Hepatic Hemangioma

Hepatic hemangiomas are benign endothelial cell neoplasms and the most common neonatal liver tumor. While benign, they are associated with a broad array of clinical outcomes from asymptomatic incidental lesions to large liver masses associated with potentially life-threatening perinatal complications ^1,2.

D18.03 Hemangioma of intra-abdominal structures.

Hemangiomas are the most common benign pediatric tumor and estimated to occur in 4-5% of all infants ^2,3. Hemangiomas are usually found on the skin or subcutaneously after birth. While the liver is the most common visceral location, the precise incidence of hepatic hemangioma is unknown. Prenatal diagnosis is rare and limited to case reports and small case series. In one retrospective review, hepatic hemangioma was seen in less than one in 10,000 prenatal ultrasounds ⁴.

Hepatic hemangiomas are differentiated into two types, congenital and infantile hepatic hemangiomas (IHH), based on the timing of peak growth and involution. Congenital hemangiomas (CH) proliferate in utero and are thought to be fully formed at birth; they may be further subdivided into rapidly involuting (RICH), partially involuting (PICH), non-involuting congenital hemangiomas (NICH) based on patterns of postnatal regression ^2,5. RICH is thought to be the most common type of hemangioma seen prenatally. IHH proliferate after birth and during the first year of life prior to undergoing gradual involution over a period of months to years. If seen prenatally, IHH may represent precursor lesions yet to undergo full proliferation ³. It follows that the definitive diagnosis of CH vs. IHH cannot be made until a period of observation after birth to establish the final growth pattern. Hepatic hemangiomas are also classified by appearance as unifocal, multifocal or diffuse lesions ². CH are generally unifocal, while IHH tend to be multifocal or diffuse ².

Historically, imprecise terminology for perinatal liver lesions has led to confusion about the imaging characteristics, diagnosis, and optimal management for hepatic hemangioma ^5,6. Visceral, liver or hepatic hemangiomas have sometimes been referred to as epithelioid hemangioendothelioma, a term which is no longer favored due to the confusion with kaposiform hemangioendothelioma, a rare pediatric vascular tumor ². Likewise, the term CH or IHH should not be used for all hypervascular liver tumors or vascular malformations such as arteriovenous malformations.

Hemangiomas are thought to arise from dysregulation of vasculogenesis and angiogenesis ³. Factors and signals leading to this dysregulation and proliferation are under investigation, and hypoxia has been proposed as one possible inciting mechanism. This theory is supported by the observation that infantile hemangiomas are associated with other clinical factors linked to hypoxia including prematurity, low birth weight, preeclampsia, placental abnormalities, and multiple gestations ^7–9.

Histologic examination of RICH shows tightly packed vascular architecture with primarily capillary-sized vessels without evidence of atypia in the endothelial cell lining ⁶. Although biopsy is rarely required to establish the diagnosis, the two primary types of hepatic hemangiomas may be differentiated based on immunohistologic studies. IHH uniformly stain positive for glucose transporter 1 (GLUT-1) while CH do not ⁵.

Hepatic hemangioma is generally an isolated prenatal finding. However, multiple cutaneous hemangiomas in infants have been associated with concomitant visceral lesions, most commonly in the liver. Case reports have also described prenatal hepatic hemangioma occurring with placenta chorioangioma and other vascular placental lesions, likely owing to a common pathogenic pathway ¹⁰.

Precise information on recurrence risk is unknown but expected to be very low due to the rarity of these lesions and lack of documented cases of recurrence in future pregnancies.

When diagnosed prenatally, hepatic hemangiomas are usually first identified in the third trimester. In a case series of 17 hepatic hemangiomas detected prenatally, the mean gestational age at diagnosis was 29 weeks (range 20 to 39 weeks) with only three of the 17 cases diagnosed in the second trimester ¹.

 Hepatic hemangiomas have a variety of sonographic presentations but most commonly present as an isolated, large, well-circumscribed, solid mass within the liver ^1,4,6. They are usually heterogeneous in appearance, often hypoechoic and may have internal anechoic cystic spaces. Hyperechoic calcifications have also been described ⁴, and the mass may be associated with dilated hepatic and feeding vessels ¹. On Color flow imaging, they tend to demonstrate peripheral flow, a feature which may differentiate hemangioma from hepatoblastoma which shows more internal vascularity ⁶. Less common presentations of prenatal hepatic hemangioma may include multiple spherical liver lesions (multifocal IHH) and innumerable small lesions with near total replacement of the liver (diffuse IHH) ⁵.

The differential diagnosis for a complex lesion of the fetal liver should include hepatoblastoma or metastasis from another malignant tumor (most commonly neuroblastoma), as well as mesenchymal hamartoma and primary vascular lesions such as arteriovenous malformations. Neuroblastomas can be seen as a cystic, solid or complex mass, occasionally with calcifications in the region of the adrenal gland. Color flow imaging is valuable for differentiating a hemangioma from other etiologies such as an arteriovenous malformation and hepatoblastoma. Hepatoblastoma are generally hyperechoic solid lesions with internal vascularity. While hemangioma and hepatoblastoma are both solid lesions, mesenchymal hamartomas are characteristically large cystic or mixed tumors with multiple cysts and internal septations. Finally, careful evaluation of the full fetal anatomy, especially the adrenal glands to ensure that normal adrenal morphology is present, will help to exclude a metastatic source.

Identification of a hepatic hemangioma should prompt careful sonographic evaluation for addition lesions in the remainder of the anatomy and placental chorioangiomas, as well as measurement of the heart size to evaluate the fetus for cardiomegaly. The fetus should be evaluated for hydrops. Some hepatic hemangiomas may present with signs of high-output cardiac failure or hydrops from vascular shunting. In addition to cardiac sequelae, hepatic hemangiomas may exhibit intratumor hemorrhage leading to the Kasabach-Merritt sequence of anemia, thrombocytopenia, and disseminated intravascular coagulopathy ^5,11.  While percutaneous umbilical cord blood sampling has been described in cases of large hepatic hemangioma ¹¹, this is not routinely recommended. Non-invasive screening for fetal anemia by MCA Doppler peak systolic velocity assessment may be considered. Fetal echocardiogram, including evaluation of cardiac size, function, valvular regurgitation, and venous Doppler can be performed to evaluate for any signs of heart failure. Though not required, fetal MRI may be a useful diagnostic adjunct following complete sonographic evaluation if there is any uncertainty regarding the origin or etiology of the lesion. 

Many hepatic hemangiomas will not require treatment, as the majority of these vascular tumors exhibit a period of active growth followed by spontaneous involution ³. Because large hepatic hemangiomas may be found incidentally during antenatal imaging for other indications or during targeted imaging in the setting of high-output cardiac failure or hydrops, prenatally-detected cases may represent a subgroup which is more likely to be have serious sequelae. In the case series of 17 fetal hepatic hemangiomas, ten patients were symptomatic at birth ¹. Five cases exhibited postnatal growth and were likely IHH. Overall mortality in this series was 30%. Prenatal ultrasound findings associated with mortality included estimated hemangioma volume, two or more enlarged hepatic vessels, and cardiac abnormalities (either cardiomegaly or signs of heart failure). Of note, prenatal cardiac findings were seen in all five patients who died ¹.

Other serious postnatal complications of hepatic hemangioma include anemia, disseminated intravascular coagulopathy, fulminant liver failure, hypothyroidism (due to overproduction of type III iodothyronine deiodinase), and abdominal compartment syndrome. Among a recent case series of multifocal and diffuse IHH detected after birth, a mortality rate of 16% was seen ¹². This risk was higher in patients presenting with congestive heart failure and diffuse liver disease.

Pregnancies diagnosed with hepatic hemangioma should be followed with serial ultrasound surveillance to monitor for the development of cardiac failure and hydrops. The development of hydrops may necessitate early delivery depending on the particular clinical scenario and gestational age ¹. For those cases with reassuring ultrasound monitoring and no evidence of cardiac failure or hydrops, timing and mode of delivery may be determined by the usual obstetric indications.

Neonatal management depends on the presentation at birth. Asymptomatic lesions may be followed with serial ultrasound imaging until resolution, while a variety of medical therapies such as corticosteroids and beta-blockers are available for symptomatic cases. In rare cases of refractory heart failure or other severe systemic complications, interventions such as embolization, tumor resection or liver transplantation may be considered ⁵. Due to the wide spectrum of clinical disease, the optimal management of hepatic hemangioma remains challenging and warrants interdisciplinary care as well as consideration of referral to tertiary care centers in more complex cases^2,5.

1.       Franchi-Abella S, Gorincour G, Avni F, Guibaud L, Chevret L, Pariente D. Hepatic haemangioma-prenatal imaging findings, complications and perinatal outcome in a case series. Pediatric Radiology. 2012;42. doi:10.1007/s00247-011-2214-0

2.       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;42:62-68. doi:10.1016/j.jpedsurg.2006.09.041

3.       Léauté-Labrèze C, Harper JI, Hoeger PH. Infantile haemangioma. The Lancet. 2017;390(10089):85-94. doi:10.1016/S0140-6736(16)00645-0

4.       Jiao-ling L, Xiu-ping G, Kun-shan C, Qiu-ming H, Xiao-fen L, Bo-yang Y, Qian F. Huge fetal hepatic Hemangioma: Prenatal diagnosis on ultrasound and prognosis. BMC Pregnancy and Childbirth. 2018;18. doi:10.1186/s12884-017-1635-7

5.       Iacobas I, Phung TL, Adams DM, Trenor CC, Blei F, Fishman DS, Hammill A, Masand PM, Fishman SJ. Guidance Document for Hepatic Hemangioma (Infantile and Congenital) Evaluation and Monitoring. Journal of Pediatrics. 2018;203. doi:10.1016/j.jpeds.2018.08.012

6.       Roebuck D, Sebire N, Lehmann E, Barnacle A. Rapidly involuting congenital haemangioma (RICH) of the liver. Pediatric Radiology. 2012;42:308-314. doi:10.1007/S00247-011-2268-Z

7.       de Jong S, Itinteang T, Withers AHJ, Davis PF, Tan ST. Does hypoxia play a role in infantile hemangioma? Archives of dermatological research. 2016;308:219-227. doi:10.1007/S00403-016-1635-X

8.       Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Garzon MC, Horii KA, Lucky AW, Mancini AJ, Metry DW, Newell B, Nopper AJ, Frieden IJ. Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics. The Journal of pediatrics. 2007;150:291-294. doi:10.1016/J.JPEDS.2006.12.003

9.       Munden A, Butschek R, Tom WL, Marshall JS, Poeltler DM, Krohne SE, Aliõ AB, Ritter M, Friedlander DF, Catanzarite V, Mendoza A, Smith L, Friedlander M, Friedlander SF. Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies. The British journal of dermatology. 2014;170:907-913. doi:10.1111/BJD.12804

10.     Paudice M, Peñuela LA, Torielli F, Spina B, Remorgida V, Buffelli F, Fulcheri E, Arioni C, Vellone VG. Giant Hepatic Hemangioma and Placental Chorangiosis: A Unique Case of Stillbirth? https://doi.org/101080/1551381520181564159. 2019;38:175-181. doi:10.1080/15513815.2018.1564159

11.     Gembruch U, Baschat AA, Gloeckner-Hoffmann K, Gortner L, Germer U. Prenatal diagnosis and management of fetuses with liver hemangiomata. Ultrasound in Obstetrics and Gynecology. 2002;19. doi:10.1046/j.1469-0705.2002.00689.x

12.     Rialon KL, Murillo R, Fevurly RD, Kulungowski AM, Christison-Lagay ER, Zurakowski D, Kozakewich HPW, Alomari AI, Fishman SJ. Risk factors for mortality in patients with multifocal and diffuse hepatic hemangiomas. Journal of Pediatric Surgery. 2015;50:837-841. doi:10.1016/J.JPEDSURG.2014.09.056

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