Prognostic value of lymphovascular and perineural invasion in stage II gastric cancer patients

Prognostic value of lymphovascular and perineural invasion in stage II gastric cancer patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Prognostic value of lymphovascular and perineural invasion in stage II gastric cancer patients Yao Cen, Yuanyuan Li, Yugang Wu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6889639/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Lymphovascular invasion(LVI) refers to the presence of cancer cells in lymphatic vessels or blood vessels. Perineural invasion (PNI) is the process of neoplastic invasion of peripheral nerves. The purpose of this study is to explore the prognostic value of stage II gastric cancer patients with LVI and PNI. Methods Of the 554 patients with gastric cancer at stage II, 103 had been examined for LVI and 95 had been examined for PNI. LVI and PNI were assessed through hematoxylin and eosin (HE) staining. Survival outcomes were evaluated using the Kaplan-Meier method, with statistical significance determined by the log-rank test. To identify prognostic factors, both univariate and multivariate analyses were conducted, employing the Cox proportional hazards regression model. Results The LVI status was associated with pT stage, pN stage, serum carcinoembryonic antigen (CEA) levels and tumor size. The PNI status was associated with pT stage, pN stage and serum CEA levels. The 5-year overall survival (OS) rate and the 5-year disease-free survival (DFS) rate of the LVI- group were greater than the LVI + group. Similarly, the 5-year OS rate and the 5-year DFS rate of the PNI- group were greater than the PNI + group. Multivariate analyses showed that pT-stage, LVI, PNI and serum CEA level were significant prognostic factors for stage II GC patients. Conclusions LVI and PNI can reduce the 5-year OS and DFS of stage II gastric cancer patients. The impact of LVI and PNI should be considered when considering the prognosis of stage II patients in clinical practice. In the meantime, we need more effective adjuvant chemotherapy for stage II patients with LVI and PNI. Gastric cancer Lymphovascular infiltration Perineural invasion Prognostic factors Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Gastric cancer (GC) is the fifth most common cancer and is also the fifth cause leading to cancer-related deaths in the world [ 1 ] . Although the treatment of gastric cancer has progressed with early detection, the survival rate of gastric cancer remains low worldwide [ 2 ] . The low survival rate of gastric cancer is mainly due to factors such as the delayed detection of the disease, the malignancy of the cancer, the limitations of treatment, and the living habits of patients. People tend to pay less attention to the treatment of relatively early gastric cancer. Accordingly, even after curative surgery and adequate lymph node dissection, survival rates for gastric cancer remain low [ 3 ] . Established clinicopathological prognostic factors in gastric cancer include the Tumor-Node-Metastasis (TNM) staging system, lymphovascular invasion (LVI), tumor differentiation grade, and molecular biomarkers, all of which significantly influence disease outcomes [ 4 ] . However, there are still many important prognostic risk factors that need to be detected clinically, such as perineural invasion (PNI) [ 5 ] . Lymphovascular invasion is histologically defined as the presence of malignant cells within either lymphatic channels or vascular structures, representing active tumor dissemination. [ 4 ] (Fig. 1 ). Numerous studies have shown that gastric cancer patients with vascular invasion have a poorer prognosis [ 6 ] . Perineural invasion (PNI) describes the infiltration of tumor cells into nerves, characterized by either their presence within the perineurium, endoneurium, or epineurium (the three layers of the peripheral nerve sheath) or in close proximity to nerve structures. [ 7 ] (Fig. 2 ). Similar to the poorer prognosis caused by LVI, it has been shown that PNI also leads to a poorer prognosis in gastric cancer patients and can even lead to tumor recurrence [ 5 , 8 , 9 ] . LVI and PNI are important metastatic routes for gastric cancer [ 10 ] . Meanwhile, most gastric cancer patients die due to cancer recurrence or metastasis [ 11 ] . Although the guidelines clearly recommend chemotherapy for stage II-IV patients, in actual clinical practice, there are many patients with earlier staging who neglect the importance of adjuvant therapy [ 12 ] . For example, some stage II patients who don't have lymph node metastases always refuse adjuvant chemotherapy, but it is possible that they have LVI and PNI. A number of studies have suggested that vascular and nerve invasion might promote cancer metastasis and recurrence in different tumors [ 13 – 17 ] . This study investigated whether LVI and PNI affect overall survival and disease-free survival of stage II gastric cancer. Meanwhile, early diagnosis of recurrence and metastasis as well as timely therapeutic intervention are very important. Therefore, in this article, we investigated the clinical features associated with LVI and PNI as well as prognostic factors. Materials and methods Patients In this study, we included totally 1392 patients from the Third Affiliated Hospital of Soochow University between December 2011 to June 2013. The inclusion criteria were as follows: all patients enrolled in this study had received curative resection with lymphadenectomy, they all be histologically confirmed as adenocarcinoma of the stomach. The exclusion were as follows: patients who had received neoadjuvant chemoradiation; patients whose clinicopathologic records were incomplete, patients who lost to follow-up, patients who had distant metastases or received palliative operation. Gastric cancer (GC) staging was determined based on the 8th edition AJCC TNM classification system. Patient follow-up was conducted via telephone interviews or clinical outpatient evaluations. This study received ethical approval from the Institutional Review Board of the Third Affiliated Hospital of Soochow University. Data collection and Histopathological evaluation We examined patient medical records to obtain their clinicopathologic characteristics included sex, age, LVI, tumor size, PNI, TNM stage, ELNs, serum CEA and so on. Surgical specimens were fixed in formalin and then they were embedded in paraffin. The specimens were cut into 5-mm-thick longitudinal whole tissue section and stained with hematoxylin-eosin (HE). All histological sections were reviewed by a minimum of two experienced pathologists, each conducting independent assessments of PNI and LVI. Determination of vascular invasion was made primarily by the following signs: presence of tumor cells in the vessel, infiltration of tumor cells into the perivascular tissue, and impairment of the vascular endothelial barrier.Pathologic diagnostic criteria for nerve invasion are primarily infiltration of tumor cells along the nerve fascicle membrane into the nerve sheaths. Statistical analysis All statistical analyses were conducted using GraphPad Prism version 10.0 (GraphPad Software, San Diego, CA, USA). The association between PNI, LVI and clinicopathologic characteristics was analyzed by the chi-squared the Fisher’s exact test. The study used a Cox proportional hazards model to get univariate and mutivariate analysis. The independence of prognostic factors was assessed through multivariate analysis using two-sided statistical tests, with statistical significance defined as p < 0.05. Hazard ratios with corresponding 95% confidence intervals were calculated to quantify the association between each independent variable and survival outcomes. The Kaplan-Meier method and the log-rank test was employed to calculate the survival rate. Overall survival was defined as the time from surgery to the death of the patients or the end of follow-up. Disease-free survival was defined as the time from surgery to the first documented recurrence. Results Patient characteristics We retrospectively analyzed 1,392 consecutive gastric cancer cases (December 2011-June 2013) that fulfilled all inclusion criteria. The clinicopathologic characteristics of 1392 GC patients are listed in Table 1. Of all GC patients, there were 496 females (35.6%) and 896 males (64.4); 58.5% of patients were ≤ 65 years of age and 41.5% of patients were > 65 years of age. 74% of patients had tumors ≤ 4cm and 26% patients had tumors >4cm. The number of stage II patients were 589. Of the 589 stage and II patients, 35 patients were lost to follow-up. At last, we included 554 stage II patients. This study analyzed the 554 patients and their clinicopathologic characteristics are listed in Table 1. 103 patients(18.6%) were LVI+ and 95 patients (17.1%) were PNI+. Table 1 Clinicopathologic characteristics of GC patients. 1392 gastric cancer patients from December 2011 to June 2013 who met the inclusion criteria were evaluated in this study. The clinicopathologic characteristics of 1392 GC patients and the 554 stage II patients are listed in Table 1. parameters Overall patients n(%) Stage II patients n(%) Sex Female Male 496(35.6) 896(64.4) 158(28.5) 396(71.5) Age(years) ≤65 ＞65 814(58.5) 578(41.5) 308(55.6) 246(44.4) Tumor size(cm) ≤4 ＞4 741(53.2) 651(46.8) 330(59.6) 224(40.4) LVI Positive Negative PNI Positive negative 442(31.8) 950(68.2) 390(28.0) 1002(72.0) 103(18.6) 451(81.4) 95(17.1) 459(82.9) T-Stage T1 T2 T3 T4 378(27.2) 166(11.9) 484(34.8) 364(26.1) 136(24.5) 100(18.1) 192(34.7) 126(22.7) N-Stage N0 N1 N2 N3 681(48.9) 212(15.2) 227(16.3) 272(19.5) 256(46.2) 154(27.8) 92(16.6) 52(9.4) CEA ≤5ng/ml ＞5ng/ml 1058(76.0) 334(24.0) 432(78.0) 122(22.0) Retrieved LN ＜16 ≥16 946(68.0) 446(32.0) 398(71.8) 156(28.2) Treatment ACT SA 338(24.3) 1054(75.7) 150(27.1) 404(72.9) Occurrence of LVI in stage II GC patients Table 2 presents the occurrence of LVI among 554 stage II gastric cancer patients, analyzed by clinicopathological characteristics. Statistical analysis revealed significant correlations between LVI status and pathological pT stage, pN stage, preoperative serum CEA levels, and tumor dimensions. However, neither patient gender nor age demonstrated significant associations with LVI prevalence. Table 2 Occurrence of LVI in 554 stage II GC patients. The incidence of LVI in stage II GC patients is listed in Table 2 according to clinicopathologic characteristics. The LVI status was significantly associated with pT stage, pN stage, serum CEA levels and tumor size. No significant difference existed with respect to sex and age. parameters LVI(+) n LVI(-) n P LVI(+) rate(%) Sex Male Female 77 26 319 132 0.469 77/396(19.4) 26/158(16.5) Age(years) ≤65 ＞65 T-stage 1 2 3 4 N-stage 0 1 2 3 57 46 15 31 24 33 36 26 28 13 251 200 121 69 168 93 220 128 64 39 0.827 <0.001 0.012 57/308(17.9) 46/246(18.7) 15/136(11.0) 31/100(31.0) 24/192(12.5) 33/126(26.2) 36/256(14.1) 26/154(16.9) 28/92(30.4) 13/52(25.0) CEA <0.001 ≤5 ＞5 62 41 370 81 62/432(14.4) 41/122(33.6) Tumor size(cm) ≤4 ＞4 51 52 279 172 0.0258 51/330(15.5) 52/224(23.2) Occurrence of PNI in stage II GC patients The clinicopathologic characteristics of stage II GC patients with PNI are listed in Table 3. The PNI status was associated with pT stage, pN stage and serum CEA levels. There was no statistically significant difference between PNI and age, sex, tumor size. Table 3 Occurrence of PNI in 554 stage II GC patients. The clinicopathologic characteristics of stage II GC patients with PNI are listed in Table 3 based on clinicopathologic characteristics. The PNI status was associated with pT stage, pN stage and serum CEA levels. There was no statistically significant difference between PNI and age, sex, tumor size. parameters PNI(+) n PNI(-) n P PNI(+) rate(%) Sex Male Female 64 31 332 127 0.322 64/396(16.2) 31/158(19.6) Age(years) ≤65 ＞65 58 37 250 209 0.258 58/308(18.8) 37/246(15.0) T-stage 1 2 3 4 N-stage 0 1 2 3 12 25 31 27 45 15 23 12 124 75 161 99 211 139 69 40 0.005 <0.001 12/136(8.8) 25/100(25.0) 31/192(16.1) 27/126(21.4) 45/256(17.6) 15/154(9.7) 23/92(25.0) 12/52(23.1) CEA <0.0001 ≤5 ＞5 52 43 380 79 52/432(12.0) 43/122(35.2) Tumor size(cm) ≤4 ＞4 52 43 278 181 0.303 52/330(15.8) 43/224(19.2) Overall survival of stage II GC patients Our analysis revealed significantly superior long-term outcomes in LVI- patients compared to their LVI+ counterparts among all stage II GC cases. Specifically, the LVI- group demonstrated a higher 5-year OS rate than the LVI+ group (53.7% vs 38.8%; P < 0.05; Fig. 3a). Similarly, the LVI- group showed an improved DFS than the LVI+ group (51.0% vs 44.7%; P < 0.05; Fig. 3b). Similarly, we also found that the 5-year OS rate of the PNI- group was greater than the PNI+ group (52.9% vs 41.1%; P < 0.05; Fig. 4a). The 5-year DFS of the PNI- group was greater than the PNI+ group (51.2% vs 43.2%; P 0.05; Figure5a). Similarly, the 5-year overall survival rate of stage II patients with PNI+ and LVI+ was lower than patients with PNI+ and LVI- (44.2% vs 44.7%; p>0.05; Figure5b). However, the two survival studies were not statistically significant. Univariate and multivariate analyses for the prognosis of stage II GC patients. Given the distinct clinical profile of stage II gastric cancer patients, we conducted focused prognostic analysis. Multivariate analyses showed that LVI, PNI, pT-stage and serum CEA level were significant prognostic factors for stage II GC patients. Table 4 Univariate and multivariate analysis of prognostic factors for stage II GC patients parameters Patients n(%) 5-Year OS(%) Univariate analysis multivariate analysis HR (95% CI) P HR (95% CI) P Sex Male Female 396 158 50.0 53.2 1.135（0.7848 to 1.644） 0.5012 Age ≤65 >65 308 246 52.6 48.8 1.165(0.8332 to 1.630) 0.3720 Tumor size ≤4 >4 330 224 56.1 43.3 1.235(0.8791 to 1.735) 0.2242 T-stage T1 T2 T3 T4 136 100 192 126 58.8 53.0 50.5 41.3 1.244(1.067 to 1.454） 0.0056 0.1826(0.1340 to 0.2311) P<0.0001 N-stage N0 N1 N2 N3 256 154 92 52 54.7 50.0 47.8 40.4 1.103(0.9331 to 1.305) 0.2512 LVI Positive Negative 103 451 38.8 53.7 2.261（1.451 to 3.575） 0.0004 0.3225(0.03472 to 0.6102) 0.0281 PNI Positive Negative 95 459 41.1 52.9 1.615（1.035 to 2.542） 0.0359 0.3265( 0.06081-0.5922) 0.0161 CEA ≤5 >5 432 122 47.8 40.4 2.381（1.574 to 3.644） P<0.001 0.5042(0.2822 to 0.7261） P<0.0001 Discussion Gastric cancer is a serious health burden worldwide. The 2022 statistics of China show that gastric cancer has the third highest mortality rate in China, after lung cancer and liver cancer [ 18 ] . This means that we still need to make great efforts in the diagnosis and treatment of stomach cancer. PNI and LVI are common pathologic feature of malignances such as pancreatic cancer, colorectal cancer, prostate cancer [ 19 ] . Previous studies have shown that the incidence of LVI in gastric cancer ranges from 12.9–44.3% [ 20 , 21 ] . PNI has been reported in 6.8%-75.6% of patients, which is also thought to be associated with a poor prognosis in gastric cancer [ 22 ] . In this study, the incidence of LVI in all GC patients was 31.8% and the incidence of PNI was 28.0%, consistent with other studies [ 20 – 22 ] . Differences in LVI rates and PNI rates across studies may be related to different diagnostic modalities [ 23 ] . In our 554 stage II patients, LVI was correlated with pT stage, pN stage, serum CEA levels and tumor size. Comparable to our results, Wang et al. reported the association between LVI and T stage, N stage, differentiation status [ 24 ] . Furthermore, it has been shown that LVI is associated with recurrence after radical gastric cancer surgery [ 25 ] . In this study, PNI was significantly associated with pT stage, pN stage and serum CEA levels. Similar to our study, Li et al. reported that PNI was significantly correlated with tumor differentiation, T stage, lymph node metastasis, and signet ring cell carcinoma components [ 26 ] . The mechanism of action of PNI in gastric cancer is unclear, and some studies suggest that it may be related to the tumor immune microenvironment [ 27 ] . These studies all support our results. It is worth noting that this study also conducted survival analysis. This study followed up on the 5-year OS of the patients. The results showed that the 5-year OS rate and the 5-year DFS rate of the LVI- group were greater than the LVI + group. Similarly, the 5-year OS rate and the 5-year DFS rate of the PNI- group were greater than the PNI + group. Similar to our results, Choi et al. also find that LVI can reduce the OS rate and DFS rate of gastric cancer patients [ 28 ] . Some researchers suggest that LVI may be an early process of lymph node metastasis, it may cause a micrometastasis [ 29 ] . Paolo et al. concluded that PNI and T stage and positive lymph nodes are independent markers of poor prognosis in patients with gastric cancer [ 30 ] . It has been reported that PNI is an independent risk factor involved in the early recurrence of gastric cancer after curative resection [ 9 ] . It is well known that lymph node metastasis is an important mode of cancer metastasis and recurrence, and articles have suggested that LVI and PNI may increase the chance of lymph node metastasis [ 23 ] . Multivariate analysis identified LVI, PNI, pT-stage and serum CEA level as independent prognostic factors in stage II GC patients. Consistent with existing literature [ 23 ] , our study confirms the prognostic significance of LVI as an independent predictor of survival in gastric cancer patients. Therefore, more benefits might be achieved by phasing in LVI and the 8th edition of the TNM staging system of AJCC [ 31 ] . The prognostic significance of serum CEA elevation was established by Fan et al., whose multivariate analysis confirmed its status as an independent risk factor for reduced survival in early gastric cancer (p < 0.05) [ 32 ] . There is also a study which suggests that elevated CEA levels may be associated with liver metastases and lymph node metastases [ 33 ] . Gao et al. reported that reduced mortality after adjuvant chemotherapy was observed in stage IB patients with positive lymphovascular invasion [ 34 ] . Not coincidentally, there have been other studies showing the benefit of adjuvant chemotherapy on OS and DFS in PNI-positive patients [ 35 , 36 ] . In accordance with National Comprehensive Cancer Network (NCCN) guidelines, adjuvant chemotherapy was indicated for patients with stage II-III gastric cancer in our study cohort [ 12 ] , but it has been reported that a portion of stage II patients (T3N0) could not gain benefit from adjuvant chemotherapy [ 37 ] . Combined with the current studies, we believe that stage II patients with LVI and PNI will benefit from adjuvant chemotherapy. Mechanisms of LVI and PNI are unclear, but there is a study showing that LVI and PNI may cause high tumor stroma percentage, low Klintrup-Mäkinen grade and high Glasgow microenvironment score, which lead to poorer prognosis of GC [ 38 ] . In addition, many scholars have attempted to study the mechanisms of LVI and PNI at the genetic level. It has been suggested that miR-199a/b increases the probability of LVI by targeting Frizzled-6, thereby promoting the progression of GC [ 39 ] . Similarly, Liu et al. reported that mammalian infertile-20-like kinase 4 (MST4) is associated with LVI and PNI and it can promote GC cell proliferation, invasion, and metastasis [ 40 ] . Perhaps more therapeutic options can be researched from these mechanisms. Several limitations should be acknowledged in this study. This study was a retrospective study from a single center and the sample size was so small that it may be subject to selection bias. Moreover, this study focused on the surface of LVI and PNI and did not delve into the pathogenesis of LVI and PNI in gastric cancer. Conclusions In conclusion, LVI and PNI can reduce the 5-year OS and DFS of stage II gastric cancer patients. The impact of LVI and PNI should be considered when considering the prognosis of stage II patients in clinical practice. In the meantime, we need more effective adjuvant chemotherapy for stage II patients with LVI and PNI. Declarations Conflict of interest statement The authors declare no conflict of interest. Author Contribution All authors contributed to the study conception and design. Data collection and analysis were performed by Yao Cen and Yuanyuan Li. The first draft of the manuscript was written by Yao Cen and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Acknowledgements The project is supported by Cultivation of Innovative Medical Talents among the Youth in the City (Grant numbers[KY201125]). References Siegel R L, Giaquinto A N, Jemal A. Cancer statistics, 2024[J]. CA Cancer J Clin, 2024,74(1):12-49. Yang W J, Zhao H P, Yu Y, et al. Updates on global epidemiology, risk and prognostic factors of gastric cancer[J]. World J Gastroenterol, 2023,29(16):2452-2468. Coccolini F, Nardi M, Montori G, et al. Neoadjuvant chemotherapy in advanced gastric and esophago-gastric cancer. Meta-analysis of randomized trials[J]. 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Sci Rep, 2023,13(1):17480. Liu P, Li L, Wang W, et al. MST4 promotes proliferation, invasion, and metastasis of gastric cancer by enhancing autophagy[J]. Heliyon, 2023,9(6):e16735. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6889639","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":472570927,"identity":"c13acc1c-96a8-4e90-8e78-b10f541c0147","order_by":0,"name":"Yao Cen","email":"","orcid":"","institution":"The Third Affiliated Hospital of Soochow","correspondingAuthor":false,"prefix":"","firstName":"Yao","middleName":"","lastName":"Cen","suffix":""},{"id":472570928,"identity":"1acf13c3-50ea-40d7-a7bd-68d8ad024a99","order_by":1,"name":"Yuanyuan Li","email":"","orcid":"","institution":"The Third Affiliated Hospital of Soochow","correspondingAuthor":false,"prefix":"","firstName":"Yuanyuan","middleName":"","lastName":"Li","suffix":""},{"id":472570929,"identity":"7ff09d5c-b937-4a7f-81af-b65208fb5f0f","order_by":2,"name":"Yugang Wu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYBADOX72xsaHH0jRYizZc7jZWIIULYkbbqS3CfAQo5S//4yZNG9brbHBzYdtDBIMdnK6DQS0SBwAazkuJ3k7se1BAUOysdkBAloMGHvMpHPbjhnz3U5sN5BgOJC4jaAWZh6wlsSGmwfbJHiI0sIG1lKTOOEGI5FaJM6wFVv/OXcAGMiJwEA2IMIv/P2HN96cUVYHjMrjDx9+qLCTI6iFgYHDRIKR7TDMnQSVgwD74w8Mf+qIUjoKRsEoGAUjFAAA1htERzah1zkAAAAASUVORK5CYII=","orcid":"","institution":"The Third Affiliated Hospital of Soochow","correspondingAuthor":true,"prefix":"","firstName":"Yugang","middleName":"","lastName":"Wu","suffix":""}],"badges":[],"createdAt":"2025-06-13 15:53:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6889639/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6889639/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85069443,"identity":"721446f2-02ba-45dd-9c71-d9f254db20af","added_by":"auto","created_at":"2025-06-20 15:30:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":523225,"visible":true,"origin":"","legend":"\u003cp\u003eAn example of positive lymphovascular invasion (LVI), H\u0026amp;E (×100)\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6889639/v1/0873ba8409c1e06610731770.png"},{"id":85069450,"identity":"e5e1e1da-1b7a-4bb7-a24f-230f51e1c6da","added_by":"auto","created_at":"2025-06-20 15:30:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1173252,"visible":true,"origin":"","legend":"\u003cp\u003eAn example of positive perineural invasion (PNI), H\u0026amp;E (×100)\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6889639/v1/6038118d36a5d4427c61645c.png"},{"id":85071965,"identity":"98350ec5-3705-4310-893b-d3ca6e5ad675","added_by":"auto","created_at":"2025-06-20 15:46:17","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":27071,"visible":true,"origin":"","legend":"\u003cp\u003eThe 5-year overall survival (OS) rate among all stage II GC patients according to lymphovascular invasion (LVI). We found that in all stage II patients, the 5-year OS rate of the LVI- group was greater than the LVI+ group (53.7% vs 38.8%; P \u0026lt; 0.05; a). The 5-year disease-free survival (DFS) of the LVI- group was greater than the LVI+ group (51.0% vs 44.7%; P \u0026lt; 0.05; b).\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-6889639/v1/7947b63af63ce5c5c7c78f54.png"},{"id":85070708,"identity":"5fdc77ec-2eef-4a9a-84e0-0c481e6cdb98","added_by":"auto","created_at":"2025-06-20 15:38:17","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":25041,"visible":true,"origin":"","legend":"\u003cp\u003eThe 5-year overall survival (OS) rate of the PNI- group was greater than the PNI+ group (52.9% vs 41.1%; P \u0026lt; 0.05; a). The 5-year disease-free survival (DFS) of the PNI- group was greater than the PNI+ group (51.2% vs 43.2%; P \u0026lt; 0.05; Fig.b).\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-6889639/v1/0d7ad64cc215b283472bfd7a.png"},{"id":85069441,"identity":"12109a2e-953f-4c03-886a-494a66ddac7a","added_by":"auto","created_at":"2025-06-20 15:30:17","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":25082,"visible":true,"origin":"","legend":"\u003cp\u003eThe 5-year overall survival (OS) rate of the stage II patients with PNI+ and LVI+ was poorer than patients with LVI+ and PNI- (44.2% vs 52.7%; p\u0026gt;0.05; a). the 5-year overall survival (OS) rate of stage II patients with PNI+ and LVI+ was lower than patients with PNI+ and LVI- (44.2% vs 44.7%; p\u0026gt;0.05; b).\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-6889639/v1/a8f150b00b0d0644edca6a31.png"},{"id":101962911,"identity":"b5b1721f-0a77-4eb4-abd8-4e765c6c4297","added_by":"auto","created_at":"2026-02-05 12:58:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2295911,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6889639/v1/779c2ff8-a588-41d2-8839-02f7813d3992.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prognostic value of lymphovascular and perineural invasion in stage II gastric cancer patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGastric cancer (GC) is the fifth most common cancer and is also the fifth cause leading to cancer-related deaths in the world\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Although the treatment of gastric cancer has progressed with early detection, the survival rate of gastric cancer remains low worldwide\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. The low survival rate of gastric cancer is mainly due to factors such as the delayed detection of the disease, the malignancy of the cancer, the limitations of treatment, and the living habits of patients. People tend to pay less attention to the treatment of relatively early gastric cancer. Accordingly, even after curative surgery and adequate lymph node dissection, survival rates for gastric cancer remain low\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eEstablished clinicopathological prognostic factors in gastric cancer include the Tumor-Node-Metastasis (TNM) staging system, lymphovascular invasion (LVI), tumor differentiation grade, and molecular biomarkers, all of which significantly influence disease outcomes\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. However, there are still many important prognostic risk factors that need to be detected clinically, such as perineural invasion (PNI)\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eLymphovascular invasion is histologically defined as the presence of malignant cells within either lymphatic channels or vascular structures, representing active tumor dissemination.\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Numerous studies have shown that gastric cancer patients with vascular invasion have a poorer prognosis\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Perineural invasion (PNI) describes the infiltration of tumor cells into nerves, characterized by either their presence within the perineurium, endoneurium, or epineurium (the three layers of the peripheral nerve sheath) or in close proximity to nerve structures.\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Similar to the poorer prognosis caused by LVI, it has been shown that PNI also leads to a poorer prognosis in gastric cancer patients and can even lead to tumor recurrence\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. LVI and PNI are important metastatic routes for gastric cancer\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. Meanwhile, most gastric cancer patients die due to cancer recurrence or metastasis\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAlthough the guidelines clearly recommend chemotherapy for stage II-IV patients, in actual clinical practice, there are many patients with earlier staging who neglect the importance of adjuvant therapy\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. For example, some stage II patients who don't have lymph node metastases always refuse adjuvant chemotherapy, but it is possible that they have LVI and PNI. A number of studies have suggested that vascular and nerve invasion might promote cancer metastasis and recurrence in different tumors\u003csup\u003e[\u003cspan additionalcitationids=\"CR14 CR15 CR16\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. This study investigated whether LVI and PNI affect overall survival and disease-free survival of stage II gastric cancer.\u003c/p\u003e \u003cp\u003eMeanwhile, early diagnosis of recurrence and metastasis as well as timely therapeutic intervention are very important. Therefore, in this article, we investigated the clinical features associated with LVI and PNI as well as prognostic factors.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Materials and methods","content":"\u003ch2\u003ePatients\u003c/h2\u003e\n\u003cp\u003eIn this study, we included totally 1392 patients from the Third Affiliated Hospital of Soochow University between December 2011 to June 2013. The inclusion criteria were as follows: all patients enrolled in this study had received curative resection with lymphadenectomy, they all be histologically confirmed as adenocarcinoma of the stomach. The exclusion were as follows: patients who had received neoadjuvant chemoradiation; patients whose clinicopathologic records were incomplete, patients who lost to follow-up, patients who had distant metastases or received palliative operation. Gastric cancer (GC) staging was determined based on the 8th edition AJCC TNM classification system. Patient follow-up was conducted via telephone interviews or clinical outpatient evaluations. This study received ethical approval from the Institutional Review Board of the Third Affiliated Hospital of Soochow University.\u003c/p\u003e\n\u003ch2\u003eData collection and Histopathological evaluation\u003c/h2\u003e\n\u003cp\u003eWe examined patient medical records to obtain their clinicopathologic characteristics included sex, age, LVI, tumor size, PNI, TNM stage, ELNs, serum CEA and so on. Surgical specimens were fixed in formalin and then they were embedded in paraffin. The specimens were cut into 5-mm-thick longitudinal whole tissue section and stained with hematoxylin-eosin (HE). All histological sections were reviewed by a minimum of two experienced pathologists, each conducting independent assessments of PNI and LVI. Determination of vascular invasion was made primarily by the following signs: presence of tumor cells in the vessel, infiltration of tumor cells into the perivascular tissue, and impairment of the vascular endothelial barrier.Pathologic diagnostic criteria for nerve invasion are primarily infiltration of tumor cells along the nerve fascicle membrane into the nerve sheaths.\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eAll statistical analyses were conducted using GraphPad Prism version 10.0 (GraphPad Software, San Diego, CA, USA). The association between PNI, LVI and clinicopathologic characteristics was analyzed by the chi-squared the Fisher\u0026rsquo;s exact test. The study used a Cox proportional hazards model to get univariate and mutivariate analysis. The independence of prognostic factors was assessed through multivariate analysis using two-sided statistical tests, with statistical significance defined as p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Hazard ratios with corresponding 95% confidence intervals were calculated to quantify the association between each independent variable and survival outcomes. The Kaplan-Meier method and the log-rank test was employed to calculate the survival rate. Overall survival was defined as the time from surgery to the death of the patients or the end of follow-up. Disease-free survival was defined as the time from surgery to the first documented recurrence.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003ch2\u003ePatient characteristics\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eWe retrospectively analyzed 1,392 consecutive gastric cancer cases (December 2011-June 2013) that fulfilled all inclusion criteria. The clinicopathologic characteristics of 1392 GC patients are listed in Table 1. Of all GC patients, there were 496 females (35.6%) and 896 males (64.4); 58.5% of patients were \u0026le; 65 years of age and 41.5% of patients were \u0026gt; 65 years of age. 74% of patients had tumors \u0026le; 4cm and 26% patients had tumors \u0026gt;4cm. The number of stage II patients were 589. Of the 589 stage and II patients, 35 patients were lost to follow-up. At last, we included 554 stage II patients. This study analyzed the 554 patients and their clinicopathologic characteristics are listed in Table 1. 103 patients(18.6%) were LVI+ and 95 patients (17.1%) were PNI+.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e Clinicopathologic characteristics of GC patients. 1392 gastric cancer patients from December 2011 to June 2013 who met the inclusion criteria were evaluated in this study. The clinicopathologic characteristics of 1392 GC patients and the 554 stage II patients are listed in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eparameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eOverall patients\u003c/p\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eStage II patients\u003c/p\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eSex\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Female\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Male\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e496(35.6)\u003c/p\u003e\n \u003cp\u003e896(64.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e158(28.5)\u003c/p\u003e\n \u003cp\u003e396(71.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eAge(years)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026le;65\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; ＞65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e814(58.5)\u003c/p\u003e\n \u003cp\u003e578(41.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e308(55.6)\u003c/p\u003e\n \u003cp\u003e246(44.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eTumor size(cm)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026le;4\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; ＞4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e741(53.2)\u003c/p\u003e\n \u003cp\u003e651(46.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e330(59.6)\u003c/p\u003e\n \u003cp\u003e224(40.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eLVI\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Positive\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Negative\u003c/p\u003e\n \u003cp\u003ePNI\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Positive\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; negative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e442(31.8)\u003c/p\u003e\n \u003cp\u003e950(68.2)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e390(28.0)\u003c/p\u003e\n \u003cp\u003e1002(72.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e103(18.6)\u003c/p\u003e\n \u003cp\u003e451(81.4)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e95(17.1)\u003c/p\u003e\n \u003cp\u003e459(82.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eT-Stage\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; T1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; T2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; T3\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; T4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e378(27.2)\u003c/p\u003e\n \u003cp\u003e166(11.9)\u003c/p\u003e\n \u003cp\u003e484(34.8)\u003c/p\u003e\n \u003cp\u003e364(26.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e136(24.5)\u003c/p\u003e\n \u003cp\u003e100(18.1)\u003c/p\u003e\n \u003cp\u003e192(34.7)\u003c/p\u003e\n \u003cp\u003e126(22.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eN-Stage\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; N0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; N1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; N2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; N3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e681(48.9)\u003c/p\u003e\n \u003cp\u003e212(15.2)\u003c/p\u003e\n \u003cp\u003e227(16.3)\u003c/p\u003e\n \u003cp\u003e272(19.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e256(46.2)\u003c/p\u003e\n \u003cp\u003e154(27.8)\u003c/p\u003e\n \u003cp\u003e92(16.6)\u003c/p\u003e\n \u003cp\u003e52(9.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eCEA\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026le;5ng/ml\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; ＞5ng/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1058(76.0)\u003c/p\u003e\n \u003cp\u003e334(24.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e432(78.0)\u003c/p\u003e\n \u003cp\u003e122(22.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eRetrieved LN\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; ＜16\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026ge;16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e946(68.0)\u003c/p\u003e\n \u003cp\u003e446(32.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e398(71.8)\u003c/p\u003e\n \u003cp\u003e156(28.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; ACT\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; SA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e338(24.3)\u003c/p\u003e\n \u003cp\u003e1054(75.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e150(27.1)\u003c/p\u003e\n \u003cp\u003e404(72.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch2\u003eOccurrence of LVI in stage II GC patients\u003c/h2\u003e\n\u003cp\u003eTable 2 presents the occurrence of LVI among 554 stage II gastric cancer patients, analyzed by clinicopathological characteristics. Statistical analysis revealed significant correlations between LVI status and pathological pT stage, pN stage, preoperative serum CEA levels, and tumor dimensions. However, neither patient gender nor age demonstrated significant associations with LVI prevalence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e Occurrence of LVI in 554 stage II GC patients. The incidence of LVI in stage II GC patients is listed in Table 2 according to clinicopathologic characteristics. The LVI status was significantly associated with pT stage, pN stage, serum CEA levels and tumor size. No significant difference existed with respect to sex and age.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eparameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eLVI(+)\u003c/p\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eLVI(-)\u003c/p\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eLVI(+) rate(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Male\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e77\u003c/p\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e319\u003c/p\u003e\n \u003cp\u003e132\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e0.469\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e77/396(19.4)\u003c/p\u003e\n \u003cp\u003e26/158(16.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eAge(years)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026le;65\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; ＞65\u003c/p\u003e\n \u003cp\u003eT-stage\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 3\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 4\u003c/p\u003e\n \u003cp\u003eN-stage\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e251\u003c/p\u003e\n \u003cp\u003e200\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e121\u003c/p\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003cp\u003e168\u003c/p\u003e\n \u003cp\u003e93\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e220\u003c/p\u003e\n \u003cp\u003e128\u003c/p\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e0.827\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e57/308(17.9)\u003c/p\u003e\n \u003cp\u003e46/246(18.7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15/136(11.0)\u003c/p\u003e\n \u003cp\u003e31/100(31.0)\u003c/p\u003e\n \u003cp\u003e24/192(12.5)\u003c/p\u003e\n \u003cp\u003e33/126(26.2)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e36/256(14.1)\u003c/p\u003e\n \u003cp\u003e26/154(16.9)\u003c/p\u003e\n \u003cp\u003e28/92(30.4)\u003c/p\u003e\n \u003cp\u003e13/52(25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eCEA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026le;5\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; ＞5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e370\u003c/p\u003e\n \u003cp\u003e81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e62/432(14.4)\u003c/p\u003e\n \u003cp\u003e41/122(33.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eTumor size(cm)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026le;4\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; ＞4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e279\u003c/p\u003e\n \u003cp\u003e172\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e0.0258\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e51/330(15.5)\u003c/p\u003e\n \u003cp\u003e52/224(23.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch2\u003eOccurrence of PNI in stage II GC patients\u003c/h2\u003e\n\u003cp\u003eThe clinicopathologic characteristics of stage II GC patients with PNI are listed in Table 3. The PNI status was associated with pT stage, pN stage and serum CEA levels. There was no statistically significant difference between PNI and age, sex, tumor size.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e Occurrence of PNI in 554 stage II GC patients. The clinicopathologic characteristics of stage II GC patients with PNI are listed in Table 3 based on clinicopathologic characteristics. The PNI status was associated with pT stage, pN stage and serum CEA levels. There was no statistically significant difference between PNI and age, sex, tumor size.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eparameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003ePNI(+)\u003c/p\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003ePNI(-)\u003c/p\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003ePNI(+) rate(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Male\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e332\u003c/p\u003e\n \u003cp\u003e127\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e0.322\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e64/396(16.2)\u003c/p\u003e\n \u003cp\u003e31/158(19.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eAge(years)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026le;65\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; ＞65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e250\u003c/p\u003e\n \u003cp\u003e209\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e0.258\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e58/308(18.8)\u003c/p\u003e\n \u003cp\u003e37/246(15.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eT-stage\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 3\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 4\u003c/p\u003e\n \u003cp\u003eN-stage\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e124\u003c/p\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003cp\u003e161\u003c/p\u003e\n \u003cp\u003e99\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e211\u003c/p\u003e\n \u003cp\u003e139\u003c/p\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12/136(8.8)\u003c/p\u003e\n \u003cp\u003e25/100(25.0)\u003c/p\u003e\n \u003cp\u003e31/192(16.1)\u003c/p\u003e\n \u003cp\u003e27/126(21.4)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e45/256(17.6)\u003c/p\u003e\n \u003cp\u003e15/154(9.7)\u003c/p\u003e\n \u003cp\u003e23/92(25.0)\u003c/p\u003e\n \u003cp\u003e12/52(23.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eCEA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026le;5\u003c/p\u003e\n \u003cp\u003e＞5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e380\u003c/p\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e52/432(12.0)\u003c/p\u003e\n \u003cp\u003e43/122(35.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eTumor size(cm)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026le;4\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; ＞4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e278\u003c/p\u003e\n \u003cp\u003e181\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.303\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e52/330(15.8)\u003c/p\u003e\n \u003cp\u003e43/224(19.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch2\u003eOverall survival of stage II GC patients\u003c/h2\u003e\n\u003cp\u003eOur analysis revealed significantly superior long-term outcomes in LVI- patients compared to their LVI+ counterparts among all stage II GC cases. Specifically, the LVI- group demonstrated a higher 5-year OS rate\u0026nbsp;than the LVI+ group (53.7% vs 38.8%; P \u0026lt; 0.05; Fig. 3a). Similarly,\u0026nbsp;the LVI- group showed an improved DFS\u0026nbsp;than the LVI+ group (51.0% vs 44.7%; P \u0026lt; 0.05; Fig. 3b).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Similarly, we also found that the 5-year OS rate of the PNI- group was greater than the PNI+ group (52.9% vs 41.1%; P \u0026lt; 0.05; Fig. 4a). The 5-year DFS of the PNI- group was greater than the PNI+ group (51.2% vs 43.2%; P \u0026lt; 0.05; Fig.4b).\u003c/p\u003e\n\u003cp\u003eWe also found that stage II patients with PNI+ and LVI+ had a poorer 5-year OS than patients with LVI+ and PNI- (44.2% vs 52.7%; p\u0026gt;0.05; Figure5a). Similarly, the 5-year overall survival rate of stage II patients with PNI+ and LVI+ was lower than patients with PNI+ and LVI- (44.2% vs 44.7%; p\u0026gt;0.05; Figure5b). However, the two survival studies were not statistically significant.\u003c/p\u003e\n\u003ch2\u003eUnivariate and multivariate analyses for the prognosis of stage II GC patients.\u003c/h2\u003e\n\u003cp\u003eGiven the distinct clinical profile of stage II gastric cancer patients, we conducted focused prognostic analysis. Multivariate analyses showed that LVI, PNI, pT-stage and serum CEA level were significant prognostic factors for stage II GC patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4\u003c/strong\u003e Univariate and multivariate analysis of prognostic factors for stage II GC patients\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"623\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003eparameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003ePatients\u003c/p\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e5-Year\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eOS(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eUnivariate analysis\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003emultivariate analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Male\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e396\u003c/p\u003e\n \u003cp\u003e158\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e50.0\u003c/p\u003e\n \u003cp\u003e53.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 139px;\"\u003e\n \u003cp\u003e1.135（0.7848 to 1.644）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e0.5012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u0026le;65\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u0026gt;65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e308\u003c/p\u003e\n \u003cp\u003e246\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e52.6\u003c/p\u003e\n \u003cp\u003e48.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e1.165(0.8332\u0026nbsp;to\u0026nbsp;1.630)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e0.3720\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003eTumor size\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026le;4\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026gt;4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e330\u003c/p\u003e\n \u003cp\u003e224\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e56.1\u003c/p\u003e\n \u003cp\u003e43.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e1.235(0.8791\u0026nbsp;to\u0026nbsp;1.735)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e0.2242\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003eT-stage\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; T1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; T2\u003c/p\u003e\n \u003cp\u003eT3\u003c/p\u003e\n \u003cp\u003eT4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e136\u003c/p\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003cp\u003e192\u003c/p\u003e\n \u003cp\u003e126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e58.8\u003c/p\u003e\n \u003cp\u003e53.0\u003c/p\u003e\n \u003cp\u003e50.5\u003c/p\u003e\n \u003cp\u003e41.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e1.244(1.067\u0026nbsp;to\u0026nbsp;1.454）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e0.0056\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e0.1826(0.1340\u0026nbsp;to\u0026nbsp;0.2311)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eP\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003eN-stage\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; N0\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eN1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; N2\u003c/p\u003e\n \u003cp\u003eN3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e256\u003c/p\u003e\n \u003cp\u003e154\u003c/p\u003e\n \u003cp\u003e92\u003c/p\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e54.7\u003c/p\u003e\n \u003cp\u003e50.0\u003c/p\u003e\n \u003cp\u003e47.8\u003c/p\u003e\n \u003cp\u003e40.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e1.103(0.9331\u0026nbsp;to\u0026nbsp;1.305)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e0.2512\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003eLVI\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Positive\u003c/p\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003cp\u003e451\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e38.8\u003c/p\u003e\n \u003cp\u003e53.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e2.261（1.451\u0026nbsp;to\u0026nbsp;3.575）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e0.0004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e0.3225(0.03472\u0026nbsp;to\u0026nbsp;0.6102)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0.0281\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003ePNI\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Positive\u003c/p\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e95\u003c/p\u003e\n \u003cp\u003e459\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e41.1\u003c/p\u003e\n \u003cp\u003e52.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e1.615（1.035\u0026nbsp;to\u0026nbsp;2.542）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e0.0359\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e0.3265(\u0026nbsp;0.06081-0.5922)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0.0161\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003eCEA\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026le;5\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026gt;5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e432\u003c/p\u003e\n \u003cp\u003e122\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e47.8\u003c/p\u003e\n \u003cp\u003e40.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e2.381（1.574\u0026nbsp;to\u0026nbsp;3.644）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eP\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e0.5042(0.2822\u0026nbsp;to\u0026nbsp;0.7261）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eP\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eGastric cancer is a serious health burden worldwide. The 2022 statistics of China show that gastric cancer has the third highest mortality rate in China, after lung cancer and liver cancer\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. This means that we still need to make great efforts in the diagnosis and treatment of stomach cancer. PNI and LVI are common pathologic feature of malignances such as pancreatic cancer, colorectal cancer, prostate cancer\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Previous studies have shown that the incidence of LVI in gastric cancer ranges from 12.9\u0026ndash;44.3%\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. PNI has been reported in 6.8%-75.6% of patients, which is also thought to be associated with a poor prognosis in gastric cancer\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn this study, the incidence of LVI in all GC patients was 31.8% and the incidence of PNI was 28.0%, consistent with other studies\u003csup\u003e[\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Differences in LVI rates and PNI rates across studies may be related to different diagnostic modalities\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. In our 554 stage II patients, LVI was correlated with pT stage, pN stage, serum CEA levels and tumor size. Comparable to our results, Wang et al. reported the association between LVI and T stage, N stage, differentiation status\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. Furthermore, it has been shown that LVI is associated with recurrence after radical gastric cancer surgery\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. In this study, PNI was significantly associated with pT stage, pN stage and serum CEA levels. Similar to our study, Li et al. reported that PNI was significantly correlated with tumor differentiation, T stage, lymph node metastasis, and signet ring cell carcinoma components\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. The mechanism of action of PNI in gastric cancer is unclear, and some studies suggest that it may be related to the tumor immune microenvironment\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. These studies all support our results.\u003c/p\u003e \u003cp\u003eIt is worth noting that this study also conducted survival analysis. This study followed up on the 5-year OS of the patients. The results showed that the 5-year OS rate and the 5-year DFS rate of the LVI- group were greater than the LVI\u0026thinsp;+\u0026thinsp;group. Similarly, the 5-year OS rate and the 5-year DFS rate of the PNI- group were greater than the PNI\u0026thinsp;+\u0026thinsp;group. Similar to our results, Choi et al. also find that LVI can reduce the OS rate and DFS rate of gastric cancer patients\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. Some researchers suggest that LVI may be an early process of lymph node metastasis, it may cause a micrometastasis\u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e. Paolo et al. concluded that PNI and T stage and positive lymph nodes are independent markers of poor prognosis in patients with gastric cancer\u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. It has been reported that PNI is an independent risk factor involved in the early recurrence of gastric cancer after curative resection\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. It is well known that lymph node metastasis is an important mode of cancer metastasis and recurrence, and articles have suggested that LVI and PNI may increase the chance of lymph node metastasis\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMultivariate analysis identified LVI, PNI, pT-stage and serum CEA level as independent prognostic factors in stage II GC patients. Consistent with existing literature\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e, our study confirms the prognostic significance of LVI as an independent predictor of survival in gastric cancer patients. Therefore, more benefits might be achieved by phasing in LVI and the 8th edition of the TNM staging system of AJCC\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. The prognostic significance of serum CEA elevation was established by Fan et al., whose multivariate analysis confirmed its status as an independent risk factor for reduced survival in early gastric cancer (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05)\u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e. There is also a study which suggests that elevated CEA levels may be associated with liver metastases and lymph node metastases\u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. Gao et al. reported that reduced mortality after adjuvant chemotherapy was observed in stage IB patients with positive lymphovascular invasion\u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e. Not coincidentally, there have been other studies showing the benefit of adjuvant chemotherapy on OS and DFS in PNI-positive patients\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn accordance with National Comprehensive Cancer Network (NCCN) guidelines, adjuvant chemotherapy was indicated for patients with stage II-III gastric cancer in our study cohort\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e, but it has been reported that a portion of stage II patients (T3N0) could not gain benefit from adjuvant chemotherapy\u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e. Combined with the current studies, we believe that stage II patients with LVI and PNI will benefit from adjuvant chemotherapy.\u003c/p\u003e \u003cp\u003eMechanisms of LVI and PNI are unclear, but there is a study showing that LVI and PNI may cause high tumor stroma percentage, low Klintrup-M\u0026auml;kinen grade and high Glasgow microenvironment score, which lead to poorer prognosis of GC\u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e. In addition, many scholars have attempted to study the mechanisms of LVI and PNI at the genetic level. It has been suggested that miR-199a/b increases the probability of LVI by targeting Frizzled-6, thereby promoting the progression of GC\u003csup\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/sup\u003e. Similarly, Liu et al. reported that mammalian infertile-20-like kinase 4 (MST4) is associated with LVI and PNI and it can promote GC cell proliferation, invasion, and metastasis\u003csup\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/sup\u003e. Perhaps more therapeutic options can be researched from these mechanisms.\u003c/p\u003e \u003cp\u003eSeveral limitations should be acknowledged in this study. This study was a retrospective study from a single center and the sample size was so small that it may be subject to selection bias. Moreover, this study focused on the surface of LVI and PNI and did not delve into the pathogenesis of LVI and PNI in gastric cancer.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, LVI and PNI can reduce the 5-year OS and DFS of stage II gastric cancer patients. The impact of LVI and PNI should be considered when considering the prognosis of stage II patients in clinical practice. In the meantime, we need more effective adjuvant chemotherapy for stage II patients with LVI and PNI.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of interest statement\u003c/h2\u003e \u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors contributed to the study conception and design. Data collection and analysis were performed by Yao Cen and Yuanyuan Li.\u0026nbsp;The first draft of the manuscript was written by Yao Cen and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThe project is supported by Cultivation of Innovative Medical Talents among the Youth in the City (Grant numbers[KY201125]).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel R L, Giaquinto A N, Jemal A. Cancer statistics, 2024[J]. CA Cancer J Clin, 2024,74(1):12-49.\u003c/li\u003e\n\u003cli\u003eYang W J, Zhao H P, Yu Y, et al. Updates on global epidemiology, risk and prognostic factors of gastric cancer[J]. World J Gastroenterol, 2023,29(16):2452-2468.\u003c/li\u003e\n\u003cli\u003eCoccolini F, Nardi M, Montori G, et al. Neoadjuvant chemotherapy in advanced gastric and esophago-gastric cancer. Meta-analysis of randomized trials[J]. Int J Surg, 2018,51:120-127.\u003c/li\u003e\n\u003cli\u003eWu L, Liang Y, Zhang C, et al. 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Heliyon, 2023,9(6):e16735.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Gastric cancer, Lymphovascular infiltration, Perineural invasion, Prognostic factors","lastPublishedDoi":"10.21203/rs.3.rs-6889639/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6889639/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eLymphovascular invasion(LVI) refers to the presence of cancer cells in lymphatic vessels or blood vessels. Perineural invasion (PNI) is the process of neoplastic invasion of peripheral nerves. The purpose of this study is to explore the prognostic value of stage II gastric cancer patients with LVI and PNI.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eOf the 554 patients with gastric cancer at stage II, 103 had been examined for LVI and 95 had been examined for PNI. LVI and PNI were assessed through hematoxylin and eosin (HE) staining. Survival outcomes were evaluated using the Kaplan-Meier method, with statistical significance determined by the log-rank test. To identify prognostic factors, both univariate and multivariate analyses were conducted, employing the Cox proportional hazards regression model.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe LVI status was associated with pT stage, pN stage, serum carcinoembryonic antigen (CEA) levels and tumor size. The PNI status was associated with pT stage, pN stage and serum CEA levels. The 5-year overall survival (OS) rate and the 5-year disease-free survival (DFS) rate of the LVI- group were greater than the LVI\u0026thinsp;+\u0026thinsp;group. Similarly, the 5-year OS rate and the 5-year DFS rate of the PNI- group were greater than the PNI\u0026thinsp;+\u0026thinsp;group. Multivariate analyses showed that pT-stage, LVI, PNI and serum CEA level were significant prognostic factors for stage II GC patients.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eLVI and PNI can reduce the 5-year OS and DFS of stage II gastric cancer patients. The impact of LVI and PNI should be considered when considering the prognosis of stage II patients in clinical practice. In the meantime, we need more effective adjuvant chemotherapy for stage II patients with LVI and PNI.\u003c/p\u003e","manuscriptTitle":"Prognostic value of lymphovascular and perineural invasion in stage II gastric cancer patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-20 15:30:12","doi":"10.21203/rs.3.rs-6889639/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1f632870-fe09-4ad6-a0cb-7e17d9b08445","owner":[],"postedDate":"June 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-05T12:57:05+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-20 15:30:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6889639","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6889639","identity":"rs-6889639","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}