Hepatocellular carcinoma (HCC) was the second leading cause of cancer-related death worldwide in 2012 [
For most cancers, vascular invasion or metastasis signifies systemic disease that is not curable with surgery. However, in real practice, preoperative MVI of HCC is clinically difficult to predict. Currently, the diagnosis of MVI is mainly based on postoperative histologic examination, which limits preoperative decision making and the identification of appropriate surgical procedures by surgeons. An increasing number of investigations have developed prognostic models using new imaging techniques other than biomarkers or various clinical indicators for the preoperative estimation of MVI risk in HCC patients [
To the best of our knowledge, there have been few attempts to evaluate the diagnostic abilities of preoperative CT value in the delayed phase and peritumoral enhancement for predicting MVI in BCLC 0/A HCC. In this study, we aim to use preoperative CT value in the delayed phase and peritumoral enhancement to objectively identify predictors of MVI in resected BCLC 0/A HCC.
A total of 89 patients with HCC admitted at Chongqing Medical University from January 2017 to June 2019 were retrospectively reviewed. Sixty and 29 patients were divided into the training and validation groups, respectively. Patient inclusion criteria are as follows: (1) HCC cases within the BCLC criteria 0/A, having undergone R0 tumor resection, with postoperative examination clearly showing hepatocellular carcinoma with MVI; (2) no preoperative treatment, such as transcatheter arterial chemoembolization; (3) preoperative imaging examination and operation interval shorter than one week, with no macrovascular tumor thrombus found. The exclusion criteria included incomplete laboratory or imaging data. General information, laboratory indicators, and imaging data from the enrolled patients were collected as shown in Table
Patient characteristics.
Variable | Training group (n=60) | Validation group (n=29) | T/ |
|
---|---|---|---|---|
Age, y | 51.7±12.7 | 57.8±10.7 | -2.238 | 0.028 |
Gender (male, female) | 50/10 | 26/3 | 0.222 | 0.637 |
BMI, Kg/m2 | 22.7±3.7 | 23.2±2.5 | -0.649 | 0.518 |
PLT, |
195.9±142.6 | 138.1±79.3 | 2.031 | 0.045 |
ALB, g/L | 40.7±6.0 | 40.0±4.2 | 0.660 | 0.511 |
TB, umol/L | 18.0±22.1 | 13.6±14.9 | 0.957 | 0.341 |
ALT, U/L | 60.0±77.1 | 47.4±43.4 | 0.816 | 0.417 |
AST, U/L | 64.2±97.2 | 40.7±30.0 | 1.270 | 0.208 |
GGT, U/L | 107.8±193.5 | 88.7±95.5 | 0.502 | 0.617 |
PT, S | 13.7±1.0 | 13.7±1.0 | -0.053 | 0.958 |
PTA, % | 93.6±12.8 | 90.5±12.0 | 1.090 | 0.279 |
Liver Function Grading (A/B) | 58/2 | 28/1 | - - - | 1.000 |
HBV DNA(<10e3, ≥ 10e3IU/mL) | 46/14 | 19/10 | 1.234 | 0.267 |
AFP(≤400,>400ng/ml) | 45/15 | 22/7 | 0.008 | 0.930 |
HCV (Absent, Present) | 59/1 | 28/1 | - - - | 0.548 |
Tumor size, cm | 6.0±3.9 | 5.0±3.7 | 1.092 | 0.278 |
CT value in unenhanced phase (≤42.5,>42.5) | 28/32 | 6/23 | 5.588 | 0.018 |
CT value in artery phase(≤66.5,>66.5) | 20/40 | 9/20 | 0.047 | 0.828 |
CT value in venous phase(≤102,>102) | 44/16 | 20/9 | 0.185 | 0.667 |
CT value in delayed phase(≤103.5,>103.5) | 51/9 | 24/5 | 0.002 | 0.970 |
Located in the left lobe (Absent, Present) | 44/16 | 20/9 | 0.185 | 0.667 |
Capsule (Absent, Present) | 44/16 | 25/4 | 1.860 | 0.173 |
With smooth margin (Absent, Present) | 51/9 | 18/11 | 5.901 | 0.015 |
Peritumoral enhancement (Absent, Present) | 47/13 | 24/5 | 0.237 | 0.626 |
Visible small blood vessel (Absent, Present) | 21/39 | 15/14 | 2.270 | 0.132 |
The distance from the IVC | 3.2±2.3 | 4.2±2.6 | -1.540 | 0.127 |
The distance from the portal vein branches | 3.6±2.3 | 5.0±2.5 | -1.770 | 0.080 |
Liver cirrhosis (Absent, Present) | 35/25 | 16/13 | 0.080 | 0.778 |
MVI (Absent, Present) | 32/28 | 16/13 | 0.027 | 0.870 |
Abbreviations: BMI: body mass index; PLT: platelet; ALB: albumin; TB: total bilirubin; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma-glutamyl transpeptidase; PT: prothrombin time; PTA: prothrombin activity; HBV: hepatitis B virus; AFP: alpha fetoprotein; HCV: hepatitis C virus; MVI: microvascular invasion.
Patient CT images on the computer PACS system were independently examined by two investigators. Tumor size, tumor location, tumor capsule, tumor margin, peritumoral enhancement, the CT value at each phase, visible small blood vessels in the arterial phase, distance from the tumor to the IVC, distance from the tumor to the portal vein branches, and liver cirrhosis were assessed and measured. When measuring the tumor size, the longest diameter of the largest cross section was selected. When measuring CT values, the most obvious enhancement area of the largest cross section was selected, avoiding cystic changes, hemorrhage, and necrosis and circling the appropriate region of interest (ROI). Different periods were measured in the same plane. Peritumoral enhancement was defined as detectable arterial-enhanced portions adjacent to the tumor border on arterial-phase images that became isodense with background liver parenchyma on delayed-phase images [
Typical CT images of patients with hepatocellular carcinoma. Figure
Statistical analyses were performed using SPSS software. Continuous variables were compared using the
The baseline characteristics of the 89 patients in this study are shown in Table
As shown in Table
Univariate analysis of factors affecting MVI positivity in the training group.
Variable | MVI Negative | MVI Positive | T/ |
|
---|---|---|---|---|
(n=32) | (n=28) | |||
Age, y | 53.9±12.9 | 49.1±12.1 | 1.489 | 0.142 |
Gender (male, female) | 28/4 | 22/6 | 0.335 | 0.563 |
BMI, Kg/m2 | 22.7±3.9 | 22.8±3.5 | -0.056 | 0.955 |
PLT, |
165.1±99.9 | 231.1±174.9 | -1.825 | 0.073 |
ALB, g/L | 41.2±5.5 | 40.1±6.5 | 0.771 | 0.444 |
TB, umol/L | 20.2±29.4 | 15.5±8.0 | 0.818 | 0.417 |
ALT, U/L | 57.4±70.4 | 63.0±85.4 | -0.278 | 0.782 |
AST, U/L | 45.5±46.0 | 85.5±131.5 | -1.615 | 0.112 |
GGT, U/L | 102.6±242.6 | 113.8±119.0 | -0.223 | 0.824 |
PT, S | 13.8±1.2 | 13.4±0.8 | 1.503 | 0.138 |
PTA, % | 91.8±14.1 | 95.6±11.1 | -1.156 | 0.253 |
Liver Function Grading (A/B) | 30/2 | 28/0 | - - - | 0.494 |
HBV DNA(<10e3, ≥ 10e3IU/mL) | 28/4 | 18/10 | 4.499 |
|
AFP(≤400,>400ng/ml) | 25/7 | 20/8 | 0.357 | 0.550 |
HCV (Absent, Present) | 31/1 | 28/0 | - - - | 1.000 |
Tumor size, cm | 4.3±2.7 | 7.9±4.1 | -3.940 |
|
CT value in unenhanced phase (≤42.5,>42.5) | 17/15 | 11/17 | 1.149 | 0.284 |
CT value in artery phase(≤66.5,>66.5) | 12/20 | 8/20 | 0.536 | 0.464 |
CT value in venous phase(≤102,>102) | 27/5 | 17/11 | 4.275 |
|
CT value in delayed phase(≤103.5,>103.5) | 31/1 | 20/8 | 5.720 |
|
Located in the left lobe (Absent, Present) | 24/8 | 20/8 | 0.097 | 0.755 |
Capsule (Absent, Present) | 24/8 | 20/8 | 0.097 | 0.755 |
With smooth margin (Absent, Present) | 26/6 | 25/3 | 0.257 | 0.612 |
Peritumoral enhancement (Absent, Present) | 29/3 | 18/10 | 6.104 |
|
Visible small blood vessel (Absent, Present) | 17/15 | 4/24 | 9.902 |
|
The distance from the IVC | 4.0±2.4 | 2.3±1.9 | 3.001 |
|
The distance from the portal vein branches | 4.0±1.8 | 3.0±2.3 | 1.870 | 0.067 |
Liver cirrhosis (Absent, Present) | 17/15 | 18/10 | 0.765 | 0.382 |
Abbreviations: BMI: body mass index; PLT: platelet; ALB: albumin; TB: total bilirubin; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma-glutamyl transpeptidase; PT: prothrombin time; PTA: prothrombin activity; HBV: hepatitis B virus; AFP: alpha fetoprotein; HCV: hepatitis C virus.
Logistic regression was employed to evaluate independent factors affecting MVI positivity. Tumor size (OR = 1.396, 95% CI 1.129-1.727; P = 0.002), CT value in the delayed phase (≤103.5 vs >103.5 OR=16.821, 95% CI 1.632-173.358; P=0.018), and peritumoral enhancement (absent vs present OR=5.220, 95% CI 0.955-28.542; P = 0.057) were independent predictors for MVI (Table
Multivariate analysis of predictors for nomogram development.
Variables |
|
standard error | OR | 95%CI | P value |
---|---|---|---|---|---|
Tumor size | 0.334 | 0.108 | 1.396 | 1.129-1.727 | 0.002 |
CT value in delayed phase | 2.823 | 1.190 | 16.821 | 1.632-173.358 | 0.018 |
Peritumoral enhancement | 1.653 | 0.867 | 5.220 | 0.955-28.542 | 0.057 |
Multivariate analysis: logistic regression model.
Abbreviations: OR: odds ratio; CI: confidence interval.
To facilitate clinical use, we established a visual nomogram based on the results of multivariate logistic regression analysis using the rms package of R, as shown in Figure
Nomogram to predict microvascular invasion (MVI) risk in BCLC 0/A hepatocellular carcinoma. To use the nomogram, find the score for each variable on the corresponding axis, add the points for all variables, and draw a line from the total points axis to the risk of MVI axis to determine the MVI risk.
Calibration curves for the nomogram in estimating the risk of MVI in the training and validation groups. On the calibration curve, the x-axis is the nomogram-predicted probability of MVI, and the y-axis is the actual probability. The dotted blue line represents the ideal curve, the red line is the nomogram curve, and the black line is the bias-corrected curve.
An ROC curve was drawn with the total points for 60 patients in the training group (Figure
The ROC curve for the selected model. This curve was drawn with the total points for 60 patients in the training group. It sets a number of different critical values for total points to calculate a series of sensitivity and specificity values and then the curve is plotted with sensitivity as the ordinate and “1-specificity” as the abscissa. The larger the area under the curve, the higher the diagnostic accuracy. The AUC was 0.851.
MVI is a microscopic feature that can significantly worsen the prognosis of early surgical HCC. However, preoperative diagnosis of MVI prior to treatment is almost impossible. The current study put forward three independent preoperative factors for predicting MVI in patients with BCLC 0/A HCC including tumor size, CT value in the delayed phase>103.5, and peritumoral enhancement. Based on these three predictors, we developed a new MVI nomogram combined with preoperative laboratory and imaging data.
In various studies, tumor size has been demonstrated to be an effective preoperative predictive factor for MVI [
In addition to clinical predictors of MVI, the identification of MVI from preoperative image analysis (e.g., ultrasound, CT, and MRI) has been attempted. In our study, peritumoral enhancement was a significant indicator of histologic MVI (P=0.013), in good agreement with the results of previous studies [
Here, for the first time, higher CT values in the delayed phase (>103.5) were found to be closely related to MVI in HCC. One explanation for continuous enhancement in the portal venous phase could be that the tumor is dually supplied by the hepatic artery and the portal vein. Microvascular invasion accelerates the release of tumor angiogenesis-promoting factors, such as hypoxia-inducible factor
In the current study, the C-index (0.851), calibration curve, and ROC curve analysis (0.851, 95% CI: 0.749-0.952) demonstrated that our nomogram was accurate in predicting MVI risk in surgical patients with BCLC 0/A HCC. However, this is a single-center retrospective study with a small sample size. The actual application efficiency of the scoring system may be affected. Therefore, multicenter and large-scale research is necessary to improve the scoring system. Moreover, a prospective study is required to further confirm the reliability of the nomogram.
In conclusion, based on three preoperative risk factors of MVI, we developed an objective scoring system to predict the MVI risk of HCC patients after curative resection and found an optimal cut-off point of 36.682. The model might help us make informed decisions based on expected survival outcomes and therapeutic assignment in patients with BCLC 0/A HCC. In the future, a large-scale prospective validation study is needed to assess the extensive applicability of the nomogram.
The clinical data used to support the findings of this study were provided by Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, and cannot be made freely available. Access to these data will be considered by the author upon request, with permission from the Director of the Department of Hepatobiliary Surgery of this hospital.
The authors declare that they have no conflicts of interest.
Shuai-Xiang Gao, Rui Liao, and Hua-Qiang Wang contributed equally to this work.
This study was supported by the National Natural Science Foundation of China (No. 81372481), the Science and Technology Research Program of Chongqing Municipal Education Commission (No. KJQN201800416), and the Basic and Advanced Research Project of Science and Technology Commission of Chongqing Municipality (No. cstc2018jcyjAX0162).
The file contains R codes.