Introduction
As the most common benign tumor of liver, hepatic hemangioma has an incidence rate between 0.4 and 20% in autopsied cases [
1]. Most hepatic hemangiomas are asymptomatic, small, and require no intervention [
2]. However, the large hepatic hemangioma with moderate or severe symptoms or rapidly growing hemangioma may require therapeutic interventions [
2‐
4]. Treatment method for hemangiomas include surgical resection (SR) [
5‐
7], radiofrequency ablation (RFA) [
8‐
10], microwave ablation (MWA) [
11‐
13] and transarterial embolization [
14‐
16]. Traditionally, SR is the most effective treatment. But surgical treatment is often associated with severe trauma, complications, and high risks. MWA and RFA can be performed percutaneously, laparoscopically or by laparotomy, and have been proved to be effective and minimally invasive treatments for patients with large hepatic hemangiomas. However, lengthy MWA or RFA is prone to discomfort and complications such as pain, liver function damage, bleeding, hemolysis, hemoglobinuria, acute kidney injury, tumor rupture and thermal injury to adjacent organs, especially in the treatment of giant hepatic hemangiomas (> 10 cm) [
11,
17]. Transarterial embolization is often used to treat acute bleeding in hemangiomas or to reduce the size of hemangiomas before surgery, and can also be used as a single treatment with acceptable outcomes [
15,
18]. But to date, there is no consensus on the best management for patients with symptomatic and/or large hemangiomas. The International Society for the Study of Vascular Anomalies has classifieds hepatic hemangiomas as low-flow venous malformations [
19]. For subcutaneous low-flow vascular malformations, percutaneous sclerotherapy (PS) has proven to be the standard therapy [
20]. Sclerosants can extend drug retention time after being injected in low-flow vascular malformations. Sclerosants retention causes permanent damage to the vascular endothelium of hemangiomas by disrupting cell membranes, leading to sustained vasospasm, tissue ischemia and necrosis [
20].
Many studies have explored percutaneous sclerotherapy with bleomycin for the treatment of hepatic hemangioma [
21,
22]. However, there is still a lack of research to assess the advantages and disadvantages of ultrasound-guided PS compared with SR for the management of hepatic hemangiomas. For the therapy of hemangioma and vascular malformations, there is no significant difference in efficacy between polidocanol and pingyangmycin sclerotherapy [
23]. The purpose of this study was to compared the effectiveness and safety of ultrasound-guided PS using pingyangmycin or lauromacrogol and SR for hepatic hemangiomas.
Materials and methods
Patient cohort
This was a single-center retrospective study. We retrieved and reviewed the medical records of patients with large hepatic hemangiomas (large than 5 cm in diameter) who had undergone PS or SR at our hospital from January 2014 to October 2020. All hepatic hemangiomas were diagnosed by two consistent radiologic findings including ultrasound (US), computed tomography (CT) before treatment. The diameters of hepatic hemangiomas were measured on US.
The inclusion criteria for patients undergoing SR are as follows: (1) single or multiple hepatic hemangiomas with a major lesion larger than 5 cm in diameter; (2) obvious symptoms (such as abdominal pain, bleeding, or serious mental burden) or enlarging hemangioma (> 0.5 cm within 12 months); (3) normal liver function (Child–Pugh A level) and normal renal function; no significant irreversible coagulopathy; (4) willingness to undergo surgery.
The inclusion criteria for patients undergoing PS are as follows: (1) single or multiple hepatic hemangiomas with a major lesion larger than 5 cm in diameter; (2) obvious symptoms (such as abdominal pain, bleeding, or serious mental burden) or enlarging hemangioma (> 0.5 cm within 12 months); (3) normal liver function (Child–Pugh A level) and normal renal function; no significant irreversible coagulopathy; (4) haven’t received any other treatment before; (5) have refused for surgery treatment and willing to undergo PS.
The exclusion criteria were listed as follows: (1) patients who did not give consent; (2) history of any prior epigastric surgeries; (3) diagnosed with other types of liver tumors; (4) pregnant woman.
In total, 89 patients with large hepatic hemangiomas were analyzed in this study, of which 14 patients received PS and 75 patients received SR.
Preprocedural management
Before the specific treatment, all patients underwent preoperative routine tests, including liver and kidney function tests, routine blood tests, coagulation tests, electrocardiogram, abdominal US and abdominal CT examination. Patients over 60 years of age also underwent cardiac US and pulmonary function tests.
Surgical resection
The surgical resection was carried out in accordance with standard procedures, According to the size and location of the tumor, different types of resection are performed on SR group. Of the 75 patients who underwent surgery, 19 patients underwent hemangioma excision, 1 patient underwent left hemihepatectomy, 8 patients underwent right hemihepatectomy, 8 patients underwent left lateral lobectomy, 2 patients underwent right posterior lobectomy, 2 patients underwent resection of middle lobe of liver, 3 patients underwent irregular hepatectomy, 14 patients underwent laparoscopic hemangioma excision, 14 patients underwent laparoscopic left lateral segmentectomy, 1 patient underwent laparoscopic left hemihepatectomy. 2 patients underwent right hemihepatectomy, 1 patient underwent laparoscopic right posterior lobectomy. In total, 31 patients had 25 cm right subcostal incisions, 12 patients had 25 cm long L-shaped incisions in the right upper abdomen and 32 patients underwent laparoscopic operation through five trocars. Hemangioma excision is generally preferred to liver resection if appropriate. When necessary, the Pringle maneuver was used to control intraoperative blood loss during the operation.
Peripheral blood tests, liver function tests and kidney function tests were performed on the first day after SR. Follow-up ultrasonography or CT examination was performed after the procedure.
Ultrasound-guided percutaneous sclerotherapy
Pingyangmycin or polidocanol was selected as Sclerosants. To prepare the injection solution, 16 mg pingyangmycin was diluted with 10 mL of physiological saline to a total volume of 10 mL, or polidocanol with the dose of 14–20 mL was injected as original solution. Sclerotherapy was performed under local anesthesia using 10 cc lidocaine 2%, with the patient in a supine position. Hepatic hemangiomas were punctured percutaneously using a 21-G needle (PTC Needle; Hakko Medical Co, Tokyo, Japan) under real-time ultrasound guidance. Then, the prepared polidocanol or pingyangmycin was slowly injected intralesionally over 20–30 s during injection.
After PS, all patients were closely monitored for signs of early complications within 30 min, such as intraperitoneal bleeding and potential sclerosants-induced allergic reactions. If vital signs were stable and ultrasound examination was negative for intra-abdominal free fluid or hematoma patients were return to the ward. Peripheral blood tests, liver and kidney function tests were performed on the first day after SR. Follow-up ultrasonography was performed at 2–8 months after the procedure. A second session of sclerotherapy was planned initially in patients with giant lesions, or with less than 50% shrinkage of lesion volume measured by follow-up imaging examination. The diameters of the treated hemangiomas were measured by US at 9–24 months after the end of the final session. In the end, six patients received two sessions of sclerotherapy, eight patients received a single session of sclerotherapy.
Criteria for outcomes evaluation
Treatment outcomes were assessed according to postoperative blood tests results, liver and renal function test results, surgical time, intraoperative blood loss, blood transfusion rate, the incidence of complications, hospital stay, hospital costs, technical success rate, and clinical response. Technical success was defined as correct delivery of sclerosants into the hemangioma confirmed by post-sclerotherapy ultrasound. Clinical efficacy is divided into four categories as complete response, marked response, moderate response and mild response. Complete response was defined as reduced scale in hemangioma maximum cross-sectional areas of > 90%. Marked response was defined as a reduced scale in hemangioma maximum cross-sectional areas of from 50 to 90% during follow-ups. Moderate response was defined as a reduced scale in hemangioma maximum cross-sectional areas of from 20 to 50%. Mild response was defined as a reduced scale in hemangioma maximum cross-sectional areas of < 20%.
Statistical analysis
Statistical analyses were performed using IBM SPSS version 26 for Windows. Parametric continuous data were expressed as means ± standard deviation (SD) and compared using Student’s t-test; Nonparametric continuous data were expressed as mean (range) and compared using Mann–Whitney U test. Categorical parameters were expressed as percentage and compared using the Chi-square test or Fisher’s exact test as appropriate. p value < 0.05 was considered statistically significant.
Discussion
To date, surgical resection is the most common and effective therapy for hepatic hemangioma [
3,
4,
6]. Although SR treatment is accurate and effective, it is often associated with high invasive, substantial trauma and high risk. Since the benign nature of hepatic hemangioma, more minimally invasive approaches should be pursued if treatment is needed.
As a minimally invasive procedure, PS is proven to be the standard therapy for low-flow subcutaneous vascular malformations [
20]. Under the guidance of imaging devices, sclerosant can be injected into the lesion percutaneously, consequently causing endothelial damage, thrombosis formation, tissue ischemia and ultimately tissue necrosis. Ultrasound guidance is widely used in the process of PS. At present, there are a variety of sclerosants used in the treatment of venous malformations, such as anhydrous alcohol [
25], sodium morrhuate [
26], pingyangmycin [
27,
28], bleomycin [
14,
29], and lauromacrogol [
30,
31] or polidocanol [
23]. In China, the most used agent of local injection therapy for venous malformations is the antitumor agent pingyangmycin, which was similar to bleomycin A5 in chemical structure [
32]. Its safety and availability in the treatment of venous malformations as a method of intralesional injection have been confirmed [
33]. However, pingyangmycin is only available in China, bleomycin was used as a substitute for pingyangmycin in studies in other countries [
14,
21,
29]. Similarly, lauromacrogol is produced in China and has a similar chemical structure to that of polidocanol. For the treatment of hemangiomas, a recent study reported that the efficacy between polidocanol and pingyangmycin is no different [
23]. Previously, using a mixture of bleomycin and ethiodized oil as sclerosants, percutaneous sclerotherapy has been reported by many studies and has been suggested as a new and promising treatment method for hepatic hemangioma [
21,
22]. However, in terms of efficacy and safety, more information was needed for PS in the treatment of large hepatic hemangioma. This study systematically compared the clinical outcomes of patients with large hepatic hemangioma treated with the SR and PS procedures using pingyangmycin or lauromacrogol.
In general, PS has many advantages in the treatment of large hepatic hemangioma. First of all, the sclerosants were injected into the designated hemangioma area during the process of PS, which causes less damage to the surrounding healthy liver tissue. As a result, there was no increase in the index of liver function tests in PS group 1 day after surgery, while all of the patients who received SR showed a significantly increased liver enzyme index. Second, compared with SR, PS does not require abdominal incision and abdominal drainage, and can be actualized in a shorter operation time. Furthermore, patients who undergone PS have a lower incidence of minor complications, shorter hospitalization stays and lower hospital cost. Third, PS has achieved acceptable therapeutic effects with less invasive. For PS group, complete response was observed in 4 of 14 patients and marked response observed in 6 of 14. Moreover, with the repeatable and less invasive feature, for patients who do not respond well to the first treatment, the second session of PS can be performed.
Just as a coin has two sides, the PS for the treatment of large hepatic hemangiomas has also some disadvantages. For example, the intraperitoneal hemorrhage may occur during puncture. A recent study reported a self-limited intraperitoneal hemorrhage in one patient after percutaneous sclerotherapy with bleomycin [
22]. In our study, one patient in SR group experienced self-limited intraperitoneal hemorrhage, while fully recovered after intravenous administration of atropine, hemocoagulase, and intravenous infusions. Nevertheless, a study suggested that the risk of hemorrhage from direct percutaneous puncture of hepatic hemangiomas was low even if large needles are used [
34]. Ayoobi et al. performed percutaneous sclerotherapy using 22-gauge needles on 28 participants, none of them had complications of intraperitoneal hemorrhage. Whether the size of puncture needle and the type of sclerosants are related to complications of abdominal bleeding remains to be further studied.
Of course, there are some limitations to our research. First, this is a retrospective study involving the experience of single center, and there might have been selection bias. Second, various surgical resection methods might have affected the incidence of surgical complications. Third, the small sample size and the short period of follow-up may limit the quality of this research. Furthermore, a large sample, prospective randomized controlled studies are required to confirm the findings of this study.
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