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Early prediction of microvascular invasion (MVI) occurrence in hepatocellular carcinoma (HCC) by 18F-FDG PET/CT and laboratory data

European Journal of Medical Research volume 29, Article number: 395 (2024) Cite this article

Abstract

Background

Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors in China. Microvascular invasion (MVI) often indicates poor prognosis and metastasis in HCC patients. 18F-FDG PET–CT is a new imaging method commonly used to screen for tumor occurrence and evaluate tumor stage.

Purpose

This study attempted to predict the occurrence of MVI in early-stage HCC through 18F-FDG positron emission tomography (PET)/computed tomography (CT) imaging findings and laboratory data.

Patients and methods

A total of 113 patients who met the inclusion criteria were divided into two groups based on postoperative pathology: the MVI-positive group and MVI-negative group. We retrospectively analyzed the imaging findings and laboratory data of 113 patients. Imaging findings included tumor size, tumor maximum standard uptake value (SUVmaxT), and normal liver maximum standard uptake value (SUVmaxL). The ratios of SUVmaxT to SUVmaxL (SUVmaxT/L) and an SUVmaxT/L > 2 were defined as active tumor metabolism. The tumor size was indicated by the maximum diameter of the tumor, and a diameter greater than 5 cm was defined as a mass lesion. The laboratory data included the alpha-fetoprotein (AFP) level and the HBeAg level. An AFP concentration > 20 ng/mL was defined as a high AFP level. A HBeAg concentration > 0.03 NCU/mL was defined as HB-positive.

Results

The SUVmaxT/L (p = 0.003), AFP level (p = 0.008) and tumor size (p = 0.015) were significantly different between the two groups. Patients with active tumor metabolism, mass lesions and high AFP levels tended to be MVI positive. Binary logistic regression analysis verified that active tumor metabolism (OR = 4.124, 95% CI, 1.566–10.861; p = 0.004) and high AFP levels (OR = 2.702, 95% CI, 1.214–6.021; p = 0.015) were independent risk factors for MVI. The sensitivity of the combination of these two independent risk factors predicting HCC with MVI was 56.9% (29/51), the specificity was 83.9% (52/62) and the accuracy was 71.7% (81/113).

Conclusion

Active tumor metabolism and high AFP levels can predict the occurrence of MVI in HCC patients.

Introduction

HCC is one of the most common malignant tumors in the world [1,2,3]. There are more than 500,000 deaths caused by HCC annually worldwide. The MVI of HCC is an important predictable marker of HCC recrudesce after surgical resection or hepatic transplantation, especially early recurrence [4,5,6]. Preoperative imaging indicators to predict MVI have important clinical significance. Many reports have shown that certain imaging findings may be helpful in the preoperative diagnosis of MVI [7,8,9,10], and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) is an imaging method that indicates metabolic function, moreover, the degree of differentiation and invasiveness of HCC are closely related to its metabolic function [11]. Therefore, compared with other traditional imaging methods, FDG can better evaluate the biological characteristics of HCC. Therefore, 18F-FDG PET has more important clinical significance for HCC screening and prognosis evaluation [12, 13]. In view of the advantages of 18F-FDG PET/CT in evaluating tumor occurrence, stage, and prognosis [14, 15], we performed a retrospective study to further explore the clinical application value of 18F-FDG PET/CT in predicting MVI in liver cancer patients. In this research, we evaluated the performance efficiency of 18F-FDG PET/CT imaging findings and laboratory data for predicting the occurrence of MVI in patients with HCC to evaluate the value of surgery.

Patients and methods

Patients

In this retrospective study, we collected and sorted data from 113 patients who underwent 18F-FDG PET/CT scan at our hospital from May 2015 to December 2020 (Fig. 1). Most of the 113 patients enrolled were male (92, 81.4%). They ranged in age from 39 to 81 years, with a mean age of 56.6 years.

Fig. 1
figure 1

Flowchart of the study population. HCC hepatocellular carcinoma, MVI microvascular invasion

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The eligibility criteria for patients were as follows: (1) 18–80 years old; (2) had hepatic occupying lesions larger than 1 cm in diameter, as detected by CT or ultrasonic images; (3) underwent 18F-FDG PET/CT examination before surgery, and the time interval between imaging and surgical treatment was no more than two weeks; (4) had no invasive examination for tumor or relevant treatment or biopsy performed before the 18F-FDG PET/CT examination. The exclusion criteria were as follows: (1) patients with recurrent HCC; (2) patients with other pathological types of liver cancer except hepatocellular carcinoma; (3) patients with a history of other malignant tumors.

18F-FDG PET/CT

Patients fasted for at least 6 h. Blood glucose levels were checked before administering the medication. Patients with blood glucose levels greater than 7 mmol/L were excluded from the examination, blood glucose was adjusted to the specified range, or the examination was rescheduled. 18F-FDG PET/CT at 185~ 70 MBq intravenously (18F-FDG concentration 370 MBq mL−1, dilution ratio 1:400, push injection volume = 0.014 mL kg−1). Normal saline was prepared according to procedures reported in the relevant literature. The scan started after 60 min, and urination was performed before the scan. A combined PET/CT system (Siemens Biograph, m CT 64R) was used to collect images and data. The CT scanning parameters were as follows: tube voltage, 110 kV; tube current, 160 mA; layer thickness, 3.0 mm. PET imaging was performed in 3D acquisition mode with a 5~6 bed position cycle and a cycle speed of 2.5 min (bed)−1. Liver function measures and the degree of injury were defined after assessment by the referring physicians.

Laboratory data and imaging findings

Laboratory data, including AFP and HBeAg levels, were obtained from clinical records. An AFP concentration > 20 ng/mL was defined as a high level (51, 45.1%). A HBeAg concentration > 0.03 NCU/mL was defined as HB-positive (82, 72.6%).

The 18F-FDG PET/CT findings were reviewed and evaluated by two senior nuclear medicine physicians for semi-quantitative analysis of SUVmaxT and SUVmaxT/L. The SUVmaxT and SUVmaxT/L were acquired, and regions of interest (ROIs) were drawn along the tumor margin and normal liver tissue of the right lobe, respectively. The ROI on the normal liver was measured as a circle with a diameter of 1.5 cm. A SUVmaxT/L > 2 was defined as active tumor metabolism (81, 71.7%). The SUVmaxT/L was calculated as SUVmaxT/SUVmaxL. The tumor size was indicated by the maximum diameter of the tumor, with a diameter greater than 5 cm was defined as a mass lesion [16].

Pathological analysis

All liver tumor sections were reviewed by two senior pathologists for conclusion. Tumor pathological sections were defined as MVI positive when the presence of cancer cell nests in the vascular lumen of the endothelial cells lined mainly by portal vein branches was observed under the microscope [17]. According to the pathological diagnostic criteria, the patients were divided into an MVI-positive group (51, 45.1%) and an MVI-negative group (62, 54.9%).

Statistical analysis

The Chi-square test was used for count data, Pearson Chi-square correction or Fisher’s exact probability method was used for data that needed to be corrected, the t test was used for normally distributed data, and analysis of variance was used for nonnormally distributed data. Univariate logistic regression analysis was used to determine the independent predictors of MVI. The independent risk factors with significant differences were included in the binary logistic analysis model. p < 0.05 was considered to indicate statistical significance. SPSS 25.0 for Windows (IBM) was used for data cleaning and descriptive statistics.

Results

Basic information

A total of 113 patients met the inclusion criteria. The interval between the 18F-FDG PET/CT examination and surgery was no more than 2 weeks for any of the patients.

The mean age of the patients was 56.58 ± 10.91 years, the mean age of patients in the MVI-negative group was 53.49 ± 11.4 years, and the mean age of patients in the MVI-positive group was 59.13 ± 9.86 years. The male-to-female ratio was 92:21. There were 62 patients in the MVI-positive group and 51 patients in the MVI-negative group. The male-to-female ratio in the MVI-positive group was 49:13. The male-to-female ratio in the MVI-negative group was 43:8 (Table 1). There were no statistically significant differences in age and sex between the two groups (p > 0.05).

Table 1 Comparison of patient characteristics according to MVI
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Laboratory data

The AFP value was divided into normal and high levels with a range of 20 ng/ml. There were 62 patients in the AFP-normal group and 51 patients in the AFP-high group. The ratio of patients with a normal to high level of MVI in the MVI-positive group was 21:30, and the ratio of patients with a normal to high level of MVI in MVI-negative group was 41:21. There was a statistically significant difference in the AFP level (p = 0.008). The patients were divided into an HBeAg-negative group and HBeAg-positive group with a range of 0.03 NCU/mL. There were 31 patients in the HBeAg-negative group and 82 patients in the HBeAg-positive group. The ratio of the HBeAg-negative group to the HBeAg-positive group in the MVI-positive group was 12:39, and the ratio of the HBeAg-negative group to the HBeAg-positive group in the MVI-negative group was 19:43. There were no statistically significant differences in the HBeAg level between the two groups (p > 0.05).

18F-FDG PET/CT imaging findings

The SUVmaxT did not significantly differ between the two groups (p = 0.063). To reduce the measurement bias of the SUVmaxT in different patients, the SUVmaxT/L was used as a new measurement index. We found statistically significant differences in the SUVmaxT/L between the MVI-positive group and MVI-negative group (p = 0.003). Moreover, for the convenience of clinical prediction, we defined SUVmaxT/L > 2 as active tumor metabolism, and there were statistically significant differences between the MVI-positive group and MVI-negative group (p = 0.003). In addition, we found statistically significant differences in tumor size (p = 0.007). With increasing tumor diameter, the likelihood of HCC developing MVI increased (Fig. 2). Similarly, we defined tumors with a longest diameter of 5 cm as small lesions and mass lesions, and significant statistical differences were also found between the MVI-positive group and MVI-negative group (p = 0.015).

Fig. 2
figure 2

A 63-year-old male with MVI of HCC. a PET images showed an uneven increase in FDG uptake, suggesting tumor metabolic activity. b CT showed that the density of the liver was unevenly decreased, lobed, and the boundary was not clear. c PET/CT fusion images showed that the degree of metabolism in the tumor area was significantly higher than that in the surrounding liver parenchyma. d PET/CT MIP showed concentration of radioactivity in the liver area with unclear boundary with the right kidney, and physiological concentration of radioactivity in the heart, pelvis, ureter, and bladder

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Combined with the above significant differences, AFP, SUVmaxT/L and tumor size were included in logistic regression. Multivariate analysis revealed that the SUVmaxT/L (OR = 3.504; 95% CI, 1.213–10.118, p = 0.020), AFP level (OR = 2.579, 95% CI, 1.147–5.797, p = 0.022), and tumor size (OR = 1.389, 95% CI, 0.573–3.366, p = 0.467), were independent risk factors for MVI (Table 2).

Table 2 Univariate and multivariate analyses of preoperative 18F-FDG PET/CT imaging laboratory examination findings in predicting MVI
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To help clinical and imaging physicians predict the occurrence of MVI in HCC patients, we constructed nomograms based on the above studies (Fig. 3).

Fig. 3
figure 3

Two patients with HCC. a, b MVI-negative patient 18F-FDG PET/CT imaging showed that a low-density mass lesion with FDG moderate metabolism. c, d MVI-positive patient 18F-FDG PET/CT imaging showed that a slightly low-density small lesion with FDG active metabolism

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Outcome

Logistic regression analysis revealed that the SUVmaxT/L and AFP level were two factors that helped to predict MVI (Fig. 4). The sensitivity, specificity, accuracy, PPV and NPV of each predictor alone and in combination for predicting MVI in HCC patients are shown in Table 3. When the two predictors combined, they were combined in the following two ways: each predictor was positive for predicting the occurrence of MVI (serial connection), and any predictor was positive for the occurrence of MVI (parallel connection). The sensitivity and specificity of parallel connectivity in the diagnosis of MVI in HCC were 88.24% (45/51) and 22.58% (14/62). The sensitivity and specificity of serial connectivity in the diagnosis of MVI in HCC patients were 56.86% (29/51) and 83.87% (52/62), respectively. The serial connection method had higher specificity, accuracy and PPV, which is more helpful for clinical diagnosis. Moreover, it can be seen from the data that increased FDG uptake in tumors has excellent sensitivity and NPV for the diagnosis of HCC with MVI. To directly reflect the accuracy of this research method, we constructed an ROC curve (Fig. 5). The ROC curve constructed according to tumor size, with an AUC of 0.628, a cut-off value of 6.6, Youden index of 0.274, a sensitivity of 45.1%, and a specificity of 82.3%. The ROC curve was constructed from SUVmaxT/L value, with an AUC of 0.671, a cut-off value of 2.0, a Youden index of 0.325, a sensitivity of 47.1%, and a specificity of 85.5%. The ROC curve was constructed by the AFP value, with an AUC of 0.631, a cut-off value of 52.2, a Youden index of 0.236, a sensitivity of 51.0%, and a specificity of 56.9%. The ROC curve constructed from the SUVmaxT/L and AFP levels had an AUC of 0.726, a cut-off value of 0.55, a Youden index of 0.407, a sensitivity of 56.9%, and a specificity of 83.9%.

Fig. 4
figure 4

A nomogram predicting the occurrence of MVI in HCC. SUVmaxT/L and AFP level were independent risk factors for MVI

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Table 3 Diagnostic performance of risk factors in prediction of MVI
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Fig. 5
figure 5

ROC curve was constructed to verify the accuracy of different indicators in predicting the occurrence of MVI in HCC. a The ROC curve constructed by tumor size. b The ROC curve constructed by SUVmaxT/L value. c The ROC curve constructed by AFP value. d The ROC curve constructed by SUVmaxT/L and AFP level

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Discussion

This study suggested that the combination of the AFP level and SUVmaxT/L has statistical significance for predicting MVI in HCC patients, and that both a high AFP level and active tumor metabolism are factors that promote MVI. The MVI is a key predictor of HCC recurrence after liver resection or transplantation [5]. In our study, there were no significant differences in patients sex, age, HBeAg level or SUVmaxT between the MVI-negative and MVI-positive groups. In the present study, there was a statistically significant difference in tumor size between the two groups; that is, the larger the tumor was, the greater the likelihood of HCC developing MVI, which is understandable. According to the Liver Imaging Reporting and Data System (LI-RADS) Version 2018, tumors were defined as small tumors or large tumors with a maximum diameter of 5 cm [16], and large tumors were significantly increased in the MVI-positive group.

A number of studies have identified tumor size, AFP, transaminase, cirrhosis, capsular invasion, tumor margin, rim enhancement, gadobenate-enhanced MRI in arterial phase peritumoral enhancement, and peritumoral hypointensity in the hepatobiliary region as risk factors for predicting MVI [18,19,20]. The results of this study are not inconsistent with those of previous studies.

A large tumor size usually indicates that HCC is more prone to microvascular invasion. The liver has a complex network of blood vessels, and a larger tumor means a great likelihood of MVI. Our data indicated that tumor size has an impact on MVI in HCC patients (p = 0.007), which is consistent with previous studies [21, 22]. Moreover, mass lesions were more likely to exist in the MVI-positive group (p = 0.015), which proved that mass lesions were a risk factor for MVI in HCC patients. Previous studies have shown that a tumor diameter greater than 5 cm in HCC patients significantly affects prognosis [23]. However, the results of binary logistic regression showed that tumor size is not an independent risk factor, which means that tumor size cannot predict the occurrence of MVI together with the other two risk factors. This may be related to the insufficient number of patients included in the statistical analysis. We will increase the sample size for further study.

As a serum marker of primary hepatocellular carcinoma, AFP has long been used in the diagnosis and curative effect monitoring of primary hepatocellular carcinoma [24, 25]. Previous studies have also shown that the preoperative serum AFP level is significantly correlated with MVI occurrence [8]. In this study, patients were divided into normal level and high level groups based on their AFP level. We observed that the incidence of AFP-high patients in the MVI-positive group was significantly greater than that in the MVI-negative group (p = 0.008). The results revealed that an abnormal AFP level was a risk factor for MVI. The inclusion of this factor in the binary logistic regression also suggested that an abnormal AFP level was an independent risk factor for MVI in HCC patients (p = 0.015).

18F-FDG is a glucose metabolism tracer, and its biological behavior in vivo is similar to that of glucose. After 18F-FDG is injected into the body, it is transported to the cell like glucose and transformed into 6-p-18FDG under the action of hexokinase. 6-p-18FDG cannot be further metabolized, but remains in the cell. Therefore, the uptake of 18F-FDG by cells is proportional to the glucose metabolism rate. One of the metabolic characteristics of malignant tumor cells is increased glucose metabolism, which is characterized by high uptake on 18F-FDG PET/CT. Similarly, tumors with active metabolism should be more aggressive and metastatic [26]. Therefore, 18F-FDG PET/CT is widely used in the preoperative and postoperative evaluation of HCC patients [27,28,29]. As an imaging technique based on tumor biological activity, 18F-FDG PET/CT has the potential to predict tumor vascular invasion. The SUVmax is the most commonly used semiquantitative parameter for PET/CT, and it is also an important factor in evaluating tumor prognosis and recurrence [26, 30, 31]. In this study, the difference in the SUVmaxT between the two groups was not statistically significant (p = 0.063). The reason for this result may be that SUVmaxT is affected by individual differences. Based on this, we introduced a new evaluation criterion, SUVmaxT/L. Previous reports have indicated that the FDG uptake capacity of tumors is correlated with tumor differentiation, the lower the differentiation degree of the tumor is, the more aggressive and the greater the FDG uptake of the tumor. The results of univariate and multivariate analyses showed that active tumor metabolism was an independent risk factor for MVI.

The current study indicated that active tumor metabolism (SUVmaxT/L > 2) and a high AFP level (AFP > 20 ng/mL) were independent risk factors for MVI in patients with HCC. The sensitivity of the combination of these two independent risk factors for predicting HCC with MVI was 56.9% (29/51), the specificity was 83.9% (52/62) and the accuracy was 71.7% (81/113).

The current study had several limitations. First, this was a retrospective study, and all the data for many patients in the early stage could not to be measured completely, therefore, only the real data included from all patients were strictly analyzed, and the conclusions were limited but true and rigorous. Second, patients enrolled in this study tended to have scattered liver tumor sizes, which could explain why there was no significant difference in tumor size in the multivariate analysis. Third, in this study, only the longest diameter was used to evaluate the size of the tumor, which inevitably caused some deviation from the actual size of the tumor.

In addition, a combined evaluation of clinical laboratory indicators and PET/CT parameters for detecting MVI in patients with HCC has not been reported. Further studies with a combination of larger sample size and more parameters should be conducted to explore the value of PET/CT in predicting the occurrence of MVI in patients with HCC.

Conclusion

Active tumor metabolism and high AFP levels were found to be independent risk factors for MVI in patients with HCC. The sensitivity of the combination of these two independent risk factors for predicting HCC with MVI was 56.9% (29/51), the specificity was 83.9% (52/62) and the accuracy was 71.7% (81/113).

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. No datasets were generated or analysed during the current study.

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Author notes

  1. Tianyi Wang, Xue Chen and Huan Huang contributed equally to this work.

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  1. Department of Imaging and Nuclear Medicine, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200438, China

    Tianyi Wang, Xue Chen, Huan Huang & Ningyang Jia

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  1. Tianyi Wang
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Contributions

W. and C. sorted out the literature, J. designed the research content and direction.H. sorted clinical data and laboratory data, W. and C. collected imaging findings. W. Statistical analysis of the data.W. and H. wrote the manuscript.J. Review the manuscript.

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Correspondence to Ningyang Jia.

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Wang, T., Chen, X., Huang, H. et al. Early prediction of microvascular invasion (MVI) occurrence in hepatocellular carcinoma (HCC) by 18F-FDG PET/CT and laboratory data. Eur J Med Res 29, 395 (2024). https://doi.org/10.1186/s40001-024-01973-7

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Keywords

European Journal of Medical Research

ISSN: 2047-783X

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