See “Pediatric Vascular Tumors of the Liver: Beware!” by Wildhaber on page 588.
Infantile multinodular hemangioma of the liver is a vascular tumor that occurs in the first weeks or months of life, mostly with liver enlargement and cutaneous hemangiomas. It has long been considered histologically benign, but in the first year of life, it carries risks of many complications that can be life threatening and requires careful management, with uncertain results (1–5). In most cases, the multinodular liver hemangiomas of infancy, like their cutaneous counterpart, tend to regress spontaneously, and the long-term prognosis is considered good for children who have overcome the initial stage of the disease (2).
Angiosarcoma of the liver, however, is a malignant vascular tumor, which is rare in both adults and children; in the latter, it is reported to occur chiefly at ages 2 to 7 years (6,7). It is considered a contraindication to liver transplantation in adults and children because of the high incidence of metastases (8,9). The histologic distinction between multinodular, supposedly benign, hepatic hemangioma of early infancy on the one hand and hepatic angiosarcoma on the other was long ago challenged by Dehner and Ishak (10). They described 2 types of histologic patterns associated with liver hemangioma in infants and children. Type 1 was described as “an orderly proliferation of small blood vessels lined by a single layer or, less often, by several layers of plump endothelial cells with an innocuous cytologic appearance”; the authors considered this type histologically benign, with a pattern identical to that of the cutaneous hemangiomas that regress spontaneously with time. Type 2 was described as “more aggressive in appearance with irregular budding and branching structures, larger endothelial cells, and mitotic figures,” and is considered histologically equivalent to angiosarcoma. The description of type 2 has acquired clinical significance (11). To provide additional examples of clinical cases and discuss their practical clinical consequences, we report 5 children whose histories illustrate the difficulties of diagnosing and managing hepatic angiosarcoma in children.
PATIENTS AND METHODS
From a database of 247 children investigated and treated at the Bicêtre Hospital for a vascular tumor of the liver between 1967 and 2010, 154 had solitary hemangioma and 93 had multinodular hemangioma. Among these, 5 were selected because histologic examination of their tumor showed features of type 2 hemangioendothelioma. The investigation consisted of clinical examinations, biochemical tests of liver function and the serum α-fetoprotein concentration, abdominal ultrasonography (US), echocardiography, computed tomography (CT) scans of the liver and lungs, and magnetic resonance imaging (MRI) of the liver. Tumor histology was studied on needle or surgical biopsies, on the liver removed at transplantation, or at postmortem examination; the criteria for defining types 1 and 2 hemangioendotheliomas were those defined by Dehner and Ishak (10). In 4 of the 5 patients, paraffin sections were immunostained for Ki-67 (MIB-1, 1:100, Dako) to assess the proportion of proliferating cells. Treatment depended on the child's condition and the trends of the time: digoxin and diuretics were given in case of heart failure, steroid therapy with prednisone at an initial dose of 1 to 3 mg · kg−1 · day−1 was given to 3 children, radiation therapy was given at a dose of 1000 Gy for several weeks to 3 children, interferon-α to 2 children, and chemotherapy with vinblastine to 1 child. When performed, interventional radiology consisted of diagnostic angiography followed by embolization of the arteries feeding the tumors by polymerizing glue mixed with lipiodol.
Three patients presented in infancy with a multinodular hemangioma of the liver and a late relapse after initial improvement.
Patient 1 was a girl, born in 1981, who presented at age 6 weeks with liver enlargement and cutaneous hemangiomas. Abdominal US and selective hepatic arteriography showed multiple vascular nodules in the liver. Between the ages of 3 and 18 months, liver nodules increased in size; were complicated by intraperitoneal bleeding, congestive heart failure, and respiratory insufficiency because of the size of the liver; were not improved by steroid therapy, radiation therapy, or hepatic artery embolization; and required continuous stay in the intensive care unit. From 18 to 30 months, improvement was noted with a decrease in the size of the liver and disappearance of the signs of respiratory and heart failure. At 30 months, diffuse pain and a rapid increase in liver volume were noted, followed by jaundice, ascites, disseminated intravascular coagulation, and death. The serum α-fetoprotein concentration was normal. Postmortem examination showed the presence of tumors in the liver, mesentery, bones, thymus, skin, thyroid, and lungs. Histology showed lesions characteristic of type 2 hemangioendothelioma.
Patient 2 was a girl who was born in 1982, who presented at birth with numerous cutaneous hemangiomas. At 3 months, she exhibited multiple liver hemangiomas, as shown on US. She was managed for 4 years in another institution, where she was treated with steroids. After a period of growth in the size and number of the cutaneous and hepatic hemangiomas, a progressive decrease was noted from the age of 8 months, and steroid therapy was stopped at age 2 years. At this time, liver US was reported to be normal and cutaneous hemangiomas were no longer visible. At 3½ years, the patient experienced intraperitoneal bleeding and a large vascular tumor of the left lobe of the liver was found on CT scan; she underwent left hepatic lobectomy. Tumor histology was that of type 1 hemangioendothelioma according to Dehner and Ishak (10). The serum α-fetoprotein concentration was normal. Five months later, several vascular nodules were found in the remaining liver and their size increased despite steroid therapy. At age 5 years, the girl was examined at Bicêtre Hospital; the liver was markedly enlarged. US, CT scan, and MRI showed diffuse vascular tumors in the liver. A review of the slides of the tumor removed at age 3½ years showed lesions that were mostly compatible with type 1 hemangioendothelioma, but a few nodules exhibited dense endothelial proliferation compatible with type 2; the proliferative index was 30%. An attempt at radiation therapy did not improve the child's condition. Progression of the tumor was combined with abdominal bleeding, jaundice, disseminated intravascular coagulation, and bleeding, and ended in death.
Patient 3 was a girl, born in 1996, who presented at age 2 months with pallor, cutaneous hemangiomas, and hepatomegaly. US and CT scans showed multiple liver hemangiomas (Fig. 1A). Because liver lesions progressed despite steroid therapy and interferon and eventually led to congestive heart failure, liver cell failure, and pulmonary hypertension, the patient underwent 2 embolizations of the feeding arteries and transhepatic embolization of portohepatic fistulas. At 10 months, this resulted in decreased nodule size and normalized liver tests and echocardiography. At 18 months, abdominal US showed a normal left lobe of the liver and 2 small 3-mm-wide nodules in the right lobe. During the following 2 years, the right lobe nodules increased in size, and at age 5, several nodules were found on US, scattered throughout the liver. The results of her CT scan are shown in Figure 1B. The serum α-fetoprotein concentration was normal. Needle biopsy of the largest nodule disclosed a pattern of type 2 infantile hemangioendothelioma, including endothelial cell hyperplasia with papillar formation and marked proliferation (30%), as shown by MIB-1 immunolabeling (Fig. 2). The size of the liver increased markedly in the months following and nodules were noted in the lungs on CT scan. Biopsy of a pulmonary nodule showed a pattern identical to that of the liver nodule. In spite of chemotherapy and radiation therapy, the tumors progressed relentlessly, together with the development of refractory ascites, and the child died of multiple organ failure.
The last 2 children presented with vascular tumors of the liver after the age of 1 year, with no previous known history of infantile hemangioma.
In patient 4, hepatomegaly was found during a routine examination. This 2-year-old girl was born in 1992 and had an uneventful history. Abdominal US revealed a large poorly defined tumor in the right lobe of the liver. CT scan with contrast injection showed early arterial (predominantly central) enhancement of the tumor that did not display the characteristic features of liver hemangioma (12). The serum α-fetoprotein concentration was normal. Surgical biopsy of the tumor showed lesions compatible with type 1 hemangioendothelioma and no features of type 2. The conclusion was that the tumor was benign, and initially, no treatment was given. Three months later, the size of the liver had increased enormously and it occupied the entire abdomen. Partial embolization of the hepatic artery branches had no effect. Right hepatectomy was performed. The histology of the liver removed displayed the features of both types 1 and 2 hemangioendothelioma in the same tumor (Fig. 3), and the proliferation index was between 10% and 30%. During follow-up, nodules and refractory ascites appeared in the remaining liver and the lungs. An attempt at interferon therapy had no effect and the child died at age 3½ years.
Hepatomegaly was found because of abdominal enlargement in a 3½-year-old girl (patient 5), born in 2003. Abdominal US and CT scan showed a huge tumor in the right lobe of the liver with small nodules in the rest of the parenchyma and thrombosis of the right portal branch and right and median hepatic veins. The largest tumor displayed central arterial enhancement after contrast injection (Fig. 4). Serum α-fetoprotein was normal. Needle biopsy of one of the nodules showed endothelial cell proliferation compatible with type 2 hemangioendothelioma, with a 50% proliferation index; angiosarcoma was diagnosed. Total-body MRI showed no metastases. Liver transplantation was performed 1 month after diagnosis. Three years later, the child is alive, with normal liver tests, immunosuppression with tacrolimus, and no signs of tumor recurrence. Histologic examination of the native liver confirmed the diagnosis of type 2 hemangioendothelioma, with predominant proliferative activity in the lesions located in segments 7 and 8; several other nodules in segment 5 and the left lobe displayed various degrees of growth, but some of these nodules seemed to have almost completely regressed.
The potentially extreme morbidity of solitary and multinodular liver hemangiomas during their initial period of growth in early infancy is widely known. Many complications may occur, including congestive heart failure, pulmonary hypertension, disseminated intravascular coagulation, hemolytic anemia, thyroid insufficiency, cholestatic jaundice, liver cell failure, intraperitoneal bleeding, and compression of adjacent organs (1–5). These complications are thought to be caused by the presence of arteriovenous or portohepatic shunts inside the tumors or to tumor size. Solitary hemangiomas always regress before the age of 1 year and we are not aware of reports of late relapses or of malignant histology. Regarding multinodular hemangiomas, it is becoming clear that the histologic nature of the liver tumors also plays a part in defining the outcome. Whereas the histology of the cutaneous hemangiomas often associated with multinodular liver hemangiomas is that of the benign type 1 hemangioendothelioma defined by Dehner and Ishak (10,11), the histology of the associated liver tumor is not always that of type 1, and there have been reports describing either type 2, which is malignant, or a mixture of type 1 and 2 components within the same liver (10,13). Because of these mixtures and the variable distribution of the components of both tumor types, the liver histology obtained by needle or even surgical biopsy that only displays features of type 1 hemangioendothelioma cannot be considered reassuring. Infantile liver hemangiomas displaying the type 2 histologic pattern are equivalent to angiosarcomas and carry a severe prognosis.
From the analysis of the cases described previously and the histories of the 5 patients reported here, 3 possible presentations of type 2 hepatic hemangioendothelioma (ie, angiosarcomas) may be suggested. The first presentation is as a particularly severe multinodular hepatic hemangioma that occurs in early infancy and is refractory to conventional treatment by medication or interventional radiology (11,14,15). In such cases, liver transplantation should be considered if metastases have been excluded. Liver transplantation may be difficult in early infancy, but it has proved lifesaving in a few cases (11,14).
Second, another possible presentation of type 2 liver hemangioendothelioma occurring in childhood consists of a relapse of liver nodules in children who, in early infancy, presented with multinodular hepatic hemangioma that regressed either spontaneously or after conventional treatment. The histories of patients 1 to 3 reported here and those of 4 children reported in the literature (16–19) are summarized in Table 1 and indicate that relapses occur at ages ranging from 2½ to 5 years, and that the outcome is almost always lethal under such conditions, despite drug therapy, radiation therapy, or partial hepatectomy. A careful follow-up of all of the infants with multinodular liver hemangioma is therefore mandatory, with regular US of the liver for several years (eg, every 6 months), to check that the liver nodules regress completely. In cases of persistence after age 2 years, or relapse of the liver nodules, MRI should be performed for early detection of suspect contrast medium enhancement of the tumor. Follow-up should be continued at least until age 5 years, even if US and MRI no longer reveal nodules. Tumor histology should be performed as soon as any relapse is detected. We suggest liver transplantation to be the best therapeutic option because of the risk of relapse in the remaining liver after partial hepatectomy (see (18) and patient 2 of the present study).
Third, the last presentation of type 2 hepatic hemangioendothelioma may be as a single or multiple liver tumor, which occurs after the age of 1 year in a patient with no particular history, although one cannot exclude the possible initial presence of an asymptomatic liver hemangioma, and which exhibits the imaging and histologic features of a tumor of vascular origin. The arterial phase enhancement on CT scan or MRI after contrast medium injection seems different between liver hemangiomas and angiosarcomas because liver hemangiomas exhibit peripheral centripetal enhancement and angiosarcomas, rather irregular central enhancement (20). This imaging pattern should give rise to a high index of suspicion; however, the number of cases in which this pattern is described with precision is limited. In addition, it may be misleading depending on the phase at which pictures are taken. In these cases, serum α-fetoprotein measurement has no diagnostic value and tumor histology is necessary. Diagnosis is easier if the histologic features are compatible with an angiosarcoma or a type 2 hemangioendothelioma according to Dehner and Ishak (10). Vigilance should be maintained if the histologic description is in favor of a type 1 hemangioendothelioma because type 1 hemangioendotheliomas are not common after the age of 1 year (16) and features of both types 1 and 2 may be present in the same liver (12,13,21), which may result in sampling errors. A high proliferative index may be a marker of aggressive behavior, as shown by the cases of angiosarcoma arising from infantile multinodular hemangiomas. In our opinion, liver transplantation should be considered rapidly in such patients, even if the tumor appears to be confined to a single lobe or segment on imaging studies, because there have been relapses in the remaining liver after partial hepatectomy under such conditions (12,15,18,20 and patient 4 of the present study). A careful search for metastases should be performed before deciding on transplantation and should be pursued in the years after transplantation. Although the risks of such late metastases cannot be excluded (13,21,22), liver transplantation may be the only lifesaving treatment possible for these children.
From the above observations, we conclude that careful follow-up is necessary for infants with infantile multinodular liver hemangiomas to detect late recurrence in the form of an angiosarcoma; vascular liver tumors occurring in children after infancy are likely to be malignant; and the high risk of relapse in the remaining liver leads us to suggest that if no metastases are detected, liver transplantation is better than surgical tumor resection in both preceding situations.
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