The Effect of Microvascular Invasion on Hepatocellular Carcinoma With Portal Vein Tumor Thrombus After Hepatectomy: A Retrospective Study

Abstract

Background

There is no report resolving whether microvascular invasion (MVI) affects the prognosis of hepatectomy for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT). The present study aimed to investigate the effect of MVI on HCC with PVTT after hepatectomy.

Methods

362 HCC patients with PVTT were included in this retrospective study. Diagnostic criteria of PVTT in HCC patients were based on typical preoperative radiological features on imaging studies. The log-rank test was utilized to differentiate overall survival (OS) and recurrence-free survival (RFS) rates between the two groups. Univariate and multivariate Cox proportional hazard regression was utilized to detect independent factors.

Results

PVTT without MVI accounted for 12.2% (n = 44). PVTT without MVI groups was significantly superior to PVTT with MVI groups in OS (the median survival = 27.1 months vs 13.7 months) and RFS (the median survival = 6.4 months vs 4.1 months). The 1-, 3-, and 5-year OS rates (65.5%, 36.8%, 21.7% vs 53.5%, 18.7%, 10.1%, P = .014) and RFS rates (47.0%, 29.7%, 19.2% vs 28.7%, 12.2%, 6.9%, P = .005) were significant different between two groups. Multivariate analysis showed that MVI was an independent risk factor for OS (hazard ratio (HR) = 1.482; P-value = .045) and RFS (HR = 1.601; P-value = .009).

Conclusions

MVI was an independent prognostic factor closely linked to tumor recurrence and poorer clinical outcomes for HCC patients with PVTT after hepatectomy. MVI should be included in current PVTT systems to supplement to the PVTT type.

Keywords

hepatocellular carcinoma microvascular invasion portal vein tumor thrombus prognosis

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death in the world.¹ Currently, hepatectomyis the most effective curative treatment for HCC in patients who is un-appropriate or has no-chance of liver transplantation.² Unfortunately, the long-term outcome remains poor because of the high incidence of tumor recurrence, which is reported to be more than 70% within 5 years.³ Vascular invasion is an important prognostic factor associated with more advanced tumor stages and poorer clinical outcomes.^4,5 Vascular invasion is generally divided into microvascular invasion (MVI) and macrovascular invasion.

Portal vein tumor thrombus (PVTT), the major component of macrovascular invasion, is a well-known poor prognosis prognostic factor for HCC patients.^6,7 The median survival time for HCC patients associated with PVTT ranged from 2.7 to 4.0 months in untreated patients.^8,9

MVI is also an independent prognostic factor closely linked to poorer clinical outcomes and tumor recurrence.^10,11 Several studies have demonstrated that MVI is significantly associated with early recurrence and is an independent predictor of both overall and disease-free survival after hepatectomy.^12,13

Previous studies have shown that MVI was not found in some HCC patients with PVTT.^14,15 However, the effect of MVI on HCC patients with PVTT after hepatectomyis not well known. Therefore, a multicenter study was conducted to investigate the effect of MVI on HCC with PVTT afterhepatectomy.

Methods

Patients and Study Design

This study was a retrospective study. This study was approved by the institutional ethics committee of Mengchao Hepatobiliary Hospital of Fujian Medical University on April 7, 2021 (NO.:2021_035_01) and followed the principles of the Declaration of Helsinki. Informed consent was written from each patient for their data to be used for research purposes. All patient details were de-identified. HCC patients with PVTT limited to the first-order branch of the main portal vein (Cheng’s type I/II) who underwent hepatectomy were organized from primary liver cancer big data by an information technology technician between January 2008 to December 2014. Then the clinical data were checked by project researchers (Dr Qingyi Xu and Dr Jianxing Zeng). The reporting of this study conforms to STROBE guidelines.¹⁶

Inclusion criteria were HCC patients with¹ performance state 0 or 1 score²; PVTT diagnosed by the diagnostic criteria as mentioned above³; Child-Pugh class A or selected B liver function (score ≤7)⁴; absence of macroscopic hepatic vein tumor thrombus, macroscopic bile duct tumor thrombus, extrahepatic spread, or distant metastases⁵; no history of other malignancies; and⁶ no other anticancer treatment which included transarterial chemoembolization, chemotherapy, radiotherapy, or sorafenib as the initial treatment. Exclusion criteria were patients with¹ Child-Pugh class C liver function²; palliative tumor resection³; incomplete data and⁴ died of severe surgical complications.

The patients received routine serological examinations and imaging examinations. Serological examinations included hepatitis B and hepatitis C virus immunology, HBV deoxyribonucleic acid (HBV-DNA) load, white blood cell count, platelet count, bilirubin, albumin and alpha-fetoprotein (AFP). Imaging examinations included contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen, chest radiography or chest CT, and abdominal ultrasonography.

Diagnostic criteria of PVTT in HCC patients were based on typical preoperative radiological features on imaging studies, which included ultrasound, CT, MRI, and intraoperative and postoperative histopathology examinations. PVTT type was based on Eastern Hepatobiliary Surgery Hospital Cheng’s classification.¹⁷ Postoperative histopathology examinations of resected specimens were performed by three pathologists independently. Histologic grading of the primary tumor was based on the Edmondson-Steiner classification. According to “Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma”, the presence of MVI was described as a cancer cell nest with >50 cells in the endothelial vascular lumen under microscopy in this study.¹⁸ Clinical diagnosis of HCC was based on the criterion of the American Association for the Study of Liver Diseases.¹⁹

Follow-Up

Patients were followed up every 3 months for the first 2 years after discharge from hospitals and every 3-6 months in subsequent years. The diagnostic criteria for tumor recurrence are based on the criterion of the American Association for the Study of Liver Diseases. The primary endpoints were overall survival (OS)and recurrence-free survival (RFS). OS was defined as the time from the date of surgery to tumor-related death. RFS was defined as the time from the date of surgery to the time when a recurrent tumor was first diagnosed. This study was censored on 31st October 2021.

Statistical Analysis

Categorical variables were grouped based on a normal reference value or clinical judgment and were presented as n (%) and compared using the chi-square test or Fisher exact test. The log-rank test was utilized to differentiate OS and RFS rates between the two groups. Univariate and multivariate Cox proportional hazard regression was utilized to detect independent factors. All statistical tests were 2-tailed and a P-value of less than .05 was considered statistically significant. All statistical analysis was performed with SPSS and R versions.

Results

Baseline Clinicopathological Characteristics

There was a total of 476 HCC patients with PVTT limited to the first-order branch of the main portal vein (Cheng’s type I/II) who underwent hepatectomyin the study period. 114 patients were excluded because of preoperative anticancer treatment (n = 15), extrahepatic metastasis (n = 20), history of other malignancies (n = 17), recurrent tumor resection (n = 21), perioperative death (n = 6), early loss to follow-up after discharge (n = 19), and incomplete clinical data (n = 16). Finally, the study consisted of 362 patients, the flow chart of this patient selection is shown in Figure 1. PVTT without MVI accounted for 12.2% (n = 44). As summarized in Table 1, PVTT without MVI groups were elder (P = .002) and had lower rates of satellite nodules (P < .001) than PVTT with MVI groups.

Figure 1.

The flow chart of selected patients. HCC, hepatocellular carcinoma; PVTT, portal vein tumor thrombus; MVI, microvascular invasion.

Table 1.

Comparison of Clinicopathological Features Between PVTT Without MVI Groups and PVTT With MVI Groups.

	PVTT Without MVI	PVTT With MVI	P-Value
	(n = 44)	(n = 318)	P-Value
Age, years
≤55	26 (59.1%)	258 (81.1%)	.002
>55	18 (40.9%)	60 (18.9%)
Gender
Female	5 (11.4%)	25 (7.9%)	.618
Male	39 (88.6%)	293 (92.1%)
Etiology
Non-hepatitis	7 (15.9%)	31 (9.7%)	.324
Hepatitis	37 (84.1%)	287 (90.3%)
White blood cell count,10⁹/L
≤4	9 (20.5%)	43 (13.5%)	.318
>4	35 (79.5%)	275 (86.5%)
Platelet count, 10⁹/L
≤100	6 (13.6%)	46 (14.5%)	.992
>100	38 (86.4%)	272 (85.5%)
Albumin level, g/L
≤35	1 (2.3%)	8 (2.5%)	1
>35	43 (97.7%)	310 (97.5%)
Total bilirubin level, umol/L
≤17	33 (75.0%)	234 (73.6%)	.986
>17	11 (25.0%)	84 (26.4%)
GGT level, U/L
≤50	7 (15.9%)	37 (11.6%)	.571
>50	37 (84.1%)	281 (88.4%)
ALBI grade
Grade 1	35 (79.5%)	249 (78.3%)	.996
Grade 2	9 (20.5%)	69 (21.7%)
AFP level, ng/mL
≤400	18 (40.9%)	104 (32.7%)	.363
>400	26 (59.1%)	214 (67.3%)
Surgical margin, cm
<1	4 (9.1%)	31 (9.7%)	1
≥1	40 (90.9%)	287 (90.3%)
Blood transfusion
No	34 (77.3%)	256 (80.5%)	.763
Yes	10 (22.7%)	62 (19.5%)
Blood loss, mL
<800	37 (84.1%)	276 (86.8%)	.798
≥800	7 (15.9%)	42 (13.2%)
Tumor diameter, cm
≤5	9 (20.5%)	38 (11.9%)	.182
>5	35 (79.5%)	280 (88.1%)
Tumor number
Solitary	33 (75.0%)	215 (67.6%)	.415
Multiple	11 (25.0%)	103 (32.4%)
Tumor differentiation
I-II	3 (6.8%)	5 (1.6%)	.095
III-IV	41 (93.2%)	313 (98.4%)
Satellite nodules
No	27 (61.4%)	87 (27.4%)	<.001
Yes	17 (38.6%)	231 (72.6%)
Liver cirrhosis
No	10 (22.7%)	60 (18.9%)	.686
Yes	34 (77.3%)	258 (81.1%)
PVTT type
I	32 (72.7%)	199 (62.6%)	.252
II	12 (27.3%)	119 (37.4%)

Abbreviations: PVTT, portal vein tumor thrombus; MVI, microvascular invasion; GGT, gamma-glutamyl transpeptidase; ALBI grade, albumin-bilirubin grade; AFP, alpha-fetoprotein.

Comparison of Prognosis Between PVTT Without MVI Groups and PVTT With MVI Groups

The median survival time was 12.4 months. PVTT without MVI groups was significantly superior to PVTT with MVI groups in OS (the median survival = 27.1 months vs 13.7 months) and RFS (the median survival = 6.4 months vs 4.1 months). The 1-, 3-, and 5-year OS rates (65.5%, 36.8%, 21.7% vs 53.5%, 18.7%, 10.1%, P = .014, Figure 2A) and RFS rates (47.0%, 29.7%, 19.2% vs 28.7%, 12.2%, 6.9%, P = .005, Figure 2B) were significant differences between two groups.

Figure 2.

Comparison of prognosis between two groups. (A) Overall survival; (B) Recurrence-free survival. PVTT, portal vein tumor thrombus; MVI, microvascular invasion.

Risk Factors Associated With OS and RFS in HCC With PVTT After Hepatectomy

The univariate COX analysis for determining the risk factors associated with OS and RFS in HCC patients with PVTT were shown in Table 2. Multivariate analysis revealed that MVI and PVTT were the independent risk factors associated with mortality (Table 3). MVI, albumin-bilirubin grade (ALBI grade), and tumor number were the independent risk factors associated with tumor recurrence by multivariate analysis (Table 3). The result showed that MVI was the independent risk factor associated with mortality (hazard ratio (HR) = 1.482; P-value = .045) and tumor recurrence (HR = 1.601; P-value = .009).

Table 2.

Univariate COX Regression for OS and RFS in HCC Patients With PVTT Afterhepatectomy.

Variables	OS			RFS
Variables	HR	95% CI	P-Value	HR	95% CI	P-Value
Age, years (≤55 as ref)
>55	.999	.757-1.319	.997	.771	.589-1.011	.060
Gender (female as ref)
Male	1.016	.663-1.556	.943	1.122	.745-1.688	.582
Etiology (non-hepatitis as ref)
Hepatitis	.972	.669-1.413	.883	1.098	.757-1.591	.623
White blood cell count, 10⁹/L (≤4 as ref)
>4	.870	.632-1.197	.393	1.001	.735-1.360	.999
Platelet count,10⁹/L (≤100 as ref)
>100	.953	.686-1.324	.773	1.080	.787-1.482	.635
Albumin level, g/L (≤35 as ref)
>35	1.500	.619-3.636	.369	1.213	.599-2.458	.592
Total bilirubin level, umol/L (≤17 as ref)
>17	1.185	.912-1.542	.204	.972	.756-1.249	.823
GGT level, U/L (≤50 as ref)
>50	1.205	.849-1.710	.296	1.266	.905-1.772	.168
ALBI grade, (Grade 1 as ref)
Grade 2	.749	.557-1.008	.057	.678	.513-.895	.006
AFP level, ng/mL (≤400 as ref)
>400	1.135	.889-1.450	.310	1.091	.864-1.376	.464
Surgical margin, cm (<1 as ref)
≥1	1.114	.758-1.636	.583	1.158	.797-1.682	.442
Blood transfusion (no as ref)
yes	1.181	.883-1.580	.261	1.040	.789-1.370	.782
Blood loss, mL (<800 as ref)
≥800	1.239	.889-1.727	.206	1.109	.806-1.526	.526
Tumor diameter, cm (≤5 as ref)
>5	1.399	.989-1.978	.058	1.281	.922-1.779	.139
Tumor number (solitary as ref)
multiple	1.150	.894-1.480	.276	1.277	1.008-1.618	.042
Tumor differentiation (I-II as ref)
III-IV	1.595	.709-3.587	.259	1.481	.699-3.136	.305
Satellite nodules (no as ref)
yes	1.312	1.016-1.692	.037	1.384	1.089-1.761	.008
Liver cirrhosis (no as ref)
yes	1.027	.768-1.374	.857	.981	.743-1.295	.891
MVI (no as ref)
yes	1.596	1.096-2.323	.015	1.644	1.154-2.342	.006
PVTT type (I as ref)
II	1.357	1.065-1.729	.014	1.284	1.022-1.615	.032

Abbreviations: OS, overall survival; RFS, recurrence-free survival; HCC, hepatocellular carcinoma; PVTT, portal vein tumor thrombus; MVI, microvascular invasion; GGT, gamma-glutamyl transpeptidase; ALBI grade, albumin-bilirubin grade; AFP, alpha-fetoprotein.

Table 3.

Multivariate COX Regression for OS and RFS in HCC Patients With PVTT Afterhepatectomy.

Variables	OS			RFS
Variables	HR	95% CI	P-Value	HR	95% CI	P-Value
ALBI grade, (Grade 1 as ref)
Grade 2	-	-	-	.649	.490-.860	.003
Tumor number (solitary as ref)
multiple	-	-	-	1.339	1.054-1.700	.017
MVI (no as ref)
yes	1.482	1.008-2.177	.045	1.601	1.123-2.282	.009
PVTT type (I as ref)
II	1.355	1.063-1.728	.014	-	-	-

Abbreviations: OS, overall survival; RFS, recurrence-free survival; HCC, hepatocellular carcinoma; PVTT, portal vein tumor thrombus; HR, Hazard ratio; MVI, microvascular invasion; ALBI grade, albumin-bilirubin grade.

Discussion

Vascular invasion is a well-known poor prognosis prognostic factor for HCC patients.²⁰ Previous studies have shown that MVI was not found in some HCC patients with PVTT. Cheng et al reported that PVTT without MVI accounted for 12.1%.²¹ Meng et al also demonstrated that the absence of MVI incidence was 33.6% in HCC patients with PVTT.¹⁵ In this study, we also found that PVTT without MVI accounted for 12.2%. Both of these two indicators belong to vascular invasion, but their relationship and effects are not well known.

Based on our large cohort study, we found that PVTT without MVI groups was significantly superior to PVTT with MVI groups in OS and RFS. Moreover, MVI was an independent risk factor associated with mortality and tumor recurrence for HCC patients with PVTT afterhepatectomy. To our knowledge, this study is the first to report the effect of MVI on HCC patients with PVTT. This indicates that MVI and PVTT are not simply progressive correlations, and molecular and hemodynamic factors may play important roles, which needs to be confirmed by further basic studies.

PVTT is one of the most significant poor prognostic factors of long-term survival for HCC patients.^22,23 The median survival time for HCC patients associated with PVTT ranged from 2.7 to 4.0 months in untreated patients.^8,9 Sorafenib was considered as standard therapy for patients with HCC associated with PVTT, but several studies have demonstrated that in selected HCC patients with PVTT limited to a first-order branch or above of the main portal vein, hepatectomyresulted in longer overall survival and tumor-free survival than non-surgical treatments.^24,25 A median survival ranging from 8 to 22 months has been reported for HCC patients with PVTT after surgical treatment.^26,27 In our study, the median survival time was 12.4 months, which was similar to previous studies.²⁸ These results show that hepatectomy is a safe and effective treatment for HCC patients with PVTT.

The current PVTT systems are mainly according to Eastern Hepatobiliary Surgery Hospital Cheng’s classification and Japanese portal vein thrombus (VP) typing.^17,29 These systems are classified by the extent of tumor thrombus in the portal vein. However, HCC patients with PVTT were not further classified according to MVI. According to our study, it is suggested that MVI should be introduced to supplement to the PVTT type.

This study has some limitations. Firstly, this is a retrospective study with its inherent defects. Secondly, this study was conducted in China, and most patients had HBV infections. Validation from study groups is required for HCV or alcoholism-related HCC.

In conclusion, MVI was an independent prognostic factor closely linked to tumor recurrence and poorer clinical outcomes for HCC patients with PVTT afterhepatectomy. MVI should be included in current PVTT systems to supplement to the PVTT type.

Supplemental Material

Supplemental Material - The Effect of Microvascular Invasion on Hepatocellular Carcinoma With Portal Vein Tumor Thrombus After Hepatectomy: A Retrospective Study

Supplemental Material for The Effect of Microvascular Invasion on Hepatocellular Carcinoma With Portal Vein Tumor Thrombus After Hepatectomy: A Retrospective Study by Qingyi Xu, Liqin Lan, Jinhua Zeng, and Jianxing Zeng in Cancer Control.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Startup Fund for scientific research, Fujian Medical University (Grant number: 2020QH1243).

Ethical Statement

ORCID iDs

Qingyi Xu

Liqin Lan

Jinhua Zeng

Jianxing Zeng

Data Availability Statement

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

Supplemental Material

Supplemental material for this article is available online.

Appendix

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