Tumor size does not affect overall survival of patients undergoing resection for a single hepatocellular carcinoma without microscopic vascular invasion.

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Yi-Hao Yen, Fang-Ying Kuo, Hock-Liew Eng, Yueh-Wei Liu, Chee-Chien Yong, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3876985/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 Whether tumor size affects the survival of patients undergoing liver resection (LR) for a single hepatocellular carcinoma (HCC) without microscopic vascular invasion (MVI), i.e., pathological T1N0M0, is controversial. We aimed to clarify this issue. Methods We enrolled 626 patients with HCC of pathological stage T1N0M0 of the 7th edition of American Joint Committee on Cancer staging who underwent LR between 2011 and 2021 at our institution. The overall survival (OS) of patients with T1N0M0 HCC > 5.0 cm and those with T1N0M0 HCC ≤ 5.0 cm was compared using the Kaplan–Meier estimator and log-rank test both before and after propensity score matching (PSM). Results Ninety-two (14.7%) patients had T1N0M0 HCC > 5.0 cm. The proportion of patients with cirrhosis was lower in the T1N0M0 HCC > 5.0 cm group than in the T1N0M0 HCC ≤ 5.0 cm group (16.3% vs 41.2%, p < 0.001). The former also had a lower proportion of patients showing anti-HCV positivity than the latter (17.4% vs 33.9%, p = 0.002). Five-year OS did not differ significantly between the two groups before PSM (82% vs 84%, p = 0.857) or after PSM (82% vs 92%, p = 0.274). Conclusion Tumor size did not affect the OS of patients undergoing LR for T1N0M0 HCC. hepatocellular carcinoma overall survival microscopic vascular invasion liver resection Figures Figure 1 Figure 2 Introduction Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide [ 1 ]. Liver resection (LR) is a curative treatment for patients with HCC [ 2 ]. Previous reports suggest that tumor size does not influence the survival of patients with a single HCC without microvascular invasion (MVI), i.e., pathological T1N0M0[ 3 – 6 ]. Therefore, the 6th (published in 2002) [ 7 ] and 7th editions of the American Joint Committee on Cancer (AJCC) staging system [ 8 ] classified a single HCC without MVI as T1. In the 8th edition, a single HCC > 2.0 cm and without MVI was classified as T1b [ 9 ]. According to these different versions of the AJCC staging system spanning two decades, a single HCC without MVI has the best prognosis for patients undergoing LR for the disease. However, recent studies have suggested that the prognosis of patients with large T1N0M0 tumors may be worse than that of patients with small T1N0M0 tumors [ 10 , 11 ]. Furthermore, a number of studies have provided evidence that tumor size does not have an impact on overall survival (OS) of patients undergoing LR for T1N0M0 HCC [ 3 – 6 ]. However, with advances in resection for HCC, e.g., advances in non-invasive selection of surgical candidates, laparoscopy liver surgery, intraoperative near-infrared imaging, and effective anti-viral treatment for surgical management of HCC [ 12 ], the outcomes of patients undergoing LR for HCC may be improved. Therefore, in this retrospective study, we aimed to evaluate whether tumor size influences the OS of patients undergoing LR for pathological T1N0M0 HCC by enrolling patients treated during the recent 10-year period. Materials and methods The Institutional Review Board of Kaohsiung Chang Gung Memorial Hospital approved this study (reference number: 202201189B0). Data were extracted from the Kaohsiung Chang Gung Memorial Hospital HCC registry database. Patients undergoing LR for HCC between 2011 and 2021 were enrolled consecutively. The T classification was determined using the 7th edition of the AJCC staging system 8 for the period 2011–2017 and the 8th edition for 2018–2021[ 9 ]. Between 2011 and 2017, 4000 patients were newly diagnosed with HCC; of these patients, 1256 underwent LR, among whom 412 were pathological stage T1N0M0. Between 2018 and 2021, 1948 patients were newly diagnosed with HCC; of these patients, 736 patients underwent LR, among whom 278 were pathological stage T1a/bN0M0. Therefore, 690 patients were pathological stage T1N0M0 in this cohort. Of these patients, five died within 90 days of surgery; therefore, the perioperative mortality of this cohort was 0.7%. After excluding patients who died within 90 days of surgery, were T1aN0M0 with MVI, received non-curative-intent resection, had a positive surgical margin, or received combined local regional therapies, the remaining 626 patients were enrolled in the analysis. Curative resection was defined as surgery in which the entire tumor was removed macroscopically. The raw data for the cohort of patients in this study are available via the following digital object identifier: https://www.dropbox.com/scl/fi/z7jryz9zxhttwig91x496/raw-data.xlsx?dl=0&rlkey=qz4m2i52vqrevg5auczrpy0sl Fibrosis was assessed using Ishak scores; cirrhosis was defined as an Ishak score of 5 or 6 [ 13 ]. OS was calculated from the date of LR to the date of the last follow-up or death. Statistical analyses The characteristics of the patients are presented as number (%) or median and interquartile range (IQR). Categorical variables were analyzed using the chi-square test and continuous variables using the Mann–Whitney U test. Kaplan–Meier survival curves and the log-rank test were used to compare OS between groups. Survival analyses were performed both for the entire cohort and after stratifying by propensity score matching (PSM). PSM was used to identify a cohort of patients with T1N0M0 HCC > 5.0 cm similar in characteristics to patients with T1N0M0 HCC ≤ 5.0 cm. PSM was estimated using a multivariate logistic regression model and the following characteristics as covariates: age, sex, alpha-fetoprotein (AFP) level, cirrhosis status, and hepatitis B surface antigen (HBsAg) and anti-hepatitis C virus (HCV) positivity status. PSM was conducted with 1:1 matching without replacement using a caliper width equal to 0.2 of the propensity score. Differences in characteristics included in the propensity scores were assessed by standardized mean differences (SMD). SMD 0.5 indicated a substantial difference [ 14 ]. To identify prognostic factors, a multivariate regression analysis was performed using the Cox proportional hazards model with p < 0.05 in univariate analysis. All p-values were two-tailed, and a p-value of < 0.05 was considered statistically significant. All statistical analyses were performed using the computing environment IBM SPSS Statistics, version 25. Results Characteristics of the cohort The median age of the 626 T1N0M0 patients enrolled in this study was 62 years; 462 (73.8%) of the patients were men and the median body mass index (BMI) was 24.8 kg/m 2 ; 194 (31.0%) patients had an AFP level ≥ 20 ng/ml, 235 (37.5%) patients were cirrhotic, 335 (53.5%) patients were HBsAg positive, 197 (31.5%) patients were anti-HCV positive, and 623 (99.5%) patients were Child–Pugh class A. The median tumor size was 2.6 cm, median creatinine level was 1.0 mg/dl, median total bilirubin was 0.8 mg/dl, and median international normalized ratio (INR) was 1.0. Tumor size was > 5.0 cm in 92 (14.7%) patients. The median tumor size was 6.75 cm in patients with a tumor size > 5.0 cm compared to 2.5 cm in patients with a tumor size ≤ 5.0 cm (p 5.0 cm compared to 220 (41.2%) patients with a tumor size ≤ 5.0 cm (p 5.0 cm were anti-HCV positive compared to 181 (33.9%) patients with a tumor size ≤ 5.0 cm (p = 0.002). There were no significant differences between the two groups in age, sex, BMI, AFP ≥ 20 ng/ml, Child–Pugh class A, creatinine level, total bilirubin, INR, and HBsAg positivity (Table 1 ). Table 1 Characteristics of a cohort of patients undergoing liver resection for pathological stage T1N0M0 hepatocellular carcinoma by tumor size. All patients, n = 626 Tumor size > 5 cm, n = 92 Tumor size ≦ 5cm, n = 534 p Age (years) 62.0(55.0–68.0) 63.0 (55.3–72.0) 62.00 (55.0–68.0) 0.125 Men 462(73.8%) 74 (80.4%) 388 (72.7%) 0.117 Tumor size (cm) 2.6(2.0–4.0) 6.8 (5.5-9.0) 2.5 (1.8–3.2) < 0.001 BMI (kg/m 2 ) 24.7(22.5–27.3) 24.6 (22.0-26.9) 24.8 (22.5–27.4) 0.428 AFP ≧ 20 ng/ml 194(31.0%) 29 (31.5%) 165 (30.9%) 0.905 Presence of cirrhosis 235(37.5%) 15 (16.3%) 220 (41.2%) < 0.001 Child Pugh A 62399.5%) 91 (98.9%) 532 (99.6%) 0.339 Creatinine (mg/dl) 1.0(0.8–1.1) 1.0 (0.8–1.2) 1.0 (0.8–1.1) 0.402 Total bilirubin(mg/dl) 0.8(0.6–1.1) 0.8 (0.6–1.1) 0.8 (0.6–1.1) 0.894 INR 1.0 (1.0–1.0) 1.0 (0.9-1.0) 1.0 (1.0–1.0) 0.426 HBs Ag positive 335 (53.5%) 44 (47.8%) 291 (54.5%) 0.236 Anti-HCV positive 197 (31.5%) 16 (17.4%) 181 (33.9%) 0.002 BMI, body mass index; AFP, alpha-fetoprotein; INR, international normalized ratio; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus Overall survival of the cohort by tumor size Seventy-six (12.1%) patients died after a median follow-up period of 3.55 years (IQR = 0.82–4.97). The five-year OS of tumor size > 5.0 cm group and ≤ 5.0 cm group was 82% and 84%, respectively (p = 0.857) (Fig. 1). Univariate and multivariate analyses of five-year overall survival Univariate analyses showed that age > 65 years (hazard ratio [HR] = 2.038; 95% confidence interval [CI] = 1.189–3.493; p = 0.01) and creatinine level > 1.2 mg/dl (HR = 2.481; 95% CI = 1.405–4.382; p = 0.002) were associated with five-year OS, while tumor size was not (HR = 1.072; 95% CI = 0.505–2.274; p = 0.857). Multivariate analyses showed that age > 65 years (HR = 1.863; 95% CI = 1.081–3.209; p = 0.025) and creatinine level > 1.2 mg/dl (HR = 2.273; 95% CI = 1.280–4.034; p = 0.005) were associated with five-year OS (Table 2 ). Table 2 Univariate and multivariate analyses of five-year overall survival of patients undergoing liver resection for pathological stage T1N0M0 hepatocellular carcinoma. Univariate Multivariate HR (95%CI) p HR (95%CI) p Sex Women Reference Men 0.833(0.463–1.497) 0.541 Age (years) ≦ 65 Reference Reference > 65 2.038(1.189–3.493) 0.010 1.863(1.081–3.209) 0.025 Tumor size ≦ 5.0 cm Reference > 5.0 cm 1.072(0.505–2.274) 0.857 Cirrhosis Absence Reference Presence 1.572 (0.917–2.694) 0.100 AFP (ng/ml) Reference 1.2 2.481(1.405–4.382) 0.002 2.273(1.280–4.034) 0.005 Total bilirubin (mg/dl) ≦ 1.4 Reference > 1.4 1.011(0.365–2.802) 0.983 INR ≦ 1.2 Reference > 1.2 4.530(0.625–32.832) 0.135 BMI (kg/m 2 ) ≦ 24 Reference > 24 1.404(0.795–2.478) 0.243 BMI, body mass index; AFP, alpha-fetoprotein; INR, international normalized ratio; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus Characteristics of patients by tumor size after propensity score matching Ninety-two patients remained in each group after PSM. The two groups did not differ significantly in any variable except for tumor size (median: 6.75 vs 3.0 cm; p 5 cm, n = 92 Tumor size ≦ 5cm, n = 92 p SMD Age (years) 63.0 (55.3–72.0) 63.0 (56.0–70.0) 0.955 0.090 Men 74 (80.4%) 72 (78.3%) 0.716 0.054 Tumor size (cm) 6.75 (5.5-9.0) 3.0 (2.1-4.0) < 0.001 BMI (kg/m 2 ) 24.6 (22.0-26.9) 25.2(23.1–28.0) 0.084 AFP ≧ 20 ng/ml 29 (31.5%) 33 (35.9%) 0.533 0.092 Presence of cirrhosis 15 (16.3%) 17 (18.5%) 0.697 0.057 Child Pugh A 91 (98.9%) 92 (100.0%) 0.316 Creatinine (mg/dl) 1.0 (0.8–1.2) 1.0(0.8–1.1) 0.569 Total bilirubin(mg/dl) 0.8 (0.6–1.1) 0.8 (0.6-1.0) 0.488 INR 1.0 (0.9-1.0) 1.0(0.9-1.0) 0.269 HBsAg positive 44 (47.8%) 45 (48.9%) 0.883 0.022 Anti-HCV positive 16 (17.4%) 14 (15.2%) 0.690 0.059 BMI, body mass index; AFP, alpha-fetoprotein; INR, international normalized ratio; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus Overall survival of patients by tumor size after propensity score matching The five-year OS was 82% and 92% for tumor > 5.0 cm and tumor ≤ 5.0 cm, respectively (p = 0.274) (Fig. 2). Discussion We enrolled 626 patients with T1N0M0 HCC in this study. Of these patients, only 92 (14.7%) had a tumor size > 5.0 cm. However, the patient group with tumor > 5cm and that with tumor ≤ 5.0 cm did not differ significantly in five-year OS both before and after PSM. Univariate and multivariate analyses showed that tumor > 5cm was not associated with five-year OS. Therefore, we conclude that tumor size did not have an impact on the OS of patients undergoing LR for pathological T1N0M0 HCC. We used 5 cm as the cutoff value based on the BCLC staging system [ 15 ]. A single large HCC was defined as a single HCC > 5cm in diameter without vascular invasion or extrahepatic metastasis; it was also defined as beyond Milan criteria [ 16 ]. We did not evaluate whether prognosis was worse for a tumor size > 5 cm because there were few patients with T1N0M0 HCC > 5 cm (14.7%). Fifty-nine (9.4%) patients had a tumor > 6.0 cm and 41(6.5%) had a tumor > 7.0 cm in this cohort. Therefore, it would not have been clinically relevant to use a tumor size larger than 5 cm as the cutoff value due to the very limited number of patients. Although a single tumor without MVI has been classified as T1 in the AJCC staging system for two decades [ 7 – 9 ], some researchers continue to challenge this classification. Shinkawa et al. enrolled 487 patients who underwent LR for a single HCC without MVI. A multivariate Cox proportional hazards model showed that tumor size > 5cm was significantly associated with an increase in cancer-specific survival (CSS) risk (p = 0.029). After PSM, the CSS of patients with tumors > 5 cm was significantly worse than that of patients with tumors ≤ 5 cm (p = 0.0077). Shinkawa et al. concluded that tumor size was associated with poor CSS in patients with a solitary HCC without MVI [ 10 ]. Lee et al. studied 2893 patients who underwent LR for pathological T1N0M0 HCC. The Kaplan–Meier estimator showed that recurrence-free survival (RFS) and liver specific-OS, i.e., liver-caused mortality, of patients with T1N0M0 tumors > 6.5 cm were similar to those of patients with T2N0M0 tumors. Multivariate Cox regression analysis showed that tumor size > 6.5 cm was an independent poor prognostic factor of RFS and liver specific-OS of patients with T1N0M0 HCC. The authors concluded that tumor size had a significant influence on the outcomes of patients undergoing LR for pathological T1N0M0 HCC [ 11 ]. However, both these studies did not analyze whether tumor size would significantly affect the OS of patients undergoing LR for T1N0M0 HCC [ 10 , 11 ].We believed that OS was more appropriate than liver specific-OS and CSS as a primary outcome measurement for patients undergoing LR for HCC because it is sometimes difficult to confirm the cause of death of these patients. For example, the course of COVID-19 in patients with advanced liver disease or cancer tends to be severe and patients have a higher risk of death. A recent Polish study of 4,314 patients hospitalized at a single institution due to COVID-19 infection between 2020 and 2022 selected a cohort of 31 patients with liver cirrhosis and seven patients with HCC for investigation. The control group included 123 patients without liver disease. Fifteen patients died, including 12 with cirrhosis and three with HCC, accounting for 39.47% of the entire cohort, 39% of the cirrhotic group, and 43% of the HCC group, while 13 patients died in the control group (10.6%); the mortality rate was significantly different between the group with liver disease and/or HCC and the control group [ 17 ]. In this scenario, it would be controversial to definitively state the cause of death of patients with cirrhosis and/or HCC as COVID-related or liver/HCC-related. Furthermore, AJCC staging of HCC was developed based on patients with HCC undergoing LR and uses OS as the primary outcome [ 18 ]. As tumor size increases, the risk of MVI increases [ 19 ]; therefore, the question why a subgroup of patients developed a large T1N0M0 HCC is interesting. The proportion of patients with cirrhosis and the proportion of patients with anti-HCV positivity were both lower in the tumor size > 5.0 cm group than in the tumor size 5.0 cm were non-cirrhotic and/or anti-HCV negative. The BCLC system designated a single large HCC (> 5 cm) as BCLC stage A rather than stage B in 2012 [ 15 ]. In clinical practice, a single large HCC (> 5 cm) is indicated for LR as early HCC (BCLC stage A) but appear to lead to worse prognosis than HCC within Milan criteria [ 16 ].The worse outcome of a single large HCC is due to the higher risk of MVI [ 19 ]. Therefore, the ability to preoperatively diagnose a single large HCC without MVI would be of great benefit, because these patients enjoy excellent outcomes after LR, with five-year OS exceeding 80%. Previous studies showed that MVI of HCC could be preoperatively diagnosed with CT or MRI [ 20 – 24 ]. Based on the imaging traits of MVI and clinical characteristics of patients, we could preoperatively identify patients with a single large HCC > 5.0 cm without MVI with greater confidence (i.e., non-cirrhotic and/or anti-HCV negative plus without imaging traits of MVI). In the present study, age > 65 years and creatinine level > 1.2 mg/dL were two independent factors associated with five-year OS. Older age represents a higher risk of comorbidities and our previous studies also showed that older age is an independent factor associated with OS of patients undergoing LR for HCC [ 25 , 26 ]. We selected patients with good liver function reserve for LR in our clinical practice; therefore, renal insufficiency is less likely to be related to advanced liver disease (i.e., hepatorenal syndrome). We infer that renal insufficiency is due to the presence of comorbidities such as diabetes and hypertension ( https://en.wikipedia.org/wiki/Kidney_disease ). Therefore, the association between renal insufficiency and five-year OS could be due to the presence of comorbidities. A strength of the current study is that the majority of patients’ pathology was reported by two senior pathologists (HLE and FYK; HLE is FYK’s mentor), which minimized interobserver variation in interpreting MVI. Limitations of the present study include the lack of tumor differentiation data. However, five-year OS was comparable between patients with T1N0M0 HCC > 5.0 cm and T1N0M0 HCC ≤ 5.0 cm before PSM. Therefore, we believe that the lack of this information would not change the results of the present study. Another limitation is that it was a retrospective study. Conclusion We enrolled patients undergoing LR for HCC in the previous 10 years at our institution. We found that tumor size did not have an impact on the OS of patients undergoing LR for pathological T1N0M0 HCC. The results of the present study provide further support for the appropriateness of the current AJCC staging system for staging HCC. Declarations Not applicable Funding: This study was supported by Grant CMRPG8N1131 from the Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan. Conflict of interest: The authors have no conflicts of interest to disclose for all authors. Data availability: all data is available Ethics approval: The Institutional Review Board of Kaohsiung Chang Gung Memorial Hospital approved this study (Reference number: 202201189B0) and waived the need for informed consent. Authors’ Contributions Study conception and design: Yi-Hao Yen, Chih-Chi Wang Acquisition of data: all authors Analysis and interpretation of data: Chih-Yun Lin Drafting of manuscript: Fang-Ying Kuo Critical revision of manuscript: all authors All authors reviewed the manuscript Acknowledgements The authors thank the Cancer Center, Kaohsiung Chang Gung Memorial Hospital for the provision of HCC registry data. The authors thank Chih-Yun Lin, Nien-Tzu Hsu, and the Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital for statistical analyses. This study was supported by Grant CMRPG8N1131 from the Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan. There were no conflicts of interest. References Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR (2019). A global view of hepatocellular carcinoma: trends, risk, prevention and management. 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Tumor Necrosis Is an Indicator of Poor Prognosis Among Hepatoma Patients Undergoing Resection. J Surg Res;283:1091–1099. doi: 10.1016/j.jss.2022.11.039 . Additional Declarations No competing interests reported. Supplementary Files Tables.docx 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-3876985","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":268307773,"identity":"67487e3f-b7f3-4ca2-8f19-9353dae33250","order_by":0,"name":"Yi-Hao Yen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYNCCAgsgwXyAgbGBaC0GEkCCLQFJSwJRWngMiNPC33788YcPBhKJ/dI93yR+7rCRY2A/fHQD44/DOLVInMkxk5wB1DJzztltkr1n0owZeNLSbjAk4NZiwJDDxswD1LLhRu42Cd62w4kNEjxmQC23cWvhf/748x+glv03cp5J/iVKi0SCgTQDyBaJHDZpomyRuPHGTLLHQMJ4xo00Y2vZtjRjNpBfEtL+49TC35/++MOPChvZ/hnJD2++bbOR42c/fOzGB5s0nFpgwLGBgYEFFDsMbCAigaAGBgZ7IGb+QITCUTAKRsEoGIEAALsOVFTD8tg8AAAAAElFTkSuQmCC","orcid":"","institution":"Kaohsiung Chang Gung Memorial Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yi-Hao","middleName":"","lastName":"Yen","suffix":""},{"id":268307774,"identity":"1c496ae8-4fcd-499d-93c8-647dc80b3260","order_by":1,"name":"Fang-Ying Kuo","email":"","orcid":"","institution":"Kaohsiung Chang Gung Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fang-Ying","middleName":"","lastName":"Kuo","suffix":""},{"id":268307775,"identity":"79fee08d-7f2d-4c50-846b-bdd49053e81d","order_by":2,"name":"Hock-Liew Eng","email":"","orcid":"","institution":"Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hock-Liew","middleName":"","lastName":"Eng","suffix":""},{"id":268307776,"identity":"1555ed11-4d39-4cc9-8c89-d9af83450afc","order_by":3,"name":"Yueh-Wei Liu","email":"","orcid":"","institution":"Kaohsiung Chang Gung Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yueh-Wei","middleName":"","lastName":"Liu","suffix":""},{"id":268307777,"identity":"bbdb8c7c-e667-482d-96ed-f9d234c2f69e","order_by":4,"name":"Chee-Chien Yong","email":"","orcid":"","institution":"Kaohsiung Chang Gung Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chee-Chien","middleName":"","lastName":"Yong","suffix":""},{"id":268307778,"identity":"656b9643-9896-45b4-bd7c-7ad8604963fd","order_by":5,"name":"Chih-Chi Wang","email":"","orcid":"","institution":"Kaohsiung Chang Gung Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chih-Chi","middleName":"","lastName":"Wang","suffix":""},{"id":268307779,"identity":"1ff64b70-bcc8-42fd-9a9f-3d0dc6b8962a","order_by":6,"name":"Wei-Feng Li","email":"","orcid":"","institution":"Kaohsiung Chang Gung Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wei-Feng","middleName":"","lastName":"Li","suffix":""},{"id":268307780,"identity":"433a95a6-e846-4901-9053-e5d504d3ca4e","order_by":7,"name":"Chih-Yun Lin","email":"","orcid":"","institution":"Kaohsiung Chang Gung Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chih-Yun","middleName":"","lastName":"Lin","suffix":""}],"badges":[],"createdAt":"2024-01-18 22:02:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3876985/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3876985/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50227586,"identity":"5ec0bf0f-5113-4e1e-af82-33c4218a448f","added_by":"auto","created_at":"2024-01-26 18:30:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":50324,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival of a cohort of patients undergoing liver resection for pathological stage T1N0M0 hepatocellular carcinoma by tumor size.\u003c/p\u003e","description":"","filename":"OnlineFig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-3876985/v1/8976d2841d9df59d366f0a92.png"},{"id":50227584,"identity":"6205d34c-6003-42a3-af95-6451747727cd","added_by":"auto","created_at":"2024-01-26 18:30:59","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":48230,"visible":true,"origin":"","legend":"\u003cp\u003e\u0026nbsp;Overall survival of a cohort of patients undergoing liver resection for pathological stage T1N0M0 hepatocellular carcinoma by tumor size after propensity score matching.\u003c/p\u003e","description":"","filename":"OnlineFig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-3876985/v1/d6bbedbbef523a3a46bb4280.png"},{"id":51678212,"identity":"aa545087-8322-4d5a-a2cb-d5d41dddc240","added_by":"auto","created_at":"2024-02-27 05:37:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1853318,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3876985/v1/304288c3-edfb-4bb4-b5a1-880f0d6b1123.pdf"},{"id":50227585,"identity":"de4861bd-1c59-48be-acd0-62d7a30b3123","added_by":"auto","created_at":"2024-01-26 18:30:59","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":18246,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-3876985/v1/1e5ab8c982bb7ed389a50ff1.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Tumor size does not affect overall survival of patients undergoing resection for a single hepatocellular carcinoma without microscopic vascular invasion.","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Liver resection (LR) is a curative treatment for patients with HCC [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevious reports suggest that tumor size does not influence the survival of patients with a single HCC without microvascular invasion (MVI), i.e., pathological T1N0M0[\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTherefore, the 6th (published in 2002) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] and 7th editions of the American Joint Committee on Cancer (AJCC) staging system [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] classified a single HCC without MVI as T1. In the 8th edition, a single HCC\u0026thinsp;\u0026gt;\u0026thinsp;2.0 cm and without MVI was classified as T1b [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. According to these different versions of the AJCC staging system spanning two decades, a single HCC without MVI has the best prognosis for patients undergoing LR for the disease.\u003c/p\u003e \u003cp\u003eHowever, recent studies have suggested that the prognosis of patients with large T1N0M0 tumors may be worse than that of patients with small T1N0M0 tumors [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Furthermore, a number of studies have provided evidence that tumor size does not have an impact on overall survival (OS) of patients undergoing LR for T1N0M0 HCC [\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, with advances in resection for HCC, e.g., advances in non-invasive selection of surgical candidates, laparoscopy liver surgery, intraoperative near-infrared imaging, and effective anti-viral treatment for surgical management of HCC [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], the outcomes of patients undergoing LR for HCC may be improved.\u003c/p\u003e \u003cp\u003eTherefore, in this retrospective study, we aimed to evaluate whether tumor size influences the OS of patients undergoing LR for pathological T1N0M0 HCC by enrolling patients treated during the recent 10-year period.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eThe Institutional Review Board of Kaohsiung Chang Gung Memorial Hospital approved this study (reference number: 202201189B0). Data were extracted from the Kaohsiung Chang Gung Memorial Hospital HCC registry database. Patients undergoing LR for HCC between 2011 and 2021 were enrolled consecutively.\u003c/p\u003e \u003cp\u003eThe T classification was determined using the 7th edition of the AJCC staging system\u003csup\u003e8\u003c/sup\u003e for the period 2011\u0026ndash;2017 and the 8th edition for 2018\u0026ndash;2021[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBetween 2011 and 2017, 4000 patients were newly diagnosed with HCC; of these patients, 1256 underwent LR, among whom 412 were pathological stage T1N0M0.\u003c/p\u003e \u003cp\u003eBetween 2018 and 2021, 1948 patients were newly diagnosed with HCC; of these patients, 736 patients underwent LR, among whom 278 were pathological stage T1a/bN0M0. Therefore, 690 patients were pathological stage T1N0M0 in this cohort. Of these patients, five died within 90 days of surgery; therefore, the perioperative mortality of this cohort was 0.7%. After excluding patients who died within 90 days of surgery, were T1aN0M0 with MVI, received non-curative-intent resection, had a positive surgical margin, or received combined local regional therapies, the remaining 626 patients were enrolled in the analysis. Curative resection was defined as surgery in which the entire tumor was removed macroscopically. The raw data for the cohort of patients in this study are available via the following digital object identifier: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.dropbox.com/scl/fi/z7jryz9zxhttwig91x496/raw-data.xlsx?dl=0\u0026amp;rlkey=qz4m2i52vqrevg5auczrpy0sl\u003c/span\u003e\u003cspan address=\"https://www.dropbox.com/scl/fi/z7jryz9zxhttwig91x496/raw-data.xlsx?dl=0\u0026amp;rlkey=qz4m2i52vqrevg5auczrpy0sl\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003cp\u003eFibrosis was assessed using Ishak scores; cirrhosis was defined as an Ishak score of 5 or 6 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. OS was calculated from the date of LR to the date of the last follow-up or death.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eThe characteristics of the patients are presented as number (%) or median and interquartile range (IQR). Categorical variables were analyzed using the chi-square test and continuous variables using the Mann\u0026ndash;Whitney \u003cem\u003eU\u003c/em\u003e test. Kaplan\u0026ndash;Meier survival curves and the log-rank test were used to compare OS between groups. Survival analyses were performed both for the entire cohort and after stratifying by propensity score matching (PSM). PSM was used to identify a cohort of patients with T1N0M0 HCC\u0026thinsp;\u0026gt;\u0026thinsp;5.0 cm similar in characteristics to patients with T1N0M0 HCC\u0026thinsp;\u0026le;\u0026thinsp;5.0 cm. PSM was estimated using a multivariate logistic regression model and the following characteristics as covariates: age, sex, alpha-fetoprotein (AFP) level, cirrhosis status, and hepatitis B surface antigen (HBsAg) and anti-hepatitis C virus (HCV) positivity status. PSM was conducted with 1:1 matching without replacement using a caliper width equal to 0.2 of the propensity score. Differences in characteristics included in the propensity scores were assessed by standardized mean differences (SMD). SMD\u0026thinsp;\u0026lt;\u0026thinsp;0.1 indicated a trivial difference in the covariate between treatment groups, whereas \u0026gt;\u0026thinsp;0.5 indicated a substantial difference [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. To identify prognostic factors, a multivariate regression analysis was performed using the Cox proportional hazards model with p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 in univariate analysis. All p-values were two-tailed, and a p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant. All statistical analyses were performed using the computing environment IBM SPSS Statistics, version 25.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of the cohort\u003c/h2\u003e \u003cp\u003eThe median age of the 626 T1N0M0 patients enrolled in this study was 62 years; 462 (73.8%) of the patients were men and the median body mass index (BMI) was 24.8 kg/m\u003csup\u003e2\u003c/sup\u003e; 194 (31.0%) patients had an AFP level\u0026thinsp;\u0026ge;\u0026thinsp;20 ng/ml, 235 (37.5%) patients were cirrhotic, 335 (53.5%) patients were HBsAg positive, 197 (31.5%) patients were anti-HCV positive, and 623 (99.5%) patients were Child\u0026ndash;Pugh class A. The median tumor size was 2.6 cm, median creatinine level was 1.0 mg/dl, median total bilirubin was 0.8 mg/dl, and median international normalized ratio (INR) was 1.0. Tumor size was \u0026gt;\u0026thinsp;5.0 cm in 92 (14.7%) patients. The median tumor size was 6.75 cm in patients with a tumor size\u0026thinsp;\u0026gt;\u0026thinsp;5.0 cm compared to 2.5 cm in patients with a tumor size\u0026thinsp;\u0026le;\u0026thinsp;5.0 cm (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Cirrhosis was present in 15 (16.3%) patients with a tumor size\u0026thinsp;\u0026gt;\u0026thinsp;5.0 cm compared to 220 (41.2%) patients with a tumor size\u0026thinsp;\u0026le;\u0026thinsp;5.0 cm (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Sixteen (17.4%) patients with a tumor size\u0026thinsp;\u0026gt;\u0026thinsp;5.0 cm were anti-HCV positive compared to 181 (33.9%) patients with a tumor size\u0026thinsp;\u0026le;\u0026thinsp;5.0 cm (p\u0026thinsp;=\u0026thinsp;0.002). There were no significant differences between the two groups in age, sex, BMI, AFP\u0026thinsp;\u0026ge;\u0026thinsp;20 ng/ml, Child\u0026ndash;Pugh class A, creatinine level, total bilirubin, INR, and HBsAg positivity (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of a cohort of patients undergoing liver resection for pathological stage T1N0M0 hepatocellular carcinoma by tumor size.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll patients, n\u0026thinsp;=\u0026thinsp;626\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTumor size\u0026thinsp;\u0026gt;\u0026thinsp;5 cm, n\u0026thinsp;=\u0026thinsp;92\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTumor size\u0026thinsp;≦\u0026thinsp;5cm, n\u0026thinsp;=\u0026thinsp;534\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62.0(55.0\u0026ndash;68.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e63.0 (55.3\u0026ndash;72.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e62.00 (55.0\u0026ndash;68.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.125\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e462(73.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e74 (80.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e388 (72.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.117\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.6(2.0\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.8 (5.5-9.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.5 (1.8\u0026ndash;3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.7(22.5\u0026ndash;27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24.6 (22.0-26.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24.8 (22.5\u0026ndash;27.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.428\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAFP\u0026thinsp;≧\u0026thinsp;20 ng/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e194(31.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29 (31.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e165 (30.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.905\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence of cirrhosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e235(37.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15 (16.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e220 (41.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChild Pugh A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62399.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e91 (98.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e532 (99.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.339\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.0(0.8\u0026ndash;1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.0 (0.8\u0026ndash;1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.0 (0.8\u0026ndash;1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.402\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal bilirubin(mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.8(0.6\u0026ndash;1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.8 (0.6\u0026ndash;1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.8 (0.6\u0026ndash;1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.894\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.0 (1.0\u0026ndash;1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.0 (0.9-1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.0 (1.0\u0026ndash;1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.426\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHBs Ag positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e335 (53.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e44 (47.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e291 (54.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.236\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-HCV positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e197 (31.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16 (17.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e181 (33.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eBMI, body mass index; AFP, alpha-fetoprotein; INR, international normalized ratio; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eOverall survival of the cohort by tumor size\u003c/h2\u003e \u003cp\u003eSeventy-six (12.1%) patients died after a median follow-up period of 3.55 years (IQR\u0026thinsp;=\u0026thinsp;0.82\u0026ndash;4.97). The five-year OS of tumor size\u0026thinsp;\u0026gt;\u0026thinsp;5.0 cm group and \u0026le;\u0026thinsp;5.0 cm group was 82% and 84%, respectively (p\u0026thinsp;=\u0026thinsp;0.857) (Fig.\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eUnivariate and multivariate analyses of five-year overall survival\u003c/h2\u003e \u003cp\u003eUnivariate analyses showed that age\u0026thinsp;\u0026gt;\u0026thinsp;65 years (hazard ratio [HR]\u0026thinsp;=\u0026thinsp;2.038; 95% confidence interval [CI]\u0026thinsp;=\u0026thinsp;1.189\u0026ndash;3.493; p\u0026thinsp;=\u0026thinsp;0.01) and creatinine level\u0026thinsp;\u0026gt;\u0026thinsp;1.2 mg/dl (HR\u0026thinsp;=\u0026thinsp;2.481; 95% CI\u0026thinsp;=\u0026thinsp;1.405\u0026ndash;4.382; p\u0026thinsp;=\u0026thinsp;0.002) were associated with five-year OS, while tumor size was not (HR\u0026thinsp;=\u0026thinsp;1.072; 95% CI\u0026thinsp;=\u0026thinsp;0.505\u0026ndash;2.274; p\u0026thinsp;=\u0026thinsp;0.857). Multivariate analyses showed that age\u0026thinsp;\u0026gt;\u0026thinsp;65 years (HR\u0026thinsp;=\u0026thinsp;1.863; 95% CI\u0026thinsp;=\u0026thinsp;1.081\u0026ndash;3.209; p\u0026thinsp;=\u0026thinsp;0.025) and creatinine level\u0026thinsp;\u0026gt;\u0026thinsp;1.2 mg/dl (HR\u0026thinsp;=\u0026thinsp;2.273; 95% CI\u0026thinsp;=\u0026thinsp;1.280\u0026ndash;4.034; p\u0026thinsp;=\u0026thinsp;0.005) were associated with five-year OS (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate analyses of five-year overall survival of patients undergoing liver resection for pathological stage T1N0M0 hepatocellular carcinoma.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95%CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR (95%CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWomen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.833(0.463\u0026ndash;1.497)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.541\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e≦\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.038(1.189\u0026ndash;3.493)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.863(1.081\u0026ndash;3.209)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e≦\u0026thinsp;5.0 cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;5.0 cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.072(0.505\u0026ndash;2.274)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.857\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCirrhosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbsence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.572 (0.917\u0026ndash;2.694)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAFP (ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e≧20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.159(0.657\u0026ndash;2.047)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.610\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHBsAg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.593(0.342\u0026ndash;1.028)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.062\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-HCV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.203(0.693\u0026ndash;2.086)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.512\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e≦\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.481(1.405\u0026ndash;4.382)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.273(1.280\u0026ndash;4.034)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal bilirubin (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e≦\u0026thinsp;1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.011(0.365\u0026ndash;2.802)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.983\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e≦\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.530(0.625\u0026ndash;32.832)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e≦\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.404(0.795\u0026ndash;2.478)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.243\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eBMI, body mass index; AFP, alpha-fetoprotein; INR, international normalized ratio; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of patients by tumor size after propensity score matching\u003c/h2\u003e \u003cp\u003eNinety-two patients remained in each group after PSM. The two groups did not differ significantly in any variable except for tumor size (median: 6.75 vs 3.0 cm; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of patients undergoing liver resection for pathological stage T1N0M0 hepatocellular carcinoma by tumor size after propensity score matching.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTumor size\u0026thinsp;\u0026gt;\u0026thinsp;5 cm, n\u0026thinsp;=\u0026thinsp;92\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTumor size\u0026thinsp;≦\u0026thinsp;5cm, n\u0026thinsp;=\u0026thinsp;92\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSMD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e63.0 (55.3\u0026ndash;72.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e63.0 (56.0\u0026ndash;70.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.955\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.090\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e74 (80.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e72 (78.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.716\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.054\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.75 (5.5-9.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.0 (2.1-4.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24.6 (22.0-26.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25.2(23.1\u0026ndash;28.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.084\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAFP\u0026thinsp;≧\u0026thinsp;20 ng/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29 (31.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e33 (35.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.533\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.092\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence of cirrhosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15 (16.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17 (18.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.697\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.057\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChild Pugh A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e91 (98.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e92 (100.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.316\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.0 (0.8\u0026ndash;1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.0(0.8\u0026ndash;1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.569\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal bilirubin(mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.8 (0.6\u0026ndash;1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.8 (0.6-1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.488\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.0 (0.9-1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.0(0.9-1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.269\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHBsAg positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e44 (47.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e45 (48.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.883\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-HCV positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16 (17.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14 (15.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.690\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.059\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eBMI, body mass index; AFP, alpha-fetoprotein; INR, international normalized ratio; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eOverall survival of patients by tumor size after propensity score matching\u003c/h2\u003e \u003cp\u003eThe five-year OS was 82% and 92% for tumor\u0026thinsp;\u0026gt;\u0026thinsp;5.0 cm and tumor\u0026thinsp;\u0026le;\u0026thinsp;5.0 cm, respectively (p\u0026thinsp;=\u0026thinsp;0.274) (Fig.\u0026nbsp;2).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe enrolled 626 patients with T1N0M0 HCC in this study. Of these patients, only 92 (14.7%) had a tumor size\u0026thinsp;\u0026gt;\u0026thinsp;5.0 cm. However, the patient group with tumor\u0026thinsp;\u0026gt;\u0026thinsp;5cm and that with tumor\u0026thinsp;\u0026le;\u0026thinsp;5.0 cm did not differ significantly in five-year OS both before and after PSM. Univariate and multivariate analyses showed that tumor\u0026thinsp;\u0026gt;\u0026thinsp;5cm was not associated with five-year OS. Therefore, we conclude that tumor size did not have an impact on the OS of patients undergoing LR for pathological T1N0M0 HCC. We used 5 cm as the cutoff value based on the BCLC staging system [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. A single large HCC was defined as a single HCC\u0026thinsp;\u0026gt;\u0026thinsp;5cm in diameter without vascular invasion or extrahepatic metastasis; it was also defined as beyond Milan criteria [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. We did not evaluate whether prognosis was worse for a tumor size\u0026thinsp;\u0026gt;\u0026thinsp;5 cm because there were few patients with T1N0M0 HCC\u0026thinsp;\u0026gt;\u0026thinsp;5 cm (14.7%). Fifty-nine (9.4%) patients had a tumor\u0026thinsp;\u0026gt;\u0026thinsp;6.0 cm and 41(6.5%) had a tumor\u0026thinsp;\u0026gt;\u0026thinsp;7.0 cm in this cohort. Therefore, it would not have been clinically relevant to use a tumor size larger than 5 cm as the cutoff value due to the very limited number of patients.\u003c/p\u003e \u003cp\u003eAlthough a single tumor without MVI has been classified as T1 in the AJCC staging system for two decades [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], some researchers continue to challenge this classification. Shinkawa et al. enrolled 487 patients who underwent LR for a single HCC without MVI. A multivariate Cox proportional hazards model showed that tumor size\u0026thinsp;\u0026gt;\u0026thinsp;5cm was significantly associated with an increase in cancer-specific survival (CSS) risk (p\u0026thinsp;=\u0026thinsp;0.029). After PSM, the CSS of patients with tumors\u0026thinsp;\u0026gt;\u0026thinsp;5 cm was significantly worse than that of patients with tumors\u0026thinsp;\u0026le;\u0026thinsp;5 cm (p\u0026thinsp;=\u0026thinsp;0.0077). Shinkawa et al. concluded that tumor size was associated with poor CSS in patients with a solitary HCC without MVI [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Lee et al. studied 2893 patients who underwent LR for pathological T1N0M0 HCC. The Kaplan\u0026ndash;Meier estimator showed that recurrence-free survival (RFS) and liver specific-OS, i.e., liver-caused mortality, of patients with T1N0M0 tumors\u0026thinsp;\u0026gt;\u0026thinsp;6.5 cm were similar to those of patients with T2N0M0 tumors. Multivariate Cox regression analysis showed that tumor size\u0026thinsp;\u0026gt;\u0026thinsp;6.5 cm was an independent poor prognostic factor of RFS and liver specific-OS of patients with T1N0M0 HCC. The authors concluded that tumor size had a significant influence on the outcomes of patients undergoing LR for pathological T1N0M0 HCC [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, both these studies did not analyze whether tumor size would significantly affect the OS of patients undergoing LR for T1N0M0 HCC [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].We believed that OS was more appropriate than liver specific-OS and CSS as a primary outcome measurement for patients undergoing LR for HCC because it is sometimes difficult to confirm the cause of death of these patients. For example, the course of COVID-19 in patients with advanced liver disease or cancer tends to be severe and patients have a higher risk of death. A recent Polish study of 4,314 patients hospitalized at a single institution due to COVID-19 infection between 2020 and 2022 selected a cohort of 31 patients with liver cirrhosis and seven patients with HCC for investigation. The control group included 123 patients without liver disease. Fifteen patients died, including 12 with cirrhosis and three with HCC, accounting for 39.47% of the entire cohort, 39% of the cirrhotic group, and 43% of the HCC group, while 13 patients died in the control group (10.6%); the mortality rate was significantly different between the group with liver disease and/or HCC and the control group [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In this scenario, it would be controversial to definitively state the cause of death of patients with cirrhosis and/or HCC as COVID-related or liver/HCC-related. Furthermore, AJCC staging of HCC was developed based on patients with HCC undergoing LR and uses OS as the primary outcome [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs tumor size increases, the risk of MVI increases [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]; therefore, the question why a subgroup of patients developed a large T1N0M0 HCC is interesting. The proportion of patients with cirrhosis and the proportion of patients with anti-HCV positivity were both lower in the tumor size\u0026thinsp;\u0026gt;\u0026thinsp;5.0 cm group than in the tumor size\u0026thinsp;\u0026lt;\u0026thinsp;5.0 cm group of patients with T1N0M0 HCC. More than 80% of patients with T1N0M0 HCC\u0026thinsp;\u0026gt;\u0026thinsp;5.0 cm were non-cirrhotic and/or anti-HCV negative.\u003c/p\u003e \u003cp\u003eThe BCLC system designated a single large HCC (\u0026gt;\u0026thinsp;5 cm) as BCLC stage A rather than stage B in 2012 [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In clinical practice, a single large HCC (\u0026gt;\u0026thinsp;5 cm) is indicated for LR as early HCC (BCLC stage A) but appear to lead to worse prognosis than HCC within Milan criteria [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].The worse outcome of a single large HCC is due to the higher risk of MVI [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTherefore, the ability to preoperatively diagnose a single large HCC without MVI would be of great benefit, because these patients enjoy excellent outcomes after LR, with five-year OS exceeding 80%. Previous studies showed that MVI of HCC could be preoperatively diagnosed with CT or MRI [\u003cspan additionalcitationids=\"CR21 CR22 CR23\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Based on the imaging traits of MVI and clinical characteristics of patients, we could preoperatively identify patients with a single large HCC\u0026thinsp;\u0026gt;\u0026thinsp;5.0 cm without MVI with greater confidence (i.e., non-cirrhotic and/or anti-HCV negative plus without imaging traits of MVI).\u003c/p\u003e \u003cp\u003eIn the present study, age\u0026thinsp;\u0026gt;\u0026thinsp;65 years and creatinine level\u0026thinsp;\u0026gt;\u0026thinsp;1.2 mg/dL were two independent factors associated with five-year OS. Older age represents a higher risk of comorbidities and our previous studies also showed that older age is an independent factor associated with OS of patients undergoing LR for HCC [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. We selected patients with good liver function reserve for LR in our clinical practice; therefore, renal insufficiency is less likely to be related to advanced liver disease (i.e., hepatorenal syndrome). We infer that renal insufficiency is due to the presence of comorbidities such as diabetes and hypertension (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://en.wikipedia.org/wiki/Kidney_disease\u003c/span\u003e\u003cspan address=\"https://en.wikipedia.org/wiki/Kidney_disease\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Therefore, the association between renal insufficiency and five-year OS could be due to the presence of comorbidities.\u003c/p\u003e \u003cp\u003eA strength of the current study is that the majority of patients\u0026rsquo; pathology was reported by two senior pathologists (HLE and FYK; HLE is FYK\u0026rsquo;s mentor), which minimized interobserver variation in interpreting MVI. Limitations of the present study include the lack of tumor differentiation data. However, five-year OS was comparable between patients with T1N0M0 HCC\u0026thinsp;\u0026gt;\u0026thinsp;5.0 cm and T1N0M0 HCC\u0026thinsp;\u0026le;\u0026thinsp;5.0 cm before PSM. Therefore, we believe that the lack of this information would not change the results of the present study. Another limitation is that it was a retrospective study.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe enrolled patients undergoing LR for HCC in the previous 10 years at our institution. We found that tumor size did not have an impact on the OS of patients undergoing LR for pathological T1N0M0 HCC. The results of the present study provide further support for the appropriateness of the current AJCC staging system for staging HCC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis study was supported by\u0026nbsp;Grant CMRPG8N1131\u0026nbsp;from the\u0026nbsp;Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest:\u0026nbsp;\u003c/strong\u003eThe authors have no conflicts of interest to disclose for all authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003eall data is available\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e The Institutional Review Board of Kaohsiung Chang Gung Memorial Hospital approved this study (Reference number:\u0026nbsp;202201189B0) and waived the need for informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy conception and design: Yi-Hao Yen, Chih-Chi Wang\u003c/p\u003e\n\u003cp\u003eAcquisition of data: all authors\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnalysis and interpretation of data: Chih-Yun Lin\u003c/p\u003e\n\u003cp\u003eDrafting of manuscript: Fang-Ying Kuo\u003c/p\u003e\n\u003cp\u003eCritical revision of manuscript: all authors\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll authors reviewed the manuscript\u003c/p\u003e \u003c/p\u003e\u003cp\u003e\u003cb\u003eAcknowledgements\u003c/p\u003e \u003cp\u003eThe authors thank the Cancer Center, Kaohsiung Chang Gung Memorial Hospital for the provision of HCC registry data. The authors thank Chih-Yun Lin, Nien-Tzu Hsu, and the Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital for statistical analyses. This study was supported by Grant CMRPG8N1131 from the Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan. There were no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eYang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR (2019). A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol;16:589\u0026ndash;604. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41575-019-0186-y\u003c/span\u003e\u003cspan address=\"10.1038/s41575-019-0186-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, et al (2018). 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J Surg Res;283:1091\u0026ndash;1099. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jss.2022.11.039\u003c/span\u003e\u003cspan address=\"10.1016/j.jss.2022.11.039\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\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":"hepatocellular carcinoma, overall survival, microscopic vascular invasion, liver resection","lastPublishedDoi":"10.21203/rs.3.rs-3876985/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3876985/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eWhether tumor size affects the survival of patients undergoing liver resection (LR) for a single hepatocellular carcinoma (HCC) without microscopic vascular invasion (MVI), i.e., pathological T1N0M0, is controversial. We aimed to clarify this issue.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e We enrolled 626 patients with HCC of pathological stage T1N0M0 of the 7th edition of American Joint Committee on Cancer staging who underwent LR between 2011 and 2021 at our institution. The overall survival (OS) of patients with T1N0M0 HCC\u0026thinsp;\u0026gt;\u0026thinsp;5.0 cm and those with T1N0M0 HCC\u0026thinsp;\u0026le;\u0026thinsp;5.0 cm was compared using the Kaplan\u0026ndash;Meier estimator and log-rank test both before and after propensity score matching (PSM).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eNinety-two (14.7%) patients had T1N0M0 HCC\u0026thinsp;\u0026gt;\u0026thinsp;5.0 cm. The proportion of patients with cirrhosis was lower in the T1N0M0 HCC\u0026thinsp;\u0026gt;\u0026thinsp;5.0 cm group than in the T1N0M0 HCC\u0026thinsp;\u0026le;\u0026thinsp;5.0 cm group (16.3% vs 41.2%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The former also had a lower proportion of patients showing anti-HCV positivity than the latter (17.4% vs 33.9%, p\u0026thinsp;=\u0026thinsp;0.002). Five-year OS did not differ significantly between the two groups before PSM (82% vs 84%, p\u0026thinsp;=\u0026thinsp;0.857) or after PSM (82% vs 92%, p\u0026thinsp;=\u0026thinsp;0.274).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eTumor size did not affect the OS of patients undergoing LR for T1N0M0 HCC.\u003c/p\u003e","manuscriptTitle":"Tumor size does not affect overall survival of patients undergoing resection for a single hepatocellular carcinoma without microscopic vascular invasion.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-26 18:30:54","doi":"10.21203/rs.3.rs-3876985/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":"17fd2adf-864f-4e4f-85fb-03b9c2ba91f5","owner":[],"postedDate":"January 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-02-27T05:29:37+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-26 18:30:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3876985","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3876985","identity":"rs-3876985","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}