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Comparison of clinical features and outcomes between HBV-related and non-B non-C hepatocellular carcinoma

Comparison of clinical features and outcomes between HBV-related and non-B non-C hepatocellular... Objective: To evaluate the difference between hepatitis B virus related hepatocellular carcinoma (HBV-HCC) and non-HBV non-HCV hepatocellular carcinoma (NBNC-HCC) patients based on clinical features and prognosis. Methods: A total of 175 patients with HCC were enrolled. Patients’ characteristics were extracted from medical records. Among them, 107 patients were positive for HBsAg and negative for HCV-Ab while 68 patients were negative for HBsAg and HCV-Ab. Results: The patients in the NBNC-HCC group were significantly older than those in the HBV-HCC group (P = 0.045). Moreover, vascular invasion was found in 23.4% of HBV-HCC patients, which was significantly higher than that in the NBNC-HCC patients with 10.3% (P = 0.029). Kaplan-Meier analysis revealed that HBV-HCC patients had significantly worse outcomes in terms of overall survival (P = 0.036). Compared with the NBNC-HCC patients, the HBV-HCC patients had a significantly worse disease-free survival (P = 0.0018). The multivariate analysis results indicated that TNM stage (HR = 1.541, 95%CI 1.072–2.412, P = 0.002) and HBV infection (HR = 1.087, 95%CI 1.012– 1.655, P = 0.042) were independent risk variables for overall survival. While vascular invasion (HR = 1.562, 95%CI 1.013–2.815, P = 0.042) and HBV infection (HR = 1.650, 95%CI 1.017–2.676, P = 0.037) were independent risk factors associated with disease-free survival. Conclusion: Our data revealed that HBV-HCC is more common in young males with vascular invasion, while NBNC- HCC occurs mostly in elderly patients, and overall survival rate is significantly better than that of HBV-HCC. Our study therefore provides evidence that patients with HBV-HCC require closer follow-up due to their poor prognosis. Keywords: Hepatitis B virus, Prognosis, Hepatocellular carcinoma, Biomarker Introduction largest proportion of patients with HCC in East Asia, the Hepatocellular carcinoma (HCC) is one of the most proportion of HCC cases without hepatitis virus surface common malignancies. Approximately 437,000 people antigen (HBsAg) and hepatitis C antibody (HCV-Ab) are diagnosed with HCC each year, of which approxi- positive (NBNC-HCC) is growing rapidly [3–5, 10]. The mately 50% belong to East Asia [1–3]. Although treat- background and molecular mechanisms of NBNC-HCC ment of HCC has improved over the decades, the 5-year are unclear. However, nonalcoholic steatohepatitis survival rate of HCC patients is still low with about only (NASH) and metabolic syndrome are considered import- 26% of HCC patients surviving [1–5]. The most promin- ant risk factors for these patients [11–14]. Although the ent causes associated with HCC include chronic infec- most important risk factors for HCC are HBV and HCV, tion with hepatitis B virus (HBV) and hepatitis C virus the alcohol consumption and exposition to aflatoxin B1 (HCV) [6–9]. Although HBV-associated HCC is the are also important risk factors for HCC [15, 16]. Chronic alcohol abuse and aflatoxin B1 exposure have been * Correspondence: xingyugang@163.com widely described as two of the leading risk factors of Xiulan Xue, Wei Liao and Yugang Xing contributed equally to this work. HCC. The annual HCC rate among Child Pugh Class A Department of Oncology, Kunshan Traditional Chinese Medicine Hospital, or B alcoholic cirrhosis is about 2.5% and the urinary Jiangsu Province, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Xue et al. Infectious Agents and Cancer (2020) 15:11 Page 2 of 6 excretion of aflatoxin metabolites have been described metastasis and (N1) regional lymph node metastasis. (3) associated with a 4 fold increase in HCC risk [15, 16]. Distant metastasis (M): (M0) no distant metastasis and Previous studies have compared the clinicopathologi- (M1) distant metastasis. cal features and prognosis of HCC patients with HBV and HCV infections [17–19]. However, both of them are Clinical features caused by chronic viral infection. The etiology of Clinical and pathological data on all patients, including NBNC-HCC is mostly a metabolic factor [20, 21]. The age, gender, preoperative alpha-fetoprotein (AFP), tumor tumor physiological characteristics are quite different size, tumor number, capsule, and tumor differentiation from HCC caused by HBV and HCV. Several studies were collected. Follow-up was conducted using tele- have compared NBNC-HCC patients with virus-related phonic interview. The postoperative survival of the two HCC patients with inconsistent results, possibly due to groups was observed. The effects of HBV- and NBNC- differences in demographic and tumor factors, and the on the clinicopathological features and prognosis of number of patients in the cohort may be insufficient HCC were analyzed. [22–24]. To further verify the difference between HBV-related Statistical analysis HCC (HBV-HCC) and NBNC-HCC patients, we ana- Statistical analysis was performed using the SPSS soft- lyzed the clinical features and prognosis to provide po- ware (version 13; SPSS Inc., Chicago, IL, USA). The Stu- tential evidence for different treatment strategies for dent’s t test and Chi square test were used to examine HCC patients. the correlation between different etiologies and clinical and pathological variables. The Kaplan-Meier method Subjects and methods (logarithmic rank test) was used to construct the survival Subjects curve. Multivariate Cox proportional hazards regression This was a retrospective study. Patients’ characteristics model was used to assess the independence of etiology were extracted from medical records. In our study, pa- in prediction results. P-values less than 0.05 were con- tients were included if they (1) had pathologically con- sidered statistically significant. firmed HCC (2) underwent hepatectomy, and (3) have medical data for hepatitis viral infection status of HBsAg Results and HCV-Ab. Patients were excluded if (1) they had an Association of etiology with HCC clinical features additional carcinoma, (2) they were HCV-Ab positive, or To determine the differences between the potential clin- (3) their clinical data were not complete. To control the ical features of NBNC-HCC and HBV-HCC, the rela- bias, patients were included in the study consecutively. tionship between etiology and the clinical features of The flow chart is shown in Additional file 1: Figure S1. patients with HCC was evaluated. The results showed A total of 175 patients with HCC, who underwent hepa- that NBNC-HCC patients were significantly older than tectomy were enrolled. Among them, 107 patients were patients with HBV-HCC (P = 0.045). Moreover, vascular positive for HBsAg and negative for HCV-Ab for at least invasion was found in 23.4% of HBV-HCC patients, 6 months [23]. A total of 68 cases were negative for which was significantly higher than that in NBNC-HCC HBsAg and negative for HCV-Ab. The study was ap- patients with 10.3% (P = 0.029), as shown in Table 1. proved by the medical ethics committee. In our study, HCC was diagnosed with pathological evidences and the Association of etiology with clinical outcomes in patients stage of HCC was determined according to the TNM with HCC classification. TNM staging was defined according to the To determine the differences in etiologies and clinical American Joint Committee on Cancer TNM Staging for outcomes among HCC patients, we conducted a Kaplan- Liver Tumors as follows: (1) Primary tumor (T): (TX) Meier survival analysis. For the HBV-HCC patients, the Primary tumor cannot be assessed; (T0) no evidence of Kaplan-Meier analysis revealed that they had signifi- primary tumor; (T1) solitary tumor without vascular in- cantly worse outcomes in terms of overall survival (P = vasion; (T2) solitary tumor with vascular invasion or 0.036). Similarly, compared with the NBNC-HCC pa- multiple tumors less than 5 cm in size; (T3a) multiple tients, HBV-HCC patients had a significantly worse tumors more than 5 cm in size; (T3b) single tumor or disease-free survival (P = 0.0018), as shown in Fig.1. multiple tumors of any size, involving a major branch of the portal vein or hepatic vein; and (T4) tumor(s) with Univariate and multivariate analyses of prognostic direct invasion of adjacent organs, other than the gall- variables in HCC bladder, or with perforation of visceral peritoneum. (2) To evaluate whether HBV infection was an independent Regional lymph nodes (N): (NX) regional lymph nodes risk factor for outcomes in HCC, both univariate and cannot be assessed; (N0) no regional lymph node multivariate analyses were conducted. The TNM stage Xue et al. Infectious Agents and Cancer (2020) 15:11 Page 3 of 6 Table 1 Clinical variables difference between NBNC-HCC and through gene integration into chromosomes and activa- HBV-HCC tion of oncogenes [25–28]. The mechanism of NBNC- Variable Etiology P HCC is still unclear, and metabolic factors may be an value important factor [21, 22]. For example, persistent non- NBNC-HCC HBV-HCC alcoholic steatohepatitis can also cause sustained prolif- Sample size 68 107 eration and repair of hepatocytes [29, 30]. During this Age, years 50.72 ± 11.90 47.09 ± 11.36 0.045 process, hepatocytes undergo malignant transformation AFP, ng/mL 13,734.7 ± 46,337.2 10,729.2 ± 23,103.5 0.570 and eventually lead to the occurrence of HCC. Different Gender 0.192 carcinogenic pathways may lead to differences in the Male 58 (85.3%) 98 (91.6%) clinicopathological features and prognosis of HCC. Our Female 10 (14.7%) 9 (8.4%) study concluded that NBNC-HCC are significantly dif- ferent from HBV-HCC in clinical features. In our study, Cirrhosis 0.408 we found that patients with HBV-HCC were younger, Yes 56 (82.4%) 93 (86.9%) while patients with NBNC-HCC were older. The study vNo 12 (17.6%) 14 (13.1%) also found that HBV-HCC has a higher proportion of Tumor size, cm 0.960 vascular invasion, which may involve certain carcino- < 5 11 (16.2%) 17 (15.9%) genic factors of HBV, such as increased cell motility ≥ 5 57 (83.8%) 90 (84.1%) caused by HBxAg [31–34]. However, there are still many gaps to be filled. Differentiation 0.313 Massimo found that patients with HBV-HCC are Well-moderate 42 (61.8%) 74 (69.2%) younger than HCV-HCC patients [35]. The data from Poor-undifferentiated 26 (38.2%) 33 (30.8%) our study confirmed that patients with HBV-HCC were TNM stage 0.322 significantly younger than NBNC-HCC. Moreover, our I–II 37 (54.4%) 50 (46.7%) study found that patients with HBV-HCC were more vIII–IV 31 (45.6%) 57 (53.3%) prone to vascular invasion. The prognosis of HBV-HCC was also worse than that of NBNC-HCC. TNM staging Vascular invasion 0.029 and vascular invasion are also factors influencing the Yes 7 (10.3%) 25 (23.4%) long-term survival of patients with HCC. No 61 (89.7%) 82 (76.6%) There have been some studies comparing the prognos- Abbreviations: NBNC:Non-HBV,Non-HCV-HCC; HBV hepatitis B virus tic differences between virus-associated HCC and NBNC-HCC [22–24]. Cescon et al. [36] reported that (P = 0.003), vascular invasion (P = 0.002), and HBV infec- patients with NBNC-HCC have a significantly better re- tion (P = 0.013) were all shown to be prognostic vari- lapse free survival rate than patients with HBV-HCC. ables for overall survival in patients with HCC. In the Other studies have indicated that the survival rate of pa- multivariate analysis, only TNM stage (HR = 1.541, tients with NBNC-HCC was significantly higher than 95%CI 1.072–2.412, P = 0.002) and HBV infection (HR = that of patients with HCV-HCC [37, 38]. Another study 1.087, 95%CI 1.012–1.655, P = 0.042) were found to be has shown that relapse free survival in patients with independent prognostic variables for overall survival NBNC-HCC is significantly better than that in patients (Table 2). with HBV-HCC [23]. Our study confirmed that the We further explored the risk factors associated with prognosis of NBNC-HCC patients was superior to that disease-free survival (Table 3). Univariate analysis of HBV-HCC patients, in terms of overall survival and showed that vascular invasion (P = 0.024) and HBV in- disease free survival. fection (P = 0.026) were risk factors associated with The relationship between prognosis and viral status in disease-free survival. In the multivariate analysis, vascu- HCC patients is controversial. Kondo et al. [37] reported lar invasion (HR = 1.562, 95%CI 1.013–2.815, P = 0.042) that the prognosis of NBNC-HCC patients is signifi- and HBV infection (HR = 1.650, 95%CI 1.017–2.676, P = cantly better than that of HBC-HCC and HCV-HCC pa- 0.037) were independent risk factors associated with tients. Another study [39] suggested that the prognosis disease-free survival. of nonalcoholic fatty liver disease related HCC was sig- nificantly better than that of HCV-HCC patients. How- Discussion ever, Akahoshi et al. [40] suggested that there is no HBV infection is the main cause of HCC [1, 2]. But the difference in prognosis between NBNC-HCC and other mechanisms of carcinogenesis are different compared type of HCCs. This may be because the etiology of with NBNC-HCC [20, 22]. HBV is a DNA virus that NBNC-HCC is not clear, and includes metabolic rea- causes malignant transformation of hepatocytes mainly sons, or alcohol abuse. In our study, we showed that Xue et al. Infectious Agents and Cancer (2020) 15:11 Page 4 of 6 Fig. 1 Different prognosis among patients with NBNC-HCC and HBV-HCC. a. Kaplan-Meier analysis revealed that HBV-HCC significantly worse outcomes in terms of overall survival (P = 0.036). b. Compared with the patients of NBNC-HCC, those with HBV-HCC had a significantly worse disease-free survival (P = 0.0018) NBNC-HCC patients have a better prognosis than HBV- 52 to 65 has been observed in the rest of the world [45, HCC patients. These results provide further evidence for 46]. In our study, the patients enrolled were all Asians the prognosis of NBNC-HCC. and therefore ethnicity cannot be used as a variable. Fur- Some studies have evaluated prognosis after hepatic ther studies are needed to evaluate the differences in resection for HCC patients with different etiologies [41, prognosis between different ethnic groups of HBV-HCC 42]. Cescon et al. [36] reported that NBNC-HCC pa- and NBNC-HCC patients. tients had significantly better outcomes than HBV-HCC There were some limitations in this study. First, the patients did. In our study, we confirmed that the prog- sample size was relatively small, so the results may be nosis of NBNC-HCC patients was significantly better biased. The data collected in this study came from a sin- than that of HBV-HCC patients. We further found that gle center and may lead to some enrollment bias; there- in patients with HCC, TNM stage and HBV infection fore, a multicenter prospective study is needed to further were independent prognostic variables for overall sur- validate the results. Thirdly, since HCV-infected patients vival, while vascular invasion and HBV infection were in- are relatively fewer in China, HCV-HCC patients were dependent risk factors associated with disease-free not enrolled in this study. survival. In summary, the clinicopathological features and Although serum viral markers are important for HCC prognosis of HBV-HCC and NBNC-HCC are signifi- screening, ethnicity is another important factor [43]. A cantly different. HBC-HCC is more common in young study has suggested that ethnicity plays an important males with vascular invasion, while NBNC-HCC oc- role in the diagnosis and treatment of HCC [44]. In curs mostly in elderly patients, and overall survival addition, the onset of HCC occurs at a median age of 45 rate is significantly higher than that of HBV-HCC in sub-Saharan African people, whereas a mean age of patients. Table 2 Univariate and multivariate analyses of variables for Table 3 Univariate and multivariate analyses for disease-free overall survival survival Variables Univariate analysis Multivariate analysis Variables Univariate analysis Multivariate analysis HR 95% CI P HR 95% CI P HR 95% CI P HR 95% CI P Age, years 1.015 0.702–1.468 0.936 Age, years 1.204 0.735–1.975 0.461 Sex 0.586 0.313–1.098 0.095 Sex 0.879 0.413–1.870 0.738 AFP 0.842 0.570–1.244 0.387 AFP 1.186 0.695–2.025 0.531 Cirrhosis 0.732 0.442–1.213 0.226 Cirrhosis 0.604 0.328–1.114 0.106 Tumor size, cm 0.997 0.637–1.560 0.988 Tumor size, cm 1.117 0.604–2.068 0.723 Differentiation 1.327 0.799–2.205 0.274 Differentiation 1.135 0.604–2.132 0.694 TNM stage 1.847 1.027–2.509 0.003 1.541 1.072–2.412 0.002 TNM stage 0.783 0.486–1.261 0.314 Vascular invasion 1.592 1.284–2.216 0.002 Vascular invasion 1.727 1.049–3.117 0.024 1.562 1.013–2.815 0.042 HBV infection 1.372 1.040–2.003 0.013 1.087 1.012–1.655 0.042 HBV infection 1.763 1.069–2.906 0.026 1.650 1.017–2.676 0.037 Abbreviations: NBNC:Non-HBV,Non-HCV-HCC; HBV hepatitis B virus Abbreviations: HBV hepatitis B virus Xue et al. 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Comparison of clinical features and outcomes between HBV-related and non-B non-C hepatocellular carcinoma

Xue, Xiulan; Liao, Wei; Xing, Yugang
Infectious Agents and Cancer , Volume 15 (1) – Feb 14, 2020
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Abstract

Objective: To evaluate the difference between hepatitis B virus related hepatocellular carcinoma (HBV-HCC) and non-HBV non-HCV hepatocellular carcinoma (NBNC-HCC) patients based on clinical features and prognosis. Methods: A total of 175 patients with HCC were enrolled. Patients’ characteristics were extracted from medical records. Among them, 107 patients were positive for HBsAg and negative for HCV-Ab while 68 patients were negative for HBsAg and HCV-Ab. Results: The patients in the NBNC-HCC group were significantly older than those in the HBV-HCC group (P = 0.045). Moreover, vascular invasion was found in 23.4% of HBV-HCC patients, which was significantly higher than that in the NBNC-HCC patients with 10.3% (P = 0.029). Kaplan-Meier analysis revealed that HBV-HCC patients had significantly worse outcomes in terms of overall survival (P = 0.036). Compared with the NBNC-HCC patients, the HBV-HCC patients had a significantly worse disease-free survival (P = 0.0018). The multivariate analysis results indicated that TNM stage (HR = 1.541, 95%CI 1.072–2.412, P = 0.002) and HBV infection (HR = 1.087, 95%CI 1.012– 1.655, P = 0.042) were independent risk variables for overall survival. While vascular invasion (HR = 1.562, 95%CI 1.013–2.815, P = 0.042) and HBV infection (HR = 1.650, 95%CI 1.017–2.676, P = 0.037) were independent risk factors associated with disease-free survival. Conclusion: Our data revealed that HBV-HCC is more common in young males with vascular invasion, while NBNC- HCC occurs mostly in elderly patients, and overall survival rate is significantly better than that of HBV-HCC. Our study therefore provides evidence that patients with HBV-HCC require closer follow-up due to their poor prognosis. Keywords: Hepatitis B virus, Prognosis, Hepatocellular carcinoma, Biomarker Introduction largest proportion of patients with HCC in East Asia, the Hepatocellular carcinoma (HCC) is one of the most proportion of HCC cases without hepatitis virus surface common malignancies. Approximately 437,000 people antigen (HBsAg) and hepatitis C antibody (HCV-Ab) are diagnosed with HCC each year, of which approxi- positive (NBNC-HCC) is growing rapidly [3–5, 10]. The mately 50% belong to East Asia [1–3]. Although treat- background and molecular mechanisms of NBNC-HCC ment of HCC has improved over the decades, the 5-year are unclear. However, nonalcoholic steatohepatitis survival rate of HCC patients is still low with about only (NASH) and metabolic syndrome are considered import- 26% of HCC patients surviving [1–5]. The most promin- ant risk factors for these patients [11–14]. Although the ent causes associated with HCC include chronic infec- most important risk factors for HCC are HBV and HCV, tion with hepatitis B virus (HBV) and hepatitis C virus the alcohol consumption and exposition to aflatoxin B1 (HCV) [6–9]. Although HBV-associated HCC is the are also important risk factors for HCC [15, 16]. Chronic alcohol abuse and aflatoxin B1 exposure have been * Correspondence: xingyugang@163.com widely described as two of the leading risk factors of Xiulan Xue, Wei Liao and Yugang Xing contributed equally to this work. HCC. The annual HCC rate among Child Pugh Class A Department of Oncology, Kunshan Traditional Chinese Medicine Hospital, or B alcoholic cirrhosis is about 2.5% and the urinary Jiangsu Province, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Xue et al. Infectious Agents and Cancer (2020) 15:11 Page 2 of 6 excretion of aflatoxin metabolites have been described metastasis and (N1) regional lymph node metastasis. (3) associated with a 4 fold increase in HCC risk [15, 16]. Distant metastasis (M): (M0) no distant metastasis and Previous studies have compared the clinicopathologi- (M1) distant metastasis. cal features and prognosis of HCC patients with HBV and HCV infections [17–19]. However, both of them are Clinical features caused by chronic viral infection. The etiology of Clinical and pathological data on all patients, including NBNC-HCC is mostly a metabolic factor [20, 21]. The age, gender, preoperative alpha-fetoprotein (AFP), tumor tumor physiological characteristics are quite different size, tumor number, capsule, and tumor differentiation from HCC caused by HBV and HCV. Several studies were collected. Follow-up was conducted using tele- have compared NBNC-HCC patients with virus-related phonic interview. The postoperative survival of the two HCC patients with inconsistent results, possibly due to groups was observed. The effects of HBV- and NBNC- differences in demographic and tumor factors, and the on the clinicopathological features and prognosis of number of patients in the cohort may be insufficient HCC were analyzed. [22–24]. To further verify the difference between HBV-related Statistical analysis HCC (HBV-HCC) and NBNC-HCC patients, we ana- Statistical analysis was performed using the SPSS soft- lyzed the clinical features and prognosis to provide po- ware (version 13; SPSS Inc., Chicago, IL, USA). The Stu- tential evidence for different treatment strategies for dent’s t test and Chi square test were used to examine HCC patients. the correlation between different etiologies and clinical and pathological variables. The Kaplan-Meier method Subjects and methods (logarithmic rank test) was used to construct the survival Subjects curve. Multivariate Cox proportional hazards regression This was a retrospective study. Patients’ characteristics model was used to assess the independence of etiology were extracted from medical records. In our study, pa- in prediction results. P-values less than 0.05 were con- tients were included if they (1) had pathologically con- sidered statistically significant. firmed HCC (2) underwent hepatectomy, and (3) have medical data for hepatitis viral infection status of HBsAg Results and HCV-Ab. Patients were excluded if (1) they had an Association of etiology with HCC clinical features additional carcinoma, (2) they were HCV-Ab positive, or To determine the differences between the potential clin- (3) their clinical data were not complete. To control the ical features of NBNC-HCC and HBV-HCC, the rela- bias, patients were included in the study consecutively. tionship between etiology and the clinical features of The flow chart is shown in Additional file 1: Figure S1. patients with HCC was evaluated. The results showed A total of 175 patients with HCC, who underwent hepa- that NBNC-HCC patients were significantly older than tectomy were enrolled. Among them, 107 patients were patients with HBV-HCC (P = 0.045). Moreover, vascular positive for HBsAg and negative for HCV-Ab for at least invasion was found in 23.4% of HBV-HCC patients, 6 months [23]. A total of 68 cases were negative for which was significantly higher than that in NBNC-HCC HBsAg and negative for HCV-Ab. The study was ap- patients with 10.3% (P = 0.029), as shown in Table 1. proved by the medical ethics committee. In our study, HCC was diagnosed with pathological evidences and the Association of etiology with clinical outcomes in patients stage of HCC was determined according to the TNM with HCC classification. TNM staging was defined according to the To determine the differences in etiologies and clinical American Joint Committee on Cancer TNM Staging for outcomes among HCC patients, we conducted a Kaplan- Liver Tumors as follows: (1) Primary tumor (T): (TX) Meier survival analysis. For the HBV-HCC patients, the Primary tumor cannot be assessed; (T0) no evidence of Kaplan-Meier analysis revealed that they had signifi- primary tumor; (T1) solitary tumor without vascular in- cantly worse outcomes in terms of overall survival (P = vasion; (T2) solitary tumor with vascular invasion or 0.036). Similarly, compared with the NBNC-HCC pa- multiple tumors less than 5 cm in size; (T3a) multiple tients, HBV-HCC patients had a significantly worse tumors more than 5 cm in size; (T3b) single tumor or disease-free survival (P = 0.0018), as shown in Fig.1. multiple tumors of any size, involving a major branch of the portal vein or hepatic vein; and (T4) tumor(s) with Univariate and multivariate analyses of prognostic direct invasion of adjacent organs, other than the gall- variables in HCC bladder, or with perforation of visceral peritoneum. (2) To evaluate whether HBV infection was an independent Regional lymph nodes (N): (NX) regional lymph nodes risk factor for outcomes in HCC, both univariate and cannot be assessed; (N0) no regional lymph node multivariate analyses were conducted. The TNM stage Xue et al. Infectious Agents and Cancer (2020) 15:11 Page 3 of 6 Table 1 Clinical variables difference between NBNC-HCC and through gene integration into chromosomes and activa- HBV-HCC tion of oncogenes [25–28]. The mechanism of NBNC- Variable Etiology P HCC is still unclear, and metabolic factors may be an value important factor [21, 22]. For example, persistent non- NBNC-HCC HBV-HCC alcoholic steatohepatitis can also cause sustained prolif- Sample size 68 107 eration and repair of hepatocytes [29, 30]. During this Age, years 50.72 ± 11.90 47.09 ± 11.36 0.045 process, hepatocytes undergo malignant transformation AFP, ng/mL 13,734.7 ± 46,337.2 10,729.2 ± 23,103.5 0.570 and eventually lead to the occurrence of HCC. Different Gender 0.192 carcinogenic pathways may lead to differences in the Male 58 (85.3%) 98 (91.6%) clinicopathological features and prognosis of HCC. Our Female 10 (14.7%) 9 (8.4%) study concluded that NBNC-HCC are significantly dif- ferent from HBV-HCC in clinical features. In our study, Cirrhosis 0.408 we found that patients with HBV-HCC were younger, Yes 56 (82.4%) 93 (86.9%) while patients with NBNC-HCC were older. The study vNo 12 (17.6%) 14 (13.1%) also found that HBV-HCC has a higher proportion of Tumor size, cm 0.960 vascular invasion, which may involve certain carcino- < 5 11 (16.2%) 17 (15.9%) genic factors of HBV, such as increased cell motility ≥ 5 57 (83.8%) 90 (84.1%) caused by HBxAg [31–34]. However, there are still many gaps to be filled. Differentiation 0.313 Massimo found that patients with HBV-HCC are Well-moderate 42 (61.8%) 74 (69.2%) younger than HCV-HCC patients [35]. The data from Poor-undifferentiated 26 (38.2%) 33 (30.8%) our study confirmed that patients with HBV-HCC were TNM stage 0.322 significantly younger than NBNC-HCC. Moreover, our I–II 37 (54.4%) 50 (46.7%) study found that patients with HBV-HCC were more vIII–IV 31 (45.6%) 57 (53.3%) prone to vascular invasion. The prognosis of HBV-HCC was also worse than that of NBNC-HCC. TNM staging Vascular invasion 0.029 and vascular invasion are also factors influencing the Yes 7 (10.3%) 25 (23.4%) long-term survival of patients with HCC. No 61 (89.7%) 82 (76.6%) There have been some studies comparing the prognos- Abbreviations: NBNC:Non-HBV,Non-HCV-HCC; HBV hepatitis B virus tic differences between virus-associated HCC and NBNC-HCC [22–24]. Cescon et al. [36] reported that (P = 0.003), vascular invasion (P = 0.002), and HBV infec- patients with NBNC-HCC have a significantly better re- tion (P = 0.013) were all shown to be prognostic vari- lapse free survival rate than patients with HBV-HCC. ables for overall survival in patients with HCC. In the Other studies have indicated that the survival rate of pa- multivariate analysis, only TNM stage (HR = 1.541, tients with NBNC-HCC was significantly higher than 95%CI 1.072–2.412, P = 0.002) and HBV infection (HR = that of patients with HCV-HCC [37, 38]. Another study 1.087, 95%CI 1.012–1.655, P = 0.042) were found to be has shown that relapse free survival in patients with independent prognostic variables for overall survival NBNC-HCC is significantly better than that in patients (Table 2). with HBV-HCC [23]. Our study confirmed that the We further explored the risk factors associated with prognosis of NBNC-HCC patients was superior to that disease-free survival (Table 3). Univariate analysis of HBV-HCC patients, in terms of overall survival and showed that vascular invasion (P = 0.024) and HBV in- disease free survival. fection (P = 0.026) were risk factors associated with The relationship between prognosis and viral status in disease-free survival. In the multivariate analysis, vascu- HCC patients is controversial. Kondo et al. [37] reported lar invasion (HR = 1.562, 95%CI 1.013–2.815, P = 0.042) that the prognosis of NBNC-HCC patients is signifi- and HBV infection (HR = 1.650, 95%CI 1.017–2.676, P = cantly better than that of HBC-HCC and HCV-HCC pa- 0.037) were independent risk factors associated with tients. Another study [39] suggested that the prognosis disease-free survival. of nonalcoholic fatty liver disease related HCC was sig- nificantly better than that of HCV-HCC patients. How- Discussion ever, Akahoshi et al. [40] suggested that there is no HBV infection is the main cause of HCC [1, 2]. But the difference in prognosis between NBNC-HCC and other mechanisms of carcinogenesis are different compared type of HCCs. This may be because the etiology of with NBNC-HCC [20, 22]. HBV is a DNA virus that NBNC-HCC is not clear, and includes metabolic rea- causes malignant transformation of hepatocytes mainly sons, or alcohol abuse. In our study, we showed that Xue et al. Infectious Agents and Cancer (2020) 15:11 Page 4 of 6 Fig. 1 Different prognosis among patients with NBNC-HCC and HBV-HCC. a. Kaplan-Meier analysis revealed that HBV-HCC significantly worse outcomes in terms of overall survival (P = 0.036). b. Compared with the patients of NBNC-HCC, those with HBV-HCC had a significantly worse disease-free survival (P = 0.0018) NBNC-HCC patients have a better prognosis than HBV- 52 to 65 has been observed in the rest of the world [45, HCC patients. These results provide further evidence for 46]. In our study, the patients enrolled were all Asians the prognosis of NBNC-HCC. and therefore ethnicity cannot be used as a variable. Fur- Some studies have evaluated prognosis after hepatic ther studies are needed to evaluate the differences in resection for HCC patients with different etiologies [41, prognosis between different ethnic groups of HBV-HCC 42]. Cescon et al. [36] reported that NBNC-HCC pa- and NBNC-HCC patients. tients had significantly better outcomes than HBV-HCC There were some limitations in this study. First, the patients did. In our study, we confirmed that the prog- sample size was relatively small, so the results may be nosis of NBNC-HCC patients was significantly better biased. The data collected in this study came from a sin- than that of HBV-HCC patients. We further found that gle center and may lead to some enrollment bias; there- in patients with HCC, TNM stage and HBV infection fore, a multicenter prospective study is needed to further were independent prognostic variables for overall sur- validate the results. Thirdly, since HCV-infected patients vival, while vascular invasion and HBV infection were in- are relatively fewer in China, HCV-HCC patients were dependent risk factors associated with disease-free not enrolled in this study. survival. In summary, the clinicopathological features and Although serum viral markers are important for HCC prognosis of HBV-HCC and NBNC-HCC are signifi- screening, ethnicity is another important factor [43]. A cantly different. HBC-HCC is more common in young study has suggested that ethnicity plays an important males with vascular invasion, while NBNC-HCC oc- role in the diagnosis and treatment of HCC [44]. In curs mostly in elderly patients, and overall survival addition, the onset of HCC occurs at a median age of 45 rate is significantly higher than that of HBV-HCC in sub-Saharan African people, whereas a mean age of patients. Table 2 Univariate and multivariate analyses of variables for Table 3 Univariate and multivariate analyses for disease-free overall survival survival Variables Univariate analysis Multivariate analysis Variables Univariate analysis Multivariate analysis HR 95% CI P HR 95% CI P HR 95% CI P HR 95% CI P Age, years 1.015 0.702–1.468 0.936 Age, years 1.204 0.735–1.975 0.461 Sex 0.586 0.313–1.098 0.095 Sex 0.879 0.413–1.870 0.738 AFP 0.842 0.570–1.244 0.387 AFP 1.186 0.695–2.025 0.531 Cirrhosis 0.732 0.442–1.213 0.226 Cirrhosis 0.604 0.328–1.114 0.106 Tumor size, cm 0.997 0.637–1.560 0.988 Tumor size, cm 1.117 0.604–2.068 0.723 Differentiation 1.327 0.799–2.205 0.274 Differentiation 1.135 0.604–2.132 0.694 TNM stage 1.847 1.027–2.509 0.003 1.541 1.072–2.412 0.002 TNM stage 0.783 0.486–1.261 0.314 Vascular invasion 1.592 1.284–2.216 0.002 Vascular invasion 1.727 1.049–3.117 0.024 1.562 1.013–2.815 0.042 HBV infection 1.372 1.040–2.003 0.013 1.087 1.012–1.655 0.042 HBV infection 1.763 1.069–2.906 0.026 1.650 1.017–2.676 0.037 Abbreviations: NBNC:Non-HBV,Non-HCV-HCC; HBV hepatitis B virus Abbreviations: HBV hepatitis B virus Xue et al. 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