Skip to content

Advertisement

Open Access

Prognostic factors in patients with HBV-related hepatocellular carcinoma following hepatic resection

Infectious Agents and Cancer201813:20

https://doi.org/10.1186/s13027-018-0192-7

Received: 4 April 2018

Accepted: 31 May 2018

Published: 8 June 2018

Abstract

Background

To analyze prognostic factors following hepatic resection in patients with HBV-related hepatocellular carcinoma.

Methods

We retrospectively analyzed 217 patients with HBV-related hepatocellular carcinoma who underwent hepatic resection at our hospital between January 2006 and December 2015. Disease-free survival and overall survival rates were analyzed using the Kaplan–Meier method and the log-rank test. The association between recurrence and survival and various clinicopathological factors, including serum alpha-fetoprotein (AFP) level, platelet count, platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, antiplatelet therapy, antiviral therapy, hepatitis C virus infection, and tumor-related characteristics, were assessed using univariate and multivariate logistic regression analysis.

Results

The 1-, 3-, and 5-year overall survival rates were 91, 84, and 79%, respectively, and the recurrence-free survival rates were 72, 51, and 44%, respectively. High post-operative AFP level (hazard ratio [HR] 1.112, 95% confidence interval [CI]: 1.02–1.21, P = 0.007), multiple tumors (HR 1.991, 95% CI: 1.11–3.56, P = 0.021), and no antiviral treatment (HR 1.823, 95% CI: 1.07–3.09, P = 0.026) were independent risk factors for recurrence. High post-operative AFP level (HR 1.222, 95% CI: 1.09–1.36, P < 0.001), multiple tumors (HR 2.715, 95% CI: 1.05–7.02, P = 0.039), and recurrence (HR 12.824, 95% CI: 1.68–97.86, P = 0.014) were independent risk factors for mortality. No other factors analyzed were associated with outcomes in this patient cohort.

Conclusions

High post-operative serum alpha-fetoprotein level and multiple tumors, but not inflammatory factors, were risk factors for poor prognosis in HBV-related hepatocellular carcinoma patients after resection.

Keywords

Alpha-fetoproteinHepatitis B virusHepatocellular carcinomaRisk factorsSurvival rate

Background

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer worldwide [1]. The Eastern Asia and sub-Saharan Africa are the highest areas in hepatitis B virus (HBV) related HCC [2]. In Thailand, HCC is most frequently caused by chronic HBV infection [3, 4]. Surgical resection is potentially curative for early-stage disease if liver functional reserve is adequate [5], but its outcome in HBV-related HCC patients is generally poor [6]. Cirrhosis, chronic hepatitis [7, 8], and chronic HBV infection are considered to be poor prognostic factors following hepatic resection in HCC patients [9].

Inflammation is a key contributor to the pathogenesis of HCC in patients with chronic HBV infection [1012]. Many studies have investigated the utility of inflammatory factors and indices as prognostic markers for HBV-related HCC patients following hepatic resection; however, the results are controversial [1319]. Recent reports suggest that platelets play a major role in the pathogenesis of HCC in HBV-infected patients [20, 21]. Indeed, antiplatelet therapy reduces the incidence of HCC in an HBV-infected mouse model [22]. In addition, Lee et al. reported that HBV-related HCC patients receiving antiplatelet therapy showed better recurrence-free and overall survival after liver resection than untreated patients [23]. Given these observations, we investigated the prognostic value of platelet counts, antiplatelet therapy, inflammatory indices, and various tumor-related characteristics in patients with HBV-related HCC following hepatic resection.

Methods

A total of 387 consecutive patients underwent liver resection and had pathologically proven HCC at the Department of Surgery, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand between January 2006 and December 2015. All patients were followed-up until December 2017. Of these, we retrospectively analyzed data from the 217 patients with HBV-related HCC. The patients who had HDV co-infection were excluded from the study. All patients underwent preoperative cross-sectional dynamic imaging using either triple-phase CT or magnetic resonance imaging (MRI). Routine blood examinations included complete blood count, coagulogram, liver and kidney function tests, and preoperative serum alpha-fetoprotein (AFP) level. The serum AFP level are measured by electrochemiluminescence immunoassay method, AFP ELISA reagent Roche Elecsys®, Roche Diagnostics USA, Indiana, United State. The neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio were calculated. The prognostic nutritional index was calculated as ([albumin {g/L} + 0.005] × [total lymphocyte count {/μL}]). A preoperative indocyanine green retention test at 15 min (ICG-R15) was performed. The Makuuchi criteria are used for patient selection for curative resection in our center [24]. The extent of liver resection was based on the patient’s liver functional reserve as assessed mainly by the Makuuchi criteria, including preoperative ascites volume, Child–Pugh score, ICG-R15 value, and, occasionally, volumetric CT analysis. Liver cirrhosis was defined by the macro or micro nodular surface of the liver intraoperatively.

Pathological specimens were reviewed by a pathologist to confirm the diagnosis of HCC. Patients with combined cholangiocarcinoma and other malignancies were excluded from this study. Microvascular invasion was defined as the presence of tumor cells in the microvasculature. Clinical and pathologic staging was performed according to the American Joint Committee on Cancer staging manual 7th edition [25].

Patients were followed up in outpatient clinics every 3 or 4 months after surgery and routinely underwent imaging studies (ultrasonography, CT, MRI) and blood examinations. Post-operative serum AFP levels were measured within 90 days after hepatic resection. Recurrent disease was defined as the presence of new tumors found by imaging (CT or MRI) during the follow-up period.

Statistical analyses

Patient characteristics with continuous variables were compared by Student’s t-test, and categorical variables were compared with χ2 or Fisher’s exact test. A P value of < 0.05 was considered statistically significant. The potential risk factors were analyzed by univariate and multivariate methods using a Cox regression model. Independent risk factors were expressed as hazard ratios (HR) with 95% confidence intervals (CI). Survival analysis was performed using the Kaplan–Meier method and evaluated by the log-rank test. The cut-off value for post-hepatectomy serum AFP level was determined by receiver operating characteristic (ROC) curve analysis with most significance in predicting tumor recurrence after hepatectomy.

Results

Patient characteristics and perioperative status

Of the 387 consecutive patients who underwent curative resection for HCC from January 2006 to December 2015, 217 (56.0%) had HBV-related HCC and were evaluated here. The clinicopathological characteristics of this cohort are summarized in Table 1.
Table 1

Clinicopathological features of patients with HBV-related hepatocellular carcinoma

Characteristic

Value

Gender, n (%) (total cohort n = 217)

 male

100 (46.08)

 female

117 (53.92)

Age (years), mean ± sd

56.12 (9.78)

HBsAg, n (%)

 negative

16 (7.37)

 positive

201 (92.62)

HBeAg, n (%), n = 119

 negative

85 (71.43)

 positive

34 (28.57)

HBV DNA, n (%), n = 103

 negative

41 (39.81)

 positive

62 (60.19)

HCV, n (%)

 no

210 (96.77)

 yes

7 (3.23)

Platelets × 103 (mm3), median (range)

190.5 (57, 568)

AFP-pre (ng/mL), median (range), n = 185

16.8 (0.89, 82,392)

AFP-post (ng/mL), median (range), n = 125

3.48 (0.83, 19,629)

Tumor size (cm), median (range), n = 216

4.5 (0.5, 26.5)

  < 5

120 (55.56)

  ≥ 5

96 (44.44)

Number of tumors, n (%)

 solitary

166 (77.57)

 multiple

48 (22.43)

Microvascular invasion, n (%)

 no

170 (79.44)

 yes

44 (20.56)

Stage, n (%)

 I

138 (63.59)

 II or higher

79 (36.41)

Resection margin, n (%), n = 185

 free margin

176 (95.14)

 positive margin

9 (4.86)

Operation type, n (%)

 non-anatomical

129 (59.45)

 anatomical

88 (40.55)

Preoperative neoadjuvant, n (%), n = 164

 no

92 (56.10)

 yes

72 (43.90)

Platelet-to-lymphocyte ratio, median (range), n = 203

101.8 (30.9, 432.8)

Prognostic nutritional index, mean ± sd n = 206

95.18 (40.21)

Neutrophil-to-lymphocyte ratio, median (range), n = 201

1.77 (0.33, 10.62)

Antiviral treatment

 no

65 (29.95)

 yes

152 (70.05)

Antiviral drug, n (%)

 Adefovir

7 (3.23)

 Lamivudine

125 (57.60)

 Tenofovir

44 (20.28)

 Entecavir

20 (9.22)

Antiplatelet treatment (ASA + Clopidogrel)

 no

199 (91.71)

 yes

18 (8.29)

Recurrence, n (%)

 no

113 (52.07)

 yes

104 (47.93)

Follow-up time (months), median (range)

36.33 (0.23, 149.07)

AFP alpha-fetoprotein, ASA aspirin, HCV hepatitis C virus, sd standard deviation

Risk factors associated with disease recurrence

A comparison between patients with and without disease recurrence is shown in Table 2. The recurrence rate following resection was 47.9% (104/217). Compared with the non-recurrence group, the recurrence group had a higher post-operative AFP level (2.8 vs 3.8 ng/mL, P = 0.045), was more likely to have multiple tumors (32 vs 16 patients, P = 0.004), and was less likely to have received preoperative neoadjuvant treatment (48/92 vs 26/72 patients, P = 0.04). Univariate analysis (Table 3) identified the following factors as significantly associated with disease recurrence: post-operative AFP level (HR 1.112, 95% CI: 1.02–1.21, P = 0.012), tumor size (HR 1.061, 95% CI: 1.01–1.11, P = 0.013), multiple tumors (HR 1.881, 95% CI: 1.23–2.86, P = 0.003), microvascular invasion (HR 1.645, 95% CI: 1.02–2.63, P = 0.037), stage II or higher (HR 1.553, 95% CI 1.04–2.31, P = 0.031), and no antiviral treatment (HR 1.519, 95% CI: 1.01–2.28, P = 0.045). In multivariate analysis (Table 3), post-operative AFP (HR 1.112, 95% CI: 1.02–1.21, P = 0.007), multiple tumors (HR 1.991, 95% CI: 1.11–3.56, P = 0.021), and no antiviral treatment (HR 1.823, 95% CI: 1.07–3.09, P = 0.026) remained independent risk factors for recurrence.
Table 2

Clinicopathological features of patients in the non-recurrence and recurrence groups

Characteristic

Non-Recurrence (n = 113)

Recurrence (n = 104)

P value

Gender, n (%) (total cohort n = 217)

 male

49 (43.36)

51 (49.04)

0.402

 female

64 (56.64)

53 (50.96)

 

Age (years), mean ± sd

56.46 (10.60)

55.76 (8.86)

0.604

HCV, n (%)

 no

111 (98.23)

99 (95.19)

0.264

 yes

2 (1.77)

5 (4.81)

 

Platelets × 103, median (range), n = 384

198.5 (57, 465)

179.5 (76, 568)

0.068

AFP-pre (ng/mL), median (range), n = 325

15.2 (0.89, 60,500)

17.03 (1.1, 82,392)

0.572

AFP-post (ng/mL), median (range), n = 226

2.8 (0.83, 5271)

3.8 (0.9, 19,629)

0.045

Tumor size (cm), median (range), n = 386

4.3 (0.6, 26.5)

5 (0.5, 18)

0.511

  < 5

63 (55.75)

57 (55.34)

0.951

  ≥ 5

50 (44.25)

46 (44.66)

 

Number of tumors, n (%), n = 382

 solitary

94 (85.45)

72 (69.23)

0.004

 multiple

16 (14.55)

32 (30.77)

 

Microvascular invasion, n (%), n = 382

 no

89 (80.91)

81 (77.88)

0.584

 yes

21 (19.09)

23 (22.12)

 

Stage, n (%)

 I

77 (68.14)

61 (58.65)

0.147

 II or higher

36 (31.86)

43 (41.35)

 

Resection margin, n (%), n = 325

 free margin

89 (94.68)

87 (95.60)

0.999

 positive margin

5 (5.32)

4 (4.40)

 

Operation type, n (%)

 non-anatomical

69 (61.06)

60 (57.69)

0.614

 anatomical

44 (38.94)

44 (42.31)

 

Preoperative neoadjuvant, n (%), n = 289

 no

44 (48.89)

48 (64.86)

0.040

 yes

46 (51.11)

26 (35.14)

 

Platelet-to-lymphocyte ratio, median (range), n = 365

106.6 (46.3, 432.8)

91.2 (30.9, 290.7)

0.128

Prognostic nutritional index, median (range), n = 370

89.12 (0.34, 265.26)

91.9 (0.41, 245.02)

0.764

Neutrophil-to-lymphocyte ratio, median (range), n = 361

1.78 (0.67, 8.11)

1.76 (0.33, 10.62)

0.770

Antiviral treatment

 no

30 (26.55)

35 (33.65)

0.254

 yes

83 (73.45)

69 (66.35)

 

Antiviral drug

 Adefovir

4 (3.54)

3 (2.88)

0.999

 Lamivudine

66 (58.41)

59 (56.73)

0.254

 Tenofovir

28 (25.66)

15 (14.42)

0.021

 Entecavir

10 (8.85)

10 (9.62)

0.846

Antiplatelet treatment (ASA + Clopidogrel)

 no

103 (91.15)

96 (92.31)

0.757

 yes

10 (8.85)

8 (7.69)

 

AFP alpha-fetoprotein, ASA aspirin, HCV hepatitis C virus, sd standard deviation

NOTE. Italic font indicates statistical significance

Table 3

Univariate and multivariate analysis of factors associated with recurrence

 

Univariate

Multivariate

HR (95% CI)

P value

HR (95% CI)

P value

Gender (male)

 female

0.894 (0.60–1.32)

0.574

  

Age (years)

0.996 (0.97–1.02)

0.719

  

HCV (no)

 yes

1.473 (0.59–3.62)

0.399

  

Platelets × 103 (mm3)

0.987 (0.96–1.01)

0.367

  

AFP-pre (ng/mL)

0.996 (0.97–1.01)

0.665

  

AFP-post (ng/mL)

1.112 (1.02–1.21)

0.012

1.129 (1.04–1.23)

0.005

Tumor size (< 5 cm)

1.061 (1.01–1.11)

0.013

  

  ≥ 5 cm

1.345 (0.90–1.99)

0.139

  

Number of tumors (solitary)

 multiple

1.881 (1.23–2.86)

0.003

1.973 (1.15–3.38)

0.013

Microvascular invasion (no)

 yes

1.645 (1.02–2.63)

0.037

  

Stage (I)

 II or higher

1.553 (1.04–2.31)

0.031

  

Resection margin (free margin)

 positive margin

0.977 (0.35–2.66)

0.964

  

Operation type (anatomical)

 non-anatomical

0.708 (0.47–1.05)

0.085

  

Preoperative neoadjuvant (no)

 yes

0.828 (0.51–1.34)

0.450

  

Platelet-to-lymphocyte ratio

0.913 (0.61–1.34)

0.648

  

Prognostic nutritional index

0.959 (0.56–1.61)

0.875

  

Neutrophil-to-lymphocyte ratio

1.052 (0.89–1.23)

0.535

  

Antiviral treatment

 no

1.519 (1.01–2.28)

0.045

1.823 (1.07–3.09)

0.026

Antiplatelet treatment (ASA + Clopidogrel)

 no

1.018 (0.49–2.09)

0.961

  

 AFP alpha-fetoprotein, ASA aspirin, CI confidence interval, HR hazard ratio, HCV hepatitis C virus

NOTE. Italic font indicates statistical significance

Risk factors associated with mortality

Table 4 shows the comparison of survivors and non-survivors. The survival rate of HBV-related HCC patients following hepatectomy was 82.5% (179/217). Compared with the survivor group, non-survivors had significantly higher pre- and post-operative AFP levels (115 vs 14.2 ng/mL, P = 0.018 and 13.11 vs 2.8 ng/mL, P < 0.001, respectively) and were more likely to have multiple tumors than a solitary tumor (14/48 vs 23/166 patients, P = 0.013). Patients undergoing anatomical resection also had a higher mortality rate than those undergoing other operations (22/88 vs 16/129, P = 0.017). As shown in Table 5, univariate analysis identified the following factors as significantly associated with survival: post-operative AFP level (HR 1.218, 95% CI: 1.10–1.35, P < 0.001), tumor size ≥5 cm (HR 1.679, 95% CI: 1.01–2.77, P = 0.044), multiple tumors (HR 2.300 95% CI: 1.18–4.47, P = 0.014), anatomical resection (HR 2.443, 95% CI: 1.28–4.65, P = 0.007), no antiviral treatment (HR 0.482, 95% CI: 0.25–0.92, P = 0.027), and recurrence (HR 2.940, 95% CI: 1.40–6.05, P = 0.003). In multivariate analysis, post-operative AFP (HR 1.222, 95% CI: 1.09–1.36, P < 0.001), multiple tumors (HR 2.715, 95% CI: 1.05–7.02, P = 0.039), and recurrence (HR 12.824, 95% CI: 1.68–97.86, P = 0.014) were independent risk factors for death (Table 5).
Table 4

Comparison of clinicopathological features of survivors and non-survivors

Characteristic

Alive (n = 179)

Dead (n = 38)

P value

Gender, n (%)

 male

76 (42.46)

24 (63.16)

0.020

 female

103 (57.54)

14 (36.84)

 

Age (years), mean ± sd

56.03 (9.44)

56.60 (11.39)

0.742

HCV, n (%)

 no

172 (96.09)

38 (100)

0.609

 yes

7 (3.91)

0

 

Platelets ×103 (mm3), median (range)

192 (57, 568)

185 (91, 332)

0.485

AFP-pre (ng/mL), median (range), n = 185

14.2 (0.89, 82,392)

115 (1.85, 60,500)

0.018

AFP-post (ng/mL), median (range), n = 125

2.8 (0.83, 5271)

13.11 (1.19, 19,629)

0.0003

Tumor size (cm), median (range), n = 216

4.3 (0.5, 26.5)

5.5 (2, 17)

0.066

  < 5

103 (57.54)

17 (45.95)

0.196

  ≥ 5

76 (42.46)

20 (54.05)

 

Number of tumors, n (%)

 solitary

143 (80.79)

23 (62.16)

0.013

 multiple

34 (19.21)

14 (37.84)

 

Microvascular invasion, n (%)

 no

141 (79.66)

29 (78.38)

0.861

 yes

36 (20.34)

8 (21.62)

 

Stage, n (%)

 I

110 (61.45)

28 (73.68)

0.155

 II or higher

69 (38.55)

10 (26.32)

 

Resection margin, n (%), n = 185

 free margin

144 (96.00)

32 (91.43)

0.375

 positive margin

6 (4.00)

3 (8.57)

 

Operation type, n (%)

 non-anatomical

113 (63.13)

16 (42.11)

0.017

 anatomical

66 (36.87)

22 (57.89)

 

Preoperative neoadjuvant, n (%) n = 164

 no

71 (53.79)

21 (65.63)

0.226

 yes

61 (46.21)

11 (34.38)

 

Platelet-to-lymphocyte ratio, median (range), n = 203

101.6 (30.9, 432.8)

107.1 (51.0, 258.9)

0.339

Prognostic nutritional index, mean ± sd, n = 206

97.35 (41.10)

84.21 (33.78)

0.082

Neutrophil-to-lymphocyte ratio, median (range), n = 201

1.73 (0.33, 10.62)

2 (0.73, 4.41)

0.298

Antiviral treatment

 no

49 (27.37)

16 (42.11)

0.072

 yes

130 (72.63)

22 (57.89)

 

Antiplatelet treatment (ASA + Clopidogrel)

 no

163 (91.06)

36 (94.74)

0.746

 yes

16 (8.94)

2 (5.26)

 

Recurrence n (%)

 no

103 (57.54)

10 (26.32)

0.000

 yes

76 (42.46)

28 (73.68)

 

AFP alpha-fetoprotein, ASA aspirin, HCV hepatitis C virus, microvascular invasion, sd standard deviation

NOTE. Italic font indicates statistical significance

Table 5

Univariate and multivariate analysis of factors associated with overall survival

 

Univariate

Multivariate

HR (95% CI)

P value

HR (95% CI)

P value

Gender (male)

 female

0.552 (0.28–1.07)

0.080

  

Age (years)

1.002 (0.96–1.04)

0.890

  

HCV (no)

 yes

   

Platelets × 103 (mm3)

0.999 (0.99–1.01)

0.829

  

AFP-pre (ng/mL)

1.011 (0.99–1.03)

0.300

  

AFP-post (ng/mL)

1.218 (1.10–1.35)

0.000

1.206 (1.08–1.34)

0.000

Tumor size (< 5 cm)

1.052 (0.99–1.12)

0.091

  

  ≥ 5 cm.

1.679 (1.01–2.77)

0.044

  

Number of tumors (solitary)

 multiple

2.300 (1.18–4.47)

0.014

2.715 (1.05–7.02)

0.039

Microvascular invasion (no)

 yes

1.598 (0.72–3.54)

0.249

  

Stage (I)

 II or higher

0.737 (0.35–1.53)

0.415

  

Resection margin (free margin)

 positive margin

2.140 (0.65–7.05)

0.211

  

Operation type (anatomical)

 non-anatomical

0.409 (0.21–0.78)

0.007

  

Preoperative neoadjuvant (no)

 yes

0.958 (0.45–2.01)

0.910

  

Platelet-to-lymphocyte ratio

1.003 (0.99–1.01)

0.195

  

Prognostic nutritional index

0.991 (0.98–1.00)

0.065

  

Neutrophil-to-lymphocyte ratio

1.070 (0.82–1.39)

0.621

  

Antiviral treatment

 no

0.482 (0.25–0.92)

0.027

  

Antiplatelet treatment (ASA + Clopidogrel)

 no

1.542 (0.37–6.41)

0.551

  

Recurrence (no)

 yes

2.940 (1.42–6.05)

0.003

12.824 (1.68–97.86)

0.014

AFP alpha-fetoprotein, ASA aspirin, HCV hepatitis C virus, sd standard deviation

NOTE. Italic font indicates statistical significance

Overall survival and recurrence-free survival analysis

The Kaplan–Meier analysis curves for recurrence-free survival (RFS) and overall survival (OS) of all patients are shown in Fig. 1. The overall 1-, 3-, and 5-year overall survival rates were 91, 84, and 79%, respectively, and the RFS rates were 72, 51, and 44%, respectively. As expected, OS was significantly poorer for patients with recurrent compared with non-recurrent disease (Fig. 2). In addition, patients with multiple tumors had poorer OS and RFS than patients with solitary tumors (Fig. 3).
Figure 1
Fig. 1

Kaplan–Meier survival analysis of HBV-related hepatocellular carcinoma following hepatic resection. a, overall recurrence; b, overall survival

Figure 2
Fig. 2

Kaplan–Meier survival analysis of the recurrence and non-recurrence groups

Figure 3
Fig. 3

Kaplan–Meier survival analysis of patients with solitary and multiple tumors. a, recurrence-free survival; b, overall survival

In addition, post-operative AFP was the risk factor of recurrence. Comparison of the patients between high and low post-operative AFP groups. As the first step, the cut-off value for post-AFP was determined by receiver operating characteristic (ROC) curve analysis as shown in Fig. 4. The area under ROC curve was 0.604. The post-operative AFP value 3.5 ng/mL was considered as the optimal cut-off value because of its highest index; the sensitivity and specificity were 56.9 and 58.3%, respectively. The Kaplan-Meier analysis curves for RFS and OS of patients with post-operative AFP level > 3.5 ng/mL had poorer overall and recurrence free survival when compared with post-operative AFP level ≤ 3.5 ng/mL(Fig. 5).
Figure 4
Fig. 4

Receiver operating characteristic curves for predicting tumor recurrence

Figure 5
Fig. 5

Kaplan-Meier survival analysis of patients with post-operative AFP < 3.5 and post-operative AFP ≥ 3.5 groups. a, recurrence-free survival; b, overall survival

Outcomes correlation stratified by antiviral treatment in solitary and multiple tumor

The Kaplan-Meier analysis curves for RFS of patients who had soliltary and multiple tumor with or without antiviral treatment (Fig. 6). The RFS in the solitary and multiple tumor groups were not significantly difference with antiviral compared with non-antiviral treatment.
Figure 6
Fig. 6

Kaplan-Meier survival analysis of patients with or without antiviral treatment according to the number of tumor. a, solitary tumor; b, multiple tumor

Discussion

Chronic HBV infection is a major risk factor for the development of HCC, especially in Southeast Asia [26]. The pathogenesis of HBV-induced HCC is complex and involves both direct and indirect mechanisms. The immune response against HBV-infected hepatocytes triggers inflammation and leads to sustained necrosis [12]. Recent work has suggested a role for platelets in promoting liver infiltration of cytotoxic T lymphocytes and non-virus-specific inflammatory cells in the pathogenesis of HCC in a HBV transgenic mouse model [20, 27]. In addition, biomarkers such as AFP and inflammatory mediators have been reported to affect the prognosis of HBV-related HCC patients [15, 18, 19, 2832], although the results are controversial.

In our study, we found that post-operative serum AFP levels and the presence of multiple tumors are predictors of poor prognosis for HBV-related HCC following hepatic resection. AFP is a large glycoprotein produced by the yolk sac and fetal liver. AFP is present in large quantities during gestation and is generally repressed in healthy adults; however, it is re-expressed in a variety of tumors [33, 34]. Several studies have reported correlations between AFP levels and the prognosis of HBV-related HCC patients after curative resection, but most of them measured only preoperative AFP levels and the prognostic impact of AFP levels following hepatic resection was unclear [15, 3540]. In other studies, post-operative AFP levels were shown to correlate with the prognosis of HCC patients, but the populations in those studies were heterogenous and included both HBV-positive and -negative patients [4147]. Here, we show for the first time that the post-operative serum AFP level is an independent prognostic factor for survival in HBV-related HCC patients following curative resection. Our results are consistent with a study by Shen et al., who reported that a ≤ 50% difference between pre- and post-operative serum AFP was predictive of poor disease-free and overall survival after hepatectomy in HCC patients, 89.3% of whom had HBV-related HCC [41]. Allard et al. reported that a post-resection AFP level of > 15 ng/mL was a poor predictor of outcome for cirrhotic HCC patients with preoperative AFP levels of > 15 ng/ml [43]. Similarly, Zhang et al. reported that high serum AFP and alpha-fetoprotein-L3 (AFP-L3) levels before and after hepatectomy predicted poor survival [46].

Several potential mechanisms could account for the association between high post-operative serum AFP levels and survival outcome in HBV-related HCC patients. First, although AFP is not present at elevated levels in early-stage HCC and is thus a poor diagnostic biomarker [29, 48, 49], high serum AFP levels may reflect an increasing disease burden due to extrahepatic metastasis, advanced stage, large tumor size, and/or portal vein thrombosis [50]. Ogden et al. and Sung et al. reported that the HBV viral protein HBx dysregulates p53-mediated AFP expression through direct binding to p53, and high HBV integration into the host genome correlated with high serum AFP levels [51, 52]. Moreover, Silva et al. reported that baseline serum AFP levels were higher in HCC patients with more advanced disease and could predict their overall survival, regardless of treatment. Therefore, the patients with high post-operative serum AFP levels in our study may have had occult intra- or extrahepatic metastasis [48]. In addition, high serum AFP may be a marker of liver inflammation in patients with chronic liver disorders [10, 12, 50]. Sitia et al. reported that inflammation was a key event in HCC carcinogenesis in HBV transgenic mice and was promoted by lymphocyte infiltration and platelet aggregation [21]. Therefore, ongoing inflammation in patients with high serum AFP could facilitate hepatic carcinogenesis.

In this study, we also found that the presence of multiple HCC tumors is a predictor of recurrence after initial hepatic resection. This is consistent with previous studies showing that multiple tumors is one of the most significant risk factors of early tumor recurrence and poor outcome in HBV-related HCC patients [5355]. Intrahepatic recurrence is also associated with survival of HCC patients [56]. In agreement with these observations, our multivariate analysis identified tumor recurrence as an independent predictor of poorer overall survival. Park et al. reported that multiple tumors resulting from intrahepatic metastasis was a strong predictor of early multinodular intrahepatic recurrence in HCC patients following hepatic resection [54]. Hao et al. reported that the presence multiple tumors was significantly associated with intrahepatic metastasis recurrence in HBV-related HCC patients, whereas liver cirrhosis and hepatic inflammation activity were associated with multi-centric recurrence [57]. These authors concluded that intrahepatic and multi-centric metastasis recurrence were mainly caused by tumor-related factors and patient-related factors, respectively [57]. Our results showing that patients with solitary and multiple tumors had significantly different recurrence-free and overall survival rates are consistent with this study. We hypothesize that our patients with multiple tumors may have had intrahepatic metastasis and multi-focal occult tumors.

We examined a number of inflammatory markers, including neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index, in our patient cohort and found that none of them predicted survival. Antiplatelet therapy also was not a prognostic indicator, although 16 of the 18 patients who received this therapy survived. The small sample population may explain why this finding was not statistically significant. The benefit of antiplatelet therapy in HBV-related HCC patients has been investigated in two large retrospective studies [23, 58]. In a study of Taiwanese patients, Lee et al. found that antiplatelet therapy, including aspirin or clopidogrel, was associated with better recurrence-free survival and overall survival following hepatic resection. However, antiplatelet use significantly increased the risk of upper gastrointestinal bleeding in that study. Lee et al. found that antiplatelet therapy reduced the risk of HCC in South Korean patients whose chronic HBV infection had been effectively suppressed. However, clopidogrel alone with aspirin was found to increase the risk of bleeding [58]. Large-scale prospective studies are clearly needed to unequivocally establish the benefits and risk of complications from antiplatelet therapy.

This study has several limitations. First, it was retrospective in nature. Second, AFP levels in patients with HBV infection could be affected by non-malignancy-related factors such as liver cirrhosis, acute hepatitis, and chronic liver disease [50]. In this study, we included HBV-infected patients with and without cirrhosis and there are seven patients enrolled in the study were co-infected with HBV and HCV. The etiology of HCC among those patients may not due to the chronic HBV infection. Third, there are a number of studies indicating that biomarkers such as protein induced by vitamin K absence-II [32], des-gamma carboxy prothrombin [39], and AFP-L3 [59] may be more accurate prognostic biomarkers than AFP level. However, these tumor markers are not currently measured at our hospital. Fourth, some patients especially in the early period of the study were not treated with anti-viral drugs. Fifth, the patients who neoadjuvant therapy were performed, the AFP level and inflammatory marker levels could be affected. Sixth, the number of death population could be slightly lower than actual due to there are some patients who had recurrence disease have loss to follow-up. Seventh, lamivudine is an anti-HBV drug of modest antiviral effect with low barrier of drug resistance and is no longer suggested by American Association for the Study of Liver Diseases and European Association of the Study of the Liver as a first-line antiviral option [60, 61]. The proportion of patients with lamivudine treatment in this study was relatively high, which may lead to underestimation of the protective effect of antiviral treatment on HBV related HCC recurrence.

Conclusions

Post-operative serum alpha-fetoprotein level and multiple tumors, but not inflammatory indices, platelet counts, or antiplatelet therapy, were found to be risk factors of poor prognosis for HBV-related HCC patients following hepatectomy. Prospective studies will be required to clarify the role of platelets in the disease and the benefits of antiplatelet therapy in this patient group. Our results indicate that patients with multiple tumors and high post-operative serum alpha-fetoprotein level should be monitored carefully following hepatic resection.

Abbreviations

AFP: 

Alpha-fetoprotein

AFP-L3: 

Alpha-fetoprotein L3

CI: 

Confidence intervals

CT: 

Computed tomography

HBV: 

Hepatitis B virus

HCC: 

Hepatocellular carcinoma

HR: 

Hazard ratio

ICG-R15: 

Indocyanine green retention at 15 min

MRI: 

Magnetic resonance imaging

Declarations

Acknowledgements

We thank Mr. Napaphat Poprom for reviewing the biostatistical analysis. We thank Edanz Group (https://www.edanzediting.com/ac) for editing a draft of this manuscript.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

RN designed the study, collected and interpreted the data, and wrote the paper; SW collected the data and wrote the paper; MS collected and analyzed the data; TP collected and analyzed the data; MP collected the data; and AS analyzed the data. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The study was reviewed and approved by the Ramathibodi Hospital Institutional Review Board Committee on Human Rights Related to Research Involving Human Subjects (protocol number ID 01–61-65).

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis 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.

Authors’ Affiliations

(1)
Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.View ArticlePubMedGoogle Scholar
  2. Petruzziello A. Epidemiology of hepatitis B virus (HBV) and hepatitis C virus (HCV) related hepatocellular carcinoma. Open Virol J. 2018;12:26–32.View ArticlePubMedPubMed CentralGoogle Scholar
  3. Chitapanarux T, Phornphutkul K. Risk factors for the development of hepatocellular carcinoma in Thailand. J Clin Transl Hepatol. 2015;3(3):182–8.View ArticlePubMedPubMed CentralGoogle Scholar
  4. Rungsakulkij N, Keeratibharat N, Suragul W, Tangtawee P, Muangkaew P, Mingphruedhi S, Aeesoa S. Early recurrence risk factors for hepatocellular carcinoma after hepatic resection: experience at a thai tertiary care center. J Med Assoc Thail. 2018;101(1):63–9.Google Scholar
  5. Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology. 2016;150(4):835–53.View ArticlePubMedGoogle Scholar
  6. Liu W, Zhou JG, Sun Y, Zhang L, Xing BC. Hepatic resection improved the long-term survival of patients with BCLC stage B hepatocellular carcinoma in Asia: a systematic review and meta-analysis. J Gastrointest Surg. 2015;19(7):1271–80.View ArticlePubMedGoogle Scholar
  7. Wang Q, Blank S, Fiel MI, Kadri H, Luan W, Warren L, Zhu A, Deaderick PA, Sarpel U, Labow DM, et al. The severity of liver fibrosis influences the prognostic value of inflammation-based scores in hepatitis B-associated hepatocellular carcinoma. Ann Surg Oncol. 2015;22(Suppl 3):S1125–32.View ArticlePubMedGoogle Scholar
  8. Choi WM, Lee JH, Ahn H, Cho H, Cho YY, Lee M, Yoo JJ, Cho Y, Lee DH, Lee YB, et al. Forns index predicts recurrence and death in patients with hepatitis B-related hepatocellular carcinoma after curative resection. Liver Int. 2015;35(8):1992–2000.View ArticlePubMedGoogle Scholar
  9. Lee JJ, Kim PT, Fischer S, Fung S, Gallinger S, McGilvray I, Moulton CA, Wei AC, Greig PD, Cleary SP. Impact of viral hepatitis on outcomes after liver resection for hepatocellular carcinoma: results from a north american center. Ann Surg Oncol. 2014;21(8):2708–16.View ArticlePubMedGoogle Scholar
  10. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–44.View ArticlePubMedGoogle Scholar
  11. Seki E, Schwabe RF. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology. 2015;61(3):1066–79.View ArticlePubMedPubMed CentralGoogle Scholar
  12. Levrero M, Zucman-Rossi J. Mechanisms of HBV-induced hepatocellular carcinoma. J Hepatol. 2016;64(1 Suppl):S84–s101.View ArticlePubMedGoogle Scholar
  13. Toyoda H, Kumada T, Kaneoka Y, Osaki Y, Kimura T, Arimoto A, Oka H, Yamazaki O, Manabe T, Urano F, et al. Prognostic value of pretreatment levels of tumor markers for hepatocellular carcinoma on survival after curative treatment of patients with HCC. J Hepatol. 2008;49(2):223–32.View ArticlePubMedGoogle Scholar
  14. Shim JH, Yoon DL, Han S, Lee YJ, Lee SG, Kim KM, Lim YS, Lee HC, Chung YH, Lee YS. Is serum alpha-fetoprotein useful for predicting recurrence and mortality specific to hepatocellular carcinoma after hepatectomy? A test based on propensity scores and competing risks analysis. Ann Surg Oncol. 2012;19(12):3687–96.View ArticlePubMedGoogle Scholar
  15. Yang SL, Liu LP, Yang S, Liu L, Ren JW, Fang X, Chen GG, Lai PB. Preoperative serum alpha-fetoprotein and prognosis after hepatectomy for hepatocellular carcinoma. Br J Surg. 2016;103(6):716–24.View ArticlePubMedGoogle Scholar
  16. Poon RT, Fan ST, Lo CM, Liu CL, Ng IO, Wong J. Long-term prognosis after resection of hepatocellular carcinoma associated with hepatitis B-related cirrhosis. J Clin Oncol. 2000;18(5):1094–101.View ArticlePubMedGoogle Scholar
  17. Tangkijvanich P, Anukulkarnkusol N, Suwangool P, Lertmaharit S, Hanvivatvong O, Kullavanijaya P, Poovorawan Y. Clinical characteristics and prognosis of hepatocellular carcinoma: analysis based on serum alpha-fetoprotein levels. J Clin Gastroenterol. 2000;31(4):302–8.View ArticlePubMedGoogle Scholar
  18. Blank S, Wang Q, Fiel MI, Luan W, Kim KW, Kadri H, Mandeli J, Hiotis SP. Assessing prognostic significance of preoperative alpha-fetoprotein in hepatitis B-associated hepatocellular carcinoma: normal is not the new normal. Ann Surg Oncol. 2014;21(3):986–94.View ArticlePubMedGoogle Scholar
  19. Zhao Z, Liu J, Wang J, Xie T, Zhang Q, Feng S, Deng H, Zhong B. Platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) are associated with chronic hepatitis B virus (HBV) infection. Int Immunopharmacol. 2017;51:1–8.View ArticlePubMedGoogle Scholar
  20. Iannacone M, Sitia G, Isogawa M, Marchese P, Castro MG, Lowenstein PR, Chisari FV, Ruggeri ZM, Guidotti LG. Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nat Med. 2005;11(11):1167–9.View ArticlePubMedPubMed CentralGoogle Scholar
  21. Sitia G. Platelets promote liver immunopathology contributing to hepatitis B virus-mediated hepatocarcinogenesis. Semin Oncol. 2014;41(3):402–5.View ArticlePubMedGoogle Scholar
  22. Sitia G, Aiolfi R, Di Lucia P, Mainetti M, Fiocchi A, Mingozzi F, Esposito A, Ruggeri ZM, Chisari FV, Iannacone M, et al. Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B. Proc Natl Acad Sci U S A. 2012;109(32):E2165–72.View ArticlePubMedPubMed CentralGoogle Scholar
  23. Lee PC, Yeh CM, Hu YW, Chen CC, Liu CJ, Su CW, Huo TI, Huang YH, Chao Y, Chen TJ, et al. Antiplatelet therapy is associated with a better prognosis for patients with hepatitis B virus-related hepatocellular carcinoma after liver resection. Ann Surg Oncol. 2016;23(Suppl 5):874–83.View ArticlePubMedGoogle Scholar
  24. Miyagawa S, Makuuchi M, Kawasaki S, Kakazu T. Criteria for safe hepatic resection. Am J Surg. 1995;169(6):589–94.View ArticlePubMedGoogle Scholar
  25. Compton CC, Byrd DR, Garcia-Aguilar J, Kurtzman SH, Olawaiye A, Liver WMK. AJCC Cancer staging atlas: a companion to the seventh editions of the AJCC Cancer staging manual and handbook. New York: Springer; 2006.Google Scholar
  26. Stanaway JD, Flaxman AD, Naghavi M, Fitzmaurice C, Vos T, Abubakar I, Abu-Raddad LJ, Assadi R, Bhala N, Cowie B, et al. The global burden of viral hepatitis from 1990 to 2013: findings from the global burden of disease study 2013. Lancet. 2016;388(10049):1081–8.View ArticlePubMedPubMed CentralGoogle Scholar
  27. Sitia G, Iannacone M, Guidotti LG. Anti-platelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma. J Hepatol. 2013;59(5):1135–8.View ArticlePubMedGoogle Scholar
  28. Pang Q, Zhou L, Qu K, Cui RX, Jin H, Liu HC. Validation of inflammation-based prognostic models in patients with hepatitis B-associated hepatocellular carcinoma: a retrospective observational study. Eur J Gastroenterol Hepatol. 2018;30(1):60–70.View ArticlePubMedGoogle Scholar
  29. You DD, Kim DG, Seo CH, Choi HJ, Yoo YK, Park YG. Prognostic factors after curative resection hepatocellular carcinoma and the surgeon's role. Ann Surg Treat Res. 2017;93(5):252–9.View ArticlePubMedPubMed CentralGoogle Scholar
  30. Zhu Q, Yuan B, Qiao GL, Yan JJ, Li Y, Duan R, Yan YQ. Prognostic factors for survival after hepatic resection of early hepatocellular carcinoma in HBV-related cirrhotic patients. Clin Res Hepatol Gastroenterol. 2016;40(4):418–27.View ArticlePubMedGoogle Scholar
  31. Giannini EG, Marenco S, Borgonovo G, Savarino V, Farinati F, Del Poggio P, Rapaccini GL, Anna Di Nolfo M, Benvegnu L, Zoli M, et al. Alpha-fetoprotein has no prognostic role in small hepatocellular carcinoma identified during surveillance in compensated cirrhosis. Hepatology. 2012;56(4):1371–9.View ArticlePubMedGoogle Scholar
  32. Kang SH, Kim DY, Jeon SM, Ahn SH, Park JY, Kim SU, Kim JK, Lee KS, Chon CY, Han KH. Clinical characteristics and prognosis of hepatocellular carcinoma with different sets of serum AFP and PIVKA-II levels. Eur J Gastroenterol Hepatol. 2012;24(7):849–56.View ArticlePubMedGoogle Scholar
  33. Gillespie JR, Uversky VN. Structure and function of alpha-fetoprotein: a biophysical overview. Biochim Biophys Acta. 2000;1480(1–2):41–56.View ArticlePubMedGoogle Scholar
  34. Mizejewski GJ. Alpha-fetoprotein structure and function: relevance to isoforms, epitopes, and conformational variants. Exp Biol Med (Maywood). 2001;226(5):377–408.View ArticleGoogle Scholar
  35. Kim JM, Kwon CH, Joh JW, Park JB, Lee JH, Kim SJ, Paik SW, Park CK, Yoo BC. Differences between hepatocellular carcinoma and hepatitis B virus infection in patients with and without cirrhosis. Ann Surg Oncol. 2014;21(2):458–65.View ArticlePubMedGoogle Scholar
  36. Yang SL, Liu LP, Sun YF, Yang XR, Fan J, Ren JW, Chen GG, Lai PB. Distinguished prognosis after hepatectomy of HBV-related hepatocellular carcinoma with or without cirrhosis: a long-term follow-up analysis. J Gastroenterol. 2016;51(7):722–32.View ArticlePubMedGoogle Scholar
  37. Wu SJ, Lin YX, Ye H, Li FY, Xiong XZ, Cheng NS. Lymphocyte to monocyte ratio and prognostic nutritional index predict survival outcomes of hepatitis B virus-associated hepatocellular carcinoma patients after curative hepatectomy. J Surg Oncol. 2016;114(2):202–10.View ArticlePubMedGoogle Scholar
  38. Li T, Wang SK, Zhou J, Sun HC, Qiu SJ, Ye QH, Wang L, Fan J. Positive HBcAb is associated with higher risk of early recurrence and poorer survival after curative resection of HBV-related HCC. Liver Int. 2016;36(2):284–92.View ArticlePubMedGoogle Scholar
  39. Meguro M, Mizuguchi T, Nishidate T, Okita K, Ishii M, Ota S, Ueki T, Akizuki E, Hirata K. Prognostic roles of preoperative alpha-fetoprotein and des-gamma-carboxy prothrombin in hepatocellular carcinoma patients. World J Gastroenterol. 2015;21(16):4933–45.View ArticlePubMedPubMed CentralGoogle Scholar
  40. Franssen B, Alshebeeb K, Tabrizian P, Marti J, Pierobon ES, Lubezky N, Roayaie S, Florman S, Schwartz ME. Differences in surgical outcomes between hepatitis B- and hepatitis C-related hepatocellular carcinoma: a retrospective analysis of a single north American center. Ann Surg. 2014;260(4):650–6. discussion 656-658View ArticlePubMedGoogle Scholar
  41. Shen JY, Li C, Wen TF, Yan LN, Li B, Wang WT, Yang JY, Xu MQ. Alpha fetoprotein changes predict hepatocellular carcinoma survival beyond the Milan criteria after hepatectomy. J Surg Res. 2017;209:102–11.View ArticlePubMedGoogle Scholar
  42. Toyoda H, Kumada T, Tada T, Ito T, Maeda A, Kaneoka Y, Kagebayashi C, Satomura S. Changes in highly sensitive alpha-fetoprotein for the prediction of the outcome in patients with hepatocellular carcinoma after hepatectomy. Cancer Med. 2014;3(3):643–51.View ArticlePubMedPubMed CentralGoogle Scholar
  43. Allard MA, Sa Cunha A, Ruiz A, Vibert E, Sebagh M, Castaing D, Adam R. The postresection alpha-fetoprotein in cirrhotic patients with hepatocellular carcinoma. An independent predictor of outcome. J Gastrointest Surg. 2014;18(4):701–8.View ArticlePubMedGoogle Scholar
  44. Toro A, Ardiri A, Mannino M, Arcerito MC, Mannino G, Palermo F, Bertino G, Di Carlo I. Effect of pre- and post-treatment alpha-fetoprotein levels and tumor size on survival of patients with hepatocellular carcinoma treated by resection, transarterial chemoembolization or radiofrequency ablation: a retrospective study. BMC Surg. 2014;14:40.View ArticlePubMedPubMed CentralGoogle Scholar
  45. Nobuoka D, Kato Y, Gotohda N, Takahashi S, Nakagohri T, Konishi M, Kinoshita T, Nakatsura T. Postoperative serum alpha-fetoprotein level is a useful predictor of recurrence after hepatectomy for hepatocellular carcinoma. Oncol Rep. 2010;24(2):521–8.PubMedGoogle Scholar
  46. Zhang XF, Yin ZF, Wang K, Zhang ZQ, Qian HH, Shi LH. Changes of serum alpha-fetoprotein and alpha-fetoprotein-L3 after hepatectomy for hepatocellular carcinoma: prognostic significance. Hepatobiliary Pancreat Dis Int. 2012;11(6):618–23.View ArticlePubMedGoogle Scholar
  47. Cai ZQ, Si SB, Chen C, Zhao Y, Ma YY, Wang L, Geng ZM. Analysis of prognostic factors for survival after hepatectomy for hepatocellular carcinoma based on a bayesian network. PLoS One. 2015;10(3):e0120805.View ArticlePubMedPubMed CentralGoogle Scholar
  48. Silva JP, Gorman RA, Berger NG, Tsai S, Christians KK, Clarke CN, Mogal H, Gamblin TC. The prognostic utility of baseline alpha-fetoprotein for hepatocellular carcinoma patients. J Surg Oncol. 2017;116(7):831–40.View ArticlePubMedGoogle Scholar
  49. Farinati F, Marino D, De Giorgio M, Baldan A, Cantarini M, Cursaro C, Rapaccini G, Del Poggio P, Di Nolfo MA, Benvegnu L, et al. Diagnostic and prognostic role of alpha-fetoprotein in hepatocellular carcinoma: both or neither? Am J Gastroenterol. 2006;101(3):524–32.View ArticlePubMedGoogle Scholar
  50. Wong RJ, Ahmed A, Gish RG. Elevated alpha-fetoprotein: differential diagnosis - hepatocellular carcinoma and other disorders. Clin Liver Dis. 2015;19(2):309–23.View ArticlePubMedGoogle Scholar
  51. Ogden SK, Lee KC, Barton MC. Hepatitis B viral transactivator HBx alleviates p53-mediated repression of alpha-fetoprotein gene expression. J Biol Chem. 2000;275(36):27806–14.PubMedGoogle Scholar
  52. Sung WK, Zheng H, Li S, Chen R, Liu X, Li Y, Lee NP, Lee WH, Ariyaratne PN, Tennakoon C, et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet. 2012;44(7):765–9.View ArticlePubMedGoogle Scholar
  53. Huang G, Lau WY, Zhou WP, Shen F, Pan ZY, Yuan SX, Wu MC. Prediction of hepatocellular carcinoma recurrence in patients with low hepatitis B virus DNA levels and high preoperative hepatitis B surface antigen levels. JAMA Surg. 2014;149(6):519–27.View ArticlePubMedGoogle Scholar
  54. Park JH, Koh KC, Choi MS, Lee JH, Yoo BC, Paik SW, Rhee JC, Joh JW. Analysis of risk factors associated with early multinodular recurrences after hepatic resection for hepatocellular carcinoma. Am J Surg. 2006;192(1):29–33.View ArticlePubMedGoogle Scholar
  55. Zhu WJ, Huang CY, Li C, Peng W, Wen TF, Yan LN, Li B, Wang WT, Xu MQ, Yang JY, et al. Risk factors for early recurrence of HBV-related hepatocellular carcinoma meeting Milan criteria after curative resection. Asian Pac J Cancer Prev. 2013;14(12):7101–6.View ArticlePubMedGoogle Scholar
  56. Hirokawa F, Hayashi M, Miyamoto Y, Asakuma M, Shimizu T, Komedo K, Inoue Y, Uchiyama K. Predictors of poor prognosis by recurrence patterns after curative hepatectomy for hepatocellular carcinoma in child-pugh classification a. Hepato-Gastroenterology. 2015;62(137):164–8.PubMedGoogle Scholar
  57. Hao S, Fan P, Chen S, Tu C, Wan C. Distinct recurrence risk factors for intrahepatic metastasis and multicenter occurrence after surgery in patients with hepatocellular carcinoma. J Gastrointest Surg. 2017;21(2):312–20.View ArticlePubMedGoogle Scholar
  58. Lee M, Chung GE, Lee JH, Oh S, Nam JY, Chang Y, Cho H, Ahn H, Cho YY, Yoo JJ, et al. Antiplatelet therapy and the risk of hepatocellular carcinoma in chronic hepatitis B patients on antiviral treatment. Hepatology. 2017;66(5):1556–69.View ArticlePubMedGoogle Scholar
  59. Zhang XF, Lai EC, Kang XY, Qian HH, Zhou YM, Shi LH, Shen F, Yang YF, Zhang Y, Lau WY, et al. Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein as a marker of prognosis and a monitor of recurrence of hepatocellular carcinoma after curative liver resection. Ann Surg Oncol. 2011;18(8):2218–23.View ArticlePubMedGoogle Scholar
  60. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560–99.View ArticlePubMedGoogle Scholar
  61. EASL. 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–98.View ArticleGoogle Scholar

Copyright

© The Author(s). 2018

Advertisement