HH is the most prevalent benign tumor of the liver, and its incidence is second to that of hepatic cyst. Previous studies have revealed that the incidence of HH in the general population is 5–20%[16–18]. Statistical analyses of data extracted from the physical examination reports of 670,000 healthy individuals in China revealed that the incidence of HH was approximately 1.5%, and the male to female ratio was approximately 1.3:1. The age group with a high incidence of HH was 40–60 years, accounting for 58%[19]. Kamyab et al. conducted abdominal ultrasound examination of 1,985 patients among the Iranian population, and the results revealed that the prevalence of HH was 2.04%, which was higher in females (2.26%) than in males (1.7%) and the age distribution of the disease was predominantly 40–50 years[20]. In addition, a study conducted by Duxbury et al. revealed that the prevalence of HH was higher in females than in males (female: male ratio = 5:1), and the average age was 50 years[2]. Mocchegiani et al. conducted a retrospective analysis of 83,181 abdominal CT or MRI records of patients who visited the radiology department over a 7-year period, and the study results revealed that the prevalence of HH was 2.5%[21]. Guang-chuan et al. conducted a retrospective analysis of 818 patients with HH who were treated at a health facility from 2003 to 2011 and the results revealed that the number of patients with HH increased annually, and distribution of patients with HH among the different age groups varied between male and female patients. The proportion of patients aged 41–60 years was the highest[22]. However, liver hemangioma is a benign disease, thus does not draw attention in some patients, and this could result in missed diagnoses. Incomplete electronic medical records due to the heavy work load of clinical doctors also result in missed diagnoses of patients. Real-world studies provide a broad inclusion criteria and limited exclusion criteria, and non-randomly selected interventions for real conditions and intentions of patients with larger sample sizes. The present study adopted a retrospective analysis design to identify the true clinical and epidemiological characteristics of single center experience HH. Retrospective analyses of outpatient and physical examination data between 2016 and 2017 revealed that the prevalence rate of HH in the outpatient population was 0.089%, with males accounting for 0.040% and females accounting for 0.049%, and the ages of patients ranged between 41 and 60 years. The prevalence of HH was 1.217% in the healthy population, with males having an incidence rate of 0.707% and females 0.510%, and the ages of participants ranged between 21 and 40 years. The high number of healthy individuals among a sick population when compared to the outpatient population could be associated with the continuous improvement in the living standards and health awareness of individuals. Furthermore, the observation could be attributed to the fact that outpatients consider the disease as a guide and only a few patients receive liver imaging examinations, but generally lower than the figures reported in previous studies. With reference to the age of outpatients and inpatients with HH, the patients were all aged 41–60 years, which was consistent with the age group in previous studies. However, the physical examination group was younger, with ages ranging from 21 to 40 years, which could be associated with the characteristics of the included population.
A few studies have revealed that female patients are more likely to develop HH than male patients, and high estrogen levels during pregnancy and long-term use of contraceptives can promote the growth of HH[23–26]. Conversely, a few studies have revealed that HH is not associated with the history of menstruation, reproduction, or contraceptive use[27]. In addition, no statistically significant difference was observed in the occurrence and development of HH between males and females, and HH prevalence in both sexes increased[28, 29]. Wang et al. established that the trend exhibited by tumors in women was associated with age and was consistent with the varying estrogen levels[30]. Tumor diameter in women increased with age and subsequently decreased. Vascular malformation caused by excessive vascular development or abnormal differentiation is the primary cause of liver hemangioma, and estrogen is largely degraded and inactivated in the liver. Presently, the mechanism of action between estrogen and liver hemangioma is still unclear; therefore, further research is required to investigate underlying mechanisms. The present study established that the number of male and female patients among outpatients and inpatients was similar, whereas the number of male patients was higher than that of female patients in the check-up population. The observation was contrary to the findings of recent studies, but a reason explaining the high number of males is unknown. This could be associated with factors identified in previous studies, such as using surgical patients as research objects, exclusion of a healthy population, and a very small sample size.
Based on the distribution of HH locations, the current research results revealed that the right lobe of the liver is mostly in the left lobe of the liver. A study by Wahab et al. that evaluated 144 patients with giant HH revealed that the right lobe of the liver accounted for 64.6% of multiple lesions, the left lobe of the liver accounted for 28.5% of multiple lesions, and the left lobe of the liver accounted for 6.9% of multiple lesions; among which, 88.9% were single lesions and 11.2% were multiple lesions[31]. Yoon et al. evaluated 115 patients with HH and established that the right lobe of the liver was more common than the left lobe of the liver[32]. A previous analysis of 818 cases of HH at the First Affiliated Hospital of Guangxi Medical University revealed that the lesions were predominantly located in the right lobe of the liver (57.2%), followed by the left lobe of the liver (27.2%), with lesions located in multiple lobules accounting for 15.6%[22]. Lesions in the right lobe of the liver among the 234 patients who underwent surgical resection accounted for 47%, lesions in the left lobe of the liver accounted for 34.6%, and lesions in multiple lobes accounted for 18.45% of the cases; single lesions accounted for 69.2% and multiple patients accounted for 30.8% of the cases. The number and location of hemangiomas could be associated with blood supply and anatomy of the liver.
Most patients with HH did not exhibit clinical symptoms. However, patients with tumors larger than 5 cm could present clinical symptoms[15]. Abdominal pain is a common clinical manifestation, especially discomfort in the right upper quadrant; other clinical symptoms are not specific. Abdominal distension can occur in patients with tumors > 10 cm[15, 33], and tumors located at different parts of the liver can cause compression of adjacent organs or tissues, consequently causing other clinical symptoms. If the pressure on the bile duct can cause obstructive jaundice, then the pressure on the portal vein can lead to intrahepatic, pre-hepatic, and other types of portal hypertension. Furthermore, pressure on the stomach can result in decreased appetite and abdominal distension after an early meal saturated with fats. Some patients may present with fever, dyspnea, heart failure, hemophilia, and other rare symptoms[34–37]. A large hemangioma of the liver could lead to Kasabach-Merrit syndrome (thrombocytopenia, disseminated intravascular coagulation, and systemic bleeding), which is manifested in laboratory disorders caused by multiple factors, leading to severe complications and pose a huge threat to a patient's life. In the current study, the incidence of Kasabach-Merrit syndrome in tumors > 15 cm was 0.3–26%[15, 38]. Another severe complication is spontaneous or traumatic rupture of the tumor (mostly seen in peripheral and exogenous giant HH), and the risk of rupture has been demonstrated to be extremely low (0.47%)[21]. The research results of a previous study conducted at the First Affiliated Hospital of Guangxi Medical University revealed that most patients (510 cases = 62.3%) with HH were identified by accidental examination during hospitalization, while 174 (21.3%) cases of HH were detected by physical examination, and only 134 cases (16.4%) exhibited clinical symptoms, predominantly abdominal discomfort and pain[22]. The proportion of patients with an abdominal mass was 1.7%, patients with upper abdominal discomfort accounted for 39.7% of the cases, which was second to 53.4%, and lumbar pain accounted for 2.6% of the cases, which were consistent with the results of previous studies.
In relation to the clinical classification of HH, relevant previous studies have revealed that the diameter and number of tumors form a critical basis for clinical classification, especially the diameter of tumors. Previously, an integrated classification standard in foreign reports did not exist, and a diameter of 4 cm was largely recommended as the cut-off point for tumor classification, while most domestic scholars recommended a diameter of 5 cm as the cut-off point for classification[31, 39]. Based on tumor diameter, HH was classified into three grades by the Chinese hepato-biliary and pancreatic expert group: (1) small hemangioma (diameter < 5.0 cm), (2) large hemangioma (diameter of 5.0–9.9 cm) and (3) giant hemangioma (diameter ≥ 10.0 cm), and most patients with tumor diameters < 5.0 cm did not exhibit clinical symptoms. Therefore, the consensus is to classify tumors based on their clinical manifestations and characteristics, diameters, numbers, and pathology[19]. The patients who underwent surgical and physical examination in this study were classified in accordance with the domestic consensus of clinical classification. The surgical patients mainly had large and giant hemangiomas, while the physical examination group mainly had small hemangiomas. Precise diagnosis and classification are the crucial preconditions that could guide appropriate treatment of patients with HH, and tumor diameter can be used as one of the indicators of classification and treatment.
Currently, the most controversial treatment indicator is prophylactic treatment of HH. In a previous study that involved 236 patients with a median follow-up time of 48 (3–26 months) months, 61% of the patients exhibited increased tumor size and peak growth rate, and patients with tumors ranging between 8 and 10 cm exhibited an increase in tumor size at a rate of 0.80 ± 0.62 cm per year[14]. In another study involving 123 patients over the age of 30 years, the mean linear size of hemangiomas increased by 5% or more in 39.3% of the patients. The average annual linear growth rate for all lesions was 0.03 cm, and that of 5% or more was 0.19 cm[40]. A previous study on 534 cases of patients with a median follow-up time of 18 months (14 to 22 months) revealed that tumor diameters increased in 215 cases (40.3%), decreased in 217 cases (40.6%), and did not change in 102 cases (19.1%). Strikingly, the researchers established that tumor diameter increased with increase in age between different genders in patients with hemangiomas aged 40 years; hemangioma in male patients over 40 years of age increased gradually, whereas hemangioma in female patients exhibited a relatively decreasing trend[30]. In this study, only 24 patients (10.3%) received surgical resection due to rapid tumor growth and 11 patients with complete follow-up data were assessed to calculate tumor growth rate. The median follow-up time was 56 (11–132 months) months and the median growth rate was 0.055 (0.019–0.08 cm) cm per month. Tumor mass in patients older than 30 years exhibited a trend of continuous and gradual enlargement. Most hemangiomas in individuals from a healthy population were small (< 5 cm), as well as the primary tumor. Therefore, tumor enlargement during follow-up should be closely monitored rather than administering aggressive treatment, and prophylactic surgical resections should be discouraged.
With the current advances in medical technology, the safety of elective resection of benign liver tumors is relatively similar to that of a major intra-abdominal surgery. Moreover, the rapid development of laparoscopic surgery confers the advantages of minimally invasive surgery in treatment. However, liver hemangioma surgery still has certain surgical risks and complications[32, 41]. Wahab et al. evaluated 144 patients with giant HH and established that 32 (22.2%) patients had postoperative complications, 20 (8.3%) had G I complications of the Clavien-Dindo classification, 7 (4.9%) had G II complications, 12 (8.3%) had G III complications, and 1 (0.7%) had G V complications[31]. In a previous study by Miura et al., 241 patients with hepatic hemangioma who underwent surgery were evaluated and the findings revealed that a total of 14 patients (5.7%) experienced postoperative complications of grade III and above based on the Clavien-Dindo classification, 2 (0.8%) patients died and 3 (1.2%) patients experienced life-threatening complications within 30 days after surgery[38]. In the present study, the incidence of grade A and Grade B complications of ISGLS[42] liver function was 11.966% and 0.427%, respectively while the incidence of grade A and Grade B bleeding complications of ISGLS postoperative hemorrhage[43] was 3.846% and 2.137%, respectively. No patients had postoperative biliary fistula and no perioperative death was recorded. A total of 16 patients (6.8%) experienced grade III complications[44] and 4 (1.7%) patients experienced grade IV complications of the Clavien-Dindo classification system.
In this study, univariate analyses of complications after Clavien-Dindo classification of hepatectomy were performed, and the results of the analyses revealed that clinical symptoms, maximum tumor diameter, blood loss, blood transfusion volume, length of hospital stay, tumor distribution, hepatic portal blockade, and treatment were correlated with postoperative complications. Furthermore, sequential logistic regression analyses revealed that treatment was a significant factor influencing postoperative complications. By contrast, Dong et al. evaluated 190 patients with HH and the results revealed that the size of HH was not an independent factor influencing postoperative complications[45]. Previous studies have revealed that perioperative blood transfusion is a crucial factor influencing postoperative complications and death after hepatectomy[46–48]. Perioperative blood transfusion affects the prognosis of patients, postoperative recovery of liver function, and increases the incidence of postoperative complications. Increased hemorrhage and coagulation abnormalities caused by delayed postoperative recovery of liver function could still occur despite of the existence of intraoperative hepatic portal occlusion. A few patients require perioperative blood transfusion therapy, and allogeneic blood transfusion can lead to immunosuppression, inflammatory reactions, postoperative infections, and other complications[49], which in turn affect postoperative recovery of patients.
HH is a tumor that originates from the mesoderm and comprises of a single layer of flattened endothelial cells and cavities filled with blood, which is mainly supplied by the hepatic artery. HHs can be classified into capillary hemangiomas and cavernous hemangiomas[50]. Pathologists have classified HHs into sclerosing hemangiomas, vascular endothelial cell tumors, capillary hemangiomas, cavernous hemangiomas, and other subtypes based on the fiber content of the tumor tissues, and cavernous hemangiomas are the most common type[19]. The pathological types of HHs in 234 patients evaluated in the present study included 224 cases (95.7%) of cavernous hemangioma, 3 cases (1.3%) of capillary hemangioma, 2 cases (0.9%) of sclerosing hemangioma, and 5 cases (2.1%) of other types of hemangiomas.
Nevertheless, the present study adopted a retrospective study design, which had a few limitations. The data used for analyses only covered a two-year period in relation to the epidemiological survey; therefore, variation in the overall incidence of HH should be validated using large sample sizes to carry out big data epidemiological survey. In addition, the lack of uniform standards in imaging reports resulted in the loss of crucial information of some patients with HH. The time span was long and a certain deviation in postoperative complication statistics could be observed with the improvement of surgical techniques. A high rate of loss to follow-up occurred because HH is a benign disease.