There is a close relationship between cirrhosis and hepatocellular carcinoma (HCC). Transjugular intrahepatic portosystemic shunt (TIPS) has good clinical effect in treating the complication of portal hypertension. However, because of the risk of postoperative liver failure, severe complications, and low survival rate for HCC, TIPS is contraindicated in patients with portal hypertension and liver cancer. We studied a large cohort of patients with cirrhosis and HCC who underwent TIPS for recurrent variceal bleeding and/or ascites.

To assess the safety, efficacy, and survival rate in patients with HCC who underwent TIPS.

Group A comprised 217 patients with HCC and portal hypertension who underwent the TIPS procedure between 1999 and 2014. After TIPS deployment, these patients received palliative treatment for HCC. Group B comprised a cohort of 136 HCC patients with portal hypertension who did not undergo TIPS placement. Group B received palliative treatment for HCC plus medical therapy for portal hypertension. The clinical outcomes and survival rate were assessed.

In Group A, the primary technical success rate was 97.69% for TIPS placement, and no severe procedure-related complications of TIPS placement were reported. The control of variceal bleeding (VB) within 1 mo did not differ significantly between the groups (P = 0.261). Absorption of refractory ascites within 1 mo, recurrence of VB, and recurrence of refractory ascites differed significantly between the groups (P = 0.017, 0.023, and 0.009, respectively). By comparison, the rate of hepatic encephalopathy in Group B was lower than that in Group A (P = 0.036). The 1-, 2-, 3-, 4-, and 5-year survival rates were significantly different between Groups A and B (χ² = 12.227, P = 0.018; χ² = 12.457, P = 0.014; χ² = 26.490, P = 0.013; χ² = 21.956, P = 0.009, and χ² = 24.596, P = 0.006, respectively). The mean survival time was 43.7 mo in Group A and 31.8 mo in Group B. Median survival time was 50.0 mo in Group A and 33.0 mo in Group B. Mean and median survival differed significantly between the two groups (P = 0.000, χ² = 35.605, log-rank test). The mortality rate from VB in Group A was low than that in Group B (P = 0.006), but the rates of hepatic tumor, hepatic failure, and multiorgan failure did not differ significantly between the two groups (P = 0.173, 0.246 and 0.257, respectively).

TIPS combined with palliative treatment is safe and effective for portal hypertension in patients with HCC.

Liver cirrhosis and hepatic cancer can occur after further evolution of liver damage[1]. Primary hepatocellular carcinoma (HCC) usually occurs due to cirrhosis of the liver, although the main cause of cirrhosis is not the same worldwide. There is a close relationship between cirrhosis and HCC; liver cancer is often complicated by cirrhosis, while cirrhosis often leads to the occurrence of liver cancer[2].

The transjugular intrahepatic portosystemic shunt (TIPS) reduces portal pressure and relieves the clinical symptoms associated with various medical conditions[3]. TIPS has found a wide range of applications, including treatment of portal hypertension due to cirrhosis, variceal bleeding (VB), refractory ascites (RA), hepatic hydrothorax, hepatorenal syndrome, Budd–Chiari syndrome, hepatopulmonary syndrome, and portal thrombosis and as a bridge to liver transplantation[4].

Because of the risk of postoperative liver failure, severe complications and low survival rate of HCC patients, TIPS is contraindicated in patients with portal hypertension and liver cancer[5,6]. We conducted a retrospective analysis of 217 cases of portal hypertension and liver cancer that were treated in our hospital between January 1999 and January 2014 with TIPS plus palliative treatment and radiofre-quency ablation (RFA) and 136 cases of liver cancer patients treated with palliative treatment and RFA to compare the safety and efficacy and survival rate.

Group A comprised 217 patients; 170 underwent TIPS for treatment of VB, 47 for RA, and 69 for both. Two hundred and twelve cases had successful TIPS placement (Figure 1). The primary technical success rate was 97.69% (212/217), and the five cases that did not undergo successful TIPS placement were excluded. After TIPS placement, the mean PSG decreased from 23.37 ± 6.51 mmHg to 9.43 ± 3.14 mmHg (P = 0.016). There was no bleeding due to rupture or puncture of the tumor during TIPS. One week after the procedure, no acute stent stenosis or occlusion occurred. There were 114 cases of VB, 22 RA, and 35 with both in Group B.

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Figure 1 Transjugular intrahepatic portosystemic shunt placement procedures. Cases of portal hypertension with hepatocellular carcinoma underwent transarterial chemoembolization (A and B) first followed by TIPS (C and D). The tumor arterial supply was embolized and prominent gastroesophageal collateral vessels observed during the TIPS procedure were embolized with coils. TIPS: Transjugular intrahepatic portosystemic shunt.

In Group A, 212 cases underwent TACE for a total of 483 times. Among the 212 cases, 133 underwent TACE first followed by TIPS after liver function recovered from TACE injury; 79 cases underwent TIPS first and then after 1 wk recovery, they underwent TACE. RFA was performed 364 times. The 136 cases in Group B underwent TACE 269 times and RFA 175 times (Table 2). There were minor differences in the number of TACE (P = 0.043) and RFA (P = 0.037) performed between the two groups.

The timing of TIPS placement was different in Group A. Among the 133 cases undergoing TIPS placement followed by TACE; 81 cases were treated after 2 wk when liver function recovered to the preoperative level, 46 cases were treated 4 wk after the liver function recovered to the preoperative level, and six cases were treated when hepatic failure occurred. In the latter cases, four recovered after the treatment, and two died.

In Group A, 79 cases underwent TIPS placement before TACE. Among them, 17 cases were treated 2 wk after liver function recovered to the preoperative level, 49 cases were treated after 4 wk when liver function recovered to the preoperative level, and 13 cases were treated when hepatic failure occurred. In the latter cases, seven recovered after the treatment, and six died. By comparison, liver function recovery in the cases of TIPS placement followed by TACE was more satisfactory than in the cases of TIPS placement before TACE, and there was a significant difference (P < 0.05) (Table 3).

In the course of follow-up, in Group A, VB was controlled in 153/168 (91.07%) cases within 30 d (2 cases were excluded due to TIPS failure). There were 28 cases of postoperative bleeding, with a rebleeding rate of 16.67% (28/168). This was because patients with TIPS stent dysfunction had PSG > 12 mmHg, after shunt revision, without recurrence of bleeding. Without TIPS treatment in Group B, VB was controlled in 98/114 (85.96%) cases within 30 d. There were 56 (49.12%) cases of rebleeding. These 114 cases were treated by endoscopy for a total of 391 times. In the two groups, there was no difference in the rate of control of VB (P = 0.261), but there was a significant difference in the rate of rebleeding (P = 0.023).

In Group A, after TIPS treatment, ascites was significantly reduced in 14 cases, and symptoms disappeared in 25 cases with complete remission (three cases were excluded due to TIPS failure) within 30 d (39/44, 86.63%). Thirteen of 44 (29.54%) patients had recurrent ascites due to stenosis or occlusion of TIPS stent, which resulted in PSG > 12mmHg. After revision of the stent, ascites symptoms disappe-ared. In six cases, shunt dysfunction was due to tumor invasion. CT and hepatic arteriography confirmed that the symptoms disappeared after balloon dilation and stent implantation. In Group B, 22 cases were treated with diuretic therapy and paracentesis, and in nine (40.90%) cases the amount of ascites was reduced within 30 d. Five cases were converted to middle volume, and 14 cases had no obvious remission (19/22, 86.36%). There was a significant difference between the two groups in the rate of absorption of ascites (P = 0.017) and recurrence of ascites (P = 0.009).

There were 32 patients with 37 times (17.45%, 37/212) occurrences of HE in Group A: 28 with grade I/II and nine with grade III/IV HE. After medical treatment to relieve symptoms, none of the patients died due to HE. There were eight patients with 12 times (8.82%, 12/136) occurrences of HE in Group B: Seven with grade I/II and five with grade III/IV HE. Ten cases of HE were relieved in symptoms after treatment, and two patients died from HE. By comparison, the rate of HE in Group B was significantly lower than in Group A (P = 0.036) (Table 4).

During follow-up at 1 year, 188 patients (188/212, 88.67%) survived in Group A and 101 (101/136, 74.26%) in Group B. At 2 years, 169 patients (169/212, 79.71%) survived in Group A and 85 (85/136, 62.50%) in Group B. At 3 years, 145 patients (145/212, 68.39%) survived in Group A and 55 (55/136, 40.44%) in Group B. At 4 years, 115 patients (115/212, 54.24%) survived in Group A and 39 (39/136, 28.67%) in Group B. The endpoint of this study was at 5 years, when 88 patients (88/212, 41.51%) survived in Group A and 22 (22/136, 16.18%) in Group B. The 1-, 2-, 3-, 4-, and 5-year survival rates differed significantly between Groups A and B (P = 0.018, 0.014, 0.013, 0.009, 0.006, respectively) (Table 5). The mean survival time was 43.7 mo in Group A and 31.8 mo in Group B. Median survival time was 50.0 mo in Group A and 33.0 mo in Group B, and there was a significant difference between the two groups (P = 0.000, χ² = 35.605, log-rank test) (Figure 2).

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Figure 2 Survival times in two groups. Mean survival time was 43.7 mo in Group A and 31.8 mo in Group B. Median survival time was 50.0 mo in Group A and 33.0 mo in Group B. There was a significant difference between the two groups (P = 0.000, χ² = 35.605, log-rank test).

At the end of follow-up in this study, in Group A, five patients achieved CR, 37 patients achieved PR, 62 patients achieved SD, 108 patients achieved PD, and the disease control rate (CR+PR+SD/total number of cases) was approximately 49.05%. In Group B, three patients achieved CR, 28 patients achieved PR, 41patients achieved SD, 64 patients achieved PD, and the disease control rate was approximately 52.94%. There was no difference between the two groups (P = 0.249) (Table 6).

In Group A, seven patients died from VB, 56 from hepatic tumor, 25 from hepatic failure, 24 from multi-organ failure, and 12 from other causes. In Group B, 42 patients died from VB, 29 from hepatic tumor, 23 from hepatic failure, 17 from multi-organ failure, and three from other causes. The mortality rate for VB in Group A was significantly lower than in Group B (P = 0.006), but the rates of hepatic tumor, hepatic failure, and multi-organ failure did not differ significantly between the two groups (P = 0.173, 0.246, 0.257, respectively) (Table 7).

Portal hypertension and HCC are common late complications of liver cirrhosis and sometimes occur simultaneously[10]. There are various treatments for HCC, depending on the nature of the tumor, and TAE/TACE and RFA have become important approaches in recent years, along with RFA for small HCC[11]. The treatment of portal hypertension included administration of oral medicine, such as non-selective beta blockers, and surgical shunts, but TIPS is used more widely due to its safety and effectiveness in patients complicated with portal hypertension. However, according to the current guidelines for the treatment of portal hypertension, TIPS is contrain-dicated in patients with liver cancer.

One of the factors limiting the application of TIPS placement in patients with portal hypertension and liver cancer is its feasibility and safety. Liu et al[12] reported 58 HCC patients with portal vein tumor thrombosis with TIPS treatment; 8.6% of the tumors ruptured and required emergency treatment. Although it has been reported that large liver tumors are prone to rupture[13], there is no evidence that the risk of rupture is associated with tumor size in the TIPS process. Qiu et al[14] reported the largest group of 209 cases, but did not find severe complications, such as abdominal bleeding and tumor rupture. Importantly, we believe that advanced surgical techniques and meticulous preoperative preparation may reduce the occurrence of serious adverse events; however, further prospective studies are needed to confirm this.

In this study, 97.69% of the TIPS procedures were completed successfully, with no serious procedure-related complications, such as tumor rupture or bleeding, either from tumor puncture or directly from venous puncture in the tumor tissue. These results suggest that, as long as there is strict selection of suitable cases combined with the experience of skilled TIPS placement, severe complications will continue to be rare.

TACE takes the advantage of the hepatic dual blood supply resulting in emboli-zation of the tumor-feeding hepatic arteries, while portal venous flow to normal hepatocytes is preserved[15]. TACE in TIPS patients may be associated with increased hepatotoxicity[16]. This important change in the blood supply may aggravate hepatic necrosis[17], and when arteries that supply HCC are embolized, many factors can compensate for liver failure[18]. In a patient with TIPS, the hepatic portal venous perfusion is altered as portal venous flow is decompressed to the systemic circulation[19]. When TIPS is created, the liver loses most of its blood supply, and if TACE is performed in the short term, local liver necrosis increases the possibility of liver failure. In Group A, 79 cases underwent TIPS first then TACE; hepatic function recovery was difficult, and 13 cases developed hepatic failure. As for safety, we suggest that TACE should precede TIPS.

Another limiting factor in the application of TIPS in patients with portal hypertension and hepatic tumor is that although it has greatly improved the survival rate of patients with HCC, it has resulted in complications in portal hypertension cases. Whether it can improve the symptoms and the overall survival rate of the patients remains unknown[20]. After TIPS treatment, in the present study, the recurrence of VB and ascites was controlled, and the response to treatment was significantly greater compared with group B. In the present study, the 1-, 2-, 3-, 4-, and 5-year survival rates were significantly different between Groups A and B. The mean survival time was 43.7 mo in Group A and 31.8 mo in Group B. Median survival time was 50.0 mo in Group A and 33.0 mo in Group B. There was a significant difference between the two groups. The Response Evaluation Criteria in Solid Tumors criteria were applied to evaluate the HCC response, and we found that the disease control rate was no different between the two groups. However, the mortality rate for VB in Group A was lower than in Group B, and the rates of hepatic tumor, hepatic failure, and multiorgan failure did not differ significantly between the two groups. It showed that there was no significant difference between the two groups in the response to interventional therapy for HCC, and TIPS significantly improved the symptoms of portal hypertension and gave patients more opportunities and time for interventional treatment of liver cancer.

This showed that cirrhosis is a major threat in patients with primary liver cancer complicated with portal hypertension. In cases of emergency during long-term cancer treatment, stopping bleeding to extend life should be prioritized when there is a conflict between treatments. Therefore, in this study, TIPS treatment was conducted first, followed by treatment of liver cancer, in order not to lose the opportunity for implementing TIPS.

Lung metastasis was reported[21] after 5 and 10 mo in nine patients with liver cancer who received TIPS treatment[21], but Bettinger et al[22] reported no metastasis in 26 patients. A hypothetical risk is the development of pulmonary metastasis from the portal vein system[23], although this possibility is low. In the present study, only 50 patients had shunt dysfunction due to tumor invasion, and therefore, we did not correlate this transfer with TIPS deployment.

Timely detection and early treatment through close postoperative observation and regular follow-up are recommended to prevent serious adverse events, such as TIPS shunt dysfunction and HE, which are inherent in TIPS placement[24]. In the present study, control of VB within 1 mo did not differ significantly between the groups. However, absorption of RA within 1 mo, recurrence of VB, and recurrence of RA were significantly different between the groups. By comparison, the rate of HE in Group B was lower than in Group A. We showed that TIPS placement in Group A and palliative treatment in Group B both controlled VB, but for other complications of portal hypertension with HCC, TIPS demonstrated good clinical outcomes.

Although TIPS showed several advantages in this study, there were still some limitations to this study (e.g., it was a single-center study with a small sample size). Overall, this study demonstrates that TIPS treatment can better control the symptoms of portal hypertension in patients with both portal hypertension and liver cancer, while further treatment of liver cancer can improve survival rates. For these reasons, TIPS is recommended for further evaluation in multicenter studies with a larger sample size.

In conclusion, TIPS combined with palliative treatment seems to be effective and safe for portal hypertension in patients with HCC. We recommend that TIPS can be used for patients with portal hypertension and liver cancer.

The authors thank all the patients who were involved in this study and colleagues of the Department of Radiology of Air Force Medical Center of PLA for their contribu-tions to the data collection.