Abstract
Background/Aim
The incidence of positive microscopic margins after gastrectomy for gastric cancer (GC) has been reported between 1% to 5%. The aim of the present study was to identify risk factors associated with positive microscopic resection margin in GC patients undergoing gastrectomy, and to assess the survival outcomes and prognostic factors in these patients.
Patients and Methods
The patients were selected from the consecutive database of Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Department of Gastric Surgery, according to the following criteria: (i) histologically proven gastric adenocarcinoma (ii) patients who underwent curative gastrectomy for gastric cancer as a primary treatment and archived R0 or R1 resection between 2005 and 2025. Positive microscopic resection margin was defined as disease present at the line of luminal transaction in mucosa, submucosa, or serosa on final pathology. Univariate and multivariate logistic regression analyses were performed to identify risk factors for resection margin positivity.
Results
A total of 1,996 patients were eligible for the present study. Among these patients, 35 patients (1.8%) had positive microscopic resection margin. Pathological type, macroscopic tumor type, and tumor size were identified as independent risk factors for positive resection margin in multivariate analysis. Moreover, positive peritoneal lavage cytology was identified as an independent predictor of poor overall survival prognostic factor in margin-positive GC patients.
Conclusion
Microscopic resection margin positivity after gastrectomy for GC was linked to specific tumor characteristics, while positive peritoneal lavage cytology independently predicted poorer survival. To minimize the occurrence of resection margin-positive GC after gastrectomy, it is essential to identify risk factors during perioperative evaluation. Furthermore, treatment strategies based on lavage cytology status could improve prognosis in high-risk patients.
Keywords: Gastric cancer, risk factors, prognostic factors, overall survival, positive resection margin
Introduction
Gastric cancer (GC) is the fifth most prevalent cancer and fourth leading cause of cancer-related death worldwide (1, 2). The standard treatment for resectable GC is gastrectomy with lymph node dissection with or without perioperative adjuvant treatment (3, 4). Achieving a negative microscopic resection margin at both proximal (oral) and distal (anal) sides of the specimen is crucial. Nevertheless, despite careful surgical technique, resection margin positivity still occurs. Previous studies have demonstrated an incidence of microscopic positive margins ranging between 1% and 5% (5-7). To prevent this, it is necessary to identify preoperative risk factors for microscopic margin positivity. However, there are limited studies that have evaluated such risk factors in GC (8-10).
Microscopic resection margin positivity has been associated with significantly poorer survival compared to margin-negative GC, due to an increased incidence of locoregional recurrence (11-13). However, the survival outcomes, recurrence and prognostic factors of GC with positive microscopic resection margins have not been sufficiently evaluated. Identification of specific risk and prognostic factors for this condition would enable more informed decision-making and improved management for these patients.
The aim of this study was therefore to identify risk factors for positive microscopic margins in GC and to clarify the associated survival outcomes and prognostic factors. Our findings provide insight into the clinical features of GC with positive resection margins and support the establishment of more effective management and treatment strategies.
Patients and Methods
Patients. The patients were selected from the consecutive database of Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Department of Gastric Surgery, Tokyo, Japan, according to the following criteria: (i) histologically proven gastric adenocarcinoma, (ii) patients who underwent curative gastrectomy for gastric cancer as a primary treatment and archived R0 or R1 resection between 2005 and 2025. We excluded the patients who archived R2 resection.
Surgical procedures and adjuvant chemotherapy. In principle, all patients underwent distal, proximal, or total gastrectomy with nodal dissection for GC. D1 or D1+ lymphadenectomy was indicated for cT1N0 tumors, while D2 for cN+ or cT2-T4 tumors, regardless of the surgical approach. Spleen-preserving D2 total gastrectomy was allowed in this study (14). GC patients with pathological stage II disease were treated with S-1 monotherapy, while those with pathological stage III disease were treated with S-1 plus docetaxel or capecitabine plus oxaliplatin (15-17).
Definition of resection margin positive. Microscopic resection margin positivity was defined as disease present at the line of luminal transaction in mucosa, submucosa, or serosa on final pathology. Patients who had positive frozen section margins but achieved negative margins after further resection were classified as a margin-negative.
Patient follow-up. After surgery, patient follow-up included physical examinations and hematological tests every 3-12 months for 5 years. Tumor marker levels, such as carcinoembryonic antigen and CA19-9, were measured at every follow-up visit. Computed tomography (CT) was performed every 6-12 months for 5 years. Endoscopy was performed 1, 3, and 5 years after surgery.
Evaluation and statistical analysis. The progression of tumors was evaluated according to the 15th edition of the Japanese Gastric Cancer Classification. Differences between the resection margin-positive group and resection margin-negative group were analyzed using the χ2 test and the Mann-Whitney U test. Univariate and multivariate logistic regression analyses were performed to identify risk factors for resection margin positivity. In the multivariate analysis, we fitted linear regression models, and we used backward elimination for model selection. Overall survival (OS) curves were calculated by the Kaplan-Meier method and were compared using the log-rank test. Univariate and multivariate survival analyses were conducted using a Cox proportional hazards model. Statistical significance was defined as p<0.05. All statistical analyses were conducted using SPSS (v27.0 J Win; SPSS, Chicago, IL, USA). This study was approved by the IRB of the Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital.
Results
Comparison of baseline characteristics of the patients and survival between the microscopic resection margin-positive and microscopic resection margin-negative groups. A total of 1,996 patients were eligible for the present study. Mean age was 69 years (SD=3). Male patients were 1,371 patients (68.6%) and female were 625 patients (31.4%). Distal gastrectomy was performed 1,315 (65.8%), total gastrectomy was 523 (26.2%), and proximal gastrectomy was 158 (8.0%). The conventional approach was 981 (49.1%) and laparoscopic or robotic approach was 1,015 (50.9%). In the resection status, 1,837 (92.0%) patients archived R0 resection, and 159 (8.0%) patients archived R1 resection. Among 1,996 patients, 35 (1.8%) were microscopic resection margin positive.
When comparing the baseline characteristics between the microscopic resection margin-positive group (n=35) and the margin-negative group (n=1,961), the former exhibited a higher clinical T stage (p<0.001), greater incidence of positive lymph node involvement, a higher proportion of macroscopic type of type 3 and type 4 tumors (p<0.001), and a higher incidence of diffuse type histology (p<0.001), indicating a more aggressive clinical tumor stage (Table I).
Table I. Comparison of baseline characteristics between gastric cancer patients with microscopic resection margin positive and microscopic resection margin negative after gastrectomy.
SD: Standard deviation. *Mean±SD. #Median (range). Statistically significant p-values are shown in bold.
The surgical and pathological findings of the two groups are presented in Table II. The microscopic resection margin–positive group was characterized by more aggressive pathological features, including higher tumor stage (p<0.001), higher incidence of positive lymph node status (p<0.001), higher incidence of positive lavage cytology (p<0.001), and larger tumor size (p<0.001).
Table II. Comparison of surgical and pathological findings between patients with positive and negative microscopic resection margins.
*Median (range). Statistically significant p-values are shown in bold.
Kaplan-Meier curves forOS of microscopic resection margin–positive and margin-negative GC patients are shown in Figure 1. The three- and five- year OS were 38.1% and 33.3%, respectively, in the microscopic margin-positive group, compared with 86.3% and 82.0% in margin-negative group. These differences in OS were statistically significant (p<0.001).
Figure 1.
Comparison overall survival between patients with microscopically positive and negative resection margins.
Risk factor analysis for microscopic resection margin positivity after gastrectomy. The risk factor analysis for microscopic resection margin positive after gastrectomy is presented in Table III. In univariate analyses, clinical T stage, clinical N stage, pathological type, microscopic tumor type, and tumor size were identified as risk factors (all p<0.001). In the multivariate analysis, pathological type [odds ratio (OR)=2.217, 95% confidence interval (CI)=1.002-4.907, p=0.049], macroscopic tumor type (OR=3.945, 95% CI=1.738-8.952, p=0.001), and tumor size (OR=9.285, 95% CI=2.103-40.911, p=0.003) emerged as independent risk factors for microscopic resection margin positive after gastrectomy.
Table III. Risk factor analysis for microscopic resection margin positivity after gastrectomy.
Statistically significant p-values are shown in bold.
Treatment for microscopic resection margin positive GC after gastrectomy and recurrence pattern. Among 35 patients, 4 underwent additional surgery and 11 received chemotherapy. The remaining 20 patients were followed up in outpatient clinic and did not receive any additional treatment. Among these 20 patients, 6 did not receive further therapy due to old age, 4 due to early recurrence, and 10 due to patient preference. Recurrence was observed in 20 patients. Among these, 13 had peritoneal, 5 had hematogenous, 3 were lymph node recurrence (including overlapping cases). There were no local recurrence patients.
Survival analysis of resection margin positive patients. Table IV shows the prognostic factor analysis for patients with microscopic resection margin positive GC. Both univariate and multivariate analyses for OS demonstrated that lavage cytology status was an independent prognostic factor for OS [hazard ratio (HR)=11.087, 95% CI=3.644-33.735, p<0.001] in GC patients with positive resection margin. One-, three-, and five- year OS rates were 27.3%, 0%, and 0% in lavage cytology positive group, while the rates in lavage cytology negative group were 87.0%, 54.2%, and 46.4%, respectively (p<0.001) (Figure 2).
Table IV. Prognostic factor analysis for overall survival in patients with gastric cancer and positive resection margins.
Figure 2.
Overall survival of margin-positive gastric cancer patients according to peritoneal lavage cytology.
Discussion
The aim of this study was to characterize the clinical features of resection margin-positive GC and to evaluate its clinical impact on patients who underwent gastrectomy. The main findings demonstrated that the pathological type, macroscopic tumor type, and tumor size were independent risk factors for positive resection margins in GC patients. Additionally, lavage cytology status was identified as an independent prognostic factor for patients with resection margin-positive GC.
In the present study, GC patients with positive resection margins had more aggressive disease characteristics, including advanced T and N stages, a higher incidence of histologically undifferentiated type and macroscopic type 3/4 tumors, and lager tumor size, compared to those with negative resection margin. Similar results were observed in the previous studies. Nakanishi et al. evaluated the prognostic impact of microscopic resection margin in 3,029 GC patients who underwent gastrectomy and identified 32 (1.1%) patients with positive margins (18). Similarly, Sun et al. examined the prognostic impact of microscopic positive margins in 2,269 GC patients after potentially curative resection (19). In their study, 110 (4.8%) patients had positive resection margin, and were characterized with a greater incidence of macroscopic type 4, undifferentiated histology, larger tumor size, and higher pathological stage, compared to the margin-negative patients. In addition, they identified tumor size, pathological T stage, and pathological N stage as independent factors associated with microscopic margin positivity. In line with these findings, our study demonstrated that pathological type, macroscopic tumor type, and tumor size were independent risk factors for microscopic margin positivity. Taken together, the present findings and previous evidence support that specific clinicopathological characteristics of GC patients may serve as predictors of microscopic resection margin positivity. Hence, attention should be paid to the risk of microscopic margin positivity in cases presenting these features.
Second, we examined potential prognostic factors and recurrence patterns of microscopic resection margin-positive GC. In the present study, positive lavage cytology and positive microscopic resection margin were identified as independent prognostic factors for poorer OS. Considering both our findings and previous evidence, patients with microscopic margin positivity in combination with other poor prognostic risk factors may have particularly poor outcomes. However, data on prognostic factors associated with microscopically positive resection margins following gastrectomy are limited. Therefore, further studies are needed to identify additional factors.
In addition, in the present study, we did not observe an increased incidence of locoregional recurrence in margin-positive patients. In contrast, previous studies have demonstrated that microscopically positive resection margin GC was associated with higher local recurrence rates (7). This discrepancy may be due to differences in cohort size, follow-up methodology, and/or the proportion of positive resection margin cases. Therefore, future studies are needed to clarify whether microscopic resection margin status affects recurrence patterns.
Study limitations. The present study has several limitations that should be acknowledged. First, its retrospective, single-center design may have introduced selection bias. Second, there may be time-related bias due to the long duration of the study, from 2005 to 2025. During this period, treatment strategies for GC were changed. In the resectable setting, several adjuvant treatments were introduced as results of pivotal phase III clinical trial (15-17). Moreover, in the advanced/unresectable setting, immune-check point inhibitors were also introduced in the treatment strategies (18, 19). Thus, the clinical impact of a microscopic resection margin may have been influenced by changes in treatment approaches. Although validation using another cohort is needed, our study included more than 2,000 GC cases with an incidence of microscopically positive resection margins of 1.8%, which is in line with other large cohort studies (5-7). Hence, despite the limitations, our findings provide clinically relevant insights into the management of GC patients with positive resection margin.
Conclusion
Pathological type, macroscopic tumor type, and tumor size were identified as independent risk factors for microscopically positive resection margin in GC following gastrectomy. In addition, positive peritoneal lavage cytology independently predicted poorer OS in margin-positive patients. To optimize the management of GC patients with microscopic margin positivity, it is necessary to identify these risk factors and integrate them into clinical decision-making.
Conflicts of Interest
The Authors declare no conflicts of interest associated with the present study.
Authors’ Contributions
TA and HC made substantial contributions to the conception and design. TA, HC, KH and HS made substantial contributions to the acquisition of data, or the analysis and interpretation of data. TA and HC were involved in drafting the manuscript or revising it critically for important intellectual content. Each Author participated sufficiently in the work to take public responsibility for appropriate portions of the content; and agreed to be 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. All Authors gave final approval for the final manuscript to be published.
Acknowledgements
The Authors express her sincere gratitude to Ms. Emiko Saito for her excellent data management in this study.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
References
- 1.Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi: 10.3322/caac.21660. [DOI] [PubMed] [Google Scholar]
- 2.Filho AM, Laversanne M, Ferlay J, Colombet M, Piñeros M, Znaor A, Parkin DM, Soerjomata-ram I, Bray F. The GLOBOCAN 2022 cancer estimates: Data sources, methods, and a snapshot of the cancer burden worldwide. Int J Cancer. 2025;156(7):1336–1346. doi: 10.1002/ijc.35278. [DOI] [PubMed] [Google Scholar]
- 3.Ajani JA, D'Amico TA, Bentrem DJ, Chao J, Cooke D, Corvera C, Das P, Enzinger PC, Enzler T, Fanta P, Farjah F, Gerdes H, Gibson MK, Hochwald S, Hofstetter WL, Ilson DH, Keswani RN, Kim S, Kleinberg LR, Klempner SJ, Lacy J, Ly QP, Matkowskyj KA, McNamara M, Mulcahy MF, Outlaw D, Park H, Perry KA, Pimiento J, Poultsides GA, Reznik S, Roses RE, Strong VE, Su S, Wang HL, Wiesner G, Willett CG, Yakoub D, Yoon H, McMillian N, Pluchino LA. Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(2):167–192. doi: 10.6004/jnccn.2022.0008. [DOI] [PubMed] [Google Scholar]
- 4.Lordick F, Carneiro F, Cascinu S, Fleitas T, Haustermans K, Piessen G, Vogel A, Smyth EC, ESMO Guidelines Committee Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(10):1005–1020. doi: 10.1016/j.annonc.2022.07.004. [DOI] [PubMed] [Google Scholar]
- 5.Morgagni P, Garcea D, Marrelli D, De Manzoni G, Natalini G, Kurihara H, Marchet A, Saragoni L, Scarpi E, Pedrazzani C, Di Leo A, De Santis F, Panizzo V, Nitti D, Roviello F. Resection line involvement after gastric cancer surgery: clinical outcome in nonsurgically retreated patients. World J Surg. 2008;32(12):2661–2667. doi: 10.1007/s00268-008-9747-x. [DOI] [PubMed] [Google Scholar]
- 6.Spicer J, Benay C, Lee L, Rousseau M, Andalib A, Kushner Y, Marcus V, Ferri L. Diagnostic accuracy and utility of intraoperative microscopic margin analysis of gastric and esophageal adeno-carcinoma. Ann Surg Oncol. 2014;21(8):2580–2586. doi: 10.1245/s10434-014-3669-7. [DOI] [PubMed] [Google Scholar]
- 7.Cho BC, Jeung HC, Choi HJ, Rha SY, Hyung WJ, Cheong JH, Noh SH, Chung HC. Prognostic impact of resection margin involvement after extended (D2/D3) gastrectomy for advanced gastric cancer: A 15-year experience at a single institute. J Surg Oncol. 2007;95(6):461–468. doi: 10.1002/jso.20731. [DOI] [PubMed] [Google Scholar]
- 8.Aurello P, Magistri P, Nigri G, Petrucciani N, Novi L, Antolino L, D'Angelo F, Ramacciato G. Surgical management of microscopic positive resection margin after gastrectomy for gastric cancer: a systematic review of gastric R1 management. Anticancer Res. 2014;34:6283–6288. [PubMed] [Google Scholar]
- 9.Guha A, Sahewalla A, Killing D, Thakkar M, Das G, Kalita DJ, Talukdar A. Real-world experience of clinical outcomes of microscopic margin positivity after radical gastrectomy from a tertiary cancer center in Northeast India. Indian J Surg Oncol. 2025;16(1):290–295. doi: 10.1007/s13193-024-02081-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Guo Z, Wang N, Zhao G, Cui C, Liu F. Risk factors and prognostic analysis of microscopic positive esophageal margins after radical surgery for proximal gastric cancer. BMC Gastroenterol. 2024;24(1):433. doi: 10.1186/s12876-024-03527-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Liang Y, Ding X, Wang X, Wang B, Deng J, Zhang L, Liang H. Prognostic value of surgical margin status in gastric cancer patients. ANZ J Surg. 2015;85(9):678–684. doi: 10.1111/ans.12515. [DOI] [PubMed] [Google Scholar]
- 12.Wang SY, Yeh CN, Lee HL, Liu YY, Chao TC, Hwang TL, Jan YY, Chen MF. Clinical impact of positive surgical margin status on gastric cancer patients undergoing gastrectomy. Ann Surg Oncol. 2009;16(10):2738–2743. doi: 10.1245/s10434-009-0616-0. [DOI] [PubMed] [Google Scholar]
- 13.Kumazu Y, Hayashi T, Yoshikawa T, Yamada T, Hara K, Shimoda Y, Nakazono M, Nagasawa S, Shiozawa M, Morinaga S, Rino Y, Masuda M, Ogata T, Oshima T. Risk factors analysis and stratification for microscopically positive resection margin in gastric cancer patients. BMC Surg. 2020;20(1):95. doi: 10.1186/s12893-020-00744-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Japanese Gastric Cancer Association Japanese Gastric Cancer Treatment Guidelines 2021 (6th edition) Gastric Cancer. 2023;26(1):1–25. doi: 10.1007/s10120-022-01331-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K, ACTS-GC Group Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007;357(18):1810–1820. doi: 10.1056/NEJMoa072252. [DOI] [PubMed] [Google Scholar]
- 16.Yoshida K, Kodera Y, Kochi M, Ichikawa W, Kakeji Y, Sano T, Nagao N, Takahashi M, Takagane A, Watanabe T, Kaji M, Okitsu H, Nomura T, Matsui T, Yoshikawa T, Matsuyama J, Yamada M, Ito S, Takeuchi M, Fujii M. Addition of docetaxel to oral fluoropyrimidine improves efficacy in patients with stage III gastric cancer: interim analysis of JACCRO GC-07, a randomized controlled trial. J Clin Oncol. 2019;37(15):1296–1304. doi: 10.1200/JCO.18.01138. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, Lee KW, Kim YH, Noh SI, Cho JY, Mok YJ, Kim YH, Ji J, Yeh TS, Button P, Sirzén F, Noh SH, CLASSIC trial investigators Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012;379(9813):315–321. doi: 10.1016/S0140-6736(11)61873-4. [DOI] [PubMed] [Google Scholar]
- 18.Nakanishi K, Kanda M, Ito S, Mochizuki Y, Teramoto H, Ishigure K, Murai T, Asada T, Ishiyama A, Matsushita H, Shimizu D, Tanaka C, Fujiwara M, Murotani K, Kodera Y. Prognostic impact of a microscopic positive margin in patients undergoing gastrectomy for gastric cancer: a propensity score-matched analysis of a multi-institutional dataset. Surg Today. 2022;52(4):559–566. doi: 10.1007/s00595-021-02365-8. [DOI] [PubMed] [Google Scholar]
- 19.Sun Z, Li DM, Wang ZN, Huang BJ, Xu Y, Li K, Xu HM. Prognostic significance of microscopic positive margins for gastric cancer patients with potentially curative resection. Ann Surg Oncol. 2009;16(11):3028–3037. doi: 10.1245/s10434-009-0624-0. [DOI] [PubMed] [Google Scholar]
- 20.Bickenbach KA, Gonen M, Strong V, Brennan MF, Coit DG. Association of positive transection margins with gastric cancer survival and local recurrence. Ann Surg Oncol. 2013;20(8):2663–2668. doi: 10.1245/s10434-013-2950-5. [DOI] [PubMed] [Google Scholar]