Reconsideration of the clinical management of hepatic hemangioma

Abstract

In this letter, we comment on the article by Zhou et al that was published in the recent issue of the World Journal of Gastrointestinal Surgery. This article proposes a new clinical grading system based on a multidisciplinary team, which prompts us to rethink the clinical management of hepatic hemangioma. Hepatic hemangioma is the most common benign solid liver tumor. In general, follow-up and observation for the vast majority of hepatic hemangioma is reasonable. For those patients with symptoms and severe complications, surgical intervention is necessary. Specific surgical indications, however, are still not clear. An effective grading system is helpful in further guiding the clinical management of hepatic hemangioma. In this article, we review the recent literature, summarize the surgical indications and treatment of hepatic hemangioma, and evaluate the potential of this new clinical grading system.

Key Words: Hepatic hemangioma; Surgical indication; Clinical management; Grading system; Multidisciplinary team

Core Tip: Hepatic hemangioma is the most common benign liver tumor, and the surgical indications and treatment methods have been controversial. With the widespread use of minimally invasive treatments such as minimally invasive hepatectomy, transarterial chemoembolization, and ablation, the treatment for hepatic hemangioma is increasing, potentially leading to overtreatment. A reasonable preoperative grading system helps screen operations to benefit patients and to reduce overtreatment.

TO THE EDITOR

Hepatic hemangioma (HH) is the most common benign solid liver tumor. It is usually a well-circumscribed hypervascular lesion with no potential for malignant transformation[1]. The incidence of HH is 1%-20%, with a detection rate of 7% in autopsy studies, and is more common in women (Female:Male ratio = 5:1). The mean age at diagnosis is about 50 years old[2]. The pathogenesis of HH remains unclear. Initially, HH was thought to be estrogen-related. Still, subsequent studies have shown that it does not express estrogen or progesterone receptors, and its growth pattern does not differ between males and females[3].

HH is mostly diagnosed incidentally by ultrasound. Other ambiguous cases can be diagnosed with contrast-enhanced ultrasound, contrast-enhanced computed tomography (CT), or magnetic resonance imaging[4,5]. HHs tend to be low-density on CT scans and exhibit features of centriolar contrast uptake[6]. Hyperintensity on T2-weighted sequences and discontinuous nodular peripheral enhancement are typical magnetic resonance imaging features of HH[7]. Diagnostic biopsy is rarely needed to distinguish HH from malignancies. A study of 151 patients showed that during the 10 years of the study, no patient had a preoperative imaging diagnosis of HH that was ultimately inconsistent with the pathology[8].

The clinical management of HH has been controversial due to the benign nature of the tumor and the risk of hepatectomy. Overall, follow-up and observation seem to be the future[9]. However, with the continuous development of minimally invasive hepatectomy, and other minimally invasive methods such as transarterial chemoembolization (TACE) and ablation, there is a possibility of overtreatment of HH. New clinical management strategies are needed to adapt to these changes.

The beneficial effect of multidisciplinary team (MDT) in liver malignant tumors has been widely recognized, however, whether MDT should be performed in benign liver tumors is still controversial. We comment on an article about the MDT grading system to guide the treatment of HH[10], the purpose is to review the management of HH and assess the value of the grading system.

Natural history of HH

The natural history of HH highlights its benign tumor character. Most HHs increase slowly, with one study reporting a growth rate of about 0.2 cm per year and a 17% increase in volume per year[11]. In patients younger than 30 years of age, the growth rate of hemangiomas was about 4.6 mm ± 4.1 mm per year, while in patients older than 50, the growth rate of hemangiomas slowed to 2.1 mm ± 4 mm per year. In addition, when the size of the hemangioma reached 8 cm to 10 cm, the growth rate was about 8 mm ± 6.2 mm per year, and when the size of the hemangioma exceeded 10 cm, the growth rate decreased to 4.7 mm ± 9.1 mm[3]. Due to the benign characteristics and predictable natural history of HH, most patients are suitable for observation and follow-up.

Surgical indication of HH

According to previous studies, one of the main surgical indications for HHs is a diameter greater than 5 cm, mainly based on the fact that hemangiomas larger than 5 cm are more likely to cause abdominal symptoms[12,13]. The common abdominal symptoms associated with HHs are mainly caused by compression, including abdominal pain and decreased appetite, as well as obstructive jaundice. However, these symptoms are not representative. Gastroduodenal diseases and gallstones, for example, can cause similar symptoms. HH resection sometimes fails to relieve upper abdominal discomfort in patients[2,14]. It seems reasonable to perform gastroduodenoscopy and other examinations before deciding on surgical intervention for HH. Some of the surgical indications that have been noted in other studies include patient anxiety, risk of rupture, Kasabach-Merritt syndrome, and Budd-Chiari syndrome[3,15-18]. Excessive growth is sometimes a concern, but spontaneous rupture is rare regardless of the size and anatomical location of HHs[19]. It is reported that the incidence of spontaneous rupture of liver hemangioma is only 0.28%[20]. Kasabach-Merritt is another rare condition, mainly due to large hemangiomas resulting in thrombocytopenia and wasting coagulation dysfunction, and surgery is necessary[21]. Surgery is considered only when there are significant symptoms and serious complications. Preventive surgery is not recommended. Surgical indications for HH are shown in Table 1.

Table 1 Surgical indications for hepatic hemangioma.

Ref.	Years	Type	Surgical indications
Miura et al[15]	2014	Multicenter retrospective study	Abdominal discomfort; Strong intention of surgery caused by anxiety; Tumor enlargement; Life-threatening complications (traumatic rupture)
Marrero et al[16]	2014	Clinical guideline	Diameter > 10 cm; Symptoms of compression; Recurrent abdominal pain
Strauss et al[17]	2015	Clinical recommendation	Large hemangioma with compression symptoms; Rare complications (tumor rupture); Kasabach-Merritt syndrome
European Association for the Study of the Liver (EASL)[18]	2016	Clinical guideline	Tumor enlargement; Symptoms of compression; Kasabach-Merrit syndrome
Yuan et al[25]	2022	Observational study	Only severe complications (Kasabach-Merritt syndrome, spontaneous rupture, obstructive jaundice, gastric outlet obstruction, Budd-Chiari syndrome)

Treatment of HH

Liver resection: Liver resection is widely used as a radical operation for liver tumors[22]. The advantages of laparoscopic hepatectomy seem to be greater in benign liver tumors, mainly due to a smaller abdominal incision and more complete relief of abdominal symptoms after surgery. Laparoscopic hepatectomy is superior to open surgery in postoperative quality of life[23]. Most HHs have obvious envelopes, and their biological characteristics are benign, so anatomic hepatectomy and HH stripping are effective. Among them, anatomical hepatectomy has been shown to reduce postoperative complications such as bleeding and bile leakage. Tumor dissection allows for greater hepatic parenchyma preservation, and since there is usually no Glisson system passing through the HH, this procedure does not increase the risk of bile leakage and bleeding. As a result, the specific surgical method needs to be determined according to the anatomic location of HHs.

Transcatheter chemoembolization

Other adjuvant treatments, such as TACE and radiofrequency ablation (RFA), have good therapeutic effects on liver malignancies, especially hepatocellular carcinoma, leading to their increasing importance in liver surgery.

Initially, transarterial embolization (TAE) was used to treat ruptured bleeding in HHs, to stop the bleeding. In recent years, TACE has been used to treat benign tumors of the liver, including HHs[6,24]. Bleomycin, a cytotoxic drug, may inhibit the growth of hemangioma by inhibiting neovascularization. A retrospective study of 241 patients with giant HHs showed that TAE with lipiodol–bleomycin emulsions resulted in an improvement of abdominal symptoms in 102 (100%) patients. The results of follow-up at 6, 12, 36, and 60 months after surgery showed that the maximum diameter of more than 50% of tumors was reduced by 88.1% (190/210), 86.7% (170/196), 85.2% (124/142), and 86.5% (45/52), respectively[25]. Two other studies reported similar results[26,27]. Another study also indicated that atypical patterns of reinforcement (minor points of reinforcement in the hepatic arterial and portal phases) and tumor-associated central arterio-portal shunt were independent predictors of TAE ineffectiveness[28]. However, the use of TACE in the treatment of HH is still controversial, mainly focusing on the use of chemotherapy drugs in patients with benign tumors and the complications of the technique itself such as pain, nausea, fever, liver abscess, sepsis, and hepatic artery dissection[27]. TACE seems to be effective in the treatment of HH, but it is difficult to ignore that most of these studies are single-center and retrospective studies, and the unavoidable bias leads to a decrease in its reliability. More prospective studies are needed to prove the universality of TACE. The efficacy of TACE in the treatment of HH is shown in Table 2.

Table 2 Efficacy of transcatheter arterial embolization or transarterial chemoembolization for hepatic hemangioma.

Ref.	Years	Type	Treatment	Efficacy
Özgür and Sindel[24]	2021	Retrospective study	TAE vs TACE	TACE is superior to TAE in reducing hepatic hemangioma volume and pain
Yuan et al[25]	2022	Retrospective study	TACE	At follow-up ≥ 5 years, 86.5% of hepatic hemangiomas had a maximum postoperative diameter reduction of more than 50%
Kacała et al[26]	2023	Retrospective study	TACE	77.5% of the patients with hepatic hemangioma embolism rate more than 75%
Kacała et al[27]	2024	Retrospective study	TACE	The volume of hepatic hemangioma was reduced by more than 50% in 80.6% of patients
Zhao D et al[28]	2024	Multicenter retrospective study	TACE	The volume of tumor was reduced by more than 50% in 80.7% of hepatic hemangiomas

TAE: Transarterial embolization; TACE: Transarterial chemoembolization.

Ablation

RFA has also been used to treat HHs. A multi-center retrospective study involving 44 patients with 50 HHs showed that RFA was safe and effective for HHs (less than 10 cm in diameter), but the incidence of complications was high, and the patients should be carefully selected[29]. Another similar technique, microwave ablation (MWA), was reported to be associated with higher rates of radiographic complete response (89.0% vs 37.7%) and clinical complete response (88.6% vs 69.2%), fewer minor complications (43.9% vs 66.0%), and shorter duration of analgesic medication and hospital stay compared with TAE[30]. Another multicenter retrospective study involving 291 patients evaluated the efficacy of RFA for HHs with a diameter of 5 cm to 10 cm and larger than 10 cm, and the results showed that more than 92.31% of patients had complete ablation; the incidence of complications related to the ablation technique was 5.14% (13/253) and 13.16% (5/38), respectively. However, the rates of hemolysis-related complications were 83.40% (211/253) and 100% (38/38), and the rates of systemic inflammatory response syndrome-related complications were 33.99% (86/253) and 86.84% (33/38), respectively[31]. A study comparing MWA with RFA for HH (5 cm to 9.9 cm in diameter) showed no differences between the two groups in terms of complete ablation, clinical response, and health-related quality of life, but MWA was associated with shorter ablation duration, fewer hemolysis related complications, and shorter hospital stay[32]. With the further exploration of RFA as an experimental technique in HH, some recent studies have shown a decrease in complication rate and an increase in symptom improvement rate[33]. For example, studies have reported that RFA with the three-step approach of ablating the feeding artery, aspirating blood from the tumor, and ablating the lesion has a higher complete ablation rate, fewer puncture times, shorter ablation time and hospital stay, and less postoperative pain than conventional RFA[34]. A recent multicenter study also affirmed the efficacy of MWA[35]. The recent meta-analysis also confirmed the efficacy of RFA in the treatment of HHs[36]. There is marked heterogeneity in the results of studies on RFA for HH, and the complication rates reported in some studies are difficult to accept, which may illustrate the need for more accurate indications. With the exploration of RFA in the treatment of HH, the complication rate seems to have decreased, but overall, further prospective studies are needed to evaluate RFA and MWA as routine treatments for HH. The efficacy of RFA in the treatment of HH is shown in Table 3.

Table 3 Efficacy of ablation for hepatic hemangioma.

Ref.	Years	Type	Treatment	Efficacy
Wen et al[29]	2018	Multicenter retrospective study	RFA	Complete ablation was achieved in 86% of hepatic hemangiomas
Shi et al[30]	2020	Multicenter retrospective study	TAE vs MWA	Microwave ablation was associated with higher rates of radiological complete response (89.0% vs 37.7%) and clinical complete response (88.6% vs 69.2%), fewer minor complications (43.9% vs 66.0%), shorter duration of analgesic drug use and hospital stay
Wu et al[31]	2021	Multicenter retrospective study	RFA	Complete ablation was achieved in 99% of hepatic hemangiomas
Kong et al[32]	2022	Multicenter retrospective study	MWA vs RFA	Microwave ablation was associated with shorter ablation duration, fewer hemolysis-related complications, and shorter hospital stays
Xu et al[33]	2023	Multicenter retrospective study	RFA	Complete ablation was achieved in 95.5% of hepatic hemangiomas. Preoperative symptoms disappeared completely in 96.4% of the patients. During follow-up, 11.4% of patients with hemangioma close to completely disappear over time
Cai et al[35]	2024	Multicenter retrospective study	MWA vs percutaneous sclerotherapy	Microwave ablation has a lower local tumor progression rate, higher volume reduction rate, and symptom remission rate

RFA: Radiofrequency ablation; TAE: Transarterial embolization; MWA: Microwave ablation.

A HH classification system based on a multidisciplinary team

The article we commented proposed a classification standard of HHs based on MDT of conscience tumors, which mainly included clinical symptoms (no, mild, obvious), diameter (< 5 cm, 5 cm to 10 cm, ≥ 10 cm), anatomical location (lateral liver segment, middle liver, caudate lobe) and tumor growth rate (0 cm/year, < 1 cm/year, ≥ 1 cm/year). Based on this criterion, patients were divided into scores < 4 and ≥ 4. For patients with a score ≥ 4, surgical treatment is recommended. For patients who cannot be operated, observation, TA), or RFA can be selected. Observation was recommended for patients with a score < 4. The clinical data of 1171 patients were retrospectively collected and analyzed according to the above system. The results of the study showed that for patients with a score ≥ 4, surgery resulted in a significant reduction in symptoms, whereas those who underwent observation had a greater incidence of adverse hemangioma events.

Our previous findings suggest that a multidisciplinary discussion of benign liver diseases with complex conditions is beneficial and necessary[37]. MDT requires the participation of multiple disciplines, and it is not practical to have a multidisciplinary discussion for every patient with HH who may need treatment, so we believe that it is beneficial to set this classification criteria prospectively. Moreover, it is an appropriate evaluation system that incorporates the main surgical indications from previous studies and includes stratification in the classification criteria to ensure that patients are not overtreated.

CONCLUSION

The surgical indications of HH should mainly depend on clinical symptoms and complications. Liver resection is preferred for patients who require surgery, and TACE and ablation are alternative but not routine treatments. The preoperative classification criteria of HH based on the MDT of benign tumors help screen patients who will benefit from surgery and avoid overtreatment as much as possible.