Burtelow, Matthew*; Garcia, Manuel†; Lucile, S‡; Cox, Kenneth†; Berquist, William†; Kemer, John Jr†
Infantile hemangioendothelioma (IHE) is the third most common hepatic tumor in childhood and the second most common hepatic tumor in children under 2 years of age (1). These tumors are composed of vascular channels lined by a single layer of endothelial cells, often with entrapped hepatocytes, bile ducts, and areas of extramedullary hematopoiesis (2). The most common presenting signs of IHE are hepatomegaly and abdominal mass, followed by cutaneous hemangiomas and congestive heart failure (3). Less common presentations include splenomegaly, jaundice, ascites, gastrointestinal bleeding, anemia, feeding difficulties, and hepatic bruit. Other reported associations are deletion of chromosome 6q (4), diaphragmatic hernia (5), trisomy 21 (6), transposition of the great arteries (7), and extranumerary digits (6). The first two cases we report had unique clinical presentations of fulminant hepatic failure and associated biliary atresia.
Although IHE is usually a benign lesion, malignant transformation has been reported (8). Although differences in histology are not proven to be predictive of malignant potential, IHE in older children are often considered at higher risk for malignancy. Our third case, who had a presumed IHE in infancy, presented at 5 years of age with metastatic hepatic angiosarcoma. This case underscores the uncertain malignant potential of even classic IHE and the need for regular evaluation of this tumor until complete regression.
A full-term male infant was transported to our institution at 4 weeks of life for evaluation and consideration for liver transplantation. At 2 weeks of age, he experienced hypovolemic shock caused by bleeding from his circumcision. He was resuscitated and stabilized. Initial evaluations included a prothrombin time (PT) of 36.8 seconds (normal 10.1-15.9) seconds, partial thromboplastin time of more than 200 (normal 31.3-54.3) seconds, alanine amino transferase (ALT) of 26 (normal <54) U/L, aspartate amino transferase (AST) of 46 (normal 20-65) U/L, and gamma glutamyl transpeptidase (GGT) of 31 (normal <130) U/L. Total bilirubin rose to 23.6 (normal <1) mg/dL, with a conjugated fraction of 7.4 (normal <0.4) mg/dL. Peak blood ammonia was 347 (normal 21-50) μmol/dL. Two liver ultrasound examinations showed no structural or blood flow abnormalities. He was treated with lactulose, phenobarbital, and fresh frozen plasma. At 4 weeks, the patient developed additional bleeding complications including pulmonary hemorrhage and cephalohematoma as well as acute respiratory distress syndrome, hepatic encephalopathy, and possible seizures. He was transferred to our institution for consideration of liver transplantation.
On our evaluation, his PT was 37.3 seconds with an International Normalized Ratio (INR) of 3.16 and D-dimers 4 to 8,000 ng/mL (normal negative). Alpha-fetoprotein (AFP) was 1,433 (normal for age 30-5,754) ng/mL, serum albumin 3.2 g/dL, and plasma ammonia 200 μmol/dL. Urine organic acids and serum amino acids were not diagnostic of a specific metabolic disease. Evaluation for infection was negative. Electroencephalogram showed frequent multifocal spikes associated with posturing. Computed tomography (CT) of the head showed diffuse brain edema with anoxic brain injury. Electrocardiogram and echocardiogram were normal. Coagulopathy persisted, and the patient's neurologic status deteriorated. Life support was withdrawn, and the child died 5 days after admission.
Postmortem examination revealed near total replacement of the liver parenchyma by an IHE (liver weight 34 g; expected 127 g). The liver was dusky red with a rim of dark green raised irregular plaque on the lateral edge of the left lobe. Microscopically, the parenchyma was totally replaced by a neoplastic proliferation of small vascular channels lined by endothelial cells with plump round nuclei within a supporting stroma of loose connective tissue with foci of fibroblastic proliferation (Fig. 1). Small bile ducts were present throughout the lesion and appeared to be increased in number. Within the tumor, erythrocytes filled the vascular spaces. Sections of the rim showed residual hepatocytes with marked bile stasis. Trichrome stain revealed extensive fibrosis of the remaining hepatic parenchyma.
A 6-week-old boy was admitted to an outside institution for evaluation of lethargy and cholestasis. CT of the liver demonstrated a 4.1 cm × 4.0 cm mass in the left lobe. Serum AFP was 28,507 (normal for age 30-5,754) ng/mL. Hepatobiliary scintigraphy demonstrated homogenous uptake of tracer in the liver but no intestinal excretion, consistent with extrahepatic biliary obstruction. Infectious and metabolic evaluations were negative.
At 8 weeks, the patient underwent exploratory laparotomy, intraoperative cholangiogram, Kasai portoenterostomy, and biopsy of the liver mass. Biopsy from the porta hepatis revealed obliteration of the bile duct lumen and fibrosis consistent with extrahepatic biliary atresia. Biopsy of the liver mass demonstrated severe cholestasis with bile duct proliferation without evidence of malignancy. This specimen was considered inadequate for diagnosis. The patient underwent percutaneous biopsy of the mass 1 week later, which revealed cords of hepatocytes separated by vascular channels lined with prominent CD34-positive endothelial cells, consistent with type I IHE. Despite therapy with prednisolone, ursodiol, and trimethoprim/sulfamethoxazole postoperatively, the patient continued to have cholestasis with acholic stools.
At 4 months of age, AFP decreased to 6,687 (normal for age 2-216) ng/mL. However, the patient developed increasing hepatomegaly and ascites and was treated with spironolactone. At 5 months, CT of the abdomen showed an enlarged hemangioendothelioma (6.0 cm × 6.4 cm). The AFP was of 499 (normal for age 1.25-129) ng/mL. Additional studies in the next 2 weeks suggested progressive hepatic decompensation with AST 378 U/L, ALT 117 U/L, alkaline phosphatase 691 (normal 150-240) U/L, GGT 169 U/L, total bilirubin 11.4 mg/dL, direct bilirubin 5.9 mg/dL, albumin 2.7 g/dL, ammonia 66 μmol/L, and INR 1.5. Because of the worsening liver disease and enlarging IHE, the patient was listed for liver transplantation.
At 6 months of age, he underwent cadaveric liver transplantation. Examination of the native liver revealed biliary cirrhosis and a 6 cm well-demarcated mass. Microscopic examination of the mass revealed a tumor composed of thin vascular channels lined by a single layer of CD31- and CD34-positive endothelial cells, consistent with type I IHE (Fig. 2). The walls of the vascular channels contained small bile ducts and entrapped hepatocytes. The interface between the cirrhotic liver parenchyma and IHE is shown in Figure 3. The patient is currently doing well 1 year after liver transplantation with good liver function.
A 1-month-old female was referred to our pediatric hepatology clinic with a history of multiple cutaneous hemangiomas and hepatomegaly. The patient had been born at term after an uncomplicated pregnancy. At birth, she had cutaneous hemangiomas over the right parietal scalp and left lower eyelid. At 4 months of age, hepatomegaly was noted. Abdominal ultrasound demonstrated innumerable hypoechoic hepatic lesions consistent with multifocal IHE. Complete blood count and coagulation studies at 6 months were normal.
At the time of referral, the patient was tachypneic with a liver span of 13 cm × 15.5 cm by palpation. Tests of liver function and AFP were normal. CT of the abdomen showed marked hepatomegaly with near total replacement of the liver by innumerable lesions of varying size without calcifications, consistent with IHE. Echocardiogram showed a large left atrium, left ventricular size at the 90% for age, and a normal fractional shortening of 36%. Therapy with prednisolone 2 mg/kg per day orally was begun.
By 15 months, the patient had no further enlargement of her liver and no signs of congestive heart failure. The prednisolone was tapered gradually and stopped. By 25 months, the liver span had decreased to 10 cm. Despite a recommendation for regular follow-up visits, the patient did not seek care for the next 3 years.
At 5 years, the patient returned with fever, hepatomegaly, and erythrocyte sedimentation rate of 52 (normal 4-20) mm/sec. Laboratory investigations included AST 71 U/L, ALT 49 U/L, lactate dehydrogenase 1,448 (normal 470-900) lU/L, and albumin 2.8 g/dL. Complete blood counts, AFP, and f3-human chorionic gonadotropin were normal. CT scan of the chest and abdomen revealed a lobulated exophytic mass involving the liver with relative sparing of the posterior segment of the right lobe; infiltration of fat anterior to the liver; multiple scattered pulmonary nodules bilaterally; and several small lymph nodes in the mediastinum. Thorascopic left lung segmentectomy revealed metastatic angiosarcoma.
The family chose to undergo therapy with α-interferon 3 million units/m2 per day and retinoic acid 1 mg/kg per day. Despite therapy, repeat CT scans showed increased number and size of pulmonary nodules in all segments; expansion of the liver mass into the anterior aspect of liver, the peritoneum, and anterior soft tissues of the anterior abdomen; compressed intrahepatic inferior vena cava; encasement of the celiac axis by tumor; and narrowed portal vein with a possible filling defect. The patient was discharged home with hospice care and expired. Autopsy was not performed.
Multiple hepatic hemangioendotheliomas were first reported in the United States in 1913 by Veeder and Austin (9). They reported a 10-week-old female infant who died with increasing abdominal distention and progressive weakness (likely from congestive heart failure). Autopsy demonstrated a liver with multiple nodules composed of dilated vascular spaces lined with endothelial cells with interposed fibrotic hepatic tissue. IHE most commonly presents with hepatomegaly (83%), abdominal mass (66%), cutaneous hemangiomata (66%), or congestive heart failure (58%) (3). Our case is the first reported to present with fulminant hepatic failure. Although the most common anomaly associated with IHR in children is cutaneous hemangiomata, we also report the first case of IHE associated with biliary atresia.
IHE arises from clonal expansion of genetically transformed, vascular endothelial cells (1). In contrast with hemangiomata, which are benign lesions composed of numerous vessels lined by benign vascular endothelial cells, IHE is composed of vessels lined by neoplastic, endothelial cells (Figs. 1 and 2) (10). These tumors grow as expansile masses without a fibrous capsule (Fig. 3). Two histologic subtypes of IHE have been described (type I and type II) (2). Although these two subtypes differ dramatically in cellular appearance, there is no statistically significant difference in prognosis between type I and type II lesions. Moreover, the two subtypes can often be found within the same tumor, confounding a simple dichotomous classification. Type I IHE accounts for more then 80% of cases and is composed of multiple vascular channels of varying caliber and configuration lined by a single layer of small, elongated endothelial cells. The neoplastic vascular channels proliferate within a background of loose, fibrous stroma with entrapment of native bile ducts. Type II IHE is composed of vascular channels lined by stratified layers of malignant-appearing endothelial cells with marked nuclear pleomorphism, nucleomegaly, nuclear hyperchromasia, and frequent mitotic figures. Type II lesions often display complex architectural patterns with branching, budding, and shedding of cells lining vascular channels. In contrast with type I tumors, type II lesions show conspicuous absence of bile ducts within the tumor mass. Lesions composed predominantly of type I cells with focal or rare type II differentiation are still classified as type II IHE. The neoplastic endothelial cells in both type I and type II IHE stain positive for the endothelial markers CD31 and CD34 (2).
The differential diagnosis of hepatic vascular lesions in children includes both benign and malignant entities (Table 1) (11). Benign lesions include hemangioma, lymphangioma, arteriovenous malformation, peliosis hepatis, angiomyolipoma, and IHE. Malignant lesions include angiosarcoma and hepatoblastoma. Hepatic vascular lesions are also found in association with congenital syndromes, including Osler-Weber-Rendu, Klippel Trenaunay-Weber, and Ehlers-Danlos. Diagnosis often depends on physical examination and characteristic findings on hepatic ultrasound, CT, or magnetic resonance imaging (MRI). Ultrasound often shows a heterogeneous, septated lesion with iso- and hypoechoic areas (11). The presence of areas of hyperechogenicity should raise the suspicion of malignancy. Color Doppler ultrasound can detect signs of increased blood flow, including a differentially enlarged proximal aorta and low-resistance flow in the hepatic artery. Further delineation can be made with biphasic contrast CT, which may show rapid peripheral enhancement during the arterial phase with delayed central filling during the venous phase. These radiologic patterns can, however, overlap with those found in malignant tumors. Dynamic gadolinium-enhanced MRI may aid in this distinction (12). Angiography should be reserved for children potentially requiring intervention for congestive heart failure.
Elevation in serum AFP can suggest the diagnosis of hepatoblastoma, but this finding has also been reported with IHE (13). The poor specificity of an elevated serum AFP is highlighted in case 2, where we assume the elevation may have been secondary to hepatic regeneration. If there is doubt as to the benign nature of a vascular lesion, biopsy can be performed either by fine needle aspiration or liver biopsy by the percutaneous, transjugular, or surgical approach. Because of the vascular nature of these lesions, appropriate supports should be available to deal with significant hemorrhage. As illustrated by case 3, it is of utmost importance to rule out malignancy in patients with IHE by either radiologic, histologic, or clinical findings.
Most lesions enlarge over the first year of life and then spontaneously regress (14). However, the development of significant respiratory or cardiac disease may prompt medical or surgical therapy. Treatment options consist of steroids (15,16), α-interferon (17,18), hepatic artery embolization (19,20), radiation therapy (21,22), surgical resection, and orthotopic liver transplantation (8,23-25). Medical therapy for congestive heart failure is indicated. Chemotherapy with cyclophosphamide, vincristine, or actinomycin D has also been used (26).
The prognosis of IHE is most often related to its impact on the child's pulmonary and cardiac function. Hepatic function may be severely affected, particularly if the lesion results in a significant loss of hepatic parenchyma, as in our case 1. A less common, possibly under-recognized morbidity of these lesions is metastatic disease. Daller et al. (3) reported a 2-year-old girl who underwent orthotopic liver transplantation for presumed type II IHE, but who was found to have metastatic hepatic angiosarcoma. Achilleos et al. (8) reported a 2-year-old girl with type II IHE who developed metastatic disease after liver transplantation. Thus, it has been suggested that hemangioendotheliomas presenting in older children may be more likely to have malignant potential (3). Our case 3 presented in infancy but nonetheless later died of metastatic angiosarcoma.
Although hepatic vascular lesions in children are rare, as a group they are not uncommon in a pediatric gastroenterology practice. They may be associated with various syndromes and extraintestinal symptoms. They may exist in the context of underlying chronic liver disease. Although children most often present with symptoms related to tumor bulk or congestive heart failure, serious hepatic dysfunction, including liver failure, can occur. Although most vascular lesions are benign, some, including IHE, have a malignant potential. If doubt exists at any point as to the benign nature of a lesion, biopsy should be considered. Given the malignant potential, we recommend long-term monitoring of patients with presumed or confirmed IHE at least until complete resolution of the hepatic lesion. Monitoring is probably best accomplished with serial clinical examinations and imaging with ultrasound or CT. Serum AFP should also be monitored if it was elevated at the time of diagnosis.
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