PEDIATRICS (doi:10.1542/peds.2006-0183)
EXPERIENCE & REASON |
Multiple Cutaneous Infantile Hemangiomas Associated With Hepatic Angiosarcoma: Case Report and Review of the Literature
Departments of a Dermatology
b Surgery
c Pathology
d Pediatrics
e Medicine, Columbia University, New York, New York
f Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin
ABSTRACT
Multiple cutaneous hemangiomas can be associated with internal hemangiomas, with the liver being the most common site. Here we report a case of a premature female neonate who presented with cardiac failure at birth and had typical-appearing infantile hemangiomas on the skin in association with vascular lesions in the liver. Her clinical presentation was felt to be consistent with cutaneous and hepatic infantile hemangiomas. After failure to respond to systemic steroids and chemotherapy, she underwent liver transplantation. Histopathologic evaluation of the liver revealed a diagnosis of type 2 infantile hepatic hemangioendothelioma (regarded as synonymous with angiosarcoma) rather than benign infantile hemangioma of the liver. Subsequent skin biopsies confirmed that her multiple cutaneous lesions were infantile hemangiomas and not metastatic angiosarcoma. We report this case and a review of the literature on pediatric angiosarcoma of the liver associated with cutaneous infantile hemangiomas.
Key Words: hemangioma • neoplasm • liver transplantation
Abbreviations: IH, infantile hemangioma • IHHE, infantile hepatic hemangioendothelioma • CT, computed tomography • GLUT1, glucose transporter protein isoform 1 • HAS, hepatic angiosarcoma
Multiple cutaneous infantile hemangiomas (IHs) are reported to arise in 10% to 25% of infants with cutaneous hemangiomas.1 A recent prospective study of infants with hemangiomas found 31% of children to have >1 hemangioma, and within this group, the majority had 2 to 5 lesions.2 Multiple cutaneous hemangiomas, in particular >5 lesions, are felt to be a marker of possible internal hemangiomatosis, with the liver being the most common extracutaneous site. Congestive heart failure is a complication of hepatic hemangiomatosis in a subset of patients with hepatic lesions. Here we report the case of a neonate with multiple small, focal, typical-appearing cutaneous IHs who also had multiple hepatic tumors. Her course was marked by severe congestive heart failure within the first several weeks of life that was unresponsive to medical therapy and embolization, and she subsequently required orthotopic liver transplantation. Histopathologic evaluation of the liver revealed a diagnosis of type 2 infantile hepatic hemangioendothelioma (IHHE), which is regarded as synonymous with angiosarcoma.
CASE REPORT
A 2952-g female infant was born at 35 weeks' gestation via uncomplicated spontaneous vaginal delivery to a 36-year-old gravida 4 para 4 mother. Apgar scores were 8 and 9 at 1 and 5 minutes, respectively, and the patient was sent to the well-infant nursery. At 4 hours of life, the patient was found to be mildly tachypneic and transferred to a special care nursery for closer monitoring.
Physical examination was significant for a grade II/VI systolic murmur and palpable liver extending 4 cm below the right costal margin. A chest radiograph showed an enlarged heart, and the initial echocardiogram revealed a patent ductus arteriosus. On day-of-life 3, 5 small red papules were noted on the trunk and extremities. An abdominal sonogram on day-of-life 4 revealed masses in the liver, which on contrast computed tomography (CT) appeared as multiple hypervascular masses in both hepatic lobes, consistent with multiple hemangiomas (Fig 1). At that time, the largest lesion was seen in the left anterior lobe and measured 5 x 2.5 cm.
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Laboratory studies were significant for a white blood cell count of 23.5 x 103/mm3 (reference range: 9–30 x 103/mm3), hematocrit of 37.3% (reference range: 47%–51%), platelets of 507 x 103/mm3 (reference range: 290–350 x 103/mm3), total bilirubin of 5.2 mg/dL (reference range: <8 mg/dL), conjugated bilirubin of 4.3 mg/dL (reference range: 0.0–0.4 mg/dL), and alanine aminotransferase of 282 U/L (reference range: <54). Thyroid-function tests showed a thyrotropin level of 1.49 µIU/mL (reference range: 0.6–10.0 µIU/mL) and thyroxine level of 16.7 µg/dL (reference range: 8.2–16.6 µg/dL).
In addition to digoxin and furosemide, the patient was started on prednisone at a dose of 2 mg/kg per day on day-of-life 7 and changed to intravenous methylprednisolone 2 mg/kg per day on day-of-life 15. Sequential echocardiograms and chest radiographs demonstrated persistent ventricular dilatation and worsening cardiac failure despite continued diuresis and systemic steroids. Her direct bilirubin and transaminase levels were rising, and on day-of-life 17, she weighed 300 g less than her birth weight despite nasogastric tube feedings with high-calorie formula.
On day-of-life 17 the patient was transferred to our institution for additional management of worsening high-output cardiac failure and failure to thrive. Dermatology was called to evaluate multiple red papules. On initial examination there were >20 bright red vascular papules, which ranged from <1 to 4 mm in size, and were distributed over the scalp, face, back, and extremities (Fig 2). All of the lesions were clinically consistent with cutaneous IHs.
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With persistent cardiac failure on 2 mg/kg per day of methylprednisolone, the steroid dose was increased to 3 mg/kg per day of methylprednisolone on day-of-life 22. Therapeutic options including vincristine administration and liver transplantation were explored. Over the next week the patient's cardiac function continued to worsen, with multiple measurements of elevated troponin levels. Having failed to show a clinical response to 3 weeks of systemic steroids and aggressive diuresis, the patient was treated with intravenous vincristine 0.05 mg (0.01875 mg/kg) on day-of-life 29 and a second dose of 0.07 mg (0.025 mg/kg) on day-of-life 36 with the intent of reducing the size of the liver lesions. After the second dose of chemotherapy, a repeat sonogram showed that the largest mass was unchanged in size.
Failure of treatment, the infeasibility of local resection because of the multilobar involvement of the hepatic lesions, and continued worsening of her cardiac failure led to the decision to place the patient on the waiting list for a liver transplant. On day-of-life 40, a liver became available. However, while the liver was in transit, the patient had another rise in her troponin I level, with a peak level of 5.7 ng/mL (reference range: 0.03–0.15 ng/mL). The decision was made to perform immediate arterial embolization of the largest hepatic mass. Unfortunately, this failed to stabilize her cardiac failure, and <24 hours later she underwent orthotopic liver transplantation.
Her postoperative course was complicated by urosepsis and hepatic artery thrombosis. After a failed attempt at catheterization of the hepatic artery and systemic anticoagulation with intravenous heparin, it was treated conservatively, and the patient was discharged from the hospital in stable condition on day-of-life 65.
Histologic examination of the explanted liver by 2 liver pathologists (J.H.L. and Z.D. Goodman, MD, PhD, at the Armed Forces Institute of Pathology, Washington, DC) showed a multicentric vascular neoplasm diagnosed as IHHE type 2, considered synonymous with angiosarcoma (Fig 3). Subsequently, 2 cutaneous lesions were biopsied, both of which demonstrated the histologic features of IH (Fig 4). Immunostaining of skin and liver specimens for hemangioma-associated markers including glucose transporter protein isoform 1 (GLUT1) and Lewis Y antigen was performed by P. North, MD, PhD (laboratory at the Arkansas Children's Hospital Department of Pathology, Little Rock, AR).3,4 The liver specimen showed focal, weak GLUT1 immunoreactivity consistent with hepatic angiosarcoma (HAS), whereas the skin specimens showed strong immunoreactivity for both GLUT1 and Lewis Y antigen, making them consistent with IHs and confirming the histologic impression.
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At the time of this writing, the patient was alive and well at 13 months of age, and in the setting of posttransplant immunosuppression with prednisone, all but 2 cutaneous hemangiomas had fully involuted by 8 months of age.
DISCUSSION
It is well recognized that multiple cutaneous IHs may be a marker of hepatic hemangiomatosis. The prognosis of patients with hepatic and cutaneous hemangiomas is quite variable. Many infants remain asymptomatic and do not require active intervention, whereas a small subset requires aggressive therapy. The need for liver transplantation is very uncommon and rarely considered in the treatment of these patients. The finding of a malignant hepatic tumor on histology was surprising in light of the extreme rarity of pediatric angiosarcoma and because the patient's clinical course could have been explained by complications associated with other, benign, high-flow vascular lesions.
This case highlights the confusing nomenclature in the literature for infantile hepatic vascular tumors, with multiple synonyms used to describe the same entities. The term "IHHE" has traditionally been used to describe tumors with both benign- and malignant-appearing histologic features, although this terminology has recently fallen into disfavor. In 1971, Dehner and Ishak5 proposed the subclassification of IHHE into 2 histologic groups. Type 1 IHHE is used to describe the more common subtype, composed of capillary-sized vessels lined by a single layer of somewhat plump but bland endothelial cells with rare mitotic figures. Type 2 IHHE was described as composed of vessels with more pleomorphic endothelial cells and was often considered difficult to distinguish from HAS.
Type 1 IHHE has also been referred to in the literature as benign hemangioendothelioma or hepatic IH. The term IH, rather than hemangioendothelioma, has been favored by the dermatology community and multidisciplinary centers specializing in vascular anomalies, because these lesions share a similar histology and natural history with cutaneous IHs and are felt to be analogous to benign cutaneous IHs. In much of the pathology and surgery literature, however, the term hemangioendothelioma, or IHHE, remains entrenched. Type 2 IHHE has also been referred to as epithelioid angiosarcoma and kaposiform angiosarcoma in the literature. The numerous synonyms and confusing terminology make it difficult to combine information and draw conclusions from case reports in the literature about these hepatic vascular tumors.
Ishak et al,6 who in 1999 wrote the most recent discussion on hepatic tumors for the Armed Forces Institute of Pathology, consider type 2 IHHE to be HAS. Although the classification remains somewhat controversial, type 1 IHHE is considered to be synonymous with hepatic IH, and type 2 IHHE can also be referred to as HAS (Fig 5).
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Pediatric HAS is not only extremely rare but has been regarded by some authors to be a distinct entity from the HAS seen in adults, which has a peak incidence in the sixth and seventh decades.6 In children, these tumors usually present with a rapidly enlarging liver, and by the time they are diagnosed, the lesion is often unresectable.7 Metastasis is common, frequently to the lung.7–12 The mortality rate for pediatric HAS is high, and death usually occurs within the first 6 months. Histologically, the tumors often consist of spindled cells that can be arranged in bundles with slit-like vascular spaces or in a whorl-like arrangement, and mitotic figures range from few to many.6 Epithelioid features may also predominate, but all variants are united by a composition of pleomorphic cells with endothelial differentiation.
The dermatology community is often involved in the care of patients with hepatic IH (so-called type 1 IHHE) because of the frequent coexistence of cutaneous IHs. The presence of multiple cutaneous IHs often prompts evaluation for hepatic infantile hemangiomatosis. The diagnosis of HAS in our patient came as a surprise not only because HAS is so rare in the pediatric population but also because the coexistence of cutaneous and hepatic lesions clinically suggested diffuse neonatal hemangiomatosis. Not only did the presence of cutaneous hemangiomas suggest that our patient's liver lesions would likely be IHs, but the presentation of liver and skin lesions in the first few days of life, with continued growth during the first few weeks, is a pattern considered classic for IHs.
We have found only 7 other cases in the literature of pediatric patients with histologic diagnoses of HAS (or type 2 IHHE) and lesions on the skin clinically consistent with IHs5,8,10,12–15 (Table 1). Including our case, 7 of 8 patients had multiple cutaneous IHs, and 1 patient had a single large hemangioma of the left forearm and hand.13 Of all of the cases listed in Table 1, Dehner and Ishak5 reported the only other case with histologic confirmation of the diagnosis of cutaneous IH, and there were no other cases with documented immunohistochemical staining for diagnostic confirmation of the cutaneous or hepatic lesions.
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Proliferation of hepatic masses after the first year is less characteristic of benign IHs and should raise suspicion of a malignant tumor. All but 2 of the previously reported cases were diagnosed with HAS at ages 1 year or older. Walsh et al15 reported a case with a clinical presentation quite similar to that of our patient. They described a 10-week-old infant girl with multiple cutaneous IHs who presented with hepatomegaly and difficulty feeding and was diagnosed with multiple IHHE on the basis of clinical and radiologic findings. Their patient was treated with systemic steroids and cyclophosphamide without benefit and also underwent orthotopic liver transplantation. After histologic examination of the explanted liver, type 2 IHHE (HAS) was diagnosed. There was very little clinical information provided about the other patient who was reported by Dehner and Ishak.5 The patient was diagnosed with type 2 IHHE at the age of 2 months and died.
We have found 3 other cases of cutaneous IHs and possible HAS without histologic diagnosis. Awan et al8 reported another patient with an initial histologic diagnosis of benign hemangioendothelioma and multiple cutaneous IH at 6 months of age who re-presented with abdominal distention at 3 years of age. Despite hepatic lobectomy, the patient died. Although there was no postmortem histology, there was clinical suspicion for HAS because of possible metastatic lesions found in the lungs. Taylor16 described a 3-month-old girl with a clinical diagnosis of multiple cutaneous IHs complicated by secondary infection of a large labial hemangioma whose death was attributed to milk aspiration. At autopsy, there were numerous vascular lesions in the lungs and liver. The histology of the hepatic lesions was described as "malignant hemangiomas," whereas the cutaneous lesions were considered consistent with ordinary "capillary hemangiomas." Finally, a female neonate with many cutaneous IHs presented with progressive abdominal distension, jaundice, and respiratory distress on the second day of life and died on the tenth day of life.17 Postmortem evaluation revealed vascular masses in the liver and one adrenal gland, and the histologic description of the hepatic lesions was also of "malignant hemangiomas." The last 2 patients described may have been cases of multifocal hemangiomas, with visceral involvement, and because the most common extracutaneous site affected in multifocal hemangiomatosis is the liver, it is not surprising that both of these patients had hepatic lesions.18 However, given the poor outcome and histologic descriptions in both of these cases, the possibility of malignant hepatic tumors associated with cutaneous IHs is raised.
Although it is beyond the scope of this article to discuss the etiology of hepatic vascular tumors, the decision to consider type 2 IHHE to be HAS leads to the question of whether there is an inherent relationship between so-called type 1 and type 2 IHHE or whether they represent etiologically unrelated tumors. There is evidence to suggest that some cases of pediatric HAS of the liver may develop within preexisting hepatic IH lesions. This is supported by case reports of patients with initial histologic diagnoses of benign cellular vascular tumors of the liver who were subsequently diagnosed with HAS.8,10,14,19,20 Awan et al8 described a 3-year-old girl who presented with abdominal distention and hepatomegaly whose initial wedge biopsy showed "benign hemangioendothelioma." When the lesion was not responsive to steroids and radiation, a liver transplant was performed, and angiosarcoma was found in the explanted liver. Awan et al also reported a 3-year-old boy with abdominal distention and hepatomegaly whose initial percutaneous biopsy showed "benign hemangioendothelioma," but a postmortem diagnosis of HAS with pulmonary metastases was made.8 Of note, this second patient had a documented clinical history of multiple cutaneous IH lesions, which had resolved by 1 year of age, preceding the onset of abdominal symptoms. Falk et al10 also described 3 patients (aged 2, 23, and 34 months at presentation, respectively) who were each initially diagnosed with IHHE, but after reevaluation of the liver postmortem, they were all found to have HAS. On clinical grounds, one of these patients had multiple cutaneous IHs as well. Furthermore, Strate et al19 reported a 5-year-old boy who initially had been diagnosed with multiple benign hemangioendotheliomas via open liver biopsy at the age of 3 months. The hepatic lesions reportedly demonstrated clinical regression with steroid treatment until the boy re-presented at the age of 5 years with progressive abdominal distention and a rapidly fatal course. Postmortem examination revealed HAS. Finally, Kirchner et al14 reported a 4-year-old boy who at the age of 6 months had hepatic lesions clinically diagnosed as hemangioendotheliomas. The lesions regressed with steroid therapy; however, the patient presented at the age of 4 years with a hepatic tumor that showed evidence of HAS on repeat biopsy.
Additional support for the theory that some HAS may develop within type 1 IHHE comes from the coexistence of these 2 histologic patterns within the same liver specimen at the same point in time. Noronha and Gonzalez-Crussi21 reported a 5-year-old girl who underwent hepatic lobectomy for a liver mass predominantly in the left lobe. Histologically, the liver specimen demonstrated features of both type 1 and type 2 IHHE. Dehner and Ishak5 described a similar situation in a 2-month-old infant whose liver specimen had features of both type 1 and type 2 IHHE.
As an added dimension to the complexity of hepatic vascular tumor classification, benign hemangiomas of the liver are now recognized to be heterogenous in histology and immunophenotype.22,23 In addition to the complex issues associated with the histologic interpretation of hepatic tumors, there is a variable spectrum of severity of benign hepatic hemangiomas. A new classification was proposed for hepatic hemangiomas at a recent National Institutes of Health–sponsored research workshop on the basis of 3 distinct clinical presentations: solitary large lesions, multifocal lesions, and diffuse lesions.24 Solitary large hepatic hemangiomas are usually present at birth and often asymptomatic, but they can be associated with mild thrombocytopenia and anemia and often occur in the absence of skin hemangiomas. On imaging, they have a heterogenous appearance without central enhancement. These solitary lesions can also have arteriovenous or portovenous shunting that can lead to cardiac failure. They resolve spontaneously, are GLUT1 negative on immunohistochemical staining, and are considered most similar to the rapidly involuting congenital hemangiomas described in the skin. In contrast, multifocal hepatic hemangiomas are considered true IHs. They stain positively for GLUT1, demonstrate the classic central enhancement on CT, and undergo spontaneous involution. Multifocal hepatic hemangiomas are typically seen in the setting of multiple cutaneous lesions and can also be asymptomatic or cause significant cardiac failure from arteriovenous or portovenous shunting. Finally, diffuse hepatic hemangiomas present with numerous tiny lesions that lead to severe hepatomegaly and impaired venous return but do not demonstrate the shunting or cause the high-output cardiac failure that is described in the solitary or multifocal variants. Although these lesions also spontaneously involute, there is a high mortality rate early on because of the severe hypothyroidism that can result from expression of type-3 iodothyronine deiodinase in these lesions.
Although a definitive diagnosis is made histologically, biopsies of hepatic vascular lesions are often not performed because of the risks of bleeding or death. Radiologic studies play an essential role in the evaluation of these patients.25–27 The clinical presentation of multiple cutaneous IHs is suggestive of possible multifocal IHs in the liver, and some clinicians advocate routine screening with a hepatic sonogram for infants with 
5 cutaneous IH lesions. Burrows et al reported their radiologic findings in a series of 58 patients with hepatic IHs.25 With sonography, the hepatic hemangiomas most often appeared as well-defined, hypoechoic lesions. On contrast-enhanced CT, multifocal hepatic hemangiomas showed peripheral enhancement in early images, whereas in later images the lesions usually enhanced uniformly, reflecting a centripetal pattern of blood flow. However, some lesions had a central area that did not enhance. With MRI, the hemangiomas were all visualized as discrete homogeneously enhanced lesions, which on T1-weighted images were hypointense and on T2-weighted images were hyperintense relative to the liver parenchyma. Kassarjian and co-workers25,27 feel that the results from MRI are the most consistent and sensitive, therefore arguing that MRI is the technique of choice for imaging of hepatic vascular lesions. However, even in the best of hands, imaging alone cannot definitively distinguish a benign from a malignant vascular tumor; therefore, histologic diagnosis remains the "gold standard."
Because the clinical presentation and radiologic findings of our patient's hepatic lesions were both consistent with IHs, the histologic diagnosis of HAS not only came as a surprise, but also raised the question of whether her skin lesions were truly IHs or possibly cutaneous metastases of the angiosarcoma in her liver. Histologic evaluation and positive immunostaining for GLUT1 of 2 skin lesions confirmed the diagnosis of cutaneous IHs in our patient. At an 8-month follow-up her cutaneous lesions continued to follow the typical pattern of regression for IHs, possibly expedited by her posttransplant immunosuppression with prednisone.
The case we have reported is important because the clinical presentation was consistent with cutaneous IHs with hepatic hemangiomas. Histologic examination of the liver came only as a result of the patient's severe high-output cardiac failure that was unresponsive to systemic steroids, chemotherapy, and hepatic embolization procedure, thus leading to orthotopic liver transplantation. The explanted liver revealed the diagnosis of HAS, and the subsequent skin biopsies confirmed that her multiple cutaneous lesions were not metastatic angiosarcoma but indeed IHs. Our patient has shown no evidence of metastatic lesions in the lungs and continues to be monitored for recurrence.
This case raises the question of whether liver biopsy should be performed in patients with cutaneous IHs and hepatic vascular lesions that are not responsive to medical therapy. Although Kassarjian et al25 suggested that hepatic vascular lesions that present after 1 year of age or do not demonstrate the classic radiologic findings of IH should be biopsied, our patient presented with hepatic lesions in the first few days of life that were consistent with hemangiomas on imaging. The other cases that we have found in which the histologic evaluation led to a corrected diagnosis of HAS came after the patients had not responded to conventional therapy or were so ill that hepatic lobectomy or transplantation was performed in a life-saving effort. It is likely that the patients who survived without biopsy did not have malignant tumors; however, we have to consider whether patients with clinical diagnoses of benign hemangiomas (or type 1 IHHE) in the liver and cutaneous hemangiomas who did not survive, and did not have postmortem analysis, may have had HAS. It seems possible that there have been other children with cutaneous IHs and liver lesions who died with undiagnosed HAS. Therefore, it may be reasonable to consider liver biopsy in patients not responsive to standard therapy with systemic steroids and chemotherapy.
The arguments against liver biopsy in these cases not only include the risks of the procedure itself but also the risk of sampling error. This may be particularly concerning in these patients because the HAS can coexist with hepatic IHs and may even develop within the latter. Therefore, a diagnosis of hepatic IHs, even if confirmed by immunostaining for IH-associated markers such as GLUT1, may provide a false sense of security.
We have raised many questions in this article that, we hope, will lead to further discussion of the appropriate evaluation for patients with cutaneous IHs and hepatic vascular lesions.
ACKNOWLEDGMENTS
We thank Dr Zachary D. Goodman for review of the pathology and a draft of the manuscript; Dr Margaret Lee for contributions to the care of this patient; and Dr Marlyanne Pol-Rodriguez for assistance in photography and patient care.
FOOTNOTES
Accepted Mar 20, 2006.
Address correspondence to Maria C. Garzon, MD, Columbia University, Department of Dermatology, 161 Fort Washington Ave, Herbert Irving Pavilion, 12th Floor, New York, NY 10032. E-mail: mcg2{at}columbia.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
This case and data were presented at the Society for Pediatric Dermatology Annual Meeting; July 15, 2005; San Diego, CA.
REFERENCES
- Achauer BM, Chang CJ, Vander Kam VM. Management of hemangioma of infancy: review of 245 patients. Plast Reconstr Surg. 1997;99:1301–1308[Web of Science][Medline]
- Garzon MC, Drolet BA, Haggstrom A, Frieden IJ. Incidence and clinical associations of multiple haemangiomas of infancy [abstract]. Presented at: the 15th Congress of the International Society for the Study of Vascular Anomalies; February 22–25, 2004; Wellington, New Zealand
- North PE, Waner M, Mizeracki A, Mihm MC Jr. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol. 2000;31:11–22[CrossRef][Web of Science][Medline]
- North PE, Waner M, Mizeracki A, et al. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol. 2001;137:559–570
[Abstract/Free Full Text] - Dehner LP, Ishak KG. Vascular tumors of the liver in infants and children: a study of 30 cases and review of the literature. Arch Pathol. 1971;92:101–111[Web of Science][Medline]
- Ishak KG, Goodman ZD, Stocker JT. Tumors of the Liver and Intrahepatic Bile Ducts (Atlas of Tumor Pathology). Washington, DC: Armed Forces Institute of Pathology; 1999:293–307
- Mo JQ, Dimashkieh HH, Bove KE. GLUT1 endothelial reactivity distinguishes hepatic infantile hemangioma from congenital hepatic vascular malformation with associated capillary proliferation. Hum Pathol. 2004;35:200–209[CrossRef][Web of Science][Medline]
- Awan S, Davenport M, Portmann B, Howard ER. Angiosarcoma of the liver in children. J Pediatr Surg. 1996;31:1729–1732[CrossRef][Web of Science][Medline]
- Weinberg AG, Finegold MJ. Primary hepatic tumors of childhood. Hum Pathol. 1983;14:512–537[Web of Science][Medline]
- Falk H, Herbert JT, Edmonds L, Heath CW Jr, Thomas LB, Popper H. Review of four cases of childhood hepatic angiosarcoma: elevated environmental arsenic exposure in one case. Cancer. 1981;47:382–391[CrossRef][Web of Science][Medline]
- Kauffman SL, Stout AP. Malignant hemangioendothelioma in infants and children. Cancer. 1961;14:1186–1196[CrossRef][Web of Science][Medline]
- Selby DM, Stocker JT, Ishak KG. Angiosarcoma of the liver in childhood: a clinicopathologic and follow-up study of 10 cases. Pediatr Pathol. 1992;12:485–498[Web of Science][Medline]
- Alt B, Hafez GR, Trigg M, Shahidi NT, Gilbert EF. Angiosarcoma of the liver and spleen in an infant. Pediatr Pathol. 1985;4:331–339[Medline]
- Kirchner SG, Heller RM, Kasselberg AG, Greene HL. Infantile hepatic hemangioendothelioma with subsequent malignant degeneration. Pediatr Radiol. 1981;11:42–45[CrossRef][Web of Science][Medline]
- Walsh R, Harrington J, Beneck D, Ozkaynak MF. Congenital infantile hepatic hemangioendothelioma type II treated with orthotopic liver transplantation. J Pediatr Hematol Oncol. 2004;26:121–123[CrossRef][Web of Science][Medline]
- Taylor A. Multiple hemangiomas showing certain malignant characteristics in an infant: report of a case. Am J Cancer. 1933;19:31–39
- Andries G. Multiple malignant hemangiomas of the liver. Am J Clin Pathol. 1944;14:489–494
- Golitz LE, Rudikoff J, O'Meara OP. Diffuse neonatal hemangiomatosis. Pediatr Dermatol. 1986;3:145–152[Medline]
- Strate SM, Rutledge JC, Weinberg AG. Delayed development of angiosarcoma in multinodular infantile hepatic hemangioendothelioma. Arch Pathol Lab Med. 1984;108:943–944[Web of Science][Medline]
- Calder CI, Raafat F, Buckels JA, Kelly DA. Orthotopic liver transplantation for type 2 hepatic infantile haemangioendothelioma. Histopathology. 1996;28:271–273[CrossRef][Web of Science][Medline]
- Noronha R, Gonzalez-Crussi F. Hepatic angiosarcoma in childhood: a case report and review of the literature. Am J Surg Pathol. 1984;8:863–871[Web of Science][Medline]
- DeAos I, James CA, North PE. Hepatic "haemangioma": not a singular entity [abstract]. Presented at: the 15th Congress of the International Society for the Study of Vascular Anomalies; February 22–25, 2004; Wellington, New Zealand
- Paltiel HJ, Burrows PE, Kozakewich HPW, Fishman SJ, Mulliken JB. Solitary infantile liver haemangioma: a distinct clinicopathologic entity [abstract]. Presented at: the 15th Congress of the International Society for the Study of Vascular Anomalies; February 22–25, 2004; Wellington, New Zealand
- Frieden IJ, Haggstrom AN, Drolet BA, et al. Infantile hemangiomas: current knowledge, future directions. Proceedings of a research workshop on infantile hemangiomas, April 7–9, 2005, Bethesda, Maryland, USA. Pediatr Dermatol. 2005;22:383–406[CrossRef][Medline]
- Burrows PE, Dubois J, Kassarjian A. Pediatric hepatic vascular anomalies. Pediatr Radiol. 2001;31:533–545[Web of Science][Medline]
- Kassarjian A, Dubois J, Burrows PE. Angiographic classification of hepatic hemangiomas in infants. Radiology. 2002;222:693–698
[Abstract/Free Full Text] - Kassarjian A, Zurakowski D, Dubois J, Paltiel HJ, Fishman SJ, Burrows PE. Infantile hepatic hemangiomas: clinical and imaging findings and their correlation with therapy. AJR Am J Roentgenol. 2004;182:785–795
[Abstract/Free Full Text]
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