Disclosure
The liver is the third-most-common site for intra-abdominal malignancy in children, following adrenal neuroblastoma and Wilms tumor. The incidence of primary malignant liver tumors per year is 1-1.5 per million children in the United States. This yields a relative low rate for hepatic tumors (1.3% of all pediatric malignancies). Of these tumors, hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the most common and account for two thirds of all hepatic neoplasms. Most children with liver tumors present with abdominal distension and/or a palpable abdominal mass. Anemia, thrombocytopenia, and leukocytosis are often present. Children with both HB and HCC may also present with weight loss, fever, and anorexia. Laboratory studies are performed to assess baseline complete blood count, electrolytes, liver synthetic function, and a-fetoprotein (AFP) levels. AFP levels are elevated in 50%-70% of children with hepatic neoplasms, and, although AFP is not a prognostic indicator, multiple studies confirm that AFP is a valuable surveillance marker in children who have previously undergone hepatic resection for malignancy. The initial workup for hepatic masses includes radiographic assessment using ultrasound (US) to confirm the location and to characterize the consistency as cystic or solid. Computed tomography (CT) or magnetic resonance imaging (MRI) is used to further delineate the location and multiplicity of the lesions and to detect metastases. These modalities facilitate surgical planning and may determine resectability; however, definitive diagnosis can be proven only through biopsy.
Benign lesions in children represent 30% of hepatic tumors and are most commonly vascular in origin (hemangiomas, hemangioendotheliomas). Hemangiomas Hemangiomas are the most common benign liver tumors in children and commonly occur within the first 6 months of life. They have endothelial-lined vascular spaces and vary from small incidentally found masses to large cavernous hemangiomas that are distinguished by large vascular spaces and lack of cellularity. Hemangioendothelioma is a subtype of hemangioma that is typically found in infants (see Images 1-2). A female predilection for hemangioendothelioma exists, with a female-to-male ratio of 4.3:1 to 2:1. Afflicted infants generally present with abdominal distension and cutaneous hemangiomas (10% of cases) that suggest the diagnosis. As many as 50% of these infants have high-output cardiac failure at initial presentation. US, CT, or MRI is used to characterize the size and location. Laboratory abnormalities associated with this tumor include anemia, elevated aspartate transaminase levels, hyperbilirubinemia, and occasionally an elevated AFP level. The significance of an elevated AFP is unknown as the levels can be elevated in normal neonates and does not decrease to normal adult levels until 6 months of age. Platelet sequestration and consumptive coagulopathy are rarely evident in these children (Kasabach-Merritt syndrome). The natural history for hemangiomas is spontaneous regression in the first 2 years of life; however, treatment is required if cardiac failure or platelet consumption occurs. Several treatment options are available, and all are associated with potential severe complications and poor outcome. Initially, high-dose steroids (3-5 mg/kg/d) are given for 3-5 weeks. Supportive care may include liberal use of diuretics and digitalis to improve the cardiac function. This regimen is discontinued if no response is observed to avoid steroid-induced complications. Daily subcutaneous administration of interferon-alfa (3 million U/m2/kg) may lead to involution of hemangiomas located throughout the body. Up to 50% regression has occurred in some reports; however, the response time is slow, and lesions can rebound once the drug is stopped. There is also the risk of spastic diplegia developing in very young children. Focal lesions are treated with complete surgical excision or with selective hepatic artery embolization. Selective hepatic artery embolization may not be as successful for multifocal lesions as for focal lesions. Regardless, the hepatic parenchyma is preserved secondary to portal flow. Antineoplastic agents and radiation are usually avoided because of limited success. Furthermore, some case reports document angiosarcomatous degeneration of a benign hemangioendothelioma, both spontaneously and following radiation treatment. Multifocal lesions prove to be more of a challenge than focal lesions, and hepatic artery ligations or embolization may decrease shunting enough to improve the cardiac output. On rare occasions, liver transplantation may be indicated for diffuse disease that is unresponsive to steroid and interferon therapy. The overall prognosis for these benign hepatic tumors in children is good. Mesenchymal hamartomas Mesenchymal hamartomas are rare tumors, comprising only 6% of liver tumors in children. They can be considered to be more malformation than true tumors, although they present as masses with their organ of origin. They are typically diagnosed when the patient is younger than 2 years. They are often multicystic, heterogeneous, confined to one lobe, and asymptomatic. Radiographic studies are helpful to suggest this lesion, but definitive diagnosis generally requires open liver biopsy (see Images 3-4). Reports of sarcoma arising from these lesions and the tendency for the lesion to recur make complete surgical excision, if possible, the treatment of choice and associated with low morbidity; some authors have advocated nonoperative therapy. Focal nodular hyperplasia and hepatic adenomas Focal nodular hyperplasia (FNH) and hepatic adenomas are rarely seen in childhood. Both of these benign lesions have an association with a high estrogen environment and frequently occur in adolescent girls. Hepatic adenomas are associated with oral contraceptive use. A characteristic central scar on CT scan is pathognomonic for FNH. Unenhanced CT scans show a hypodense well-defined lesion (see Image 5). A 3-phase CT scan is the optimal study to make the diagnosis of FNH, including an arterial phase, portal venous phase, and delayed images. During the arterial phase, an FNH appears as an early contrast-enhanced homogenous lesion that becomes isodense with the normal liver parenchyma on delayed images. A less enhanced central scar can be seen in fewer than 50% of lesions. Differentiating FNH from adenomas may require technetium sulphur colloid scan, which shows uniform uptake by FNH lesions. Open biopsy may be required for definitive diagnosis in rare circumstances (see Image 7). FNH lesions have no malignant potential and are often asymptomatic. Many surgeons advocate elective resection to prevent spontaneous rupture and hemorrhage; however, other surgeons follow these lesions with serial US monitoring. If the lesions are symptomatic or rapidly enlarging, complete surgical resection, embolization, or hepatic artery ligation may be used for treatment. Hepatic adenomas are treated with complete surgical excision because these lesions have a small risk for rupture, hemorrhage, or malignant transformation to hepatocellular carcinoma.
Hepatoblastoma Hepatoblastoma (HB) is the most common primary hepatic malignancy in childhood, accounting for 43% of all pediatric liver tumors. The typical presentation is a child younger than 3 years with an abdominal mass, anemia, failure to thrive, and vomiting. Associated laboratory abnormalities include an elevated AFP and thrombocytosis. An increased risk of HB exists in association with hemihypertrophy and Beckwith-Wiedemann syndrome, which indicates possible involvement of a chromosome 11 deletion. In addition, an increased incidence of HB is associated with familial adenomatous polyposis syndrome. The workup begins with an abdominal US to localize the mass and estimate the extent of tumor within the liver. Doppler evaluation can be used to evaluate the patency of the inferior vena cava, the hepatic veins, and the portal vein. CT scans of the abdomen and chest are used to assess respectability and evaluate for the presence of pulmonary metastasis (see Images 8-9). Hepatic angiography or MRI angiography is frequently helpful preoperatively to determine resectability because it delineates the vascular anatomy more precisely. The serum tumor marker, AFP, is obtained during the workup; more that 90% of patients with HB have elevated AFP levels. Multiple staging systems are used worldwide. In the United States, staging of tumors is based on guidelines established by the Children's Oncology Group (COG) using the extent of tumor and outcome of surgical resection as critical criteria. Histologic subtype also plays an important role in survival.
Recently, the pretreatment and presurgery system used in the study of the International Society of Pediatric Oncology on childhood liver tumors (SIOPEL) is being used by COG for the next clinical study. This system divides the liver into 4 sectors; the anterior and posterior on the right side and the medial and lateral sectors on the left. Based on the tumor location, the patient is placed in one of 4 categories: Stage I if three adjoining sectors are free; Stage 2 with two adjoining sectors free; Stage III with one sector free; and Stage IV when no sectors are free of tumor (see Images 11-12). It is also taken into account whether portal or hepatic veins are involved or if extra hepatic spread has occurred. Both staging systems directly correlate with patient survival.
Table 1. Outcomes based on the Children's Oncology Group Staging System
Table 2. Outcomes based on the SIOP PRETEXT STAGING
Complete surgical resection remains the goal of current therapy for HB. Treatment begins with laparotomy for resection if possible or biopsy if the tumor is unresectable. About half of tumors can be resected, and postoperative chemotherapy consists of cisplatin, vincristine, and 5-fluorouracil. Approximately 50% of tumors are deemed unresectable and require chemotherapy before definitive resection can be performed. Characteristics of an unresectable tumor include multicentricity, invasion of the inferior vena cava (IVC) or portal vein, or distant metastases. Adequate response to chemotherapy is observed in 70% of patients who then go on to complete resection followed by additional postoperative chemotherapy. In patients with tumors that do not adequately respond to resection, orthotopic liver transplantation is an option if there is no evidence of regional or distant metastases. AFP is considered an early marker for recurrence, and elevated levels should prompt thorough investigation. The survival rate has improved steadily over the last 3 decades, and the overall survival is currently 85%-92% (see Table). Hepatocellular carcinoma Hepatocellular carcinoma (HCC) accounts for 23% of pediatric hepatic malignancies and typically presents in 2 incidence peaks, the first occurring at ages 0-4 years and the second between ages 10-14 years. Predisposing conditions include hepatic fibrosis and cirrhosis secondary to metabolic liver disease, viral hepatitis, extrahepatic biliary atresia, total parenteral nutrition, and chemotherapy-induced fibrosis. Less commonly, HCC occurs in children without preexisting liver disease. Patients with HCC typically present with abdominal pain caused by the large size of the lesion (see Image 13). Associated weight loss, anemia, and fever may also be present. Liver function tests are routinely elevated; the AFP is elevated in half of the cases. Metastases usually occur in the lung and lymph nodes. Workup and staging are similar to those used in HB (see staging systems). More than 70% of these tumors are considered unresectable at the time of presentation and, unlike HB, they respond poorly to chemotherapy. Treatment is a combination of chemotherapy and surgery. Vincristine, cisplatin, 5-FU, and doxorubicin have had little impact on the progression of this disease. Newer therapeutic strategies have included chemoembolization, intra-arterial chemotherapy, and intraoperative cryotherapy. The overall survival rate remains poor, with a 41% disease-free survival rate at 2 years and a 27% disease-free survival rate at a longer follow-up interval. In children with recurrent liver disease or multifocal extensive primary malignancies, hepatic transplantation is an option. Hepatic metastases Hepatic metastases in the pediatric population arise from a variety of primary malignancies, including neuroblastoma, Wilms tumor, rhabdomyosarcoma, rhabdoid tumor, non-Hodgkin lymphoma, adrenal cortical carcinoma, and osteogenic sarcoma. Current criteria for resection of these hepatic metastases include control of the primary tumor, a solitary or limited number of metastases, and a reasonable expectation of prolonged survival. |
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Planning a major hepatic resection begins with adequate imaging studies to ensure resectability. Doppler US used in combination with MRI provides excellent information regarding the vascular and biliary anatomy. Resection is typically performed through a bilateral subcostal incision, and, occasionally, a right thoracoabdominal approach is necessary for large lesions arising high in the right lobe. The most frequently performed procedure is a right hepatectomy (60%) because hepatoblastomas occur 3 times more often in the right lobe than in the left. The hilar plate is divided, exposing the bifurcation of the hepatic artery and portal vein. These structures are ligated. The right hepatic vein is identified and ligated before any division of the hepatic parenchyma. In an extended right hepatectomy, the middle hepatic vein is ligated and segment IV is resected. At completion, only segments II and III and the caudate lobe remain. Left hepatic lobectomy begins the same way right hepatectomy, with division of the left hepatic artery and left branch of the portal vein. The left and middle hepatic veins are identified after dissection through the sinus venosus. The liver then is transected after vascular isolation of the resected segments. An extended left hepatectomy includes removal of all or most of segments V and VIII. Major intraoperative complications include hemorrhage, air embolism, tumor embolus, and bile duct injury. Postoperative complications include hemorrhage, bile leak, abscess formation, pulmonary complications, and wound problems. Only 20% of the liver is necessary to maintain hepatic function; thus, postoperative insufficiency is rare. Postoperative care consists of adequate fluid replacement, intravenous albumin supplementation, vitamin K, and clotting factors for the first 3-4 days. The liver function test results generally normalize within the first 2 weeks, and hepatic insufficiency is reasonably rare. Postoperative monitoring consists of frequent US, chest radiographs, and serial AFP levels, generally at 3- to 6-month intervals.
Orthotopic liver transplantation was first described in 1968 by Thomas Starzl, MD, PhD. Hepatoblastoma now constitutes an indication for 3% of all pediatric liver transplantations. Additionally, successful transplantation has been used for HCC and benign lesions such as diffuse hepatic hemangiomas. Survival rates for children with transplantation for malignancy have increased steadily over the last 10 years and currently range from 25%-90%, depending on the series. The availability of donor organs has increased with the use of split-liver grafting and living-related liver transplant techniques. Generally, preoperative and postoperative chemotherapy are recommended in addition to postoperative immunosuppression.
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