Introduction
Cirrhosis, portal hypertension (PH), and hepatocellular carcinoma (HCC) are inseparable and mutually influence each other.
1 Patients with HCC and PH usually have impaired liver function, excessive portal blood flow and pressure, high risk of bleeding tendency, and poor performance status, which both affect the prognosis and limit the opportunity for most curative treatment modalities for HCC, precluding subsequent treatment options in recurrent patients, including liver resection, local ablation, and transarterial chemoembolization (TACE).
2,3 Theoretically, liver transplantation seems to be the optimal method to simultaneously cure the tumor and replace the cirrhotic liver for patients with early stage HCC and severe cirrhosis.
4 However, due to the shortage of liver donors, only a small proportion of patients can successfully undergo liver transplantation. Alternative treatment deserves to be explored for this specific group of patients.
According to the European Association for the Study of Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) treatment guidelines for HCC, PH and decompensated liver function are considered contraindications for liver resection due to a very high risk of post-hepatectomy liver failure (PHLF) and mortality.
2,3 However, remarkable advances in preoperative evaluation, surgical techniques, and perioperative care have reinforced the role of liver resection for patients with HCC and PH.
5‐7 Even in some selective candidates with significant PH, liver resection can receive a long-term survival and relatively low perioperative mortality. Local ablation has been reported as an alternative to liver resection for patients with small HCC (tumor diameter less than 3 cm) or those who cannot endure a resection and have achieved long-term survival.
8‐10 After curative treatment for HCC, two other lethal factors in patients with HCC and PH are variceal bleeding resulting from the development of PH and the decompensation of liver function.
11 Splenectomy is an effectively preventable measurement to reduce the portal flow and decrease the tendency of variceal bleeding, and it can also improve the liver function in some decompensated patients.
12‐14
Several studies have also reported that synchronous splenectomy and liver resection or splenectomy combined with local ablation in patients with HCC and splenomegaly achieve both short-term and long-term survival.
15‐21 However, patients enrolled in these studies were heterogeneous, either with good liver function reserve or with large tumor burden. In this study, we enrolled more cirrhotic patients with limited tumor burden and PH who were treated by synchronous splenectomy and curative treatment, and both the short- and long-term outcomes, including perioperative mortality and morbidity, the liver function test 1 year after surgery, and long-term follow-up, were evaluated to identify who could benefit from this surgical procedure.
Discussion
In the present study, we evaluated the short-term and long-term outcomes in a cohort of 239 consecutive patients with HCC and PH who underwent simultaneous splenectomy and curative treatment. The low perioperative mortality, low morbidity, remarkable improvement in liver function 1 year after splenectomy and a high long-term survival suggested that curative treatments for HCC and splenectomy for PH offer an alternative option for these patients.
Whether patients with Child B grade liver function should perform surgical treatment are still controversial. Almost half of the patients in our study are Child B grade liver function, and both of them underwent aggressive surgical treatments. The long-term outcome is different, but the perioperative outcome is acceptable, showing that surgical treatments are feasible. To clarify which patients could benefit from this surgical procedure, as well as decrease the bias and confounding, we took into account the factors that may affect long-term prognosis as much as possible. Multivariable analysis revealed that tumor size, tumor number, and Child score were independent risk factors for long-term survival. In spite of the fact that all patients had limited tumor burden, the prognosis of patients with larger or multiple tumors was relatively poor. This finding indicates that patients with great tumor burden benefit very little from this surgical procedure. Even though the Child score has several limitations in evaluating the preoperative liver function reserve,
22 it remains the most frequently used tool to assess liver function reserve. We evaluated the OS in patients with different Child scores and found that a high Child score was a strong independent risk factor for poor prognosis. Although patients enrolled in this study had limited tumor burden, some patients had a poor prognosis, showing that the preoperative liver function was an important prognostic factor. Using the Child score system, we divided all patients into 5 subgroups and found that patients with Child score 8 or 9 had an inferior long-term survival, indicating that patients with limited tumor burden and relatively good liver function reserve could benefit from splenectomy combined with curative treatments, and liver transplantation should be the optimal selection for patients with limited tumor burden but poor liver function reserve.
High incidence of liver-related surgical complications, such as postoperative liver failure, delayed surgical site bleeding, and overloaded hydrothorax, is observed in cirrhotic patients.
25 Postoperative liver failure is a troublesome and potentially life-threatening complication that occurs 1.2–32% of the time, especially in the cirrhotic background.
26 In the current study, even though the overall morbidity as high as 75.3%, the PHLF rate was 3.3%, which was lower than most previous reports. The total mortality in our study was 2.1%: 5 patients died after surgery within 30 days. Our relatively low incidence of postoperative liver failure and perioperative mortality were mainly due to strictly preoperative patient selection, solid intraoperative hemostasis technique, and flexible postoperative management. In addition, most patients received minor hepatectomy to decrease the risk of postoperative liver function decompensated. Given that liver tumor resection could remove much functional liver parenchyma, patients with severe cirrhosis or small tumor (the largest tumor diameter less than 3 cm) but located deep in the liver parenchyma should not undergo liver resection as the first therapeutic option; rather microwave ablation is the optimal selection.
10 The laparoscopic technique can also minimize the interruption of the portosystemic collateral vessels because only several trocar incisions in the anterior abdominal wall are enough to operate. The rate of liver failure and the overload of ascites after this procedure in patients with severe cirrhosis are lower.
27 However, only a small proportion of patients in our study received laparoscopic surgery, and the benefit of the laparoscopic technique in patients with cirrhosis and PH should be further evaluated in a large cohort. Poor liver function and coagulation dysfunction also made it difficult to control the intraoperative blood loss, resulting in more blood loss and blood transfusion. In our study, the proportion of patients with an estimated intraoperative blood loss and an intraoperative transfusion volume were also more significant than previous studies.
16‐19 The portion of postoperative transfusion is also very high: as high as 58.6% of all patients received a transfusion. This result was attributed to a high percentage of patients with Child grade B liver function. Patients who needed a postoperative transfusion in this study usually had hypoalbuminemia and prolonged prothrombin time, resulting in overloaded ascites and delayed surgical site bleeding. Transfusion is a necessary and useful measure to correct hypoalbuminemia, reduce the overload of ascites, and improve the coagulative function.
Most HCCs develop in the setting of liver cirrhosis and are accompanied by PH, splenomegaly and liver decompensation, resulting in an impaired liver function and terrible performance status, which are also potentially lethal factors. Curative treatments can remove the liver tumor, but the cirrhotic liver background is not so natural to reverse. The tendency of liver decompensation and risk of variceal bleeding will increase with the evolution of cirrhosis and PH. After liver resection, other measures to extend survival time should be taken to improve decompensated liver function and to decrease the variceal bleeding tendency. In one study, varices were presented in approximately 50% of patients with cirrhosis and up to 85% of patients with decompensated cirrhosis.
28 The variceal bleeding rate for cirrhotic patients with gastroesophageal varices is approximately 10–15% per year, and the six-week mortality for this group of patients ranges between 15 and 25%.
29 Splenectomy combined with or without pericardial devascularization has been a standard surgical method to prevent the variceal bleeding tendency for almost 40 years in patients with PH and splenomegaly and has proved useful in avoiding repeated bleeding and extending the estimated survival time. In our study, 104 patients received pericardial devascularization. Half of these patients had a history of variceal bleeding, and others had tortuous varices in endoscopy screening. Variceal bleeding during the perioperative period was present in 5 patients before they were discharged, and all 5 had a bleeding history, 3 of them accompanied by the presence of PVT. Both of them recovered after thrombolytic therapy.
PVT is a potentially lethal complication, and the incidence of PVT varies from 10 to 36% after splenectomy.
30‐32 In the present study, PVT was observed in 65 patients (27.2%). In our center, LMWH was injected subcutaneously on the third day after splenectomy to prevent PVT before it was detected. However, thrombolytic therapy and surgical site bleeding are two contradictory phenomena and are difficult to balance. Once the PVT was detected, thrombolytic treatment with a hefty dose of LMWH or oral warfarin was initiated immediately if no active bleeding was observed. Patients with PVT after splenectomy had an increasingly high tendency of variceal bleeding and liver failure due to the increased portal vein pressure and the decreased hepatic inflow. Given that anticoagulant was given after splenectomy, no PHLF secondary to PVT was observed, and only five patients had transient variceal bleeding from the presence of PVT, and all five patients recovered smoothly with conservative therapy.
A series of previous reports have demonstrated that patients could benefit from splenectomy, especially for those with a Child grade B liver function.
12,13 Once the hypertrophic spleen was removed, portal vein inflow reduced 20–30%, thereby significantly decreasing the portal pressure and the decompensated liver function, and the coagulation dysfunction can be markedly improved, resulting in good performance status and long-term survival.
33,34 In our study, the routine blood test, coagulation, and liver function were successfully tested in 209 of 239 patients 1 year after splenectomy. We found that serum albumin level and prothrombin activity significantly increased, and although not significant, serum total bilirubin decreased, which resulted in a marked improvement of liver function in most Child grade B patients. Only a small proportion of patients still had a poor liver function. The Child classification improved in 98 of 101 patients (97%) who had been classified as Child grade B preoperatively. In the subgroup of patients with a preoperative Child A classification, even though the Child score and classification in most patients did not change 1 year after splenectomy, serum albumin increased significantly. Interestingly, liver function in 9 patients (8.3%) with preoperative Child A classification deteriorated into Child B classification 1 year after splenectomy. Decompensated liver function and hypersplenism preclude most aggressive therapies, such as liver resection, local ablation and TACE for HCC due to pancytopenia, hypoproteinemia and terrible performance status. Our study suggests that splenectomy combined with hepatectomy or local ablation not only removed the tumor but also promoted the amelioration of liver function, which was a significant factor for the aggressive therapy of recurrent liver tumor.
This study had several limitations. First, all of these cases were from only one center, and the sample was small, especially the proportion of patients with a Child score of 8 or 9. No comparison group without splenectomy also limited the interpretation of the results. Even though univariate and multivariate analysis had identified that splenectomy was a protective factor, selection bias and confounding factors may still exist. Second, the improvement of liver function 1 year after splenectomy may have been due to other reasons, such as antivirus therapy, nutrition therapy, and application of liver protective drugs. Our data do not allow any interpretation regarding the inner mechanism of liver function change. Therefore, cellular and molecular research is necessary to strengthen the role of splenectomy in liver function improvement. In addition, the postoperative liver function was evaluated only 1 year after splenectomy, and the long-term liver function change was not investigated. Since most of the survival information was obtained from telephone follow-up, the long-term change in liver function after splenectomy and curative treatment was difficult to record. To reduce these biases and get more long-term information, a large, randomized, controlled, rigorous study is needed to emphasize the role of synchronous splenectomy and curative treatment for short-term and long-term outcomes in patients with HCC and PH.
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