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Local ablation treatment of liver cancer with portal hypertension
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Local ablation treatment of liver cancer with portal hypertension. Patients with liver cancer and portal hypertension have complex conditions, and there are still many challenges in their treatment.
Primary liver cancer is one of the leading causes of cancer deaths worldwide. In recent years, with the comprehensive application of multiple treatment methods, the survival rate of patients has been increasing.
At present, local ablation therapy has been recognized as one of the effective methods for the treatment of liver cancer, especially early hepatocellular carcinoma (HCC), mainly including radiofrequency ablation, ethanol injection, microwave ablation, etc. [2-3].
The advantages of local ablation therapy in preserving liver parenchyma and high treatment safety make it an alternative choice for liver cancer patients who have lost the opportunity for surgery.
However, most liver cancers are associated with liver cirrhosis, and liver cirrhosis often leads to different degrees of portal hypertension , and there are not a few patients with portal hypertension in ablation therapy. Liver cancer, liver cirrhosis, and portal hypertension are not independent of each other and often affect each other .
Factors such as hypersplenism, esophageal varices, and decreased liver function caused by patients with portal hypertension also bring risks for ablation therapy.
With the development of treatment technology and the improvement of perioperative management, the application of local ablation in the treatment of liver cancer with portal hypertension has been continuously strengthened for many years.
It reviewed the research results and progress at home and abroad in recent years, hoping to provide ideas and countermeasures for the local ablation treatment of liver cancer with portal hypertension.
1 Overview of clinical treatment of liver cancer with portal hypertension
For early liver cancer with portal hypertension, liver transplantation is widely regarded as the best treatment option .
For HCC with a diameter of ≤ 5 cm and a number of ≤ 3 with portal hypertension, such as liver dysfunction, poor location of liver cancer, no tumor thrombus in the portal vein or hepatic vein, and no extrahepatic metastases, liver transplantation can be performed treatment.
However, due to the shortage of donated organs and the continued development and deterioration of tumors while waiting for the donor, liver transplantation has been greatly restricted.
Surgical resection is the first-line treatment for liver cancer in addition to liver transplantation .
However, liver cancer patients with severe portal hypertension greatly increase the risk of liver resection. The number of hepatic sinuses decreased, the portal hypertension further aggravated, the rupture of esophageal and gastric varices, and the risk of refractory ascites and liver failure increased significantly.
Due to the complexity of the disease and the high risk of surgery, liver cancer patients with portal hypertension were previously considered unsuitable for surgical resection .
In recent years, with the advancement of medical technology and the improvement of perioperative management, surgical resection is required for patients with good general conditions, Child-Pugh classification of liver function A or B, normal liver reserve function, and no distant metastases outside the liver.
The treatment of liver cancer with portal hypertension is also gradually developing, especially laparoscopic hepatectomy, which may become the treatment of BCLC stage 0 or A HCC with portal hypertension .
For patients with early liver cancer with portal hypertension, or patients who cannot tolerate surgery, local ablation has less trauma, fewer complications, relatively little impact on liver function, and faster recovery.
Local ablation causes necrosis of cells in the target area through physical or chemical action, mainly including thermal ablation (radio frequency, microwave, laser), chemical ablation (anhydrous ethanol injection), and cryoablation (argon-helium knife).
Currently, radiofrequency and microwave ablation are widely used in clinical practice. For liver cancer with a diameter of less than 3 cm, the same therapeutic effect as liver resection and liver transplantation can be achieved . After hepatectomy, the portal pressure will increase further, but local ablation has little effect on portal pressure.
For early liver cancer patients with portal hypertension complications such as esophageal varices bleeding and ascites, transjugular intrahepatic portosystemic shunt (TIPS) can be performed to treat the complications of portal hypertension, and then ablation treatment.
Transcatheter arterial chemoembolization (TACE) is an alternative treatment method when some liver cancer patients with portal hypertension complications cannot be operated or local ablation cannot be performed, and it is also a transitional treatment method for potentially resectable patients.
For different conditions, ablation can be combined with other methods such as TACE, TIPS, splenectomy, and devascularization to achieve better therapeutic effects. In short, patients with liver cancer and cirrhosis and portal hypertension have complex conditions, and treatment options are still controversial.
The principle of treatment must first consider the location of the tumor, liver function, liver reserve function, and the degree of portal hypertension, and evaluate whether there are indications for surgery.
For patients who have lost the opportunity for surgery, depending on their condition, consider choosing local ablation methods such as radiofrequency or minimally invasive methods such as TACE.
Especially for patients with small liver cancer (≤3 cm) who have lost the opportunity for surgery, local ablation alone can not only ensure tumor inactivation, but also have a positive effect on preserving liver function and reducing postoperative complications.
For 3~5 cm HCC that has lost the opportunity for surgery, TACE combined with local ablation is currently considered as the first-line treatment .
2 The effect of ablation treatment of liver cancer with portal hypertension
2.1 Compared with surgical resection
Although surgical resection is still the first-line treatment of liver cancer, surgical resection of liver cancer with portal hypertension may face the risks of bleeding and postoperative liver damage.
Many studies have shown that radiofrequency ablation for the treatment of early liver cancer (BCLC 0-A) combined with portal hypertension has similar effects as surgical resection (Table 1) [8, 11-15], which can reduce postoperative complications and shorten hospitalization Time [12-13].
According to literature , the average hospital stay for local ablation is 1 to 3 days, and the average hospital stay for hepatectomy is 6 to 8 days. However, the surgical resection group may have a slight advantage in improving the long-term survival rate and prolonging the time of tumor recurrence .
After hepatectomy, the portal pressure will increase further, but radiofrequency ablation has little effect on portal pressure. For early liver cancer, repeated radiofrequency ablation will not cause changes in portal pressure. Lee et al.  analyzed 24 patients with repeated radiofrequency ablation of HCC and portal hypertension, and the results showed that radiofrequency ablation had no effect on the liver function and portal pressure of patients with HCC and portal hypertension.
However, in recent years, the literature  reported that about 25% of HCC could not be displayed on transcutaneous ultrasound. Due to the location and size of the lesion, if percutaneous local ablation is limited, laparoscopic ablation will be an alternative method.
To deal with the lesions located at the top of the liver, the edges of the liver and other organs nearby, the local ablation under laparoscopic technique is more flexible, which can better show the lesions and avoid damage to the surrounding organs.
A study  analyzed the long-term effects of local ablation of early liver cancer under laparoscopic surgery, and the survival rates of 1, 3, and 5 years after surgery can reach 80%, 47% to 55%, and 34%. Cillo et al.  performed laparoscopic local ablation treatment on 169 HCC patients who lost the opportunity for surgery and could not undergo percutaneous ablation (most of them with portal hypertension), including 103 cases of radiofrequency ablation, 8 cases of microwave ablation, and absolute ethanol 58 cases were injected.
No patient died after surgery, and the 3-year survival period reached 47%. However, some patients who have undergone hepatectomy in the early stage may have abdominal adhesions, which makes the operation of laparoscopic surgery more difficult, prolongs the operation time, and increases the risk of other organ damage.
In addition to HCC, the local ablation treatment of other types of liver tumors with portal hypertension has also been initially explored in recent years. Díaz-González et al.  performed thermal ablation on most intrahepatic cholangiocarcinomas with cirrhosis and portal hypertension, and achieved good therapeutic effects. The complete ablation rate can reach 92.6%, and the average survival time is 30.6 months. With 2 cm lesions, the average survival time was 94.5 months.
2.2 Ablation of liver cancer with portal hypertension combined with other treatments
Local ablation combined with splenectomy can benefit liver cancer patients with portal hypertension. Jia et al.  combined laparoscopic splenectomy and simultaneous radiofrequency ablation in the treatment of early liver cancer, the incidence of postoperative moderate to severe complications was 30%, and no patients died during the perioperative period.
The overall survival rates of 1, 3, and 5 years can reach 90.5%, 73.3% and 60.4%. According to literature , tumor size, number, liver failure caused by postoperative liver resection, and Child score of liver function are independent risk factors that affect overall survival.
Cheng Jian et al.  performed ultrasound-guided microwave ablation combined with laparoscopic splenectomy and pericardial vascular dissection for small liver cancer.
The postoperative hospital stay was (12.1±4.6) d. The liver tumor was completely ablated and there was no gastrointestinal bleeding. There were no other serious complications after surgery. Zhang et al.  performed splenectomy and upper gastric blood supply occlusion in 35 patients with HCC and esophageal varices who failed endoscopic treatment, followed by liver resection (n=19) or radiofrequency ablation (n=16) ). Three months after surgery, only 2 patients had esophageal varices after endoscopy.
One patient had bleeding from esophageal varices, which improved after endoscopic sclerotherapy. There were no deaths, liver failure, hepatic encephalopathy, and fatal infection after splenectomy in each group after operation.
Among them, 14 patients in the liver resection group had abdominal effusion, and only 6 patients in the radiofrequency ablation group (P<0.05). Nine patients in the liver resection group had pulmonary infections after surgery, and there was no such complication in the radiofrequency ablation group (P=0.001).
Laparoscopic radiofrequency ablation combined with splenectomy and endoscopic esophageal varices ligation may provide help in reducing surgical risks, rapidly increasing platelets, and reducing serious complications. Hu et al.  used laparoscopic radiofrequency ablation combined with splenectomy and endoscopic variceal ligation for single small liver cancer (≤3 cm) with portal hypertension, and the 1-year tumor-free survival rate could reach 78%, 21 The monthly tumor-free survival rate can reach 61.4%. Ten patients had liver function decline, abdominal effusion, or portal vein thrombus formation after the operation, but there were no deaths.
For 3~5 cm HCC that has lost the opportunity for surgery, TACE combined with local ablation is currently considered as the first-line treatment [10, 27]. In recent years, there have been many studies on radiofrequency ablation combined with TACE in the treatment of patients with advanced liver cancer.
Studies have shown that radiofrequency ablation combined with TACE significantly improves the survival rate and prolongs the survival of patients. Saviano et al.  performed radiofrequency ablation combined with TACE treatment on 25 patients with compensated liver cirrhosis and single HCC (≥3 cm) who lost the opportunity for surgery, and 65% of them had severe portal hypertension.
The long-term survival rate of the radiofrequency ablation combined with TACE group was no different from that of the surgical resection group, although the local tumor progression rate (58.1%) was higher than that of the surgical resection group (21.8%). Radiofrequency ablation combined with TACE treatment showed no serious complications. In the surgical resection group, 1 case died and 1 case developed serious complications.
3 Risks faced by local ablation treatment
Portal hypertension and its complications are the main risks faced by local ablation. Portal hypertension is a clinical syndrome, which is defined in hemodynamics as an increase in the pressure difference of the blood flow across the liver (the pressure difference between the portal vein pressure and the inferior vena cava) exceeding the normal value (5 mm Hg) .
Esophageal varices in the fundus of the stomach is a direct consequence of portal hypertension. The incidence of gastrointestinal bleeding in patients with HCC complicated by portal hypertension accounted for about 76.5%, and 41.6% of HCC patients died of bleeding from esophageal varices.
Varicose vein bleeding caused by portal hypertension is one of the main causes of death after local ablation. In addition to the higher risk of bleeding, liver cancer patients with portal hypertension often have liver damage and poor general health conditions. These factors can affect the prognosis and limit local ablation treatment, especially for patients with local recurrence.
After local ablation of liver cancer with portal hypertension, the factors affecting the prognosis of patients are more complicated. Current studies [13, 16, 30-31] believe that splenomegaly, age> 60 years, albumin <3.5 g/dl, AFP> 200 ng/ml, and the number of tumors are more risk factors that affect the prognosis.
Patients with splenomegaly have poor liver function reserve, which affects the long-term survival of patients with small liver cancer after ablation. Wu et al.  found that the 5-year cumulative survival rate of patients with splenomegaly was 54.8% without splenomegaly.
The proportion of patients was 77.8% (P<0.05). Yang et al.  observed and followed up 316 patients after radiofrequency ablation for a period of 10 years and found that Child-Pugh grade, portal hypertension, and the number of tumors were related to overall survival.
For laparoscopic local ablation treatment, intraoperative ultrasound found infiltrating HCC, the lesion is located on the liver surface, and the recurrence of HCC is also considered to be an independent risk factor for postoperative intrahepatic recurrence .
Portal hypertension and esophageal varices are also factors that affect the long-term survival rate and tumor recurrence of patients after local ablation [30, 33-34]. Fang et al.  performed local radiofrequency ablation on 280 early HCC patients (68.6% with portal hypertension), and the 5-year cumulative survival rates were 50.6% (portal hypertension group) and 76.7% (non-portal hypertension group). In addition to the endoscopic evaluation of esophageal varices, Kim et al.  found that after HCC radiofrequency ablation, CT showed that the internal diameter of the esophageal vein ≥ 2 mm or the internal diameter of the fundus vein ≥ 10 mm were independent predictors of tumor recurrence in the liver. Therefore, the esophageal and gastric varices on CT may be used to predict intrahepatic recurrence after radiofrequency ablation.
According to the literature [11-13], HCC patients with portal hypertension generally have milder complications after local ablation alone. Complications above grade III are less than 3%, and mild complications (I/II) are less than 30%. The main manifestations are pain, fever, abdominal/pleural effusion, cholangitis, bile leakage, liver injury, intra-abdominal infection, etc. Rare complications include postoperative blood transfusion, pneumonia, skin burns, esophageal vein rupture and bleeding, portal vein thrombosis, surgery Posterior respiratory distress, subcapsular hematoma formation, hepatic encephalopathy, spontaneous peritonitis, arrhythmia, etc. .
After laparoscopic local ablation, the incidence of abdominal effusion may increase. However, after local ablation combined with other treatments, the incidence of serious complications increased. Pei et al.  found that the most common complication after radiofrequency ablation combined with splenectomy is the need for blood transfusion due to hypoproteinemia and poor coagulation status. A small number of patients require secondary surgery due to intra-abdominal bleeding or esophageal veins during hospitalization. Rupture bleeding. The larger the tumor, the worse the liver function, and the more severe chronic hepatitis, the higher the incidence of postoperative complications. Of course, local ablation therapy may also have complications such as damage to nearby organs caused by ablation, bleeding caused by puncture, especially liver cancer located at risk sites (next to large blood vessels, on the edge of the liver, or close to cavities).
4.1 Evaluation of portal hypertension
Portal hypertension is directly related to the complications after local ablation and the patient’s survival. Therefore, the objective evaluation of portal hypertension during the perioperative period of local ablation is of great significance for guiding the treatment of patients.
For patients with liver cirrhosis, the hepatic venous pressure gradient (HVPG) is usually used to reflect the portal vein pressure, and direct puncture of the portal vein is avoided, which is also the current gold standard for diagnosis and evaluation. HVPG greater than 10 mm Hg is considered to be clinically significant portal hypertension because all clinical symptoms are above this threshold level. However, HVPG measurement is an invasive operation, which is expensive and requires high operator skills and equipment.
In clinical practice, many non-invasive examination results can be used to comprehensively evaluate portal hypertension . (1) The performance of endoscopic esophageal and gastric varices has 100% specificity for the diagnosis of portal hypertension.
However, about 50% of patients with compensated liver cirrhosis have not developed esophageal and gastric varices, but have shown portal hypertension in hemodynamics, which has become a high risk factor for liver decompensation and HCC. (2) Ultrasound is a first-line imaging diagnostic method for patients with suspected liver cirrhosis and portal hypertension, with high specificity.
Splenomegaly (spleen length> 12 cm) is the most frequently reported ultrasound sign that suggests portal hypertension, with high sensitivity but low specificity.
On the contrary, the portal vein collateral circulation has 100% specificity in the diagnosis of portal hypertension, but the sensitivity is low. When there is no positive findings on ultrasound, portal hypertension cannot be completely ruled out.
Transient elastography evaluation of liver stiffness also has a good correlation with portal hypertension . (3) In the laboratory test results, the decline of platelets (and/or enlargement of the spleen) is a non-invasive index that is considered to be related to portal hypertension, but there is currently no standard for direct diagnosis and exclusion of portal hypertension using platelet values.
The results of multiple examinations often complement each other and provide a reference for the diagnosis of portal hypertension. Some studies  believe that the overall consideration of liver stiffness, platelets and spleen size can increase the diagnostic accuracy to 86%.
Doppler ultrasound can be used to evaluate and monitor portal hypertension after local ablation. CT can also be used to observe splenomegaly and esophageal varices. El Sherbiny et al.  found that Doppler ultrasound showed an increase in splenic artery resistance index after radiofrequency ablation, but microwave ablation did not cause changes in Doppler blood flow parameters. After TACE, there will be a significant increase in hepatic vascular parameters.
Kim et al.  found that the average sensitivity, specificity, positive predictive value, and negative predictive value of using CT cross-sectional images of the liver to diagnose high-risk esophageal varices after ablation were 90.1%, 86.39%, 70.9%, and 95.9%, respectively.
4.2 perioperative countermeasures
A reasonable treatment plan for HCC combined with portal hypertension should be to treat liver cancer while taking into account the prevention of bleeding from esophageal varices, correcting hypersplenism and preventing postoperative liver failure.
Before local ablation therapy, the imaging images should be evaluated, the ablation scope and the ablation needle puncture path should be planned, and the possible damage of adjacent organs and large blood vessels should be fully considered, and necessary protective measures, such as artificial ascites, should be given; liver function reserve and hemostasis should be evaluated Coagulation function predicts possible complications such as liver failure and bleeding.
According to blood routine and coagulation function test results, preoperative blood preparation, platelet transfusion, vitamin K, etc. are used to improve coagulation function. Pay attention to the Child-Pugh grading assessment of liver function, evaluate the status of abdominal effusion through imaging, and detect liver function through serum biochemistry.
For patients with poor liver function before surgery, treatments such as albumin supplementation, jaundice and liver protection can be given first.
For patients with ablative HCC combined with moderate to severe portal hypertension, before local ablation treatment, if serious complications such as rupture and bleeding of esophageal and gastric varices occur, endoscopic vascular ligation, sclerosing agent injection, or TIPS surgery should be performed first Hemostasis and/or prevention of rebleeding, followed by local ablation treatment.
For patients with liver function in the decompensated stage, in addition to assessing the tumor condition before surgery, the liver reserve function and the degree of portal hypertension should be fully considered. The treatment plan should take into account both HCC and portal hypertension to choose a reasonable ablation method. , To achieve individualized treatment.
TIPS before local ablation can reduce portal pressure. Qiu et al.  performed TIPS combined with radiofrequency ablation on 113 patients with small liver cancer combined with portal hypertension. The portal pressure decreased from (29.0±4.1) mm Hg before TIPS to (18.1±2.9) mm Hg after TIPS, with portal hypertension. The symptoms are relieved.
Then radiofrequency ablation was performed (89 cases were treated with TACE/TAE before radiofrequency ablation). 44.9% of patients who underwent radiofrequency ablation combined with TACE/TAE after TIPS had a survival time of more than 5 years, which was higher than that of patients who underwent TACE/TAE alone (29.2%). Park et al.  retrospectively studied the radiofrequency ablation treatment of 19 patients with HCC who were previously implanted with TIPS stents.
Among them, the liver function of 18 patients was classified as Child-Pugh B or C. All lesions were completely ablated, and 100% TIPS stent was evaluated immediately after ablation, and 95% TIPS stent remained patency one month after surgery. Research suggests that radiofrequency ablation will not affect the patency of TIPS stent, and stent implantation is not radiofrequency. Absolute contraindications for ablation.
Hepatic artery-portal fistula is a rare complication, with an incidence of about 0.3%. However, a larger hepatic artery-portal fistula may further increase the pressure of the portal vein, leading to esophageal vein bleeding. Sonomura et al.  reported a 70-year-old patient with multiple HCC. After radiofrequency ablation, esophageal varices rapidly progressed to F3 due to portal hypertension and hepatic artery-portal fistula.
They used α-cyanoacrylic acid positive Butyric acid (tissue medical adhesive) was used to embolize the hepatic artery-portal fistula, and then the esophageal varices returned to F1 grade, and the risk of varicose bleeding was reduced through endoscopic sclerotherapy.
Portal vein tumor thrombus is a common complication of advanced liver cancer, and it is also one of the complications after local ablation. Portal vein tumor thrombus can not only cause recurrence and metastasis in the liver, but also aggravate portal hypertension and even lead to liver failure. Wu et al.  can safely and effectively ablate the embolus in the portal vein and open the portal vein through percutaneous intraportal radiofrequency ablation to reduce portal vein pressure, but prospective research is still needed.
After local ablation, attention should be paid to the dynamic monitoring of liver function in patients with portal hypertension, the management of fluid intake and output, the rational use of liver protection drugs, and gastric mucosal protection drugs and hemostatic drugs can be used according to the situation. In addition, patients with portal hypertension have low immunity, coupled with the effects of surgery and bleeding on the body’s immune function, and there is a risk of spontaneous peritonitis.
Regular follow-up observation is required after local ablation. Portal hypertension may be a predictor of postoperative HCC recurrence. Therefore, patients with portal hypertension should emphasize regular and regular review after local ablation, so as to find the recurrence lesions in time and make it under control at an early stage. Regular CT follow-up after operation is of great significance for timely detection of high-risk esophageal varices.
In addition, multidisciplinary teamwork plays an important role in achieving the root therapeutic effect and prolonging survival of early liver cancer . The multi-disciplinary team may include liver disease experts, transplantation experts, interventional experts, tumor medical and surgical experts, etc., through regular discussion of treatment plans, and reach a unified opinion on patient management, which will help improve the efficiency of patient management.
In summary, patients with liver cancer and portal hypertension have complex conditions, and there are still many challenges in their treatment. For patients who have lost the opportunity for surgery, local ablation therapy and its combination with other treatment methods are options.
Especially for patients with small hepatocellular carcinoma (≤ 3 cm), local ablation alone can ensure tumor inactivation, while also having a positive effect on preserving liver function and reducing postoperative complications. For 3~5 cm HCC, TACE combined with local ablation is currently considered as the first-line treatment.
Objectively evaluate portal pressure during the perioperative period, reasonably plan the ablation range and puncture path, prevent esophageal varices bleeding, correct hypersplenism and prevent postoperative liver failure, and do a good job in multidisciplinary team management, which will help improve the efficiency of patient management after ablation .
Local ablation treatment of liver cancer with portal hypertension
(source:internet, reference only)