Insufficient sampling and underreporting from the pathologists can be a general problem in the previous studies, which may have led to the possibly underestimated MVI rate. No direct evidence can be provided on this issue, while here we offer two likely examples for a brief glimpse into the problem. One is Huang et al. [
16] and the colleagues reporting significantly different MVI rate (25.3 vs. 32.5%,
p < 0.001) in two similar cohorts (Table
1). Applying the same eligibility criteria in the same ethnic group, the discovery and validation cohorts in the study are similar in a variety of aspects regarding age, gender percentage, HCC etiology, liver cirrhosis, Barcelona Clinic Liver Cancer (BCLC) stage, mean tumor size, tumor number, tumor encapsulation type (complete or none), histological grade, and AFP level, except for types of resection (anatomic or non-anatomic) (
p = 0.046). Surgical approach was indicated to have no influence on MVI rate in the study by Shindoh et al [
17]. With the most frequently reported MVI-associated risk factors considered, the difference in MVI rate seems explainable only with the possible different sampling methods.
Table 1
Comparisons between the two cohorts reported by Huang et al.
Age (year, median (range)) | 53.0(10–86)※ | 53.0(12–92)※ | 1.00 |
Male (n/N) | 1305/1540 | 530/630 | 0.78 |
HBV (n/N) | 1255/1540 | 527/630 | 0.25 |
Liver cirrhosis (n/N) | 1268/1540 | 512/630 | 0.62 |
BCLC stage (B/N) | 154/1540 | 59/630 | 0.73 |
AFP > 200 ng/dL (n/N) | 593/1540 | 259/630 | 0.28 |
Mean tumor size (cm, mean ± SD) | 5.3 ± 3.5 | 5.5 ± 3.7 | 0.23 |
Patients with multiple tumors (n/N) | 199/1540 | 78/630 | 0.81 |
Encapsulation (complete/N) | 733/1540 | 294/630 | 0.74 |
Tumor differentiation (III–IV/N) | 421/1540 | 171/630 | 0.97 |
Types of resection (anatomic/non-anatomic) | 1222/318 | 475/155 | < 0.05 |
MVI (n/N) | 389/1540 | 205/630 | < 0.05 |
Another example is the MVI rate (26.6 vs. 74.4%,
p < 0.001) of two cohorts (Table
2), one reported by Qiao et al. [
18] as the external validation for an HCC prognostic system, and another by Cucchetti et al. [
4]. The two cohorts are derived from the same ethnic group from the University of Bologna, with possible overlapping population. They are different regarding percentage of patients with liver cirrhosis (10.0 vs. 79.2%,
p < 0.001), CTP score (percentage of class C, 9.2 vs. 0%,
p < 0.001), and AFP level (percentage of patients with AFP greater than 400 ng/ml, 23.5 vs. 10.0%,
p < 0.001). Liver cirrhosis and CTP score have been reported to have no significant association with MVI risk by all previous studies. With a higher AFP level, the cohort in Qiao et al. presents an even lower MVI rate than that in Cucchetti et al. did. We notice that Cucchetti et al. included 20.0% of patients who have undergone liver transplantation, compared with no transplantation in Qiao et al. Thus, the possible different sampling methods resulted from the two different surgical procedures can be the most likely cause of different MVI detection rates.
Table 2
Comparisons between the two cohorts reported by Cucchetti et al. and Qiao et al.
Origin of patients | University of Bologna (1999 to 2008) | University of Bologna (2000 to 2011) | – |
Age (years, mean ± SD) | 62.8 ± 9.9 | 63.5 ± 9.4 | 0.40 |
Male (n/N) | 193/250 | 227/293 | 0.98 |
HBV (n/N) | 65/250 | 68/293 | 0.51 |
HCV (n/N) | 164/250 | 202/293 | 0.47 |
Mean tumor size (cm, mean ± SD) | 3.7 ± 1.8 | 3.9 ± 2.1 | 0.24 |
Moderate or poor tumor differentiation (n/N) | 174/250 | 198/293 | 0.68 |
Patients with multiple tumors (n/N) | 55/250 | 60/293 | 0.75 |
Liver cirrhosis (n/N) | 250/250 | 232/293 | < 0.05 |
CTP score (class C) (%) | 9.2 | 0 | < 0.05 |
AFP > 400 ng/ml (n/N) | 25/250 | 69/293 | < 0.05 |
MVI (n/N) | 186/250 | 78/293 | < 0.05 |