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    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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    Veterans Affairs Medical Center, Univ. California San Francisco
    San Francisco, USA

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    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
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Reappraisal of Portal Vein Tumor Thrombosis as a Prognostic Factor for Patients with Hepatocellular Carcinoma

Young Chang1 , Su Jong Yu2 , Hyo-Cheol Kim3 , Yun Bin Lee2 , Eun Ju Cho2 , Jeong-Hoon Lee2 , Yoon Jun Kim2 , Jin Wook Chung3 , Jung-Hwan Yoon2

1Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Korea; 2Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea; 3Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

Correspondence to: Su Jong Yu
ORCID https://orcid.org/0000-0001-8888-7977
E-mail ydoctor2@snu.ac.kr

Hyo-Cheol Kim
ORCID https://orcid.org/0000-0002-6016-247X
E-mail radioembolization@snu.ac.kr

Received: February 23, 2023; Revised: May 17, 2023; Accepted: June 15, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver 2024;18(1):156-164. https://doi.org/10.5009/gnl230057

Published online November 28, 2023, Published date January 15, 2024

Copyright © Gut and Liver.

Background/Aims: This study aimed to assess whether hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) could have favorable prognoses with proper treatment under selective conditions.
Methods: This retrospective, single-center study involved 1,168 patients diagnosed with HCC between January 2005 and December 2006, before the introduction of sorafenib. Overall survival (OS) was estimated using the Kaplan-Meier method, and the Cox proportional hazards model was used to identify and adjust the variables associated with OS.
Results: In nodular-type HCC, the OS differed significantly according to the presence of PVTT (log-rank p<0.001), and the level of PVTT, not only its presence, was a major independent factor affecting OS. PVTT at the Vp1-3 branch was associated with significantly longer OS than was PVTT at the Vp4 level (hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.04 to 3.21). In multivariate analysis, the OS was further stratified according to the PVTT level and tumor type, representing that nodular HCC without PVTT exhibited the best OS, whereas nodular HCC with Vp4 PVTT (adjusted HR, 2.59; 95% CI, 1.57 to 4.28) showed a poor prognosis similar to that of infiltrative HCC. The PVTT level was consistently correlated with OS in patients treated with transarterial chemoembolization. Nodular HCC without PVTT showed the best prognosis, while nodular HCC with Vp1-3 PVTT also exhibited a favorable OS, although inferior to that without PVTT (adjusted HR, 1.47, 95% CI, 0.92 to 2.36).
Conclusions: Active treatment such as transarterial chemoembolization can be considered for selected PVTT cases. The level of PVTT and type of HCC were independent prognostic factors.

Keywords: Hepatocellular carcinoma, Thrombosis, Therapeutic chemoembolization

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths and ranks sixth in cancer incidence globally.1 HCC-related mortality is still increasing, despite overall declining trends in cancer incidence and death rates.2 HCC is one of the most fatal cancers; however, its prognosis varies highly according to the clinical stage. Since the treatment modality and prognosis closely depend on the clinical stage of HCC,3,4 precise stratification and proper treatment strategy according to the clinical stage are crucial in treating HCC patients.

Portal vein tumor thrombosis (PVTT) is one of the most robust predictors of mortality in HCC patients;4,5 the median survival of HCC patients with PVTT reportedly ranges from 2.7 to 4.0 months.6,7 As PVTT is considered a critical adverse predictor, HCC with PVTT is classified as an advanced stage of HCC according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Approximately 20% to 30% of newly diagnosed HCC patients have PVTT, the proportion of which increases up to 42% in patients without HCC surveillance,8,9 all of whom are assigned to the advanced stage.

The advanced stage of HCC comprises a heterogeneous population, since the extent of PVTT and extrahepatic spread is not considered. The extent of PVTT can vary, ranging from involvement of the small segmental branch to the main trunk and beyond, and it has been frequently reported that the extent of PVTT, not just its presence, is an important determinant factor for survival.10-12 Nevertheless, the presence of PVTT severely restricts treatment options according to most treatment guidelines, regardless of its extent. In fact, systemic chemotherapy, rather than local treatment, is the only proven standard treatment.13-15

Conversely, most HCC staging systems, including the BCLC staging system, have been developed and validated for tumors presenting with discrete and nodular patterns. Although infiltrative HCC, characterized by the spread of cancerous cells throughout the liver tissue without forming distinct masses, comprises approximately 8% to 24% of newly diagnosed HCC, little is known about its clinicopathological presentation,16,17 and clinical guidelines barely account for infiltrative HCC. Historically, infiltrative HCC was suggested as T3a or T3b by the American Joint Committee on Cancer staging system because of its spreading nature, resulting in a large volume and vascular invasion.18,19

Prior to the sorafenib era, the only treatment option for HCC patients with PVTT was selective transarterial chemoembolization (TACE), as long as their liver function allowed. At this time, authors experienced a poor prognosis for patients with infiltrative HCC, whereas some patients with nodular HCC had favorable clinical outcomes with locoregional therapy, even with PVTT. Under these circumstances, we aimed to compare the treatment outcomes of HCC patients according to the extent of PVTT and tumor morphology.

1. Study population

This retrospective, single-center study included 1,168 patients newly diagnosed with HCC at Seoul National University Hospital between January 2005 and December 2006 before the sorafenib era. Patients’ medical records were retrospectively reviewed, and data including sex, age at diagnosis, liver function, tumor characteristics (morphology, number of tumors, maximal tumor size), vessel invasion, extrahepatic metastasis, and the first treatment modality were collected. Among the 1,168 newly diagnosed HCC patients, 608 who received TACE as the first treatment were identified.

Diagnosis of HCC was determined based on radiologic or histologic findings mainly according to the American Association for the Study of Liver Diseases guidelines.14 Two independent expert radiologists reviewed all radiologic images, and in cases of discordance, an additional experienced radiologist reviewed them, and consensus was achieved. If there was no clear radiological diagnosis, a liver biopsy was performed for a histological diagnosis.

2. Protocol of TACE

Conventional TACE using iodized oil (Lipiodol; Andre Guerbet, Aulnay-sous-Bois, France) was conducted by two expert interventional radiologists. Chemoembolization was performed as selectively as possible using a 2.4-F (MircoFerret: Cook Medical, Bloomington, IN, USA) or 2.4-F (Progreat 2.0; Terumo, Tokyo, Japan) microcatheter through segmental, subsegmental, or more distal levels of hepatic arteries according to the tumor distribution and the patient’s hepatic reservoir. An emulsion of 10 to 60 mg of doxorubicin hydrochloride (Adriamycin RDF; Ildong Pharmaceutical, Seoul, Korea) and 2 to 12 mL of iodized oil was administered into the targeted tumor feeders. The amount of chemoembolic emulsion was determined based on the tumor size and vascularity. Thereafter, gelatin sponge particles (Gelfoam; Upjohn, Kalamazoo, MI, USA or Cutanplast; Mascia Brunelli, Milano, Italy) mixed with 20 mg of doxorubicin hydrochloride were administered until stasis of arterial blood flow was achieved.

3. Classification of tumor type and PVTT

HCC is categorized into three types based on pathologic characteristics: nodular, massive, and infiltrative.20 The nodular type comprises a single or multiple discrete nodular tumors, and the massive type involves a large tumor that replaces most of the hepatic lobe. The infiltrative type represents the spread of minute tumor nodules without a dominant nodule.21 For this study, we classified HCCs into two groups radiologically: nodular HCC including massive HCC, and infiltrative HCC. Infiltrative HCC was identified by patchy, minimal, or miliary arterial phase enhancement without discrete nodules and inhomogeneous portal or delayed phase washout pattern,19,22 whereas nodular HCC was identified by typical enhancement and washout patterns on dynamic computer tomography or magnetic resonance imaging scan. PVTT was diagnosed as areas of streaky or solid arterial phase enhancement within the portal vein23 on dynamic computer tomography or magnetic resonance imaging scan. We classified PVTT by the involved level of the portal branch as Vp1-4.24

4. Statistical analysis

The clinical variables of each group were analyzed and compared using the independent-sample t-test, or Pearson chi-square test, as appropriate. Overall survival (OS) was estimated and plotted using the Kaplan-Meier method. The Cox proportional hazards model was used to identify and adjust the variables associated with OS. Statistically significant variables in the univariate analysis were included in the multivariate analysis. To calculate the survival rates of each balanced group, Kaplan-Meier plots were fitted. The cumulative probabilities of events were compared using log-rank tests. Differences were regarded as statistically significant at a p-value of <0.05. All statistical analyses were performed using SPSS version 26 (IBM Corp., Armonk, NY, USA).

5. Ethical considerations

This study followed the most recent ethical guidelines of the World Medical Association Declaration of Helsinki and was reviewed and approved by the Seoul National University Institutional Review Board (IRB number: SNUH 1505-049-671). The need for written informed consent was waived because this study was retrospective in nature and there were no study-specific interventions other than routine clinical practice. The medical records of the patients were anonymized and de-identified before analysis.

1. Baseline characteristics of the study population

Table 1 presents the baseline characteristics of the study population. A total of 1,168 patients were included in the study. The mean age of the study population was 57.1 years, and most (79.8%) were male. When classified into four groups according to the tumor type and the presence of PVTT, baseline liver function and tumor stage significantly differed between the groups. The group with infiltrative HCC or PVTT had lower albumin levels and higher total bilirubin levels than the group with nodular HCC or no PVTT. The mean model for end-stage liver disease score was higher in the infiltrative HCC group than in the nodular HCC group. The nodular HCC without PVTT group consisted mostly of American Joint Committee on Cancer (8th edition) stage I, while the other groups consisted mostly of American Joint Committee on Cancer stage III.

Table 1. Baseline Characteristics of the Study Population According to the Tumor Type and PVTT

CharacteristicTotal
(n=1,168)
Nodular typeInfiltrative typep-value
Without PVTT (n=859)With PVTT (n=79)Without PVTT (n=29)With PVTT (n=201)
Age, yr57.1±10.1857.87±10.3257.19±10.5753.83±8.7954.25±9.04<0.001
Sex
Male932 (79.79)672 (78.23)64 (81.01)25 (86.21)171 (85.07)0.13
Female236 (20.21)187 (21.77)15 (18.99)4 (13.79)30 (14.93)
Platelet, ×103/µL142.83±81.68131.81±70.10193.76±127.38155.14±72.40168.15±92.59<0.001
Albumin, g/dL3.63±0.583.68±0.583.57±0.563.53±0.633.49±0.57<0.001
Total bilirubin, mg/dL1.70±2.581.38±1.281.50±1.202.29±2.703.07±5.29<0.001
Creatinine, mg/dL1.07±0.731.09±0.831.02±0.171.16±0.641.01±0.300.08
PT INR1.34±3.491.38±4.041.18±0.181.18±0.181.23±0.910.47
MELD10.47±4.5110.25±4.4210.15±3.2811.35±4.4611.38±5.160.02
Child-Pugh class<0.001
A881 (75.43)684 (79.63)59 (74.68)17 (58.62)121 (60.20)
B245 (20.98)148 (17.23)19 (24.05)9 (31.03)69 (34.33)
C42 (3.60)27 (3.14)1 (1.27)3 (10.34)11 (5.47)
Tumor size, cm3.91±1.553.37±1.294.86±1.335.03±1.505.66±1.05<0.001
Tumor number2.01±1.421.63±1.102.33±1.443.31±1.693.29±1.69<0.001
PVTT level
Vp1-3NANA59 (74.68)NA90 (44.78)
Vp4NANA20 (25.32)NA111 (55.22)
AJCC stage<0.001
IA203 (17.38)198 (23.05)2 (2.53)00
IB363 (31.08)360 (41.91)03 (10.34)0
II325 (27.83)240 (27.94)18 (22.78)15 (51.72)16 (7.96)
IIIA39 (3.34)15 (1.75)2 (2.53)3 (10.34)2 (0.99)
IIIB116 (9.93)8 (0.93)42 (53.16)3 (10.34)119 (59.20)
IVA33 (2.83)11 (1.28)6 (7.59)2 (6.90)14 (6.97)
IVB89 (7.62)27 (3.14)9 (11.39)3 (10.34)50 (24.88)
BCLC stage<0.001
0118 (10.10)118 (13.74)000
1401 (34.33)382 (44.47)9 (11.39)2 (6.90)8 (3.98)
2288 (24.66)207 (24.10)22 (27.85)8 (27.59)51 (25.37)
3263 (22.52)114 (13.27)38 (48.10)12 (41.38)99 (49.25)
498 (8.39)38 (4.42)10 (12.66)7 (24.14)43 (21.39)
Initial treatment<0.001
Surgery214 (18.32)189 (22.00)15 (18.99)1 (3.45)9 (4.48)
RFA/PEI204 (17.47)201 (23.40)2 (2.53)1 (3.45)0
TACE607 (51.97)417 (48.54)48 (60.76)20 (68.97)122 (60.70)
Radiation or chemotherapy15 (1.28)4 (0.47)1 (1.27)2 (6.90)8 (3.98)
No treatment or etc.128 (10.96)48 (5.59)13 (16.46)5 (17.24)62 (30.85)

Data are presented as mean±SD or number (%).

PVTT, portal vein tumor thrombosis; PT, prothrombin time; INR, international normalized ratio; MELD, Model for End Stage Liver Disease; AJCC, American Joint Committee on Cancer (8th edition); BCLC stage, Barcelona Clinic Liver Cancer stage; RFA, radiofrequency ablation; PEI, percutaneous ethanol injection; NA, not applicable.

p-values were calculated using one-way analysis of variance for continuous variables and chi-square test for categorical variables.



2. OS according to tumor type and the presence of PVTT

Patients without PVTT (n=888) showed significantly longer OS than patients with PVTT (n=280; log-rank p<0.001) (Fig. 1A). When the study population was further classified into four groups according to the tumor type and the presence of PVTT, patients with nodular HCC without PVTT showed significantly longer OS than those with PVTT (log-rank p<0.001). In patients with infiltrative HCC (n=230), the OS was dismal regardless of the presence of PVTT (median OS: 5.0 months vs 3.9 months, log-rank p=0.445) (Fig. 1B).

Figure 1.Kaplan-Meier curves representing overall survival according to (A) the presence of portal vein tumor thrombosis (PVTT) and (B) the tumor type combined with the presence of PVCC. HCC, hepatocellular carcinoma.

3. OS according to the level of PVTT in nodular type HCC

In nodular HCC (n=938), there were significant differences in OS according to the level of PVTT, as well as the presence of PVTT. As shown in Fig. 2A, the survival rates of nodular HCC with Vp1/2 and Vp3 PVTT were similar, with distinct differences from nodular HCC with Vp4 PVTT. When PVTT levels were classified into two groups based on the main portal vein, nodular HCC with Vp1-3 PVTT showed significantly longer OS than those with Vp4 PVTT (hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.04 to 3.21; log-rank p=0.034) (Fig. 2B).

Figure 2.Kaplan-Meier curves representing overall survival according to the level of portal vein tumor thrombosis (PVTT) (A) in overall study population and (B) in patients with nodular-type hepatocellular carcinoma (HCC).

4. Multivariate analysis of the effect of tumor type and PVTT level on OS

In multivariate analysis, the baseline levels of platelet count, albumin, total bilirubin, tumor stage, and tumor type combined with PVTT level significantly influenced OS (Table 2). The OS was further stratified according to PVTT level and tumor type. Nodular HCC patients with Vp1-3 PVTT showed 1.5-fold higher risk of death compared to those without PVTT after adjusting for several variables (adjusted HR [aHR], 1.47; 95% CI, 1.01 to 2.14; p=0.042). Furthermore, nodular HCC patients with Vp4 PVTT showed a 2.6-fold higher risk of death compared to those without PVTT (aHR, 2.59; 95% CI, 1.57 to 4.28; p<0.001), and there was no significant difference in OS compared with infiltrative HCC (p=0.833) (Fig. 3).

Figure 3.The survival probability according to the type of tumor and the level of portal vein tumor thrombosis (PVTT) after adjusting for baseline variables. HCC, hepatocellular carcinoma.

Table 2. Multivariate Analysis of the Effect of Tumor Type and PVTT Level on Overall Survival

VariableModel 1Model 2Model 3
aHR (95% CI)p-valueaHR (95% CI)p-valueaHR (95% CI)p-value
Age1.01 (0.999–1.02)0.0781.01 (1.00–1.02)0.064
Sex1.001 (0.80–1.24)0.9750.99 (0.80–1.24)0.899
Platelet1.002 (1.001–1.003)<0.0011.002 (1.001–1.003)<0.0011.002 (1.001–1.003)<0.001
Albumin0.56 (0.48–0.64)<0.0010.55 (0.48–0.64)<0.0010.55 (0.48–0.63)<0.001
Total bilirubin1.10 (1.08–1.13)<0.0011.10 (1.08–1.13)<0.0011.10 (1.07–1.12)<0.001
Creatinine1.05 (0.94–1.18)0.354
PT INR1.00 (0.98–1.02)0.971
AJCC stage1.59 (1.43–1.78)<0.0011.59 (1.43–1.78)<0.0011.59 (1.43–1.78)<0.001
Tumor type & PVTT<0.001<0.001<0.001
Nodular type without PVTTReferenceReferenceReference
Nodular type with Vp1-3 PVTT1.51 (1.04–2.19)0.0321.50 (1.03–2.18)0.0331.47 (1.01–2.14)0.042
Nodular type with Vp4 PVTT2.62 (1.58–4.33)<0.0012.60 (1.57–4.31)<0.0012.59 (1.57–4.28)<0.001
Infiltrative type without PVTT3.76 (2.45–5.78)<0.0013.75 (2.44–5.76)<0.0013.61 (2.35–5.55)<0.001
Infiltrative type with PVTT2.43 (1.85–3.21)<0.0012.43 (1.85–3.19)<0.0012.37 (1.80–3.11)<0.001

PVTT, portal vein tumor thrombosis; aHR, adjusted hazard ratio; CI, confidence interval; PT, prothrombin time; INR, international normalized ratio; AJCC, American Joint Committee on Cancer (8th edition).



5. Subgroup analysis of patients receiving TACE

Out of the study population of 1,168, 607 patients received TACE as the first treatment for HCC (Supplementary Table 1). In the subgroup analysis of patients undergoing TACE, tumor type combined with PVTT level was consistently associated with OS (Table 3). One-year and 3-year survival rates of patients with nodular HCC without PVTT were 82.5% and 62.6%, respectively, and those of nodular HCC patients with Vp1-3 PVTT were 47.2% and 33.3%, respectively. In contrast, nodular HCC patients with Vp4 PVTT showed a 1-year survival rate of 41.7% and a 3-year survival rate as low as 8.3%. In multivariate analysis, patients with nodular HCC with Vp1-3 PVTT exhibited favorable OS, without statistically significant difference with those without PVTT (aHR, 1.47; 95% CI, 0.92 to 2.36; p=0.106). Nodular HCC patients with Vp4 PVTT had dismal OS along with infiltrative HCC patients, showing a 2.8-fold higher risk of death compared to those without PVTT (aHR, 2.82; 95% CI, 1.49 to 5.35; p=0.001) (Fig. 4).

Figure 4.The survival probability according to the type of tumor and the level of portal vein tumor thrombosis (PVTT) in patients receiving transarterial chemoembolization after adjusting for baseline variables. HCC, hepatocellular carcinoma.

Table 3. Multivariate Analysis of the Effect of Tumor Type and PVTT Level on Overall Survival in Patients Receiving Transarterial Chemoembolization

VariableModel 1Model 2
aHR (95% CI)p-valueaHR (95% CI)p-value
Age1.00 (0.99–1.01)0.933
Sex1.00 (0.74–1.34)0.995
Platelet1.002 (1.001–1.003)0.0011.002 (1.001–1.003)0.004
Albumin0.49 (0.40–0.60)<0.0010.49 (0.40–0.60)<0.001
Total bilirubin1.08 (1.03–1.12)<0.0011.08 (1.04–1.12)<0.001
AJCC stage1.56 (1.36–1.79)<0.0011.56 (1.36–1.79)<0.001
Tumor type & PVTT<0.001<0.001
Nodular type without PVTTReferenceReference
Nodular type with Vp1-3 PVTT1.47 (0.92–2.36)0.1101.47 (0.92–2.36)0.106
Nodular type with Vp4 PVTT2.82 (1.49–5.35)0.0022.82 (1.49–5.35)0.001
Infiltrative type without PVTT2.76 (1.63–4.68)<0.0012.77 (1.64–4.67)<0.001
Infiltrative type with PVTT2.20 (1.59–3.05)<0.0012.20 (1.59–3.05)<0.001

PVTT, portal vein tumor thrombosis; aHR, adjusted hazard ratio; CI, confidence interval; AJCC, American Joint Committee on Cancer (8th edition).


In this large-scale retrospective cohort study, we demonstrated that the prognosis of HCC patients differed significantly depending on the tumor type, as well as the presence and level of PVTT. Although the presence of PVTT was a major prognostic factor in patients with HCC, in infiltrative HCC patients, the presence of PVTT did not affect OS, and their prognosis was consistently dismal regardless of PVTT. In nodular HCC, the level and presence of PVTT had a significant effect on survival. Nodular HCC with main PVTT showed poor prognosis as infiltrative HCC, whereas nodular HCC with Vp1-3 PVTT showed an intermediate prognosis compared to nodular HCC without PVTT after adjusting for baseline liver function and tumor stage. When treated with TACE, nodular HCC patients with Vp1-3 PVTT showed a comparable prognosis to those without PVTT, suggesting that active treatments such as TACE can be considered for selected HCC patients with PVTT to improve OS.

Among the various HCC staging systems, the BCLC staging system is endorsed by international guidelines14,15 and is widely used in practice because it has been externally validated in diverse settings25-27 and assigns treatment allocation to all stages of HCC.15,28 According to the BCLC staging system, HCC with any portion of portal vein invasion or PVTT is considered an advanced stage with poor prognosis, and systemic chemotherapy using molecular targeting agents or immune checkpoint inhibitors is the only recommended treatment option. In contrast to the European and U.S. guidelines, the Hong Kong Liver Cancer staging system recommends locally advanced HCC with intrahepatic venous invasion or diffuse HCC treated with TACE if there is no evidence of extrahepatic vascular invasion/metastasis,29 and a Japanese nationwide survey has proposed hepatic resection in selected HCC patients with PVTT.30,31 In addition, many other treatment strategies have been attempted showing variable results, including TACE, radiation therapy, transarterial radioembolization, and surgical options such as resection and liver transplantation.32,33

TACE has been largely considered as a preferential palliative therapy for patients with multinodular HCC with well-preserved liver function. A meta-analysis of 13 studies with 1,933 HCC patients with PVTT treated with TACE demonstrated a 1- and 3-year survival rate of 29% and 4%, respectively, of which patients with main PVTT showed the worst survival rate.34 Pooled estimates for survival demonstrated that HCC patients with main PVTT showed 1- and 3-year survival rates of 16% and 2%, respectively, and patients with portal vein branch thrombosis showed 37% and 10%, respectively. In this study, the survival rates in patients with PVTT treated with TACE were much better, with 1-and 3-year survival rates of 47.2% and 33.3% in nodular HCC with Vp1-3 PVTT and 41.7% and 8.3% in those with Vp4 PVTT. These differences are presumed to be due to further stratification by tumor type and PVTT levels in this study.

It has been demonstrated that infiltrative HCCs are associated with a worse prognosis than nodular HCCs in the same stage.16,18,19 Infiltrative HCC is commonly associated with a high rate of microvascular invasion and frequently spreads through the liver via PVTT, often presenting as an advanced disease. Portal vein thrombus often appears as the first imaging feature of infiltrative HCC, a key clue for the diagnosis of infiltrative HCC, and is reported to be present in 68% to 100% of infiltrative HCCs.21,35 The poor prognosis of infiltrative HCC is because it is usually diagnosed at an advanced stage with a high tumor burden and vascular invasion. In addition, it has been suggested that the infiltrative feature itself exhibits aggressive biological behavior in infiltrative HCC, which can be used as an independent prognostic factor.36

In this study, HCC patients with PVTT demonstrated remarkably poor OS compared to patients without PVTT. However, when the tumor type was further stratified, nodular HCC patients without PVTT showed the best OS, whereas infiltrative HCC patients had dismal prognosis regardless of the presence of PVTT. Notably, nodular HCC patients with PVTT showed better survival than those with infiltrative HCC without PVTT. These findings can be explained by the fact that a substantial number of PVTTs are accompanied by infiltrative HCCs with an extremely poor prognosis. Indeed, 87.4% of infiltrative HCCs (201/230) had PVTT and 71.8% of PVTTs (201/280) were accompanied by infiltrative HCC. Moreover, when levels of PVTT were further stratified, nodular HCC patients with main PVTT had a poor prognosis as infiltrative HCC patients. Nodular HCC with Vp1-3 PVTT had intermediate OS, which was lower than that without PVTT, but better than that with main PVTT and infiltrative HCC. When treated with TACE, nodular HCC with Vp1-3 PVTT showed comparable OS to nodular HCC without PVTT, indicating that TACE can improve the prognosis in selected HCC patients, even in the presence of PVTT. There is a possibility that the OS of nodular HCC without PVTT might have been downgraded because only patients who could not receive curative treatment were included. In nodular HCC patients, not only PVTT but also initial treatment modality were analyzed as independent factors affecting survival (Supplementary Table 2). However, the fact that the prognosis of nodular HCC with Vp1-3 PVTT was favorable is robust. Therefore, when selecting a treatment option for HCC patients with PVTT, tumor type and PVTT level should be considered comprehensively, rather than considering HCC with PVTT as a contraindication for TACE unconditionally.

This study has several limitations. Due to its retrospective nature, treatment strategies for patients were individually determined on the basis of the attending clinician’s judgment, which was likely to induce selection bias in the study population treated by TACE, which might have downgraded the OS of nodular HCC without PVTT. In addition, the prognosis might also have been influenced by subsequent treatment strategies. Multivariate analyses were conducted to overcome the bias; however, the statistical complementation may have been insufficient. Further prospective studies are required to validate our findings.

In conclusion, the level of PVTT and type of HCC were independent prognostic factors. In nodular HCC, prognosis can be improved by active treatment such as TACE even with PVTT if the extent is under the main portal vein level.

Study concept and design: S.J.Y., H.C.K. Data acquisition: J.W.C. Data analysis and interpretation: Y.B.L., E.J.C., J.H.L., Y.J.K., J.H.Y. Drafting of the manuscript: Y.C. Critical revision of the manuscript for important intellectual content: J.W.C., J.H.L. Statistical analysis: Y.C. Study supervision: S.J.Y., H.C.K.

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

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Article

Original Article

Gut and Liver 2024; 18(1): 156-164

Published online January 15, 2024 https://doi.org/10.5009/gnl230057

Copyright © Gut and Liver.

Reappraisal of Portal Vein Tumor Thrombosis as a Prognostic Factor for Patients with Hepatocellular Carcinoma

Young Chang1 , Su Jong Yu2 , Hyo-Cheol Kim3 , Yun Bin Lee2 , Eun Ju Cho2 , Jeong-Hoon Lee2 , Yoon Jun Kim2 , Jin Wook Chung3 , Jung-Hwan Yoon2

1Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Korea; 2Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea; 3Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

Correspondence to:Su Jong Yu
ORCID https://orcid.org/0000-0001-8888-7977
E-mail ydoctor2@snu.ac.kr

Hyo-Cheol Kim
ORCID https://orcid.org/0000-0002-6016-247X
E-mail radioembolization@snu.ac.kr

Received: February 23, 2023; Revised: May 17, 2023; Accepted: June 15, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims: This study aimed to assess whether hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) could have favorable prognoses with proper treatment under selective conditions.
Methods: This retrospective, single-center study involved 1,168 patients diagnosed with HCC between January 2005 and December 2006, before the introduction of sorafenib. Overall survival (OS) was estimated using the Kaplan-Meier method, and the Cox proportional hazards model was used to identify and adjust the variables associated with OS.
Results: In nodular-type HCC, the OS differed significantly according to the presence of PVTT (log-rank p<0.001), and the level of PVTT, not only its presence, was a major independent factor affecting OS. PVTT at the Vp1-3 branch was associated with significantly longer OS than was PVTT at the Vp4 level (hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.04 to 3.21). In multivariate analysis, the OS was further stratified according to the PVTT level and tumor type, representing that nodular HCC without PVTT exhibited the best OS, whereas nodular HCC with Vp4 PVTT (adjusted HR, 2.59; 95% CI, 1.57 to 4.28) showed a poor prognosis similar to that of infiltrative HCC. The PVTT level was consistently correlated with OS in patients treated with transarterial chemoembolization. Nodular HCC without PVTT showed the best prognosis, while nodular HCC with Vp1-3 PVTT also exhibited a favorable OS, although inferior to that without PVTT (adjusted HR, 1.47, 95% CI, 0.92 to 2.36).
Conclusions: Active treatment such as transarterial chemoembolization can be considered for selected PVTT cases. The level of PVTT and type of HCC were independent prognostic factors.

Keywords: Hepatocellular carcinoma, Thrombosis, Therapeutic chemoembolization

INTRODUCTION

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths and ranks sixth in cancer incidence globally.1 HCC-related mortality is still increasing, despite overall declining trends in cancer incidence and death rates.2 HCC is one of the most fatal cancers; however, its prognosis varies highly according to the clinical stage. Since the treatment modality and prognosis closely depend on the clinical stage of HCC,3,4 precise stratification and proper treatment strategy according to the clinical stage are crucial in treating HCC patients.

Portal vein tumor thrombosis (PVTT) is one of the most robust predictors of mortality in HCC patients;4,5 the median survival of HCC patients with PVTT reportedly ranges from 2.7 to 4.0 months.6,7 As PVTT is considered a critical adverse predictor, HCC with PVTT is classified as an advanced stage of HCC according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Approximately 20% to 30% of newly diagnosed HCC patients have PVTT, the proportion of which increases up to 42% in patients without HCC surveillance,8,9 all of whom are assigned to the advanced stage.

The advanced stage of HCC comprises a heterogeneous population, since the extent of PVTT and extrahepatic spread is not considered. The extent of PVTT can vary, ranging from involvement of the small segmental branch to the main trunk and beyond, and it has been frequently reported that the extent of PVTT, not just its presence, is an important determinant factor for survival.10-12 Nevertheless, the presence of PVTT severely restricts treatment options according to most treatment guidelines, regardless of its extent. In fact, systemic chemotherapy, rather than local treatment, is the only proven standard treatment.13-15

Conversely, most HCC staging systems, including the BCLC staging system, have been developed and validated for tumors presenting with discrete and nodular patterns. Although infiltrative HCC, characterized by the spread of cancerous cells throughout the liver tissue without forming distinct masses, comprises approximately 8% to 24% of newly diagnosed HCC, little is known about its clinicopathological presentation,16,17 and clinical guidelines barely account for infiltrative HCC. Historically, infiltrative HCC was suggested as T3a or T3b by the American Joint Committee on Cancer staging system because of its spreading nature, resulting in a large volume and vascular invasion.18,19

Prior to the sorafenib era, the only treatment option for HCC patients with PVTT was selective transarterial chemoembolization (TACE), as long as their liver function allowed. At this time, authors experienced a poor prognosis for patients with infiltrative HCC, whereas some patients with nodular HCC had favorable clinical outcomes with locoregional therapy, even with PVTT. Under these circumstances, we aimed to compare the treatment outcomes of HCC patients according to the extent of PVTT and tumor morphology.

MATERIALS AND METHODS

1. Study population

This retrospective, single-center study included 1,168 patients newly diagnosed with HCC at Seoul National University Hospital between January 2005 and December 2006 before the sorafenib era. Patients’ medical records were retrospectively reviewed, and data including sex, age at diagnosis, liver function, tumor characteristics (morphology, number of tumors, maximal tumor size), vessel invasion, extrahepatic metastasis, and the first treatment modality were collected. Among the 1,168 newly diagnosed HCC patients, 608 who received TACE as the first treatment were identified.

Diagnosis of HCC was determined based on radiologic or histologic findings mainly according to the American Association for the Study of Liver Diseases guidelines.14 Two independent expert radiologists reviewed all radiologic images, and in cases of discordance, an additional experienced radiologist reviewed them, and consensus was achieved. If there was no clear radiological diagnosis, a liver biopsy was performed for a histological diagnosis.

2. Protocol of TACE

Conventional TACE using iodized oil (Lipiodol; Andre Guerbet, Aulnay-sous-Bois, France) was conducted by two expert interventional radiologists. Chemoembolization was performed as selectively as possible using a 2.4-F (MircoFerret: Cook Medical, Bloomington, IN, USA) or 2.4-F (Progreat 2.0; Terumo, Tokyo, Japan) microcatheter through segmental, subsegmental, or more distal levels of hepatic arteries according to the tumor distribution and the patient’s hepatic reservoir. An emulsion of 10 to 60 mg of doxorubicin hydrochloride (Adriamycin RDF; Ildong Pharmaceutical, Seoul, Korea) and 2 to 12 mL of iodized oil was administered into the targeted tumor feeders. The amount of chemoembolic emulsion was determined based on the tumor size and vascularity. Thereafter, gelatin sponge particles (Gelfoam; Upjohn, Kalamazoo, MI, USA or Cutanplast; Mascia Brunelli, Milano, Italy) mixed with 20 mg of doxorubicin hydrochloride were administered until stasis of arterial blood flow was achieved.

3. Classification of tumor type and PVTT

HCC is categorized into three types based on pathologic characteristics: nodular, massive, and infiltrative.20 The nodular type comprises a single or multiple discrete nodular tumors, and the massive type involves a large tumor that replaces most of the hepatic lobe. The infiltrative type represents the spread of minute tumor nodules without a dominant nodule.21 For this study, we classified HCCs into two groups radiologically: nodular HCC including massive HCC, and infiltrative HCC. Infiltrative HCC was identified by patchy, minimal, or miliary arterial phase enhancement without discrete nodules and inhomogeneous portal or delayed phase washout pattern,19,22 whereas nodular HCC was identified by typical enhancement and washout patterns on dynamic computer tomography or magnetic resonance imaging scan. PVTT was diagnosed as areas of streaky or solid arterial phase enhancement within the portal vein23 on dynamic computer tomography or magnetic resonance imaging scan. We classified PVTT by the involved level of the portal branch as Vp1-4.24

4. Statistical analysis

The clinical variables of each group were analyzed and compared using the independent-sample t-test, or Pearson chi-square test, as appropriate. Overall survival (OS) was estimated and plotted using the Kaplan-Meier method. The Cox proportional hazards model was used to identify and adjust the variables associated with OS. Statistically significant variables in the univariate analysis were included in the multivariate analysis. To calculate the survival rates of each balanced group, Kaplan-Meier plots were fitted. The cumulative probabilities of events were compared using log-rank tests. Differences were regarded as statistically significant at a p-value of <0.05. All statistical analyses were performed using SPSS version 26 (IBM Corp., Armonk, NY, USA).

5. Ethical considerations

This study followed the most recent ethical guidelines of the World Medical Association Declaration of Helsinki and was reviewed and approved by the Seoul National University Institutional Review Board (IRB number: SNUH 1505-049-671). The need for written informed consent was waived because this study was retrospective in nature and there were no study-specific interventions other than routine clinical practice. The medical records of the patients were anonymized and de-identified before analysis.

RESULTS

1. Baseline characteristics of the study population

Table 1 presents the baseline characteristics of the study population. A total of 1,168 patients were included in the study. The mean age of the study population was 57.1 years, and most (79.8%) were male. When classified into four groups according to the tumor type and the presence of PVTT, baseline liver function and tumor stage significantly differed between the groups. The group with infiltrative HCC or PVTT had lower albumin levels and higher total bilirubin levels than the group with nodular HCC or no PVTT. The mean model for end-stage liver disease score was higher in the infiltrative HCC group than in the nodular HCC group. The nodular HCC without PVTT group consisted mostly of American Joint Committee on Cancer (8th edition) stage I, while the other groups consisted mostly of American Joint Committee on Cancer stage III.

Table 1 . Baseline Characteristics of the Study Population According to the Tumor Type and PVTT.

CharacteristicTotal
(n=1,168)
Nodular typeInfiltrative typep-value
Without PVTT (n=859)With PVTT (n=79)Without PVTT (n=29)With PVTT (n=201)
Age, yr57.1±10.1857.87±10.3257.19±10.5753.83±8.7954.25±9.04<0.001
Sex
Male932 (79.79)672 (78.23)64 (81.01)25 (86.21)171 (85.07)0.13
Female236 (20.21)187 (21.77)15 (18.99)4 (13.79)30 (14.93)
Platelet, ×103/µL142.83±81.68131.81±70.10193.76±127.38155.14±72.40168.15±92.59<0.001
Albumin, g/dL3.63±0.583.68±0.583.57±0.563.53±0.633.49±0.57<0.001
Total bilirubin, mg/dL1.70±2.581.38±1.281.50±1.202.29±2.703.07±5.29<0.001
Creatinine, mg/dL1.07±0.731.09±0.831.02±0.171.16±0.641.01±0.300.08
PT INR1.34±3.491.38±4.041.18±0.181.18±0.181.23±0.910.47
MELD10.47±4.5110.25±4.4210.15±3.2811.35±4.4611.38±5.160.02
Child-Pugh class<0.001
A881 (75.43)684 (79.63)59 (74.68)17 (58.62)121 (60.20)
B245 (20.98)148 (17.23)19 (24.05)9 (31.03)69 (34.33)
C42 (3.60)27 (3.14)1 (1.27)3 (10.34)11 (5.47)
Tumor size, cm3.91±1.553.37±1.294.86±1.335.03±1.505.66±1.05<0.001
Tumor number2.01±1.421.63±1.102.33±1.443.31±1.693.29±1.69<0.001
PVTT level
Vp1-3NANA59 (74.68)NA90 (44.78)
Vp4NANA20 (25.32)NA111 (55.22)
AJCC stage<0.001
IA203 (17.38)198 (23.05)2 (2.53)00
IB363 (31.08)360 (41.91)03 (10.34)0
II325 (27.83)240 (27.94)18 (22.78)15 (51.72)16 (7.96)
IIIA39 (3.34)15 (1.75)2 (2.53)3 (10.34)2 (0.99)
IIIB116 (9.93)8 (0.93)42 (53.16)3 (10.34)119 (59.20)
IVA33 (2.83)11 (1.28)6 (7.59)2 (6.90)14 (6.97)
IVB89 (7.62)27 (3.14)9 (11.39)3 (10.34)50 (24.88)
BCLC stage<0.001
0118 (10.10)118 (13.74)000
1401 (34.33)382 (44.47)9 (11.39)2 (6.90)8 (3.98)
2288 (24.66)207 (24.10)22 (27.85)8 (27.59)51 (25.37)
3263 (22.52)114 (13.27)38 (48.10)12 (41.38)99 (49.25)
498 (8.39)38 (4.42)10 (12.66)7 (24.14)43 (21.39)
Initial treatment<0.001
Surgery214 (18.32)189 (22.00)15 (18.99)1 (3.45)9 (4.48)
RFA/PEI204 (17.47)201 (23.40)2 (2.53)1 (3.45)0
TACE607 (51.97)417 (48.54)48 (60.76)20 (68.97)122 (60.70)
Radiation or chemotherapy15 (1.28)4 (0.47)1 (1.27)2 (6.90)8 (3.98)
No treatment or etc.128 (10.96)48 (5.59)13 (16.46)5 (17.24)62 (30.85)

Data are presented as mean±SD or number (%)..

PVTT, portal vein tumor thrombosis; PT, prothrombin time; INR, international normalized ratio; MELD, Model for End Stage Liver Disease; AJCC, American Joint Committee on Cancer (8th edition); BCLC stage, Barcelona Clinic Liver Cancer stage; RFA, radiofrequency ablation; PEI, percutaneous ethanol injection; NA, not applicable..

p-values were calculated using one-way analysis of variance for continuous variables and chi-square test for categorical variables..



2. OS according to tumor type and the presence of PVTT

Patients without PVTT (n=888) showed significantly longer OS than patients with PVTT (n=280; log-rank p<0.001) (Fig. 1A). When the study population was further classified into four groups according to the tumor type and the presence of PVTT, patients with nodular HCC without PVTT showed significantly longer OS than those with PVTT (log-rank p<0.001). In patients with infiltrative HCC (n=230), the OS was dismal regardless of the presence of PVTT (median OS: 5.0 months vs 3.9 months, log-rank p=0.445) (Fig. 1B).

Figure 1. Kaplan-Meier curves representing overall survival according to (A) the presence of portal vein tumor thrombosis (PVTT) and (B) the tumor type combined with the presence of PVCC. HCC, hepatocellular carcinoma.

3. OS according to the level of PVTT in nodular type HCC

In nodular HCC (n=938), there were significant differences in OS according to the level of PVTT, as well as the presence of PVTT. As shown in Fig. 2A, the survival rates of nodular HCC with Vp1/2 and Vp3 PVTT were similar, with distinct differences from nodular HCC with Vp4 PVTT. When PVTT levels were classified into two groups based on the main portal vein, nodular HCC with Vp1-3 PVTT showed significantly longer OS than those with Vp4 PVTT (hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.04 to 3.21; log-rank p=0.034) (Fig. 2B).

Figure 2. Kaplan-Meier curves representing overall survival according to the level of portal vein tumor thrombosis (PVTT) (A) in overall study population and (B) in patients with nodular-type hepatocellular carcinoma (HCC).

4. Multivariate analysis of the effect of tumor type and PVTT level on OS

In multivariate analysis, the baseline levels of platelet count, albumin, total bilirubin, tumor stage, and tumor type combined with PVTT level significantly influenced OS (Table 2). The OS was further stratified according to PVTT level and tumor type. Nodular HCC patients with Vp1-3 PVTT showed 1.5-fold higher risk of death compared to those without PVTT after adjusting for several variables (adjusted HR [aHR], 1.47; 95% CI, 1.01 to 2.14; p=0.042). Furthermore, nodular HCC patients with Vp4 PVTT showed a 2.6-fold higher risk of death compared to those without PVTT (aHR, 2.59; 95% CI, 1.57 to 4.28; p<0.001), and there was no significant difference in OS compared with infiltrative HCC (p=0.833) (Fig. 3).

Figure 3. The survival probability according to the type of tumor and the level of portal vein tumor thrombosis (PVTT) after adjusting for baseline variables. HCC, hepatocellular carcinoma.

Table 2 . Multivariate Analysis of the Effect of Tumor Type and PVTT Level on Overall Survival.

VariableModel 1Model 2Model 3
aHR (95% CI)p-valueaHR (95% CI)p-valueaHR (95% CI)p-value
Age1.01 (0.999–1.02)0.0781.01 (1.00–1.02)0.064
Sex1.001 (0.80–1.24)0.9750.99 (0.80–1.24)0.899
Platelet1.002 (1.001–1.003)<0.0011.002 (1.001–1.003)<0.0011.002 (1.001–1.003)<0.001
Albumin0.56 (0.48–0.64)<0.0010.55 (0.48–0.64)<0.0010.55 (0.48–0.63)<0.001
Total bilirubin1.10 (1.08–1.13)<0.0011.10 (1.08–1.13)<0.0011.10 (1.07–1.12)<0.001
Creatinine1.05 (0.94–1.18)0.354
PT INR1.00 (0.98–1.02)0.971
AJCC stage1.59 (1.43–1.78)<0.0011.59 (1.43–1.78)<0.0011.59 (1.43–1.78)<0.001
Tumor type & PVTT<0.001<0.001<0.001
Nodular type without PVTTReferenceReferenceReference
Nodular type with Vp1-3 PVTT1.51 (1.04–2.19)0.0321.50 (1.03–2.18)0.0331.47 (1.01–2.14)0.042
Nodular type with Vp4 PVTT2.62 (1.58–4.33)<0.0012.60 (1.57–4.31)<0.0012.59 (1.57–4.28)<0.001
Infiltrative type without PVTT3.76 (2.45–5.78)<0.0013.75 (2.44–5.76)<0.0013.61 (2.35–5.55)<0.001
Infiltrative type with PVTT2.43 (1.85–3.21)<0.0012.43 (1.85–3.19)<0.0012.37 (1.80–3.11)<0.001

PVTT, portal vein tumor thrombosis; aHR, adjusted hazard ratio; CI, confidence interval; PT, prothrombin time; INR, international normalized ratio; AJCC, American Joint Committee on Cancer (8th edition)..



5. Subgroup analysis of patients receiving TACE

Out of the study population of 1,168, 607 patients received TACE as the first treatment for HCC (Supplementary Table 1). In the subgroup analysis of patients undergoing TACE, tumor type combined with PVTT level was consistently associated with OS (Table 3). One-year and 3-year survival rates of patients with nodular HCC without PVTT were 82.5% and 62.6%, respectively, and those of nodular HCC patients with Vp1-3 PVTT were 47.2% and 33.3%, respectively. In contrast, nodular HCC patients with Vp4 PVTT showed a 1-year survival rate of 41.7% and a 3-year survival rate as low as 8.3%. In multivariate analysis, patients with nodular HCC with Vp1-3 PVTT exhibited favorable OS, without statistically significant difference with those without PVTT (aHR, 1.47; 95% CI, 0.92 to 2.36; p=0.106). Nodular HCC patients with Vp4 PVTT had dismal OS along with infiltrative HCC patients, showing a 2.8-fold higher risk of death compared to those without PVTT (aHR, 2.82; 95% CI, 1.49 to 5.35; p=0.001) (Fig. 4).

Figure 4. The survival probability according to the type of tumor and the level of portal vein tumor thrombosis (PVTT) in patients receiving transarterial chemoembolization after adjusting for baseline variables. HCC, hepatocellular carcinoma.

Table 3 . Multivariate Analysis of the Effect of Tumor Type and PVTT Level on Overall Survival in Patients Receiving Transarterial Chemoembolization.

VariableModel 1Model 2
aHR (95% CI)p-valueaHR (95% CI)p-value
Age1.00 (0.99–1.01)0.933
Sex1.00 (0.74–1.34)0.995
Platelet1.002 (1.001–1.003)0.0011.002 (1.001–1.003)0.004
Albumin0.49 (0.40–0.60)<0.0010.49 (0.40–0.60)<0.001
Total bilirubin1.08 (1.03–1.12)<0.0011.08 (1.04–1.12)<0.001
AJCC stage1.56 (1.36–1.79)<0.0011.56 (1.36–1.79)<0.001
Tumor type & PVTT<0.001<0.001
Nodular type without PVTTReferenceReference
Nodular type with Vp1-3 PVTT1.47 (0.92–2.36)0.1101.47 (0.92–2.36)0.106
Nodular type with Vp4 PVTT2.82 (1.49–5.35)0.0022.82 (1.49–5.35)0.001
Infiltrative type without PVTT2.76 (1.63–4.68)<0.0012.77 (1.64–4.67)<0.001
Infiltrative type with PVTT2.20 (1.59–3.05)<0.0012.20 (1.59–3.05)<0.001

PVTT, portal vein tumor thrombosis; aHR, adjusted hazard ratio; CI, confidence interval; AJCC, American Joint Committee on Cancer (8th edition)..


DISCUSSION

In this large-scale retrospective cohort study, we demonstrated that the prognosis of HCC patients differed significantly depending on the tumor type, as well as the presence and level of PVTT. Although the presence of PVTT was a major prognostic factor in patients with HCC, in infiltrative HCC patients, the presence of PVTT did not affect OS, and their prognosis was consistently dismal regardless of PVTT. In nodular HCC, the level and presence of PVTT had a significant effect on survival. Nodular HCC with main PVTT showed poor prognosis as infiltrative HCC, whereas nodular HCC with Vp1-3 PVTT showed an intermediate prognosis compared to nodular HCC without PVTT after adjusting for baseline liver function and tumor stage. When treated with TACE, nodular HCC patients with Vp1-3 PVTT showed a comparable prognosis to those without PVTT, suggesting that active treatments such as TACE can be considered for selected HCC patients with PVTT to improve OS.

Among the various HCC staging systems, the BCLC staging system is endorsed by international guidelines14,15 and is widely used in practice because it has been externally validated in diverse settings25-27 and assigns treatment allocation to all stages of HCC.15,28 According to the BCLC staging system, HCC with any portion of portal vein invasion or PVTT is considered an advanced stage with poor prognosis, and systemic chemotherapy using molecular targeting agents or immune checkpoint inhibitors is the only recommended treatment option. In contrast to the European and U.S. guidelines, the Hong Kong Liver Cancer staging system recommends locally advanced HCC with intrahepatic venous invasion or diffuse HCC treated with TACE if there is no evidence of extrahepatic vascular invasion/metastasis,29 and a Japanese nationwide survey has proposed hepatic resection in selected HCC patients with PVTT.30,31 In addition, many other treatment strategies have been attempted showing variable results, including TACE, radiation therapy, transarterial radioembolization, and surgical options such as resection and liver transplantation.32,33

TACE has been largely considered as a preferential palliative therapy for patients with multinodular HCC with well-preserved liver function. A meta-analysis of 13 studies with 1,933 HCC patients with PVTT treated with TACE demonstrated a 1- and 3-year survival rate of 29% and 4%, respectively, of which patients with main PVTT showed the worst survival rate.34 Pooled estimates for survival demonstrated that HCC patients with main PVTT showed 1- and 3-year survival rates of 16% and 2%, respectively, and patients with portal vein branch thrombosis showed 37% and 10%, respectively. In this study, the survival rates in patients with PVTT treated with TACE were much better, with 1-and 3-year survival rates of 47.2% and 33.3% in nodular HCC with Vp1-3 PVTT and 41.7% and 8.3% in those with Vp4 PVTT. These differences are presumed to be due to further stratification by tumor type and PVTT levels in this study.

It has been demonstrated that infiltrative HCCs are associated with a worse prognosis than nodular HCCs in the same stage.16,18,19 Infiltrative HCC is commonly associated with a high rate of microvascular invasion and frequently spreads through the liver via PVTT, often presenting as an advanced disease. Portal vein thrombus often appears as the first imaging feature of infiltrative HCC, a key clue for the diagnosis of infiltrative HCC, and is reported to be present in 68% to 100% of infiltrative HCCs.21,35 The poor prognosis of infiltrative HCC is because it is usually diagnosed at an advanced stage with a high tumor burden and vascular invasion. In addition, it has been suggested that the infiltrative feature itself exhibits aggressive biological behavior in infiltrative HCC, which can be used as an independent prognostic factor.36

In this study, HCC patients with PVTT demonstrated remarkably poor OS compared to patients without PVTT. However, when the tumor type was further stratified, nodular HCC patients without PVTT showed the best OS, whereas infiltrative HCC patients had dismal prognosis regardless of the presence of PVTT. Notably, nodular HCC patients with PVTT showed better survival than those with infiltrative HCC without PVTT. These findings can be explained by the fact that a substantial number of PVTTs are accompanied by infiltrative HCCs with an extremely poor prognosis. Indeed, 87.4% of infiltrative HCCs (201/230) had PVTT and 71.8% of PVTTs (201/280) were accompanied by infiltrative HCC. Moreover, when levels of PVTT were further stratified, nodular HCC patients with main PVTT had a poor prognosis as infiltrative HCC patients. Nodular HCC with Vp1-3 PVTT had intermediate OS, which was lower than that without PVTT, but better than that with main PVTT and infiltrative HCC. When treated with TACE, nodular HCC with Vp1-3 PVTT showed comparable OS to nodular HCC without PVTT, indicating that TACE can improve the prognosis in selected HCC patients, even in the presence of PVTT. There is a possibility that the OS of nodular HCC without PVTT might have been downgraded because only patients who could not receive curative treatment were included. In nodular HCC patients, not only PVTT but also initial treatment modality were analyzed as independent factors affecting survival (Supplementary Table 2). However, the fact that the prognosis of nodular HCC with Vp1-3 PVTT was favorable is robust. Therefore, when selecting a treatment option for HCC patients with PVTT, tumor type and PVTT level should be considered comprehensively, rather than considering HCC with PVTT as a contraindication for TACE unconditionally.

This study has several limitations. Due to its retrospective nature, treatment strategies for patients were individually determined on the basis of the attending clinician’s judgment, which was likely to induce selection bias in the study population treated by TACE, which might have downgraded the OS of nodular HCC without PVTT. In addition, the prognosis might also have been influenced by subsequent treatment strategies. Multivariate analyses were conducted to overcome the bias; however, the statistical complementation may have been insufficient. Further prospective studies are required to validate our findings.

In conclusion, the level of PVTT and type of HCC were independent prognostic factors. In nodular HCC, prognosis can be improved by active treatment such as TACE even with PVTT if the extent is under the main portal vein level.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Study concept and design: S.J.Y., H.C.K. Data acquisition: J.W.C. Data analysis and interpretation: Y.B.L., E.J.C., J.H.L., Y.J.K., J.H.Y. Drafting of the manuscript: Y.C. Critical revision of the manuscript for important intellectual content: J.W.C., J.H.L. Statistical analysis: Y.C. Study supervision: S.J.Y., H.C.K.

SUPPLEMENTARY MATERIALS

Supplementary materials can be accessed at https://doi.org/10.5009/gnl230057.

DATA AVAILABILITY STATEMENT

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

Fig 1.

Figure 1.Kaplan-Meier curves representing overall survival according to (A) the presence of portal vein tumor thrombosis (PVTT) and (B) the tumor type combined with the presence of PVCC. HCC, hepatocellular carcinoma.
Gut and Liver 2024; 18: 156-164https://doi.org/10.5009/gnl230057

Fig 2.

Figure 2.Kaplan-Meier curves representing overall survival according to the level of portal vein tumor thrombosis (PVTT) (A) in overall study population and (B) in patients with nodular-type hepatocellular carcinoma (HCC).
Gut and Liver 2024; 18: 156-164https://doi.org/10.5009/gnl230057

Fig 3.

Figure 3.The survival probability according to the type of tumor and the level of portal vein tumor thrombosis (PVTT) after adjusting for baseline variables. HCC, hepatocellular carcinoma.
Gut and Liver 2024; 18: 156-164https://doi.org/10.5009/gnl230057

Fig 4.

Figure 4.The survival probability according to the type of tumor and the level of portal vein tumor thrombosis (PVTT) in patients receiving transarterial chemoembolization after adjusting for baseline variables. HCC, hepatocellular carcinoma.
Gut and Liver 2024; 18: 156-164https://doi.org/10.5009/gnl230057

Table 1 Baseline Characteristics of the Study Population According to the Tumor Type and PVTT

CharacteristicTotal
(n=1,168)
Nodular typeInfiltrative typep-value
Without PVTT (n=859)With PVTT (n=79)Without PVTT (n=29)With PVTT (n=201)
Age, yr57.1±10.1857.87±10.3257.19±10.5753.83±8.7954.25±9.04<0.001
Sex
Male932 (79.79)672 (78.23)64 (81.01)25 (86.21)171 (85.07)0.13
Female236 (20.21)187 (21.77)15 (18.99)4 (13.79)30 (14.93)
Platelet, ×103/µL142.83±81.68131.81±70.10193.76±127.38155.14±72.40168.15±92.59<0.001
Albumin, g/dL3.63±0.583.68±0.583.57±0.563.53±0.633.49±0.57<0.001
Total bilirubin, mg/dL1.70±2.581.38±1.281.50±1.202.29±2.703.07±5.29<0.001
Creatinine, mg/dL1.07±0.731.09±0.831.02±0.171.16±0.641.01±0.300.08
PT INR1.34±3.491.38±4.041.18±0.181.18±0.181.23±0.910.47
MELD10.47±4.5110.25±4.4210.15±3.2811.35±4.4611.38±5.160.02
Child-Pugh class<0.001
A881 (75.43)684 (79.63)59 (74.68)17 (58.62)121 (60.20)
B245 (20.98)148 (17.23)19 (24.05)9 (31.03)69 (34.33)
C42 (3.60)27 (3.14)1 (1.27)3 (10.34)11 (5.47)
Tumor size, cm3.91±1.553.37±1.294.86±1.335.03±1.505.66±1.05<0.001
Tumor number2.01±1.421.63±1.102.33±1.443.31±1.693.29±1.69<0.001
PVTT level
Vp1-3NANA59 (74.68)NA90 (44.78)
Vp4NANA20 (25.32)NA111 (55.22)
AJCC stage<0.001
IA203 (17.38)198 (23.05)2 (2.53)00
IB363 (31.08)360 (41.91)03 (10.34)0
II325 (27.83)240 (27.94)18 (22.78)15 (51.72)16 (7.96)
IIIA39 (3.34)15 (1.75)2 (2.53)3 (10.34)2 (0.99)
IIIB116 (9.93)8 (0.93)42 (53.16)3 (10.34)119 (59.20)
IVA33 (2.83)11 (1.28)6 (7.59)2 (6.90)14 (6.97)
IVB89 (7.62)27 (3.14)9 (11.39)3 (10.34)50 (24.88)
BCLC stage<0.001
0118 (10.10)118 (13.74)000
1401 (34.33)382 (44.47)9 (11.39)2 (6.90)8 (3.98)
2288 (24.66)207 (24.10)22 (27.85)8 (27.59)51 (25.37)
3263 (22.52)114 (13.27)38 (48.10)12 (41.38)99 (49.25)
498 (8.39)38 (4.42)10 (12.66)7 (24.14)43 (21.39)
Initial treatment<0.001
Surgery214 (18.32)189 (22.00)15 (18.99)1 (3.45)9 (4.48)
RFA/PEI204 (17.47)201 (23.40)2 (2.53)1 (3.45)0
TACE607 (51.97)417 (48.54)48 (60.76)20 (68.97)122 (60.70)
Radiation or chemotherapy15 (1.28)4 (0.47)1 (1.27)2 (6.90)8 (3.98)
No treatment or etc.128 (10.96)48 (5.59)13 (16.46)5 (17.24)62 (30.85)

Data are presented as mean±SD or number (%).

PVTT, portal vein tumor thrombosis; PT, prothrombin time; INR, international normalized ratio; MELD, Model for End Stage Liver Disease; AJCC, American Joint Committee on Cancer (8th edition); BCLC stage, Barcelona Clinic Liver Cancer stage; RFA, radiofrequency ablation; PEI, percutaneous ethanol injection; NA, not applicable.

p-values were calculated using one-way analysis of variance for continuous variables and chi-square test for categorical variables.


Table 2 Multivariate Analysis of the Effect of Tumor Type and PVTT Level on Overall Survival

VariableModel 1Model 2Model 3
aHR (95% CI)p-valueaHR (95% CI)p-valueaHR (95% CI)p-value
Age1.01 (0.999–1.02)0.0781.01 (1.00–1.02)0.064
Sex1.001 (0.80–1.24)0.9750.99 (0.80–1.24)0.899
Platelet1.002 (1.001–1.003)<0.0011.002 (1.001–1.003)<0.0011.002 (1.001–1.003)<0.001
Albumin0.56 (0.48–0.64)<0.0010.55 (0.48–0.64)<0.0010.55 (0.48–0.63)<0.001
Total bilirubin1.10 (1.08–1.13)<0.0011.10 (1.08–1.13)<0.0011.10 (1.07–1.12)<0.001
Creatinine1.05 (0.94–1.18)0.354
PT INR1.00 (0.98–1.02)0.971
AJCC stage1.59 (1.43–1.78)<0.0011.59 (1.43–1.78)<0.0011.59 (1.43–1.78)<0.001
Tumor type & PVTT<0.001<0.001<0.001
Nodular type without PVTTReferenceReferenceReference
Nodular type with Vp1-3 PVTT1.51 (1.04–2.19)0.0321.50 (1.03–2.18)0.0331.47 (1.01–2.14)0.042
Nodular type with Vp4 PVTT2.62 (1.58–4.33)<0.0012.60 (1.57–4.31)<0.0012.59 (1.57–4.28)<0.001
Infiltrative type without PVTT3.76 (2.45–5.78)<0.0013.75 (2.44–5.76)<0.0013.61 (2.35–5.55)<0.001
Infiltrative type with PVTT2.43 (1.85–3.21)<0.0012.43 (1.85–3.19)<0.0012.37 (1.80–3.11)<0.001

PVTT, portal vein tumor thrombosis; aHR, adjusted hazard ratio; CI, confidence interval; PT, prothrombin time; INR, international normalized ratio; AJCC, American Joint Committee on Cancer (8th edition).


Table 3 Multivariate Analysis of the Effect of Tumor Type and PVTT Level on Overall Survival in Patients Receiving Transarterial Chemoembolization

VariableModel 1Model 2
aHR (95% CI)p-valueaHR (95% CI)p-value
Age1.00 (0.99–1.01)0.933
Sex1.00 (0.74–1.34)0.995
Platelet1.002 (1.001–1.003)0.0011.002 (1.001–1.003)0.004
Albumin0.49 (0.40–0.60)<0.0010.49 (0.40–0.60)<0.001
Total bilirubin1.08 (1.03–1.12)<0.0011.08 (1.04–1.12)<0.001
AJCC stage1.56 (1.36–1.79)<0.0011.56 (1.36–1.79)<0.001
Tumor type & PVTT<0.001<0.001
Nodular type without PVTTReferenceReference
Nodular type with Vp1-3 PVTT1.47 (0.92–2.36)0.1101.47 (0.92–2.36)0.106
Nodular type with Vp4 PVTT2.82 (1.49–5.35)0.0022.82 (1.49–5.35)0.001
Infiltrative type without PVTT2.76 (1.63–4.68)<0.0012.77 (1.64–4.67)<0.001
Infiltrative type with PVTT2.20 (1.59–3.05)<0.0012.20 (1.59–3.05)<0.001

PVTT, portal vein tumor thrombosis; aHR, adjusted hazard ratio; CI, confidence interval; AJCC, American Joint Committee on Cancer (8th edition).


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May, 2024

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