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R. Romeo, A. Petruzziello, E. Pécheur, F. Facchetti, R. Perbellini, E. Galmozzi, N. Khan, L. Capua, R. Sabatino, G. Botti, Giovanna Loquercio (2018)Hepatitis delta virus and hepatocellular carcinoma: an update
Epidemiology and Infection, 146
Shi‐Lu Chen, Li-Li Liu, Shi-xun Lu, R. Luo, Chun-Hua Wang, Hong Wang, Shao-hang Cai, Xia Yang, D. Xie, C. Zhang, J. Yun (2017)HBx‐mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis
Molecular Oncology, 11
A. Ozakyol (2017)Global Epidemiology of Hepatocellular Carcinoma (HCC Epidemiology)
Journal of Gastrointestinal Cancer, 48
M. Maini, A. Gehring (2016)The role of innate immunity in the immunopathology and treatment of HBV infection.
Journal of hepatology, 64 1 Suppl
S. Cai, Zhandong Li, Tao Yu, Muye Xia, Jie Peng (2018)Serum hepatitis B core antibody levels predict HBeAg seroconversion in chronic hepatitis B patients with high viral load treated with nucleos(t)ide analogs
Infection and Drug Resistance, 11
S. Cai, Jiawei Cao, Tao Yu, Muye Xia, Jie Peng (2017)Effectiveness of entecavir or telbivudine therapy in patients with chronic hepatitis B virus infection pre-treated with interferon compared with de novo therapy with entecavir and telbivudine
Won-Ho Kim, F. Hong, B. Jaruga, Zongyi Hu, S. Fan, T. Liang, B. Gao (2001)Additive activation of hepatic NF‐κB by ethanol and hepatitis B protein X (HBX) or HCV core protein: involvement of TNF‐α receptor 1‐independent and ‐dependent mechanisms
The FASEB Journal, 15
Kuniya Tanaka, H. Shimada, K. Matsuo, Y. Nagano, I. Endo, S. Togo (2007)Clinical Characteristics and Surgical Outcome in Hepatocellular Carcinoma without Hepatitis B Virus Surface Antigen or Hepatitis C Virus Antibody
Annals of Surgical Oncology, 14
Guías Clínica (1971)European Association for the Study of the Liver
Caixia Zheng, Honghong Yan, Jianyong Zeng, S. Cai, Xiaolu Wu (2019)Comparison of pegylated interferon monotherapy and de novo pegylated interferon plus tenofovir combination therapy in patients with chronic hepatitis B
Infection and Drug Resistance, 12
K. Jeng, Chiung-Fang Chang, W. Jeng, I. Sheen, Chi-Juei Jeng (2015)Heterogeneity of hepatocellular carcinoma contributes to cancer progression.
Critical reviews in oncology/hematology, 94 3
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations
M. Luzi, A. Capucci, G. Pasquale, Silvia Zagnoni (2016)[The BRIDGE study].
Giornale italiano di cardiologia, 17 1
D. Woodfield (1986)Hepatocellular carcinoma.
The New Zealand medical journal, 99 795
I. Hassan, E. Gane (2019)Improving survival in patients with hepatocellular carcinoma related to chronic hepatitis C and B but not in those related to non‐alcoholic steatohepatitis or alcoholic liver disease: a 20‐year experience from a national programme
Internal Medicine Journal, 49
S. Cai, Zejin Ou, Duan Liu, Lili Liu, Ying Liu, Xiaolu Wu, Tao Yu, Jie Peng (2018)Risk factors associated with liver steatosis and fibrosis in chronic hepatitis B patient with component of metabolic syndrome
United European Gastroenterology Journal, 6
S. Reddy, J. Steel, Hui‐Wei Chen, David DeMateo, Jon Cardinal, J. Behari, A. Humar, J. Marsh, D. Geller, A. Tsung (2012)Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease
C. Hester, N. Rich, A. Singal, A. Yopp (2019)Comparative Analysis of Nonalcoholic Steatohepatitis- Versus Viral Hepatitis- and Alcohol-Related Liver Disease-Related Hepatocellular Carcinoma.
Journal of the National Comprehensive Cancer Network : JNCCN, 17 4
Andre Costa, A. Plymoth, D. Santos-Silva, S. Ortiz-Cuaran, S. Camey, Paule Guilloreau, S. Sangrajrang, T. Khuhaprema, Maimuna Mendy, O. Lesi, H. Chang, Jin-Kyoung Oh, D. Lee, Hai-rim Shin, G. Kirk, P. Merle, L. Beretta, P. Hainaut (2015)Osteopontin and latent‐TGF β binding‐protein 2 as potential diagnostic markers for HBV‐related hepatocellular carcinoma
International Journal of Cancer, 136
H. Oh, Tae Kim, Y. Sohn, Y. Kim, Y. Oh, E. Cho, S. Shim, S. Shin, A. Han, S. Yoon, Haak-Cheoul Kim (2011)Association of serum alanine aminotransferase and γ-glutamyltransferase levels within the reference range with metabolic syndrome and nonalcoholic fatty liver disease
The Korean Journal of Hepatology, 17
Xiulan Xue, S. Cai, Hong-jie Ou, Caixia Zheng, Xiaolu Wu (2017)Health-related quality of life in patients with chronic hepatitis B during antiviral treatment and off-treatment
Patient preference and adherence, 11
Y. Okuda, S. Mizuno, T. Shiraishi, Y. Murata, A. Tanemura, Y. Azumi, N. Kuriyama, M. Kishiwada, M. Usui, H. Sakurai, M. Tabata, Tomomi Yamada, S. Isaji (2014)Clinicopathological Factors Affecting Survival and Recurrence after Initial Hepatectomy in Non-B Non-C Hepatocellular Carcinoma Patients with Comparison to Hepatitis B or C Virus
BioMed Research International, 2014
H. Togt (2003)Publisher's Note
J. Netw. Comput. Appl., 26
A. Forner, J. Llovet, J. Bruix (2012)Hepatocellular carcinoma
The Lancet, 379
L. Kulik, H. El‐Serag (2019)Epidemiology and Management of Hepatocellular Carcinoma.
Gastroenterology, 156 2
Huang Jia-yi, F. Tao (2008)Effects of HBx on localization of PPARγ in HepG2 cell line
T. Utsunomiya, M. Shimada, M. Kudo, T. Ichida, O. Matsui, N. Izumi, Y. Matsuyama, M. Sakamoto, O. Nakashima, Y. Ku, T. Takayama, N. Kokudo (2015)A comparison of the surgical outcomes among patients with HBV-positive, HCV-positive, and non-B non-C hepatocellular carcinoma: a nationwide study of 11,950 patients.
Annals of surgery, 261 3
Jihye Kim, W. Kang, D. Sinn, G. Gwak, Y. Paik, M. Choi, J. Lee, K. Koh, S. Paik (2019)Potential etiology, prevalence of cirrhosis, and mode of detection among patients with non-B non-C hepatocellular carcinoma in Korea
The Korean Journal of Internal Medicine, 35
Hiroshi Akahoshi, N. Taura, T. Ichikawa, H. Miyaaki, Motohisa Akiyama, S. Miuma, E. Ozawa, S. Takeshita, Toru Muraoka, Toshihisa Matsuzaki, M. Ohtani, H. Isomoto, Takehiro Matsumoto, F. Takeshima, K. Nakao (2010)Differences in prognostic factors according to viral status in patients with hepatocellular carcinoma.
Oncology reports, 23 5
Ruili Zhang, Shasha Zhou, L. Xiao, Hua Zhang, Aisikeer Tulahong, Yue-fen Zhang, H. Wen, Y. Bao (2015)[Comparison of clinical characteristics of non-B non-C hepatocellular carcinoma and hepatitis virus-related hepatocellular carcinoma and prognosis in Uighur patients].
Zhonghua zhong liu za zhi [Chinese journal of oncology], 37 7
Massimo Colombo (1999)Natural history and pathogenesis of hepatitis C virus related hepatocellular carcinoma.
Journal of hepatology, 31 Suppl 1
R. Tateishi, Koji Uchino, N. Fujiwara, T. Takehara, T. Okanoue, M. Seike, H. Yoshiji, H. Yatsuhashi, M. Shimizu, T. Torimura, M. Moriyama, I. Sakaida, H. Okada, T. Chiba, M. Chuma, K. Nakao, H. Isomoto, Y. Sasaki, S. Kaneko, T. Masaki, K. Chayama, K. Koike (2018)A nationwide survey on non-B, non-C hepatocellular carcinoma in Japan: 2011–2015 update
Journal of Gastroenterology, 54
I. Hassan, E. Gane, D. Prasad, A. Bartlett, O. Lithgow (2018)Improving survival in patients with hepatocellular carcinoma related to chronic hepatitis C and B but not in those related to non-alcoholic steatohepatitis or alcoholic liver disease: A 20 year experience from a national programme
Journal of Hepatology, 68
M. Ringelhan, T. O’Connor, U. Protzer, M. Heikenwalder (2015)The direct and indirect roles of HBV in liver cancer: prospective markers for HCC screening and potential therapeutic targets
The Journal of Pathology, 235
H. El‐Serag (2011)Hepatocellular carcinoma.
The New England journal of medicine, 365 12
Shao-hang Cai, Fangfang Lv, Yong-hong Zhang, Yegui Jiang, Jie Peng (2014)Dynamic comparison between Daan real-time PCR and Cobas TaqMan for quantification of HBV DNA levels in patients with CHB
BMC Infectious Diseases, 14
M. Cescon, A. Cucchetti, G. Grazi, A. Ferrero, L. Viganó, G. Ercolani, M. Ravaioli, M. Zanello, P. Andreone, L. Capussotti, A. Pinna (2009)Role of hepatitis B virus infection in the prognosis after hepatectomy for hepatocellular carcinoma in patients with cirrhosis: a Western dual-center experience.
Archives of surgery, 144 10
P. Galle, A. Forner, J. Llovet, V. Mazzaferro, F. Piscaglia, J. Raoul, P. Schirmacher, V. Vilgrain (2018)EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma.
Journal of hepatology, 69 1
S. Cai, Tao Yu, Yegui Jiang, Yonghong Zhang, Fangfang Lv, Jie Peng (2016)Comparison of entecavir monotherapy and de novo lamivudine and adefovir combination therapy in HBeAg-positive chronic hepatitis B with high viral load: 48-week result
Clinical and Experimental Medicine, 16
K. Hobbs, G. Dusheiko (1992)Management of hepatocellular carcinoma.
Journal of hepatology, 15 3
S. Hees, P. Michielsen, T. Vanwolleghem (2016)Circulating predictive and diagnostic biomarkers for hepatitis B virus-associated hepatocellular carcinoma
World Journal of Gastroenterology, 22
Qiang Li, Huikai Li, Yu Qin, P. Wang, X. Hao (2007)Comparison of surgical outcomes for small hepatocellular carcinoma in patients with hepatitis B versus hepatitis C: A Chinese experience
Journal of Gastroenterology and Hepatology, 22
M. El-Maksoud, Maha Habeeb, H. Ghazy, M. Nomir, H. Elalfy, S. Abed, M. Zaki (2019)Clinicopathological study of occult hepatitis B virus infection in hepatitis C virus-associated hepatocellular carcinoma
European Journal of Gastroenterology & Hepatology, 31
P. Bertuccio, F. Turati, G. Carioli, T. Rodríguez, C. Vecchia, M. Malvezzi, E. Negri (2017)Global trends and predictions in hepatocellular carcinoma mortality.
Journal of hepatology, 67 2
A. Petruzziello (2018)Epidemiology of Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) Related Hepatocellular Carcinoma
The Open Virology Journal, 12
C. Gonçalves, F. Pereira, M. Zago (1988)[Hepatocellular carcinoma].
Arquivos de gastroenterologia, 25 4
Kazuhisa Kaneda, S. Kubo, Hiromu Tanaka, S. Takemura, K. Ohba, T. Uenishi, S. Kodai, H. Shinkawa, Yorihisa Urata, Masayuki Sakae, Takatsugu Yamamoto, S. Suehiro (2012)Features and outcome after liver resection for non-B non-C hepatocellular carcinoma.
Hepato-gastroenterology, 59 118
A. Chan, G. Wong, H. Chan, J. Tong, Yau-Hei Yu, P. Choi, H. Chan, K. To, V. Wong (2017)Concurrent fatty liver increases risk of hepatocellular carcinoma among patients with chronic hepatitis B
Journal of Gastroenterology and Hepatology, 32
K. Kondo, K. Chijiiwa, M. Funagayama, Masa-hiro Kai, K. Otani, J. Ohuchida (2008)Differences in Long-term Outcome and Prognostic Factors According to Viral Status in Patients with Hepatocellular Carcinoma Treated by Surgery
Journal of Gastrointestinal Surgery, 12
J. Bruix, M. Sherman (2005)Management of hepatocellular carcinoma
Shao-hang Cai, Shi-xun Lu, Li-Li Liu, C. Zhang, J. Yun (2017)Increased expression of hepatocyte nuclear factor 4 alpha transcribed by promoter 2 indicates a poor prognosis in hepatocellular carcinoma
Therapeutic Advances in Gastroenterology, 10
Joong-Won Park, Minshan Chen, M. Colombo, L. Roberts, M. Schwartz, Pei-Jer Chen, M. Kudo, P. Johnson, S. Wagner, L. Orsini, M. Sherman (2015)Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study
Liver International, 35
Ju Yang, A. Gyedu, M. Afihene, B. Duduyemi, Eileen Micah, P. Kingham, M. Nyirenda, A. Nkansah, S. Bandoh, M. Duguru, E. Okeke, Marie-Jeanne Kouakou-Lohoues, A. Abdo, Y. Awuku, Akande Ajayi, A. Omonisi, P. Ocama, A. Malu, S. Mustapha, U. Okonkwo, M. Kooffreh-Ada, J. Debes, C. Onyekwere, Francis Ekere, Igetei Rufina, Lewis Roberts (2015)Hepatocellular Carcinoma Occurs at an Earlier Age in Africans, Particularly in Association With Chronic Hepatitis B
The American Journal of Gastroenterology, 110
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: email@example.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 . 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 . 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.  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 . 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.  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  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.  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.  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 . 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 . 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. Infectious Agents and Cancer (2020) 15:11 Page 5 of 6 Supplementary information 10. Cai S, Ou Z, Liu D, Liu L, Liu Y, Wu X, Yu T, Peng J. Risk factors associated with Supplementary information accompanies this paper at https://doi.org/10. liver steatosis and fibrosis in chronic hepatitis B patient with component of 1186/s13027-020-0273-2. metabolic syndrome. United European Gastroenterol J. 2018;6(4):558–66. 11. Jeng KS, Chang CF, Jeng WJ, Sheen IS, Jeng CJ. Heterogeneity of hepatocellular carcinoma contributes to cancer progression. Crit Rev Oncol Additional file 1. The flow chart of the study is shown. Hematol. 2015;94(3):337–47. 12. Kulik L, El-Serag HB. Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 2019;156(2):477–91. Acknowledgements 13. Ozakyol A. Global epidemiology of hepatocellular carcinoma (HCC We wish to thank Hongjie Ou for his helpful assistance in the study. epidemiology)[J]. J Gastrointest Cancer. 2017;48(3):238–40. 14. Cai S, Cao J, Yu T, Xia M, Peng J. Effectiveness of entecavir or telbivudine Authors’ contributions therapy in patients with chronic hepatitis B virus infection pre-treated with XY and WL designed and guided this study, XX and XY wrote the main interferon compared with de novo therapy with entecavir and telbivudine. manuscript text, prepared all figures and data analysis. All authors reviewed Medicine (Baltimore). 2017;96(22):e7021. the manuscript. 15. Petruzziello A. Epidemiology of hepatitis B virus (HBV) and hepatitis C virus (HCV) related hepatocellular carcinoma. Open Virol J. 2018;12:26–32. Funding 16. Romeo R, Petruzziello A, Pecheur EI, Facchetti F, Perbellini R, Galmozzi E, None. Khan NU, Di Capua L, Sabatino R, Botti G, et al. Hepatitis delta virus and hepatocellular carcinoma: an update. Epidemiol Infect. 2018;146(13):1612–8. Availability of data and materials 17. El-Maksoud MA, Habeeb MR, Ghazy HF, Nomir MM, Elalfy H, Abed S, Zaki M. Authors can confirm all relevant data are included in the article and Clinicopathological study of occult hepatitis B virus infection in hepatitis C virus- materials are available on request from the authors. associated hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2019;31(6):716–22. 18. Hassan I, Gane E. Improving survival in patients with hepatocellular Ethics approval and consent to participate carcinoma related to chronic hepatitis C and B but not in those related to The Institutional Review Board of First affiliated hospital of Xiamen university non‐alcoholic steatohepatitis or alcoholic liver disease: a 20‐year experience had approved this study. All procedures followed were in accordance with from a national programme[J]. Intern Med J. 2019;49(11):1405–11. the ethical standards of the responsible committee on human 19. Hester CA, Rich NE, Singal AG, Yopp AC. Comparative analysis of nonalcoholic experimentation and with the Helsinki Declaration of 1975, as revised in Steatohepatitis- versus viral hepatitis- and alcohol-related liver disease-related hepatocellular carcinoma. J Natl Compr Cancer Netw. 2019;17(4):322–9. 20. Kim J, Kang W, Sinn D H, et al. Potential etiology, prevalence of cirrhosis, Consent for publication and mode of detection among patients with non-B non-C hepatocellular Not applicable. carcinoma in Korea[J]. Korean J Intern Med. 2020;35(1):65. 21. Tateishi R, Uchino K, Fujiwara N, Takehara T, Okanoue T, Seike M, Yoshiji H, Yatsuhashi H, Shimizu M, Torimura T, et al. A nationwide survey on non-B, Competing interests non-C hepatocellular carcinoma in Japan: 2011-2015 update. J The authors declare that they have no financial or non-financial interests Gastroenterol. 2019;54(4):367–76. with other people or organizations that could inappropriately influence this work. 22. Okuda Y, Mizuno S, Shiraishi T, Murata Y, Tanemura A, Azumi Y, Kuriyama N, Kishiwada M, Usui M, Sakurai H, et al. Clinicopathological factors affecting Author details survival and recurrence after initial hepatectomy in non-B non-C Department of Infectious Diseases, First Affiliated Hospital of Xiamen hepatocellular carcinoma patients with comparison to hepatitis B or C virus. University, Xiamen, Fujian Province, China. Intensive Care Unit, Sun Yat-sen Biomed Res Int. 2014;2014:975380. University Cancer Center, Guangzhou, China. Department of Oncology, 23. Utsunomiya T, Shimada M, Kudo M, Ichida T, Matsui O, Izumi N, Matsuyama Kunshan Traditional Chinese Medicine Hospital, Jiangsu Province, China. Y, Sakamoto M, Nakashima O, Ku Y, et al. A comparison of the surgical outcomes among patients with HBV-positive, HCV-positive, and non-B non- Received: 22 July 2019 Accepted: 12 January 2020 C hepatocellular carcinoma: a nationwide study of 11,950 patients. Ann Surg. 2015;261(3):513–20. 24. Zhang R, Zhou S, Xiao L, Zhang H, Tulahong A, Zhang Y, Wen H, Bao Y. Comparison of clinical characteristics of non-B non-C hepatocellular References carcinoma and hepatitis virus-related hepatocellular carcinoma and 1. Clinical Practice Guidelines EASL. Management of hepatocellular carcinoma. prognosis in Uighur patients. Zhonghua Zhong Liu Za Zhi. 2015;37(7):540–4. J Hepatol. 2018;69(1):182–236. 25. Cai S, Li Z, Yu T, Xia M, Peng J. Serum hepatitis B core antibody levels 2. Bertuccio P, Turati F, Carioli G, Rodriguez T, La Vecchia C, Malvezzi M, Negri predict HBeAg seroconversion in chronic hepatitis B patients with high viral E. Global trends and predictions in hepatocellular carcinoma mortality. J load treated with nucleos(t) ide analogs. Infect Drug Resist. 2018;11:469–77. Hepatol. 2017;67(2):302–9. 26. Maini MK, Gehring AJ. The role of innate immunity in the immunopathology 3. El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365(12):1118–27. and treatment of HBV infection. J Hepatol. 2016;64(1 Suppl):S60–70. 4. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. LANCET. 2012; 27. Cai S, Yu T, Jiang Y, Zhang Y, Lv F, Peng J. Comparison of entecavir 379(9822):1245–55. monotherapy and de novo lamivudine and adefovir combination therapy in 5. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. LANCET. 2018; HBeAg-positive chronic hepatitis B with high viral load: 48-week result. Clin 391(10127):1301r1314. Exp Med. 2016;16(3):429–36. 6. Chan AW, Wong GL, Chan HY, Tong JH, Yu YH, Choi PC, Chan HL, To KF, 28. Xue X, Cai S, Ou H, Zheng C, Wu X. Health-related quality of life in patients Wong VW. Concurrent fatty liver increases risk of hepatocellular carcinoma with chronic hepatitis B during antiviral treatment and off-treatment. among patients with chronic hepatitis B. J Gastroenterol Hepatol. 2017; Patient Prefer Adherence. 2017;11:85–93. 32(3):667–76. 7. Cai SH, Lu SX, Liu LL, Zhang CZ, Yun JP. Increased expression of hepatocyte 29. the European Association for the Study of the Liver (EASL), European nuclear factor 4 alpha transcribed by promoter 2 indicates a poor prognosis Association for the Study of Diabetes (EASD), European Association for the in hepatocellular carcinoma. Ther Adv Gastroenterol. 2017;10(10):761–71. Study of Obesity (EASO). Clinical Practice Guidelines for the management of 8. Cai SH, Lv FF, Zhang YH, Jiang YG, Peng J. Dynamic comparison between non-alcoholic fatty liver disease. J HEPATOL. 2016;64(6):1388–402. Daan real-time PCR and Cobas TaqMan for quantification of HBV DNA levels 30. Oh HJ, Kim TH, Sohn YW, Kim YS, Oh YR, Cho EY, Shim SY, Shin SR, in patients with CHB. BMC Infect Dis. 2014;14:85. HanAL, YoonSJ, et al. Associationof serum alanine aminotransferase 9. Zheng C, Yan H, Zeng J, Cai S, Wu X. Comparison of pegylated interferon and gamma-glutamyltransferase levels within the reference range with monotherapy and de novo pegylated interferon plus tenofovir combination metabolic syndrome and nonalcoholic fatty liver disease. Korean J therapy in patients with chronic hepatitis B. Infect Drug Resist. 2019;12:845–54. Hepatol. 2011;17(1):27–36. Xue et al. Infectious Agents and Cancer (2020) 15:11 Page 6 of 6 31. Chen SL, Liu LL, Lu SX, et al. HB x‐mediated decrease of AIM 2 contributes to hepatocellular carcinoma metastasis[J]. Mol Oncol. 2017;11(9):1225–40. 32. Huang JY, Bi Y, Zuo GW, et al. Effects of HBx on localization of PPARγ in HepG2 cell line[J]. Acta Acad Med Militaris Tertiae. 2008;18:1693–96. 33. Kim WH, Hong F, Jaruga B, Hu Z, Fan S, Liang TJ, Gao B. Additive activation of hepatic NF-kappaB by ethanol and hepatitis B protein X (HBX) or HCV core protein: involvement of TNF-alpha receptor 1-independent and -dependent mechanisms. FASEB J. 2001;15(13):2551–3. 34. Ringelhan M, O'Connor T, Protzer U, Heikenwalder M. The direct and indirect roles of HBV in liver cancer: prospective markers for HCC screening and potential therapeutic targets. J Pathol. 2015;235(2):355–67. 35. Colombo M. Natural history and pathogenesis of hepatitis C virus related hepatocellular carcinoma. J Hepatol. 1999;31(Suppl 1):25–30. 36. Cescon M, Cucchetti A, Grazi GL, Ferrero A, Vigano L, Ercolani G, Ravaioli M, Zanello M, Andreone P, Capussotti L, et al. Role of hepatitis B virus infection in the prognosis after hepatectomy for hepatocellular carcinoma in patients with cirrhosis: a Western dual-center experience. Arch Surg. 2009;144(10): 906–13. 37. Kondo K, Chijiiwa K, Funagayama M, Kai M, Otani K, Ohuchida J. Differences in long-term outcome and prognostic factors according to viral status in patients with hepatocellular carcinoma treated by surgery. J Gastrointest Surg. 2008;12(3):468–76. 38. Kaneda K, Kubo S, Tanaka H, Takemura S, Ohba K, Uenishi T, Kodai S, Shinkawa H, Urata Y, Sakae M, et al. Features and outcome after liver resection for non-B non-C hepatocellular carcinoma. Hepatogastroenterology. 2012;59(118):1889–92. 39. Reddy SK, Steel JL, Chen HW, DeMateo DJ, Cardinal J, Behari J, Humar A, Marsh JW, Geller DA, Tsung A. Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease. HEPATOLOGY. 2012;55(6):1809–19. 40. Akahoshi H, Taura N, Ichikawa T, Miyaaki H, Akiyama M, Miuma S, Ozawa E, Takeshita S, Muraoka T, Matsuzaki T, et al. Differences in prognostic factors according to viral status in patients with hepatocellular carcinoma. Oncol Rep. 2010;23(5):1317–23. 41. Li Q, Li H, Qin Y, Wang PP, Hao X. Comparison of surgical outcomes for small hepatocellular carcinoma in patients with hepatitis B versus hepatitis C: a Chinese experience. J Gastroenterol Hepatol. 2007;22(11):1936–41. 42. Tanaka K, Shimada H, Matsuo K, Nagano Y, Endo I, Togo S. Clinical characteristics and surgical outcome in hepatocellular carcinoma without hepatitis B virus surface antigen or hepatitis C virus antibody. Ann Surg Oncol. 2007;14(3):1170–81. 43. Van Hees S, Michielsen P, Vanwolleghem T. Circulating predictive and diagnostic biomarkers for hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol. 2016;22(37):8271–82. 44. Da CA, Plymoth A, Santos-Silva D, Ortiz-Cuaran S, Camey S, Guilloreau P, Sangrajrang S, Khuhaprema T, Mendy M, Lesi OA, et al. Osteopontin and latent-TGF beta binding-protein 2 as potential diagnostic markers for HBV- related hepatocellular carcinoma. Int J Cancer. 2015;136(1):172–81. 45. Yang JD, Gyedu A, Afihene MY, Duduyemi BM, Micah E, Kingham TP, Nyirenda M, Nkansah AA, Bandoh S, Duguru MJ, et al. Hepatocellular carcinoma occurs at an earlier age in Africans, particularly in association with chronic hepatitis B. Am J Gastroenterol. 2015;110(11):1629–31. 46. Park JW, Chen M, Colombo M, Roberts LR, Schwartz M, Chen PJ, Kudo M, Johnson P, Wagner S, Orsini LS, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE study. Liver Int. 2015;35(9):2155–66. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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