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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