The relationship between age and the prognosis of patients with hepatocellular carcinoma (HCC) has been widely investigated. However, few studies have focused on the influence of patient age on the prognosis of HCC with microvascular invasion (MVI). Patients with histologically confirmed HCC with MVI who underwent hepatectomy between 2008 and 2016 were retrospectively enrolled in this study and allocated to younger (young group) and older age groups (old group) according to age< or ≥60 years. A propensity score matching analysis was performed, and prognostic factors evaluated by Kaplan–Meier curves and Cox proportional hazards regression. Intraoperative and postoperative characteristics were compared between the two groups. A total of 374 patients were enrolled in this study. There were 84 patients in each group after a 1 : 1 propensity score matching analysis. The rates of both disease-free survival (DFS) and overall survival (OS) differed significantly between the age groups. By univariate and multivariate analyses,
Liver cancer has recently been reported to have the sixth highest incidence and to be the fourth leading cause of cancer death among all neoplasms worldwide [
Tumor-related problems in older individuals have recently aroused great concern [
In terms of the established correlation between MVI and prognosis of HCC and the possible difference in prognosis between younger and older patients, few studies have compared the outcomes of patients with MVI according to age group. Therefore, the aim of this study was to investigate the differences in prognosis between younger and older patients with HCC and MVI (HCC-MVI).
Data of 714 patients with HCC-MVI who had undergone hepatectomy in our department from January 2008 to November 2016 were retrospectively collected. All enrolled patients had pathologically confirmed HCC-MVI. The definition of MVI was microscopic tumor invasion identified in the portal or hepatic vein of the surrounding liver tissue, contiguous with the tumor. In accordance with the definition of the World Health Organization, older patients were defined as those aged 60 years or older [
To avoid bias, 1 : 1 propensity score matching (PSM) between the two cohorts was performed, and 84 patients enrolled into each group. Inclusion criteria comprised of (1) generally good condition without major organ dysfunction, (2) no history of another malignant tumor, (3) pathologically confirmed MVI, and (4) having undergone curative resection.
Patients diagnosed with HCC in accordance with published diagnostic criteria for HCC [
Follow-up ended in November 2016 or at death. DFS was defined as time from hepatectomy to the first detectable recurrence and OS time as time from hepatectomy to death or last follow-up. After the operation, the patient was followed up for the first month and thereafter every three months. Routine blood examination, liver function, serum AFP concentrations, and ultrasonic examinations (ultrasound, contrast-enhanced ultrasound) were routinely performed at each follow-up. If a definite or possible recurrence was detected, further tests, such as abdominal enhanced CT or abdominal enhanced magnetic resonance imaging, were performed and treatment decisions made after the patient’s condition had been fully assessed by our multidisciplinary team, which consisted of hepatic surgeons, an oncologist, and a radiologist.
Categorical variables were compared using the
A total of 714 eligible patients were retrospectively identified. The final analysis did not include individuals who were excluded because they were found to have other malignancies during follow-up (
Flow chart of the study participants.
Baseline characteristics of the study participants before PSM.
Variable | Young group | Old group | |
---|---|---|---|
Gender (male) | 250 (88.7%) | 78 (84.8%) | 0.326 |
Adjuvant TACE | 126 (44.7%) | 32 (34.8%) | 0.095 |
Reoperation | 29 (10.3%) | 5 (5.4%) | 0.160 |
Tumor diameter (cm) | 0.154 | ||
Tumor number (single) | 209 (74.1%) | 67 (72.8%) | 0.807 |
GVI | 97 (34.4%) | 27 (29.3%) | 0.372 |
Transfusion | 43 (15.2%) | 12 (13.0%) | 0.604 |
Diabetes | 11 (3.9%) | 10 (10.9%) | 0.012 |
HBsAg positivity | 261 (92.6%) | 71 (77.2%) | <0.001 |
AFP (ng/mL) (IQR) | 1210.0 (45.8-1210.0) | 324.1 (17.2-1210.0) | 0.046 |
Invading adjacent organs | 33 (11.7%) | 11 (12.0%) | 0.948 |
Anatomic resection | 175 (62.1%) | 55 (59.8%) | 0.697 |
Well differentiation | 121 (42.9%) | 48 (52.2%) | 0.121 |
Invasion of liver capsule | 81 (28.7%) | 28 (30.4%) | 0.754 |
Satellite nodules | 65 (23.0%) | 9 (9.8%) | 0.006 |
Lymphatic metastasis | 11 (3.9%) | 3 (3.3%) | 0.779 |
Cirrhosis | 140 (49.6%) | 40 (43.5%) | 0.304 |
GGT level (U/L) (IQR) | 101.0 (50.0-201.0) | 77.5 (43.5-119.8) | 0.006 |
ALT level (U/L) (IQR) | 42.0 (30.0-67.0) | 36.0 (25.0-59.3) | 0.028 |
AST level (U/L) (IQR) | 50.0 (33.8-78.0) | 45.5 (31.0-70.8) | 0.217 |
TBIL level (mmol/L) | 0.006 | ||
LYM count (109/L) (IQR) | 1.4 (1.0-1.8) | 1.3 (1.0-1.9) | 0.933 |
WBC count (109/L) (IQR) | 5.5 (4.5-6.8) | 5.4 (4.3-6.7) | 0.928 |
BCLC staging | 0.597 | ||
A | 48 (17.0%) | 15 (16.3%) | |
B-C | 234 (82.9%) | 77 (83.7%) | |
Child-Pugh | 0.592 | ||
A | 262 (92.9%) | 88 (95.7%) | |
B | 17 (6.0%) | 3 (3.3%) | |
C | 3 (1.1%) | 1 (1.1%) |
Abbreviations: TACE: transcatheter arterial chemoembolization; GVI: giant vascular invasion; HBsAg: hepatitis B surface antigen; AFP: alpha fetoprotein; IQR: interquartile range; GGT: gamma-glutamyl transpeptidase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; TBIL: total bilirubin; LYM: lymphocyte; WBC: white blood cell; BCLC: Barcelona Clinic Liver Cancer.
Baseline characteristics of the study participants after PSM.
Variable | Young group | Old group | |
---|---|---|---|
Gender (male) | 71 (84.5%) | 70 (83.3%) | 0.834 |
Adjuvant TACE | 37 (44.0%) | 29 (34.5%) | 0.206 |
Reoperation | 10 (11.9%) | 5 (6.0%) | 0.176 |
Tumor diameter (cm) | 0.583 | ||
Tumor number (single) | 65 (77.4%) | 61 (72.6%) | 0.476 |
GVI | 24 (28.6%) | 25 (29.8%) | 0. 865 |
Transfusion | 8 (9.5%) | 10 (11.9%) | 0.618 |
Diabetes | 8 (9.5%) | 5 (6.0%) | 0.386 |
HBsAg positivity | 73 (86.9%) | 68 (81.0%) | 0.294 |
AFP (ng/mL) (IQR) | 1210.0 (65.4-1210.0) | 324.1 (17.2-1210.0) | 0.134 |
Invading adjacent organs | 10 (11.9%) | 9 (10.7%) | 0.808 |
Anatomic resection | 48 (57.1%) | 50 (59.5%) | 0.754 |
Well differentiation | 33 (39.3%) | 42 (50.0%) | 0.162 |
Invasion of liver capsule | 22 (26.2%) | 25 (29.8%) | 0.606 |
Satellite nodules | 11 (13.1%) | 9 (10.7%) | 0.634 |
Lymphatic metastasis | 4 (4.8%) | 3 (3.6%) | 0.699 |
Cirrhosis | 40 (47.6%) | 37 (44.0%) | 0.642 |
GGT level (U/L) (IQR) | 75.5 (43.5-129.5) | 67.0 (42.3-119.8) | 0.526 |
ALT level (U/L) (IQR) | 43.0 (28.5-66.8) | 37.5 (25.0-60.8) | 0.124 |
AST level (U/L) (IQR) | 45.5 (33.0-69.5) | 47.0 (32.3-71.0) | 0.858 |
TBIL level (mmol/L) | 0.852 | ||
LYM count (109/L) | 0.876 | ||
WBC count (109/L) (IQR) | 5.4 (4.4-6.9) | 5.4 (4.3-6.7) | 0.878 |
BCLC stage | 0.592 | ||
A | 18 (21.4%) | 13 (15.5%) | |
B-C | 64 (78.6%) | 71 (84.6%) | |
Child-Pugh | 0.592 | ||
A | 79 (94.0%) | 81 (96.4%) | |
B | 2 (2.4%) | 3 (3.6%) | |
C | 3 (3.6%) | 0 (0.0%) |
Abbreviations: TACE: transcatheter arterial chemoembolization; GVI: giant vascular invasion; AFP: alpha fetoprotein; IQR: interquartile range; GGT: gamma-glutamyl transpeptidase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; TBIL: total bilirubin; LYM: lymphocyte; WBC: white blood cell; BCLC: Barcelona Clinic Liver Cancer.
Intraoperative and postoperative characteristics of the study participants after PSM.
Variable | Young group | Old group | |
---|---|---|---|
Intraoperative blood loss (mL) (IQR) | 300 (200-437.5) | 300 (200-575.5) | 0.398 |
Intraoperative RBC transfusion (U) (EVR) | 0 (0-17.5) | 0 (0-7) | 0.779 |
Intraoperative plasma transfusion (mL) (EVR) | 0 (0-1800) | 0 (0-400) | 0.680 |
Postoperative RBC transfusion (U) (EVR) | 0 (0-3) | 0 (0-2) | 0.690 |
Postoperative plasma transfusion (mL) (EVR) | 0 (0-2100) | 0 (0-400) | 0.972 |
Postoperative hospital stays (day) (IQR) | 7 (6-9.75) | 8 (7-10) | 0.175 |
Postoperative complications1 | 0.801 | ||
Grade I | 5 (6.0%) | 3 (3.6%) | |
Grade II | 8 (9.5%) | 12 (14.3%) | |
Grade IIIa | 2 (2.4%) | 1 (1.2%) | |
Grade IIIb | 0 (0.0%) | 0 (0.0%) | |
Grade IVa | 2 (2.4%) | 2 (2.4%) | |
Grade IVb | 0 (0.0%) | 0 (0.0%) | |
Grade V | 0 (0.0%) | 0 (0.0%) | |
Liver failure2 | 1.000 | ||
Grade A | 1 (1.2%) | 1 (1.2%) | |
Grade B | 1 (1.2%) | 1 (1.2%) | |
Grade C | 0 (0.0%) | 0 (0.0%) |
1Postoperative complication is graded according to the Clavien-Dindo classification of surgical complications. 2Liver failure is graded according to the International Study Group of Liver Surgery (ISGLS) classification. Abbreviations: IQR: interquartile range; EVR: extreme value range; RBC: red blood cell.
Before PSM analysis, the estimated 6-month, 1-year, 2-year, and 5-year recurrence rates in the younger group were 62.8%, 76.4%, 83.7%, and 90.3%, respectively, and in the older group were 43.5%, 56.5%, 68.5%, and 82.2%, respectively (Figure
Kaplan–Meier analysis of disease-free survival and overall survival for hepatocellular carcinoma patients with microvascular invasion: (a) disease-free survival for the young group and old group before PSM. (b) Overall survival for the young group and old group before PSM. (c) Disease-free survival for the young group and old group after PSM. (d) Overall survival for the young group and old group after PSM.
As shown in Table
Uni- and multivariate analyses of disease-free survival (DFS) and overall survival (OS).
Variable | Number | Univariate | Multivariate | ||
---|---|---|---|---|---|
HR (95% CI) | HR (95% CI) | ||||
DFS | |||||
Age, <60/≥60 y | 84/84 | 1.562 (1.119–2.181) | 0.009 | 1.590 (1.135–2.228) | 0.007 |
Postoperative adjuvant TACE, no/yes | 102/66 | 1.652 (1.176–2.320) | 0.004 | 1.647 (1.170–2.320) | 0.004 |
BCLC staging, B-C stage/A stage | 137/31 | 1.293 (1.000–1.671) | 0.050 | 1.288 (0.995–1.667) | 0.055 |
LYM count, ≤1100/>1100/ |
50/118 | 0.672 (0.507–0.890) | 0.006 | 0.653 (0.484–0.880) | 0.005 |
OS | |||||
Age, <60/≥60 y | 84/84 | 1.608 (1.110–2.328) | 0.012 | 1.837 (1.259–2.680) | 0.002 |
Reoperation, no/yes | 153/15 | 2.313 (1.075–4.976) | 0.032 | 1.647 (1.170–2.320) | 0.011 |
GVI, yes/no | 49/119 | 1.795 (1.217–2.648) | 0.003 | 1.293 (0.670–2.494) | 0.443 |
BCLC staging, B-C stage/A stage | 137/31 | 1.543 (1.164–2.045) | 0.003 | 1.349 (0.846–2.151) | 0.209 |
LYM count, ≤1100/>1100/ |
50/118 | 0.645 (0.467–0.891) | 0.008 | 0.592 (0.419–0.838) | 0.003 |
Abbreviations: HR: hazard ratio; CI: confidence interval.
Our study was large, enabling us to perform PSM. There were no statistically significant differences in baseline data between the age groups selected by PSM. We mainly investigated the difference in prognosis between older and younger patients with MVI. Unlike other studies that have reported that age is not a risk factor for prognosis or that older adults have a worse prognosis than younger ones [
The biological behaviour of HCC reportedly differs greatly between younger and older individuals. The reasons for this difference are not fully understood but are likely due to differences in hepatocarcinogenesis [
This discrepancy may be attributable to the fact that our study included only patients with MVI. Some previous studies have reported that younger patients have a worse prognosis, which is consistent with our results; however, those researchers considered that the poorer prognosis is mainly attributable to worse tumor-related indicators, such as larger tumor diameter, later tumor stage, and higher AFP concentration [
One of the drivers of the increasing incidence of HCC is the progressive aging of the population, which reportedly contributed 16% of the 38% increase in cases from 2006 to 2016 [
The BCLC classification system for HCCs does not include age or MVI [
This study had some limitations. First, it was a retrospective study, albeit including PSM. Randomized controlled trials are needed to confirm our findings. Second, the sample size was relatively small after PSM. Thus, our findings should be verified in larger studies. Future studies should also investigate the correlation of other risk factors, especially those that are well recognized, and age in the prognoses of patients with HCC-MVI.
In patients with histologically confirmed HCC-MVI, the prognosis of those older than 60 years is superior to that of younger patients. Older individuals can undergo hepatectomy safely, and postoperative complications are no longer a barrier to surgery for them.
The data used to support the findings of this study are available from the corresponding author upon request.
The authors declare that there is no conflict of interest regarding the publication of this paper.
This work was supported by grants from the National Natural Science Foundation of China (No. 71673193).