A three month old female presented with weight loss, poor feeding, and oligouria. Imaging studies
revealed heart failure and massive hepatomegaly. The liver contained multiple vascular lesions measuring
up to 6 cm in greatest dimension. Malrotation of the gut was also noted, with the appendix located in
the left upper quadrant. Medical therapy including steroids and embolization failed and a liver
transplant was performed.
Gross examination showed a 1200 gram liver with multiple red spongy nodules ranging in size from 1 to
Sections showed a vascular neoplasm composed of dilated and irregular capillary-like vessels in a
dense collagenous background. Entrapped bile ducts were common, especially at the periphery. The
centers of the larger lesions had cavernous hemangioma like appearances with areas of thrombosis. In
most sections, the neoplastic endothelial cells were plump to flattened with no atypia. However, in
several sections from the largest lesion near the hilum (an example submitted for your review) there were
multiple areas of atypia with endothelial cell tufting as well as a focal solid area.
Angiosarcoma Arising in an Infantile Hemangioendothelioma (Type 2 Infantile Hemangioendothelioma)
|Infantile hemangioendotheliomas are vascular neoplasms mostly occurring in infants less than 6 months of age.|
|Most are benign (type 1) though a minority have malignant potential (type 2).|
|Clinical management includes resection, medical therapy, and transplantation for those who fail medical and surgical therapy.|
|The 6 month survival rate is 60-70% with most deaths resulting from poor post-operative clinical courses secondary to cardiac failure and related complications. |
Infantile hemangioendotheliomas are the most common vascular tumor of the liver in infants/toddlers
aged 0-3, with about 90% of tumors occurring before 6 months of age. Rare cases have been reported in
teen-agers and adults. There is a female predominance of about 2:1.
Most cases (60%) present with clinical symptoms, while the remainder are first detected by parents or
physicians as asymptomatic enlargement of the liver. Clinical symptoms are often non-specific such as
failure-to-thrive or gastrointestinal problems. Other cases can present with cardiac or respiratory
failure resulting from hemodynamic compromise. A classic, though uncommon, presentation is with a
bleeding diathesis from platelet sequestration and consumption (Kasabach-Merritt syndrome).
Infantile hemangioendotheliomas are associated with numerous congenital anomalies as illustrated in
this case and listed in Table 1. The anomalies are varied and show no clear patterns, ranging from
extranumerary digits to hydrocephalus. The frequency of extra-hepatic hemangiomas is approximately
10-30%. Skin hemangiomas are the most common, but other reported sites include the lungs,
gastrointestinal tract, adrenal gland, and thymus.
Table 1. Reported associations with infantile hemangioendothelioma
Congenital heart disease
Unilateral or bilateral renal agenesis
Heterotopic liver in thorax
Absent common bile duct
Cornelia de Lange syndrome
Malrotation of gut
Deletion of 6q
Slightly more than ½ (~55%) of infantile hemangioendotheliomas are single lesions and range in
size from sub-cm incidental findings to 15 cm, with a mean of 4 cm.
The tumors are usually well demarcated and non-encapsulated with a spongy appearance and vary from red
to gray in color. The centers of large lesions can be fibrotic and even calcified.
The neoplasm may be supplied by the hepatic artery and/or extrahepatic arteries as well as the portal
vein. Arteriovenous shunting can often be demonstrated by radiolographic studies.
The tumor is composed of vascular channels which can resemble small capillaries or may be more dilated
and irregular in shape. The endothelial cells may have flattened or plump nuclei but show fine chromatin
with a single nucleoli. Up to 12 mitoses per 10 HPF have been reported, but high mitoses does not
appear to impact prognosis. In the case illustrated here, mitoses were nearly absent in most sections
but were very high in sections near embolic material.
Bile ducts are often entrapped within the lesion especially at the periphery. About 1/3 of cases have
an infiltrative margin and in these cases the hepatocytes at the interface can take on a ductular
morphology. The centers of larger neoplasms often resemble cavernous hemangiomas though similar changes
can be seen at the periphery of some tumors. In addition, the centers of larger tumors frequently have
areas of fibrosis, thrombosis, myxoid change, and calcification.
Type 2 change:
In a comprehensive review of this tumor by Dehner and Ishak in 1971, the authors divided infantile
hemangioendotheliomas into types 1 and 2 based on histological findings, with type 2 showing larger
irregular endothelial nuclei with clumped chromatin and irregular budding or branching of endothelial
cell clusters. Type 2 change was referred to as more "aggressive in appearance" and significant
histological overlap was noted between type 2 changes and frank angiosarcoma.
In a 1994 study of 91 cases, the frequency of type 2 change was found to be 19%, but type 2 change did
not impact prognosis and the nuclear atypia seen in type 2 was felt to possibly be degenerative in
While rare, accumulated case reports and small series demonstrate a low but clear risk for aggressive
behavior in some infantile hemangioendotheliomas. In these reports, tumor recurrence is much more common
than metastases. Type 2 change appears to the best available histological marker for aggressive
potential. While the clinical outcome in most cases is similar regardless of the presence or absence of
type 2 change, almost all tumors with malignant behavior have been described as having type 2 changes.
Thus, type 2 changes does not equal malignancy, but type 2 change is an important marker for potential
aggressive behavior. In fact, some authors (though not all) currently regard type 2 changes as
equivalent to low grade angiosarcoma.
Regardless of the label placed on tumors with type 2 changes, it is important to adequately section
the neoplasm and document type 2 changes in the pathology report when present. In many cases, including
this case, type 2 changes can be patchy. In addition to atypia and endothelial tufting, other features
indicating angiosarcoma degeneration are solid areas and spindly, kaposiform like areas (see
3rd series of AFIP fascicle for illustrations and discussion).
5-10% of infantile hemangioendotheliomas regress spontaneously. Nevertheless, current management of
symptomatic tumors often involves resection when possible and medical therapy when the tumor is
unresectable. Steroids, embolization, or chemotherapy have all been employed with some success. In
symptomatic cases that fail to respond to medical therapy, liver transplantation is an important option.
Brief Annotated Bibliography
- 1919 - Foote J. Hemangio-endotheliosarcoma of the liver in infancy: A disease of early life. JAMA 1901; 73:1042-1045.
• Early review of infantile hemangioendothelioma.
- 1971 - Dehner LP, Ishak KG. Vascular tumors of the liver in infants and children. A study of 23 cases and review of the literature. Arch Pathol 1971; 92:101-11
• Review of 23 cases with definition of type 1 and type 2 changes.
- 1994 - Selby DM, Stocker JT, Waclawiw MA, Hitchcock CL, Ishak KG. Infantile hemangioendothelioma of the liver. Hepatology 1994; 20:39-45
• Comprehensive review of clinical and histological findings of 91 cases including univariate analysis of risk factors for death.
- 1996 - Achilleos OA, Buist LJ, Kelly DA, Raafat F, McMaster P, Mayer AD, Buckels JA. Unresectable hepatic tumors in childhood and the role of liver transplantation. J Pediatr Surg 1996; 31:1563-7.
• Tumor recurrence following liver transplantation
- 1996 - Awan S, Davenport M, Portmann B, Howard ER. Angiosarcoma of the liver in children. J Pediatr Surg 1996; 31:1729-32.
• Malignant transformation of infantile hemangioendothelioma.