Hepatic Hemangioma


Article Author:
Deirdre Lewis


Article Editor:
Ruben Vaidya


Editors In Chief:
David Wood
Andrew Wilt
Mary Cataletto


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
3/25/2019 12:05:02 AM

Introduction

Hemangiomas are benign vascular tumors of infancy that may involve either the skin or viscera, including the liver. Understanding of these lesions has advanced rapidly in the last several years, resolving previous wide variability in nomenclature and description. This article will focus on two distinct types of hemangioma: infantile hemangioma (IH) including infantile hepatic hemangioma (IHH) and congenital hemangioma (CH). They are notable for their varying clinical course. IH grows rapidly after birth then involutes slowly; whereas, CH is fully formed at birth and then involutes in early infancy.[1] IHH may be further characterized by its pattern of involvement whether focal, multifocal, or diffuse.[2] CH may be further characterized by its pattern of involution, whether rapidly involuting (RICH), partially involuting, (PICH), or non-involuting (NICH). [3] Awareness of these diagnoses is important as both IH and CH are expected to resolve on their own; however, serious complications may occur requiring further intervention.

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 post-natal factors or epigenetics.[5]

Epidemiology

IHs 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

IHH 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 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 multi-system 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 undergo 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 which grows rapidly from birth until about eight months of age then begins to regress is consistent with IH, whereas a lesion which 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 heterogenous 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 is aimed at addressing potential complications, as both lesions generally resolve without intervention. Treatment is indicated in cases where complications are present.[4]

Historically for IH, steroids 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’ 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 the case of 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.

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]

Pearls and Other Issues

Considerable confusion exists in the literature regarding the nomenclature of these lesions which has been clarified in recent years. Infantile hemangioma historically may be referred to as “infantile hemangioendothelioma,” a term which is not preferred due to its implication for malignant potential and the potential confusion with “kaposiform hemangioendothelioma” or “epithelioid hemangioendothelioma” a malignant vascular tumor of infancy. Both IH and CH should be distinguished from the hepatic hemangiomas of adulthood which is a separate disease process.

Enhancing Healthcare Team Outcomes

Hepatic hemangiomas are benign vascular tumors of infancy involving the liver, with two distinct types including infantile hepatic hemangioma (IHH) and congenital hemangioma (CH). Diagnosis of types are generally based on their clinical course, but it is important to note that both the lesions are expected to resolve over time. Both lesions require close monitoring with serial ultrasounds and generally do not require specific intervention, and only needing supportive treatment focussing on the complications. These lesions should be closely followed by the a multidisciplinary team consisting of a pediatrician or nurse practitioner, with a pediatric hematologist/oncologist, with serial imaging and close monitoring for complications.


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Hepatic Hemangioma - Questions

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A well-appearing, 4-month-old infant presents to her primary care provider. The medical history is pertinent for premature birth at 35 weeks. Physical exam reveals multiple cutaneous hemangiomas involving the extremities, trunk, and one on the forehead but none adjacent to the eyes. Exam is otherwise within normal limits. Six hemangiomas are counted in total. What additional evaluation should the infant undergo?



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A 3-day old infant presents with a fine petechial rash across the face. Physical exam reveals a hepatic mass. Laboratory study shows a platelet count of 55,000 K/mL. Abdominal MRI reveals a large heterogeneous mass within the liver with a peripheral rim of contrast enhancement and minimal central enhancement. The infant is otherwise well-appearing without evidence of high output heart failure or bleeding. What is the most likely diagnosis?



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A 14-day-old infant presents to the emergency room with difficulty breathing. The infant is found to be in distributive shock. Massive hepatomegaly is felt on exam. MRI reveals near-total displacement of the liver parenchyma with innumerable hemangiomas. In addition to clinical stabilization, what additional laboratory study should be checked?



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A 4-week old infant recently diagnosed with hepatic rapidly involuting congenital hemangioma arrives for follow up evaluation and ultrasound. The infant is thriving with a benign physical exam. Ultrasound reveals the lesion has shrunk slightly. The parents question whether their child should undergo any medical or surgical intervention for this lesion. What is the best treatment for this infant?



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A 2-month-old infant presents after hepatomegaly was found incidentally on physical exam. MRI shows a focal hepatic lesion with peripheral rim enhancement and central calcifications. What additional study could be deferred in making the diagnosis?



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Hepatic Hemangioma - References

References

Rapidly involuting congenital hemangioma: clinical and histopathologic features., Berenguer B,Mulliken JB,Enjolras O,Boon LM,Wassef M,Josset P,Burrows PE,Perez-Atayde AR,Kozakewich HP,, Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society, 2003 Nov-Dec     [PubMed]
Rapidly involuting congenital haemangioma (RICH) of the liver., Roebuck D,Sebire N,Lehmann E,Barnacle A,, Pediatric radiology, 2012 Mar     [PubMed]
Gnarra M,Behr G,Kitajewski A,Wu JK,Anupindi SA,Shawber CJ,Zavras N,Schizas D,Salakos C,Economopoulos KP, History of the infantile hepatic hemangioma: From imaging to generating a differential diagnosis. World journal of clinical pediatrics. 2016 Aug 8;     [PubMed]
Léauté-Labrèze C,Harper JI,Hoeger PH, Infantile haemangioma. Lancet (London, England). 2017 Jul 1;     [PubMed]
Ayturk UM,Couto JA,Hann S,Mulliken JB,Williams KL,Huang AY,Fishman SJ,Boyd TK,Kozakewich HPW,Bischoff J,Greene AK,Warman ML, Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma. American journal of human genetics. 2016 Jun 2;     [PubMed]
Yang B,Li L,Zhang LX,Sun YJ,Ma L, Clinical Characteristics and Treatment Options of Infantile Vascular Anomalies. Medicine. 2015 Oct;     [PubMed]
Christison-Lagay ER,Burrows PE,Alomari A,Dubois J,Kozakewich HP,Lane TS,Paltiel HJ,Klement G,Mulliken JB,Fishman SJ, Hepatic hemangiomas: subtype classification and development of a clinical practice algorithm and registry. Journal of pediatric surgery. 2007 Jan;     [PubMed]
Mortelé KJ,Vanzieleghem B,Mortelé B,Benoit Y,Ros PR, Solitary hepatic infantile hemangioendothelioma: dynamic gadolinium-enhanced MR imaging findings. European radiology. 2002 Apr;     [PubMed]
Zenge JP,Fenton L,Lovell MA,Grover TR, Case report: infantile hemangioendothelioma. Current opinion in pediatrics. 2002 Feb;     [PubMed]
Keslar PJ,Buck JL,Selby DM, From the archives of the AFIP. Infantile hemangioendothelioma of the liver revisited. Radiographics : a review publication of the Radiological Society of North America, Inc. 1993 May;     [PubMed]
Peddu P,Huang D,Kane PA,Karani JB,Knisely AS, Vanishing liver tumours. Clinical radiology. 2008 Mar;     [PubMed]
Gorincour G,Kokta V,Rypens F,Garel L,Powell J,Dubois J, Imaging characteristics of two subtypes of congenital hemangiomas: rapidly involuting congenital hemangiomas and non-involuting congenital hemangiomas. Pediatric radiology. 2005 Dec;     [PubMed]
Boon LM,Enjolras O,Mulliken JB, Congenital hemangioma: evidence of accelerated involution. The Journal of pediatrics. 1996 Mar;     [PubMed]
Krol A,MacArthur CJ, Congenital hemangiomas: rapidly involuting and noninvoluting congenital hemangiomas. Archives of facial plastic surgery. 2005 Sep-Oct;     [PubMed]
Browning JC,Metry DW, Rapidly involuting congenital hemangioma: case report and review of the literature. Dermatology online journal. 2008 Apr 15;     [PubMed]
Lewis D,Hachey K,Fitzgerald S,Vaidya R, Rapidly involuting congenital haemangioma of the liver. BMJ case reports. 2018 Jun 5;     [PubMed]

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