Congenital hepatic hemangioma: a review

INTRODUCTION

Congenital hepatic hemangiomas (CHH) are benign vascular tumors of the liver detected primarily in the neonatal period. Unlike other congenital hemangiomas, CHH can present a variety of symptoms, ranging from asymptomatic to severe complications such as congestive heart failure, coagulopathies, and hemorrhages. Specific management is essential to prevent these complications.¹

Precise classification of CHH and differentiation from other hepatic vascular malformations is fundamental for guiding clinical management. For instance, hepatic arteriovenous malformations may require completely different therapeutic approaches compared to CHH.^1,2

The International Society for the study of vascular anomalies (ISSVA) has developed a detailed classification of vascular anomalies, updated in 2024 to reflect recent advances in understanding these conditions. The ISSVA classification divides vascular anomalies into two main categories: vascular tumors and vascular malformations.²

CHH is classified as a congenital hemangioma within the vascular tumors category. Unlike infantile hemangioma, which appears postnatally and follows a characteristic course of rapid proliferation followed by involution, CHH is present at birth and can exhibit different clinical patterns, such as rapid involution (RICH) or non-involution (NICH).^1,3

The incidence of CHH is low, estimated at approximately 1 in 20,000 live births, with a higher prevalence in females. Genetic and environmental factors, including mutations in angiogenesis-regulating genes and conditions during fetal development, play significant roles in its pathogenesis.⁴

Diagnosis of CHH relies on imaging techniques such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), and in some cases may require liver biopsy. Treatment may include medications like propranolol, surgical interventions, and endovascular techniques such as arterial embolization.^1,3,4 Continued research is vital to improve treatment options and reduce associated complications.

CLASSIFICATION

The classification of CHH can be better understood by considering several aspects such as hemangioma involution, ISSVA classification, and criteria based on tumor size and extent.^1,3

Classification by involution

Rapid involution congenital hemangioma (RICH) are hemangiomas that show a rapid decrease in size during the first months of life.⁵

Non-involuting congenital hemangioma (NICH) are hemangiomas that do not show a significant decrease in size over time.^4,5

ISSVA classification

The recent ISSVA classification, published in 2024, categorizes hemangiomas within "vascular tumors", distinguishing between: infantile hemangiomas which appear postnatally and have a growth cycle followed by involution, and congenital hemangiomas which are present at birth, with variants that either rapidly involute or do not involute.^2,3,5

Classification by size and extent

According to Mulliken et al, CHH can be classified by size and extent - small: generally, less than 2 cm, asymptomatic, and often do not require intervention, moderate: between 2 cm and 5 cm, may require monitoring due to the risk of complications, large: over 5 cm, with a higher risk of causing symptoms or complications such as congestive heart failure and coagulopathies, and diffuse or multifocal: hemangiomas that encompass a large part of the liver or present multiple nodes, involving more complex clinical management.¹

EPIDEMIOLOGY

CHH is one of the most common forms of liver tumors in neonates, although it remains a rare condition.^1,6 The incidence and prevalence of this condition are low, but studying it is crucial to improve diagnosis and clinical management.

Relevant studies on the incidence, prevalence, risk factors, and demographic distribution of CHH will be described to provide a comprehensive understanding of its epidemiology.

Incidence

The incidence of CHH is estimated at approximately 1 in 20,000 live births, although this figure may vary slightly depending on the region and access to advanced diagnostic techniques.⁵

Prevalence

Studies suggest a higher prevalence in females compared to males, with a ratio of approximately 2:1.^6,7

Risk factors

Genetic and environmental factors

While the exact etiology of CHH is not fully understood, both genetic and environmental factors are believed to play significant roles in its development. Studies suggest a possible association with certain genetic syndromes and vascular malformations.^5,7

Demographic distribution

Sex and age

CHH is primarily detected in the neonatal period, with a higher prevalence in females. Prenatal imaging studies have improved early detection, allowing more effective management of the condition.^8,9

Race and ethnicity

Reviewed literature does not show significant differences in the prevalence of CHH among different racial or ethnic groups, although most studies have been conducted in Western populations.⁹

PATHOGENESIS

Understanding its pathogenesis is crucial for developing effective diagnostic and treatment strategies. This review aims to explore the pathogenic mechanisms involved in the formation of CHH, including genetic factors, abnormalities in vascular development, and the contribution of environmental factors.

Genetic factors

Genetics and associated syndromes

Some studies have identified a possible genetic predisposition to the development of CHH. For example, mutations in genes regulating angiogenesis, such as vascular endothelial growth factor (VEGF) and tyrosine kinase with immunoglobulin-like and EGF-like domains (TIE2), may play a significant role in its pathogenesis.^10,11 Additionally, CHH may be associated with genetic syndromes such as Klippel-Trenaunay syndrome.¹²

Family and twin studies

The occurrence of CHH in monozygotic twins suggests a genetic basis for the disease. Family studies have also demonstrated a higher incidence of CHH in families with a history of vascular malformations.¹³

Vascular development abnormalities

Fetal vascular development

CHH is believed to result from abnormalities in fetal vascular development. During embryonic development, deregulated angiogenesis can lead to hemangioma formation.

The abnormal expression of angiogenic growth factors such as VEGF and FGF plays a crucial role in this process.^12,14

Hypoxia and angiogenesis

The hypoxia hypothesis suggests that tissue hypoxia during fetal development may trigger compensatory angiogenesis, resulting in hemangioma formation. Studies have shown elevated levels of HIF-1α in hemangiomas, indicating a response to hypoxia.^15,16

Molecular and cellular factors

Endothelial proliferation

Hepatic hemangiomas are characterized by excessive endothelial cell proliferation. This proliferation is mediated by abnormal angiogenic signals, including the overexpression of VEGF and other endothelial growth factors.^10,11,14

Tumor microenvironment

The tumor microenvironment, including inflammatory cells and the extracellular matrix, also plays an important role in CHH pathogenesis. The interaction between endothelial cells and the microenvironment can promote tumor cell proliferation and survival.^12,14,15,17

Environmental factors

Maternal influence

Environmental factors such as maternal infections and exposure to toxins during pregnancy can influence CHH pathogenesis. Exposure to teratogenic factors may alter fetal vascular development, contributing to hemangioma formation.^12,15

Hormones

Hormones, particularly estrogens, can influence the growth of CHH. The high incidence of CHH in females suggests a possible role of sex hormones in its development.^15,18 The pathogenesis of congenital hepatic hemangioma is multifactorial, involving a complex interaction of genetic factors, vascular development abnormalities, and environmental contributions. Understanding these mechanisms is essential for developing more effective treatment protocols and diagnostic strategies. Future research should focus on unraveling the specific molecular pathways and genetic factors contributing to this disease.

CLINICAL PRESENTATION

The identification and management of CHH can be challenging due to variability in its clinical presentation. Understanding the clinical manifestations and potential complications is crucial for effective treatment.

Clinical manifestations

Asymptomatic

Many cases of CHH are asymptomatic and discovered incidentally during imaging studies conducted for other reasons.^1,3,19

Palpable abdominal mass

A common presentation of CHH is a palpable abdominal mass. In some cases, this may be the only clinical manifestation.^7,20

Congestive heart failure

CHH can cause congestive heart failure due to a significant arteriovenous shunt within the tumor, leading to increased venous return to the heart.²¹

Hepatomegaly

Hepatomegaly is a frequent manifestation in patients with CHH, especially when tumors are large or multiple.^20,22

Jaundice

In cases where CHH causes biliary obstruction or cholestasis, patients may present with jaundice.^19,20

Complications

Kasabach-Merritt syndrome

This syndrome, characterized by thrombocytopenia and consumptive coagulopathy, can be associated with CHH, especially in large or multifocal tumors.^23,24

Intra-abdominal hemorrhage

Although rare, intra-abdominal hemorrhage is a potentially life-threatening complication of CHH.²⁵

DIAGNOSIS AND DIAGNOSTIC METHODS

Diagnosis of CHH can be challenging due to variability in its clinical presentation and imaging characteristics. Accurate diagnosis and characterization are essential for appropriate management. This review focuses on available diagnostic methods, including imaging techniques and invasive procedures, and provides a detailed overview of their applications and limitations.

Diagnostic imaging methods

Ultrasound (US)

Ultrasound is generally the first diagnostic method used to detect CHH due to its availability and safety. This method can reveal a hyperechoic hepatic mass, although sensitivity and specificity may vary.²⁴

Computed tomography (CT)

CT is useful for further evaluation of hepatic masses detected by ultrasound. It provides details on the tumor's structure and vascularization and is useful for planning surgical interventions.^6,26

Magnetic resonance imaging (MRI)

MRI is the preferred technique for the detailed characterization of CHH. It offers excellent soft tissue resolution and is particularly useful for evaluating the tumor's relationship with vascular and biliary structures.^22,27

B

Invasive diagnostic methods

Liver biopsy

Liver biopsy is reserved for cases where the diagnosis is unclear with imaging techniques. It can provide a definitive histopathological diagnosis, although it is associated with risks of complications.²⁵

Advanced techniques and functional evaluation

Angiography

Angiography can be used in complex cases to assess CHH vascularization and plan therapeutic interventions such as embolization.^11,18,21

Positron emission tomography (PET)

Although not routine, PET can be useful in selected cases to assess the tumor's metabolic activity and differentiate between benign and malignant lesions.^16,24,26

Clinical evaluation

Medical history and physical examination are fundamental for the initial evaluation and follow-up of patients with CHH. Symptoms such as hepatomegaly, jaundice, and heart failure can indicate the need for additional studies.^7,19

The diagnosis of congenital hepatic hemangioma requires a combination of imaging techniques and, in some cases, invasive procedures to obtain a definitive diagnosis. The choice of diagnostic method depends on the patient's clinical presentation and the availability of techniques.

MEDICAL, SURGICAL, AND ENDOVASCULAR TREATMENT

The treatment of CHH varies according to the patient's clinical presentation, symptom severity, and presence of complications. Its management requires a comprehensive understanding of the available treatment options, including medical therapies, surgical interventions, and endovascular procedures.

Medical treatment

Propranolol

Propranolol, a non-selective beta-blocker, has become a first-line treatment for infantile hemangiomas due to its efficacy in reducing tumor size and relieving symptoms. Propranolol induces vasoconstriction, decreases cell proliferation, and promotes apoptosis of hemangioma cells. Studies have shown a high success rate in reducing CHH size and improving symptoms.^3,10,11,18

Corticosteroids

Corticosteroids, such as prednisolone, act by reducing inflammation and decreasing endothelial cell proliferation.

They have been historically used to treat CHH, although their use has decreased with the introduction of propranolol. Clinical evidence shows a lower success rate and higher incidence of side effects compared to propranolol.²⁸

Interferon alpha

Interferon alpha has been used in cases resistant to other treatments, although its use is limited due to side effects from neurotoxicity and other significant adverse effects. Interferon alpha inhibits angiogenesis and endothelial cell proliferation.²⁹

Surgical treatment

Surgical resection

Surgery may be necessary in symptomatic CHH cases that do not respond to medical treatment or in the presence of severe complications such as bleeding or heart failure. Indications for surgical treatment include large tumors (greater than 5 cm), hemorrhagic complications, and cases resistant to medical treatments. Complete resection of the hemangioma can cure the disease but carries significant surgical risks.^1,11,17,30

Endovascular treatment

Arterial embolization

Arterial embolization is an endovascular technique used to reduce blood flow to the hemangioma, promoting tumor regression. In CHH with severe symptoms or complications, particularly in cases where surgery is not viable, it has shown high efficacy in reducing hemangioma size and improving symptoms, although with possible complications such as hepatic necrosis.^3,30,31

New therapies and experimental treatments

Sirolimus therapy

Sirolimus, an mTOR pathway inhibitor that reduces cell proliferation and angiogenesis, has shown promise in treating CHH, especially in complicated or treatment-resistant cases. Preliminary studies indicate efficacy in reducing hemangioma size and improving symptoms, although further research is needed.^3,31-33

Surveillance and observation

The treatment of CHH may include surveillance and observation in certain cases. This approach avoids invasive procedures and the associated risks, such as hemorrhages or infections and it is particularly relevant for asymptomatic hemangiomas or those of small to moderate size that do not present immediate complications. The decision to opt for surveillance and observation is based on the clinical evaluation of the patient, the severity of symptoms, and the potential risk of complications.^1,5,7,24

CONCLUSION

Congenital hepatic hemangioma, although rare, requires a deep understanding for adequate management. Most cases do not need intervention, but in complicated cases, managing congenital hepatic hemangioma requires a multidisciplinary approach that includes medical, surgical, and endovascular therapies. The choice of treatment depends on clinical presentation, symptom severity, and response to initial treatments. Continuous research is necessary to better understand pathogenesis, improve and develop more effective treatments, and reduce associated complications.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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