraoperative frozen section (IFS) is widely used to ensure margin clearance during surgery in Eastern [3].
However, in clinical practice, positive margins can sometimes be detected on IFS due to factors such as unclear tumor borders, histologic features (diffuse or linitis plastica), tumor location (esophagogastric junction), or mismatch between gross and pathological findings. These situations require critical intraoperative decisions regarding additional resection or change in surgical strategy. In some cases, further resection may not be feasible due to the patient’s condition or technical challenges, which may compromise curative intent.
Despite being a common challenge in gastric cancer surgery, studies regarding the characteristics of positive IFS remain underreported, and evidence on long-term outcomes in these patients is scarce. This lack of data contributes to uncertainty in surgical decision-making and prognosis when positive margins are encountered.
This study aims to evaluate the clinicopathological characteristics and long-term outcomes of patients with positive resection margins identified during gastrectomy through a single-cohort analysis. The findings are expected to provide real-world evidence that may serve as a reference for intraoperative decision-making in the specific context of IFS-positive proximal margins.
METHODS
Study design and data collection
This was designed as a retrospective single-cohort study. We reviewed the 5,894 patients who underwent gastrectomy for gastric cancer between May 2005 and December 2023 at the Department of Surgery, Pusan National University Hospital. Among them, we extracted patients who had a positive resection margin on IFS during gastrectomy, and excluded those with R2 resection, distant metastasis (stage IV). In addition, patients with Siewert type I esophagogastric junction cancer and those with a positive distal margin were excluded. Although Siewert type I technically involves the proximal resection margin, these tumors are treated according to the principles of distal esophageal cancer and thus represent a different disease entity. Likewise, distal margin positivity often indicates duodenal or pancreatic invasion, requiring distinct surgical strategies (such as pancreaticoduodenectomy) and carrying different prognostic implications. By excluding these heterogeneous groups, we tried to reduce heterogeneity and minimize bias or confounding in the analysis. Patients were divided into survivor group (SG) and non-survivor group (NSG) for comparison. Although we initially considered a study design comparing R0 and R1 resections, IFS positivity itself represents a violation of the principle of en-bloc resection. Therefore, to directly reflect and evaluate the clinical course of these patients, we grouped the patients by survival status rather than final margin status. Demographic, perioperative, and pathological data were collected from electronic medical records, and additional mortality data were obtained through the Microdata Integrated Service. Tumor staging was classified according to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system. The patient selection process is summarized in Fig. 1.
Surgical procedure
All patients included in this study underwent a distal or total gastrectomy, accompanied by D1+, D2, or D2+ lymphadenectomy in accordance with the Japanese Gastric Cancer Association (JGCA) and Korean Gastric Cancer Association (KGCA) guidelines. The procedures were performed via open surgery, laparoscopy-assisted gastrectomy, or totally laparoscopic gastrectomy, with reconstruction using Billroth-I, Billroth-II (+Braun anastomosis), or Roux-en-Y anastomosis. The tumor location was confirmed preoperatively using endoscopy and abdominal computed tomography. For laparoscopic procedures, if the lesion was considered difficult to identify from the serosal surface, hemostatic clips were preoperatively placed 2–3 cm proximal to the tumor. Resection was performed with an adequate margin from the presumed tumor location, as determined visually or by the position of the clips. In a totally laparoscopic gastrectomy, the clips could not be palpated; therefore, it was confirmed after resection that the clips were included in the specimen. IFS biopsy of the resection margin was performed by experienced pathologists, and after a positive margin was confirmed, either further resection was performed or the procedure was concluded without additional resection. If no further resection was performed, the tissue within the anvil of the resected proximal side during anastomosis was examined for repeated IFS or final pathologic confirmation.
Margin assessment
Proximal margin length was assessed by experienced gastrointestinal pathologists. R0 resection was defined as the absence of invasive carcinoma at any resection margin on permanent sections, and R1 resection as the presence of microscopic tumor at the margin. When the tumor grossly abutted the resection margin (“abutting”) but no microscopic invasion was found, and the final pathology reported a clear margin, the case was classified as R0. The margin length was recorded as 0 cm. If necessary, ink staining was performed to confirm margin involvement [4]. When the anvil ring specimen obtained from the circular stapler was submitted and confirmed tumor-negative on final pathology, the resection was classified as R0. However, as no measurable clearance could be determined, the proximal margin length was also recorded as 0 cm by protocol.
Statistical analysis
Categorical variables were analyzed using the chi-square test, with Fisher exact test. Continuous variables were expressed as median (interquartile range, IQR), and comparisons between groups were performed using the Mann-Whitney U test as a nonparametric analysis.
Survival analysis was conducted using the Kaplan-Meier method to estimate survival curves and survival rates. Since the number of patients in each group became too small when TNM stages were subdivided, the analysis was conducted by grouping them into stage I, II, and III for appropriate statistical comparisons. Kaplan-Meier curves were generated using the 5-year follow-up dataset. When the median survival was not reached, restricted mean survival time (RMST) analysis was applied to estimate survival. For subgroup analysis, patients were categorized according to stage-based risk (low-risk: stage I–II; high-risk: stage III) and resection status (R0 or R1). These two factors created four subgroups (Group 1: low-risk/R0, Group 2: low-risk/R1, Group 3: high-risk/R0, Group 4: high-risk/R1). Due to the imbalance in case numbers among individual TNM stages, risk comparison was performed using this grouping, and survival outcomes were compared among the subgroups. Prognostic factors were assessed using univariate and multivariate Cox proportional hazards regression models. Results were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Statistical analyses were performed using SPSS software (version 22.0; IBM Corp.) and Python (version 3.10) with relevant statistical libraries.
Ethics statement
This study was conducted in accordance with the ethical standards of the Declaration of Helsinki and was approved by the Institutional Review Board of Pusan National University Hospital (IRB No. H-1701-006-051). Informed consent was obtained from all patients included in the study. Survival status was additionally verified through linkage with the national death registry using the Microdata Integrated Service (MDIS) platform, which was also covered under the IRB approval.
RESULTS
Patient selection
Among 5,894 patients who underwent gastrectomy for gastric cancer during the study period, 207 patients had a positive resection margin on IFS. Of these, 86 patients were excluded according to the exclusion criteria, leaving 121 patients enrolled in the study. Additional resection was performed in 87 patients, while 34 patients did not undergo further resection after the positive margin was confirmed. In the additional resection group, IFS was repeated in 84 patients, excluding three cases. A second positive margin was identified in eight patients, and two of these were confirmed to have negative margins on final pathology. Of the 76 patients with a negative margin on repeat IFS, three were later found to have a positive margin on final pathology. In the group without additional resection (n=34), 22 patients were confirmed to have negative margins on final pathology. Overall, R0 resection was achieved in 100 patients, while R1 resection was identified in 21 patients. During follow-up, 76 patients survived and 45 patients died.
Patients’ demographics and clinicopathologic outcomes
The median age of the entire cohort was 62.0 years (IQR, 53.0–71.5 years), and 79 patients (65.3%) were male. The median body mass index (BMI) was 22.4 kg/m2 (IQR, 20.5–25.5 kg/m2). There were no significant differences between the SG and NSG in age, sex, BMI, or American Society of Anesthesiologists classification (Table 1).
Regarding perioperative outcomes, there were differences in surgical approach, extent of resection, co-resection, blood loss, hospital stay, and receipt of adjuvant chemotherapy between two groups. The NSG had a higher proportion of open surgery (93.3% vs. 61.8%, P<0.001) and total gastrectomy (66.7% vs. 43.4%, P=0.015). NSG also had a higher rate of co-resection (51.1% vs. 18.4%, P<0.001), greater intraoperative blood loss (400.0 mL [210.0–520.0] vs. 300.0 mL [100.0–437.5], P=0.012), and longer hospital stays (12 days [9–16] vs. 9 days [8–12], P=0.001). Adjuvant chemotherapy was more frequently administered in the NSG (77.8% vs. 51.3%, P=0.007).
Pathologic findings showed that the NSG had a greater metastatic lymph nodes (8.0 [2.5–22.0] vs. 1.0 [0–6.8], P<0.001), as well as higher rates of lymphovascular invasion (LVI; 80.0% vs. 52.6%, P=0.003) and perineural invasion (PNI; 91.1% vs. 52.6%, P<0.001). The rate of R1 resection was significantly higher in the NSG (35.6% vs. 6.6%, P<0.001). In terms of tumor stage, advanced stage (stage III) disease was more prevalent in the NSG (82.2% vs. 40.8%, P<0.001). Tables 2 and 3 summarize perioperative and pathologic outcomes, respectively.
The length of proximal margin according to lesion location
The proximal margin length varied according to tumor location and survival status (data not shown). In upper-third lesions, the median proximal margin was 0.60 cm (IQR, 0–0.55 cm) in the SG and 0.88 cm (IQR, 0–0.50 cm) in the NSG. For middle-third lesions, the corresponding values were 2.30 cm (IQR, 0–1.75 cm) and 0.57 cm (IQR, 0–1.50 cm), and for lower-third lesions, 4.14 cm (IQR, 0.55–7.65 cm) and 2.97 cm (IQR, 0.05–5.90 cm), respectively. No statistically significant differences were observed between the SG and NSG within each tumor location (all P>0.05, Mann-Whitney U test). Fig. 2 visualizes the proximal margin length according to each tumor location.
Overall, patients with lower-third tumors tended to have longer proximal margins regardless of survival outcome, whereas those with upper-third tumors had the shortest. In the middle-third, the survival group demonstrated a notably greater margin compared with the NSG. These patterns are likely related to anatomical limitations and differences in surgical strategies depending on tumor location. For upper-third tumors, the surrounding anatomy may limit the ability to secure an extensive proximal margin. In contrast, the longer margins observed in middle-third survivors may indicate more extensive resections in this subgroup. In lower-third tumors, the tumor location seems to offer surgeons more flexibility in performing additional proximal resections when needed.
Survival analysis
Kaplan-Meier curves for overall survival (OS) and disease-free survival (DFS) demonstrated a clear separation among the three TNM stages (Fig. 3). The 5-year OS rates were 95.7% for stage I, 56.6% for stage II, and 32.9% for stage III disease. The median OS was not reached for stage I and II, whereas it was 20.3 months (95% CI, 13.1–35.8) for stage III. RMST was 58.2 months (95% CI, 56.8–59.6) for stage I, 49.3 months (95% CI, 44.7–53.8) for stage II, and 34.6 months (95% CI, 30.2–39.0) for stage III. Pairwise log-rank tests indicated significantly longer OS in lower stages (P<0.001).
For DFS, stage I patients experienced no recurrences during the follow-up period (not reached). The 5-year DFS rates were 69.7% for stage II and 29.5% for stage III disease. The median DFS was not reached for stage II and 15.7 months (95% CI, 11.4–28.6) for stage III. The RMST was 58.9 months (95% CI, 57.7–60.0) for stage I, 51.2 months (95% CI, 46.9–55.5) for stage II, and 32.4 months (95% CI, 28.1–36.7) for stage III. DFS was significantly worse in higher stages (P<0.001).
In the univariate Cox proportional hazards regression analysis (Table 4), several clinicopathologic factors, including BMI (HR, 0.91; 95% CI, 0.83–0.99; P=0.033), total gastrectomy (HR, 2.14; 95% CI, 1.15–3.98; P=0.016), LVI (HR, 2.90; 95% CI, 1.40–6.03; P=0.004), PNI (HR, 7.28; 95% CI, 2.60–20.36; P<0.001), TNM stage, and resectability were significantly associated with OS. However, in the multivariate model, only TNM stage (stage II: HR, 9.97; 95% CI, 1.21–81.86; P=0.032; stage III: HR, 26.94; 95% CI, 3.68–197.03; P=0.001) and R1 resection (HR, 2.67; 95% CI, 1.44–4.94; P=0.002) remained independent prognostic factors for OS.
Subgroup analysis
Kaplan-Meier curves for OS and DFS according to the four risk groups are shown in Fig. 4, respectively. Median survival for OS was not reached in Group 1, but was 59.3 months in Group 2, 39.4 months in Group 3, and 11.7 months in Group 4. For DFS, the median was not reached in Groups 1 and 2, whereas Groups 3 and 4 showed median DFS of 28.6 and 11.5 months, respectively.
RMST for OS was 55.66 months (95% CI, 51.22–58.82) in Group 1, 40.94 months (95% CI, 27.93–52.95) in Group 2, 36.90 months (95% CI, 30.83–43.15) in Group 3, and 18.43 months (95% CI, 9.64–29.22) in Group 4. For DFS, RMST was 57.50 months (95% CI, 53.58–60.00) in Group 1, 41.00 months (95% CI, 24.90–60.00) in Group 2, 29.18 months (95% CI, 23.19–35.66) in Group 3, and 18.95 months (95% CI, 7.48–32.49) in Group 4.
Both OS and DFS showed a stepwise decrease across increasing risk groups (log-rank P<0.001 for both), supporting the prognostic relevance of the predefined stratification (Fig. 4).
Clinical outcome of patients with Anvil site negative without additional resection
Table 5 summarizes the outcomes of patients who had positive IFS but no additional resection, and whose resected anvil rings were later confirmed to be tumor-negative on final pathology. Among nine such patients, eight survived without recurrence, while one patient died during follow-up.
In most cases, the decision not to perform further resection was due to anatomical limitations, especially during total gastrectomy, where securing an additional margin within the abdominal cavity is technically challenging. In other cases, the decision reflected patient or guardian preferences against surgical extension, particularly in early-stage disease.
Patient No. 25, the only fatal case, had stage IIIC (T4aN3) disease with a large tumor (11.0×8.5 cm) and highly aggressive histologic features (poorly-differentiated tubular adenocarcinoma with diffuse-type Lauren classification, LVI+, PNI+). Despite completing adjuvant chemotherapy with doxifluridine, the patient experienced recurrence at 11.2 months postoperatively and died at 14.3 months. In comparison, Patient No. 78 showed a similarly advanced stage and histological characteristics but received XELOX (apecitabine+oxaliplatin) chemotherapy and remains alive without recurrence at 16.6 months of follow-up.
DISCUSSION
This study is a single-center, retrospective cohort analysis that evaluated the long-term survival outcomes of patients with positive IFS margins during gastric cancer surgery. Among all surgical cases, IFS positivity occurred in approximately 3.5%, which has been variably reported in previous studies, ranging from 3.6% to 12.9% [5–7]. Watanabe et al. [8] reported that IFS assessment reduces the incidence of margin positivity and that patients who achieved negative margins through additional resection had survival rates comparable to those with negative IFS findings. Similarly, in our study, we observed that achieving an R0 resection after initial IFS positivity was associated with improved outcomes, whereas the R1 status was significantly more frequent in the mortality group. This finding confirms what many researchers have already demonstrated. Tu et al. [9] reported decreased 5-year survival in a large cohort of R1 patients (24.2% vs. 36.8%), and Guo et al. [10] confirmed a similar trend in patients with proximal gastric cancer (45.8% vs. 65.2%). In addition, a systematic review by Raziee et al. [11] emphasized that margin positivity exerts a particularly strong adverse effect on prognosis in early-stage disease. This observation is consistent with our findings, where R1 resection had a greater negative impact on survival in the low-risk group (stage I–II).
In this study, we intentionally excluded patients with distal (duodenal) margin positivity. Distal margin involvement often represents a distinct oncologic scenario, as it usually reflects direct invasion into the duodenum or pancreas. Such cases frequently require pancreatoduodenectomy or multivisceral resection, and their prognostic trajectories differ substantially from proximal margin-positive disease. Several studies have demonstrated that duodenal margin positivity is an independent adverse prognostic factor following gastrectomy for resectable gastric cancer [12,13]. Moreover, even when radical procedures such as pancreatoduodenectomy are performed, survival outcomes remain poor [14]. Therefore, by excluding distal IFS-positive cases, we sought to improve internal validity and minimize bias or confounding, allowing a clearer interpretation of the prognostic impact of proximal IFS positivity.
IFS positivity is a challenge frequently encountered by surgeons. The main causes of positive frozen sections during gastric cancer surgery include tumor biology, anatomical constraints, and limitations in both surgical and pathological techniques. For example, signet ring cell carcinoma, a diffuse-type gastric cancer, is well known to spread microscopically along the submucosa in the form of so-called skip lesions, which may extend to the resection margin unexpectedly. Because of this diffuse growth pattern, pathological interpretation is also difficult. In poorly cohesive carcinoma, including signet ring cell carcinoma, tumor cells are often subtle and may resemble inflammatory cells or stromal tissue, making frozen section diagnosis prone to oversight. As a result, discrepancies between frozen and permanent pathology are frequently observed in diffuse histology, and signet ring cell carcinoma in particular has been associated with higher false-negative rates [15].
IFS positivity is also more common at sites where securing an adequate margin is technically difficult, such as the esophagogastric junction or the duodenal margin. Tumors located at the esophagogastric junction are known to carry a higher risk of positive margins, and in female patients with diffuse-type tumors, studies have reported an increased incidence of positive distal (duodenal) margins [16]. Larger tumors, those with serosal invasion (T3–T4), and tumors with LVI are also associated with a higher likelihood of margin involvement [17]. Poorly-differentiated, high-grade tumors have similarly been linked with an increased frequency of positive margins [18]. From a diagnostic perspective, errors can occur because of specimen misorientation, inadequate sampling, or freezing artifacts, all of which may result in false-positive or false-negative findings. Reports have described cases of reoperation caused by frozen section misinterpretation, as well as unnecessary additional resections due to false-positive diagnoses [15]. These situations highlight the importance of close communication between the surgeon and the pathologist, along with a careful and individualized intraoperative strategy. The general principle is to perform additional resection to secure an R0 margin. However, in practice, additional resection is not always possible because of anatomical limitations, patient condition, tumor location, or histologic uncertainty.
Although Table 3 shows no significant difference in the rate of re-resection between the SG and NSG, this does not contradict the prognostic significance of achieving R0 resection. The absence of difference likely reflects that “no re-resection” does not necessarily indicate “R1 resection.” In the subgroup analysis (data not shown), R0 resection was consistently associated with superior survival in both re-resected and non–re-resected cohorts, suggesting that the prognostic advantage arises from complete tumor clearance rather than from the act of performing re-resection itself. These findings support that the key determinant of long-term outcome is not whether re-resection was performed, but whether complete (R0) resection was ultimately achieved.
As shown in Fig. 1, among the 34 patients who did not undergo additional resection, 22 (22/34, 64.7%) were confirmed to have R0 resection on final pathology. These cases included five cases of atypia, one adenoma, seven negative margins from anvil ring specimens, and nine cases where frozen positivity was attributed to technical errors.
Many patients with negative anvil ring margins were early-stage cases and achieved long-term recurrence-free survival. Most of these cases involved total gastrectomy, where further resection would have extended into the thoracic cavity. In total gastrectomy, once the anvil is inserted into the esophagus and transected, the distal esophagus is removed in a ring-shaped segment that can be submitted for frozen section as a proximal margin. Even if the margin is reported negative, the actual clearance is minimal, and oncologic safety cannot be fully guaranteed. This method should therefore be used selectively depending on the patient’s condition. In distal gastrectomy, the anvil ring is generally inappropriate as a proximal margin, although in a few unexpected situations it was applied. For instance, in case number 38, preoperative endoscopy suggested only mucosal invasion, but adenocarcinoma was confirmed on first and second frozen sections. Because the guardians did not consent to further resection, the anvil ring and additional remnant gastric margin were tested and reported negative on frozen section. The final pathology, however, revealed advanced gastric cancer staged as T2N1, Borrmann type IV, with a positive proximal margin (R1). The patient subsequently received TS-1 adjuvant chemotherapy and remains alive without recurrence at 103.3 months of follow-up. Nevertheless, the lack of clinical evidence and systematic analysis makes these outcomes difficult to draw firm conclusions from our study alone, and further evidence is required.
In gastric cancer with pathologic high-risk features such as LVI, PNI, or poor differentiation, even after achieving an R0 curative gastrectomy, the risk of recurrence remains significantly elevated. For example, Yu et al. [19] reported that in stage IB gastric cancer, LVI-positive patients had markedly lower 5-year disease-specific survival rates 89.3% compared to 96.8% in LVI negative patients. PNI, in particular, has been identified as an independent prognostic factor for early recurrence and OS, leading to the recommendation that patients with PNI-positive status should undergo more intensive postoperative surveillance [20]. Moreover, even when standard D2 R0 resection is achieved, the local recurrence rate has been reported to range between 20% and 40%, suggesting that margin negativity alone may be insufficient for some high-risk patients [21]. In our study cohort, both LVI and PNI were numerically more frequent in the mortality group. These factors emerged as strong prognostic markers in univariate Cox models, yet they lost significance in multivariate analysis, likely due to limited statistical power from a small sample size.
As mentioned earlier, microscopically positive margins (R1) are well known to markedly worsen prognosis. Therefore, major guidelines emphasize achieving R0 resection whenever possible. Specifically, the National Comprehensive Cancer Network (NCCN) guideline recommends securing at least a 4 cm gross resection margin from the visible tumor edge [22]. The European Society for Medical Oncology (ESMO) guideline advises proximal margins of 3 cm for expansive growth patterns and 5 cm for infiltrative growth patterns [23]. The JGCA guideline further refines this by tumor growth pattern, recommending a proximal margin of at least 3 cm for expansive tumors and at least 5 cm for infiltrative tumors. It also mandates frozen section confirmation when these distances are difficult to achieve [24]. However, these numerical margin guidelines aim only to ensure R0 status. They do not directly guarantee improved survival. In fact, Berlth et al. [25] demonstrated that in advanced gastric cancer, achieving a minimum 3 cm proximal margin with negative frozen section effectively prevented R1 resection, but extending the margin beyond 3 cm in R0 patients did not confer additional benefits in survival or recurrence rates.
Lee et al. [26], in their large study of 1,788 gastric cancer patients, demonstrated that when R0 resection was achieved, proximal and distal margin length did not affect prognosis. Similarly, Kim et al. [27] reported that proximal margin length was not associated with survival outcomes in 1,518 patients undergoing gastrectomy for advanced gastric cancer. Recent multicenter meta-analyses have further suggested that the survival benefit of extending resection margins in advanced gastric cancer is limited, and that the absence of microscopic residual tumor (achieving R0) is a more critical determinant of prognosis than the absolute margin length [28]. In our study, there was no significant difference in proximal margin length between the SG and NSG, and it was not identified as an independent prognostic factor. However, given that all patients in this cohort were margin-positive on IFS, it should be noted that accurate evaluation of margin length may have been compromised when additional resection was performed.
In the survival analysis, the significant differences in OS and DFS according to TNM stage confirmed that tumor stage itself is the most powerful prognostic factor. In the univariate analysis, several factors showed significant associations with prognosis, such as BMI, total gastrectomy, LVI, PNI, stage, and resectability. However, in the multivariate analysis, only stage and resectability remained significant.
It is possible that inherent risk factors could not be fully identified due to the small number of cases. Nonetheless, as demonstrated in the subgroup analysis, even among patients with positive IFS margins, those in the low-risk group (stage I/II) who achieved R0 resection showed the most favorable outcomes. Conversely, low-risk patients who underwent R1 resection had worse outcomes than high-risk patients (stage III/IV) who achieved R0 resection. In a multicenter study by Squires et al. [7], it was reported that even when additional resection secured negative margins (R0) after a positive proximal margin was identified on IFS, there was no improvement in OS compared to cases without additional resection. The only difference was a reduction in local recurrence. This suggests that in advanced gastric cancer, survival may be more influenced by other prognostic factors, such as tumor stage, rather than margin status alone. However, this remains a subject of debate [14,29]. In our study as well, although the effect was less pronounced than in the low-risk group, R0 resection still demonstrated better outcomes than R1 resection in the high-risk group. Previous studies have consistently emphasized that microscopic residual tumor (R1 resection) is associated with poor prognosis, reinforcing that achieving complete resection (R0) whenever possible is crucial for improving long-term survival [30].
This study has several limitations. First, as a retrospective single-cohort study conducted at a single institution, it did not include a comparison group of patients with negative IFS results, limiting the ability to identify factors influencing IFS positivity. The retrospective design introduces potential selection and information biases, and the relatively small number of cases in the overall cohort and certain subgroups (e.g., R1 resection, stage III) may have reduced statistical power, potentially obscuring significant prognostic factors in multivariate analysis. Second, some discrepancies between IFS and final pathology were observed, but this study was limited in its ability to analyze the underlying causes, such as histologic ambiguity or sampling errors. Third, despite heterogeneity in adjuvant chemotherapy regimens and strategies, their differential impact on survival could not be thoroughly evaluated. Lastly, although univariate analysis identified pathological high-risk features such as LVI and PNI, we did not construct a predictive model that integrates these factors. Nevertheless, this study provides meaningful clinical insights into long-term outcomes in patients with positive IFS margins based on real-world data. Notably, the use of RMST allowed for long-term survival estimation even in groups where median survival was not reached, offering a quantitative advantage over conventional measures such as median survival or 5-year survival rates used in prior studies.
In conclusion, margin length was not associated with survival outcomes in patients with IFS-positive proximal margins, whereas TNM stage and R0 resection status were identified as the most significant prognostic factors. These results emphasize that whenever technically feasible, additional resection to achieve R0 should be pursued, as this remains the strongest determinant of long-term survival. When further resection is not possible, outcomes may be driven primarily by tumor stage rather than by the absolute margin length. Although we describe a few exceptional cases with negative margin in anvil ring, these were presented for reference only and their clinical impact remains still uncertain. Overall, this study provides practical, real-world evidence to inform intraoperative decision-making in this challenging scenario of IFS-positive proximal margins. But multicenter studies with well-controlled cohorts are needed to refine management strategies of these cases.
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