Congenital and Infantile Hepatic Hemangioma

Etiology

IH and CH are both vascular tumors of infancy but differ in their underlying cause and clinical course. The underlying pathogenesis in both cases is only partially understood. In the case of IH, it is theorized lesions form as a product of dysregulation of vasculogenesis and angiogenesis. Hypoxic stress appears to be a triggering signal, prompting over-expression of VEG-F and other angiogenic factors, leading to an abnormal proliferation of fetal endothelial cells.[4]

In the case of CH, somatic activating mutations are implicated in their pathogenesis. Recent studies have demonstrated mutations in the alleles GNAQ and GNA11 in CH. Interestingly, both RICH and NICH demonstrate similar mutations, suggesting their different clinical behavior may be the result of postnatal factors or epigenetics.[5]

Epidemiology

Infantile hemangiomas are the most common vascular tumor of infancy, affecting 4 to 5% of term infants with a female and white predominance.[4] Similarly, IHH is the most common hepatic tumor of infancy. Risk factors include low birth weight, prematurity, and positive family history.  In contrast, CH is rare. The precise incidence is not known but likely occurs in less than 1% of all infants. In one case series CH represented only 14% of all vascular tumors of infancy.[6] There are no reported risk factors for CH in the literature.

Pathophysiology

Infantile hepatic hemangioma has been noted to have three distinct patterns of involvement: focal, multifocal, or diffuse.[2]

Focal IHH is a single hepatic lesion that is typically asymptomatic and rarely associated with cutaneous IH. Of note, they also stain negative for GLUT-1, unlike other forms of IH, prompting some authors to pose that focal IH likely represents hepatic RICH.[1][7]

Multifocal IHH is comprised of several distinct lesions in the liver, variably defined in the literature as at least five lesions or up to ten lesions. They also are often asymptomatic, although they are more likely to cause high output heart failure due to arteriovenous or portovenous shunting.

Diffuse IHH, also known as diffuse neonatal hemangiomatosis, is marked by significant liver involvement with near complete displacement of the liver parenchyma.[2] These children are much more likely to come to medical attention for complications. First, the massive hepatomegaly can lead to compression of nearby local structures, including the thoracic cavity, inferior cava, and abdominal contents. This can lead to abdominal compartment syndrome, respiratory failure, and ultimately multisystem organ failure. Diffuse IHH may also overproduce type III iodothyronine deiodinase which deactivates thyroxine, leading to profound hypothyroidism. This can lead to significant developmental delay and cardiac failure due to poor contractility. High output cardiac failure due to the highly vascular nature of the lesion has been reported.

CH may demonstrate three distinct patterns. Tumors may rapidly involute in infancy and are therefore known as rapidly involuting congenital hemangioma (RICH), do not involute and are therefore known as non-involuting congenital hemangioma (NICH), or partially involute and are known as partially involuting congenital hemangioma (PICH).[3]

CH may be asymptomatic or identified on routine screening. When symptomatic, they may cause transient thrombocytopenia and coagulopathy, which is distinct from the Kasabach-Merritt phenomenon, an aggressive and life-threatening process exclusively associated with kaposiform hemangioendothelioma and tufted angioma[8]. Other rare complications include disseminated intravascular coagulation, hepatic failure due to the displacement of liver parenchyma, and high output cardiac failure due to arteriovenous and portovenous shunting.

Histopathology

IH uniformly stains positive for the glucose transporter GLUT-1, which is considered pathognomonic for IH. In contrast, CH stains negative for GLUT-1.[1][3][4]

History and Physical

Both IHH and hepatic CH may be clinically silent and may only be detected on ultrasonography performed for other indications, such as routine prenatal ultrasound. When of significant size, they may be detected as hepatomegaly on physical exam.

Most lesions are asymptomatic at presentation. If symptomatic, presenting features may include high output heart failure, hypothyroidism, or compression of local structures, as discussed in the pathophysiology section. In the case of CH, a mild transient coagulopathy may produce a petechial rash. 

In the case of multifocal and diffuse IHH, an association has been noted between cutaneous and hepatic IH. Multiple cutaneous IHs may indicate an underlying IHH. It is recommended if 5 or more cutaneous IH are noted the infant undergoes a liver ultrasound.[2]

Evaluation

The diagnosis of cutaneous IH and CH may be made on clinical grounds. However, hepatic lesions may not be fully assessed with physical exam alone. Definitive diagnosis of IH and CH may be made with biopsy and subsequent histopathological examination; however, this is often difficult as lesions are highly vascular and represent a bleeding risk. Therefore, clinical course, classic radiographic findings, and exclusion of malignant processes with laboratory studies can be used to make the diagnosis. 

Diagnosis of IH and CH may be based on their clinical course. Both lesions should be monitored with serial ultrasounds. A lesion that grows rapidly from birth until about eight months of age then begins to regress is consistent with IH, whereas a lesion that is fully formed at birth and slowly regresses is consistent with CH. 

Distinctive characteristics on imaging may be helpful in establishing the diagnosis of either CH or IH. In the case of CH, the lesion may appear strikingly heterogeneous on US, CT, or MRI, with a peripheral rim of contrast enhancement and minimal central enhancement.[9][10][11][12] IH may have similar features. A possible distinguishing feature between the two may be calcifications, which are often present in CH but never present in IH.[13]

In both cases, documentation of a falling serum AFP and negative urine catecholamines may be helpful in excluding hepatoblastoma or neuroblastoma.

Treatment / Management

Treatment of both IH and CH is supportive and aims to address potential complications, as both lesions generally resolve without intervention. Treatment is indicated in cases where complications are present.[4]

Historically for IH, corticosteroids were the treatment of choice. In the case of cutaneous IH causing either disfigurement or interfering with vision, oral propranolol has become the treatment of choice. The exact mechanism is not understood but is theorized to regulate the VEGF pathway implicated in the lesion’s development.[4] Propranolol has also been shown to be effective for IHH.

Surgical resection and embolization of IHH are reserved for cases of severe complications, including high output heart failure, abdominal compartment syndrome, and respiratory failure. Complications of surgical resection include bleeding, while embolization may lead to hepatic necrosis, cirrhosis, and sepsis. Infants with diffuse IHH with hypothyroidism will require thyroid replacement. 

In congenital hemangioma, no medical therapy has been noted to induce regression of the lesion. Corticosteroids have been trialed in the past without success. Surgical resection or embolization may rarely be indicated in the setting of active bleeding or severe heart failure.

In both cases, serial ultrasounds should be performed to document regression. IH grows rapidly in early infancy, typically reaches peak size by nine months, and is expected to regress by 80% by age 4, whereas RICH is expected to regress completely by 12 to 14 months.[14][15][16] Minimal regression or partial regression may be seen in NICH or PICH.(B2)

Differential Diagnosis

Differential diagnosis of a hepatic hemangioma includes metastatic or atypical neuroblastoma, hepatoblastoma, mesenchymal hamartoma, kaposiform hemangioendothelioma, embryonal sarcoma, or angiosarcoma. Given the malignant potential of many of these lesions, careful evaluation and serial monitoring of the lesion is critical.[2]