Tumors of the liver may be either malignant or benign. 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 malignant tumors, hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the most common and account for two thirds of all hepatic neoplasms. Benign liver tumors include hemangiomas, hamartomas, and focal nodular hyperplasia (FNH).
Presentation and workup
Most children with liver tumors present with abdominal distension, a palpable abdominal mass, or both. Anemia, thrombocytopenia, and leukocytosis are sometimes present. Children with both HB and HCC may also present with weight loss, fever, and anorexia.
Fetal and neonatal presentations include hydramnios, fetal hydrops, congestive heart failure, and respiratory distress. Patients with congestive heart failure have been shown to have lower survival rates. Cesarean delivery is recommended in cases when a hepatic tumor is found using prenatal ultrasonography to prevent rupture. 
Laboratory studies are performed to assess baseline CBC count, electrolyte levels, liver enzyme levels, liver synthetic function, and α -fetoprotein (AFP) levels. AFP levels are elevated in 50%-70% of children with hepatic neoplasms, and 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 ultrasonography to confirm the location and to characterize the consistency as cystic or solid. Cystic or vascular lesions may not require any further imaging. CT scanning and MRI (MRI) of the abdomen and chest are used for indeterminate or solid lesions to further delineate the location, extent, 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 findings.
Benign lesions in children represent 30% of hepatic tumors and are most commonly vascular in origin (eg, hemangiomas, hemangioendotheliomas). 
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 the images below). A female predilection for hemangioendothelioma is noted, 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. Most hemangiomas are incidentally discovered on imaging studies.  As many as 50% of these infants have high-output cardiac failure at initial presentation. Ultrasonography, CT scanning, or MRI is used to characterize the size and location. CT scanning reveals typical features of peripheral contrast enhancement with subsequent isodense filling of the lesion and liver. 
Laboratory abnormalities associated with this tumor include anemia, elevated aspartate transaminase levels, hyperbilirubinemia, and occasionally an elevated α-fetoprotein (AFP) level. The significance of an elevated AFP level is unknown because the levels can be elevated in healthy neonates and does not decrease to normal adult levels until age 6 months. Platelet sequestration and consumptive coagulopathy are rarely evident in these children (see Kasabach-Merritt Syndrome), and they may present with hemorrhage and respiratory distress.
Hypothyroidism has been observed in large tumors secondary to antibodies to thyroid-stimulating hormone (TSH), and screening for secondary hypothyroidism is recommended.  Resolution of hypothyroidism after transplant in patients who were initially resistant to medical management has been reported. [5, 6]
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 corticosteroids (3-5 mg/kg/d) are administered for 3-5 weeks. Supportive care may include liberal use of diuretics and digitalis to improve the cardiac function in cases of failure.  Correction of anemia and coagulopathy is performed with blood product replacement. This regimen is discontinued if no response is observed, in order to avoid steroid-induced complications.
More recently, the use of propranolol has been shown to help with resolution of these lesions; however, it does require several months to have an effect. One can follow the reverse T3 as a marker of resolution of the hemangioma. [8, 6]
Daily subcutaneous administration of interferon-alfa (3 million U/m2/kg) may lead to involution of hemangiomas located throughout the body. As much as 50% regression has occurred in some reports; however, the response time is slow, and lesions can rebound once the drug is stopped. Case reports have described spastic diplegia in very young children who have received interferon, but the actual risk of this therapy is unknown.
Other treatment options include aminocaproic acid, vincristine, and cyclophosphamide. [9, 10, 11] Aminocaproic acid may be used in addition to cryoprecipitate to ameliorate the coagulopathy associated with Kasabach-Merritt syndrome, and antineoplastics may inhibit the proliferation and subsequent extension of the hemangioma.
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 it is for focal lesions. Regardless, the hepatic parenchyma is preserved secondary to portal flow. Operative ligation of the hepatic artery can also be used to decrease shunting through the lesion, with subsequent improvement in cardiac output. 
Radiation therapy is usually avoided because angiosarcomatous degeneration of benign hemangiomas following radiation and spontaneously occurring have been reported. Rarely, liver transplantation may be indicated for diffuse disease that is unresponsive to steroid and interferon therapy.
Mesenchymal hamartomas are rare tumors, comprising only 6% of liver tumors in children. They can be considered to be more of a 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 usually grow during the first few months of life, then may stabilize, grow, or regress. These tumors are more common in the right lobe of the liver.  They are often multicystic, heterogeneous, confined to one lobe, and asymptomatic.
Signs and symptoms include a palpable mass with smooth borders and evidence of venous enlargement on physical examination. AFP levels may be variably elevated. 
CT scanning reveals a well-circumscribed, multilocular cystic mass with solid septae and stroma (see the images below). Biopsy is recommended if cysts are small or appear more solid rather than septated due to concern for malignancy. 
Enucleation and marsupialization of the mass are treatment options. However, reports of sarcoma and hepatoblastoma (HB) arising from these lesions and the tendency for the lesion to recur make complete surgical excision, with a rim of normal tissue (if possible), the treatment of choice. 
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.
Signs and symptoms may be absent or are nonspecific and include abdominal pain and mass symptoms.
A characteristic central scar on CT scan is pathognomonic for FNH. Unenhanced CT scans reveal a hypodense well-defined lesion (see the image below). 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 lesion 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 less than 50% of lesions.
Differentiating FNH from adenomas may require a technetium sulphur colloid scan, which reveals uniform uptake by FNH lesions. Hepatocellular carcinomas (HCCs) and hepatoblastomas (HBs) have been reported after a benign diagnosis on imaging studies.  Open biopsy may be required for definitive diagnosis in rare circumstances, especially if observation is considered (see the image below).
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 ultrasonography 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 (see the images below). [14, 15, 16]
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, although no pathognomonic presentation is noted. [17, 18]
Associated laboratory finding abnormalities include an elevated α-fetoprotein (AFP) level and thrombocytosis. Genetic syndromes are associated with approximately 15% of HBs. An increased risk of HB is noted 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 as well as case series of HB associated with trisomy 18. Future whole-genome sequencing may elucidate the combination of genetic and epigenetic changes that drive tumorigenesis in HB.
The workup begins with an abdominal ultrasonography 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 scanning of the abdomen and chest is used to assess resectability and evaluate for the presence of pulmonary metastasis (see the images below). 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 than 90% of patients with HB have elevated AFP levels. A low AFP level (< 100 ng/mL) in children with HB is an indicator of a high-risk subgroup with unfavorable tumor biology, poor response to chemotherapy, and poor outcomes.  In addition to low AFP level, older age, multifocality of tumors, higher stage, and involvement of major vessels were associated with an inability to achieve curative resection. 
HB histologic subtypes may impact on prognosis. In one series, the pure fetal hepatoblastoma subtype demonstrated 50% survival in compared with those who had fetal and embryonal histology (30% survival).  A recent Children's Oncology Group (COG) study has shown that complete resection of stage I patients with pure fetal histology are cured with surgery alone and require no chemotherapy.
Multiple staging systems are used worldwide. In the United States, staging of tumors is based on the extent of tumor and outcome of surgical resection as critical criteria. Histologic subtype also plays an important role in survival.
The staging system is as follows:
Stage I - Complete resection
Stage II - Resection with microscopic residual disease
- Resection with gross residual tumor
- Tumor spill, positive lymph node findings, or both
- Incomplete resection of primary tumor
Stage IV - Distant metastases
Future COG protocols plan to introduce a risk-based determination of treatment, with low, intermediate, and high-risk categories. These categories will also aid in follow-up and prognosis.
COG protocols have introduced a risk-based determination of treatment with very low-, low-, intermediate-, and high-risk categories. These categories have aided in follow-up and prognosis. Already, they have discovered that the very low–risk group is cured with surgery alone and no longer requires adjuvant chemotherapy.
Very low risk - Stage 1 with pure fetal histology
Low risk - Resected lesions with favorable biology
Intermediate risk - Unresected lesions without metastases or resected lesions with unfavorable biology
High risk - Metastatic disease or AFP level of less than 100 at diagnosis
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. [20, 22] 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. These have been derived from Couinaud's system of liver segmentation.
The right anterior consists of segments 5 and 8, and the right posterior consists of segments 6 and 7. The left lateral consists of segments 2 and 3, and left medial consists of segments 4a and 4b. Involvement of the caudate lobe (segment 1) is given separate staging consideration, as are extrahepatic disease, tumor focus, tumor rupture, distant metastasis, lymph node involvement, portal, hepatic, and inferior vena cava (IVC) involvement.
Based on the tumor location, the patient is placed in one of 4 categories: Stage I if 3 adjoining sectors are free; stage 2 if 2 adjoining sectors free; stage III if one sector is free; and stage IV if no sectors are free of tumor (see the images below). Both staging systems directly correlate with patient survival. 
The 5-year survival rates based on the COG staging system are as follows:
Stage I (Favorable histology) - 100%
Stage I (Unfavorable histology) - 98%
Stage II - 100%
Stage III - 69%
Stage IV - 37%
The 5-year survival rates based on the SIOPEL staging are as follows:
Stage I - 100%
Stage II - 91%
Stage III - 68%
Complete surgical resection remains the goal of current therapy for HB for cure. Two main strategies for approaching resection of the tumor are noted. In the United States, the bias is towards early resection of tumor at diagnosis. Proponents of this therapy argue that the cumulative toxicity of chemotherapy can be reduced, some agents can be entirely avoided, and a reduction of in vivo development of tumor resistance may also occur. An opportunity to delay resection until after neoadjuvant therapy is observed in patients with stage III and IV tumors.
In contrast, the SIOPEL group advocates neoadjuvant therapy in all patients. They argue that primary systemic chemotherapy may reduce the size of the tumor and may allow for easier complete resection and lower morbidity; they also argue that the toxicity of chemotherapy is offset by the high rates of complete excision. 
Approximately 50% of tumors are deemed unresectable at diagnosis and require chemotherapy before definitive resection can be performed. Characteristics of an unresectable tumor include multicentricity, invasion of the IVC or portal vein, or distant metastases. Isolated pulmonary metastases that persist after neoadjuvant chemotherapy may be treated with pulmonary metastasectomy.  Adequate response to chemotherapy is observed in 70% of patients who then go on to complete resection followed by additional postoperative chemotherapy.
A study by Venkatramani et al assessed radiographic images from 20 patients with grade III and IV hepatoblastoma for the potential for surgical resection at diagnosis and after two to four cycles of neoadjuvant chemotherapy. The study found that number of tumors considered unresectable decreased from 80% at initial diagnosis, to 35% after two cycles of chemotherapy and then to 20% after four cycles. [24, 25]
Resection of tumors that are multifocal or have major venous involvement should be considered only in selected centers with the capabilities for appropriate postoperative care and the ability to provide for transplant, should that option become necessary. Major complications following resection have been reported to be as much as 20-30%, with complications following resection of HB more prevalent than complications after resection of hepatocellular carcinoma (HCC).
In patients with tumors that do not adequately respond to resection, orthotopic liver transplantation is an option if no evidence of regional or distant metastases is noted or when that metastatic disease has been surgically removed. 
AFP is considered an early marker for recurrence, and elevated levels should prompt thorough investigation. The survival rate has steadily improved over the last 3 decades, and the overall survival rate is currently 85%-92%. The outcome, in terms of survival, for patients with HB appears to be better than patients with HCC. 
HCC accounts for 23% of pediatric hepatic malignancies and typically presents in 2 incidence peaks: the first is at age 0-4 years and the second is at age 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.
Patients with HCC typically present with abdominal pain caused by the large size of the lesion (see the image below). Multiple lesions, intravascular spread and metastases are more common in HCC compared with HB. Associated weight loss, anemia, and fever may also be present. Liver function test findings are routinely elevated; the AFP level is elevated in approximately half of the cases. Unlike adult types, the fibrolamellar variant of HCC has not been found to be associated with a better prognosis or improved response to treatment in children. 
Metastases usually occur in the lung and lymph nodes. The workup and staging are similar to those used in HB.
More than 70% of these tumors are considered unresectable at the time of presentation and, unlike HB, respond poorly to chemotherapy. Combination chemotherapy, as is used for HB, has been administered to patients with HCC but has been largely ineffective in shrinking tumors to the point of respectability and in eradicating metastases. Vincristine, cisplatin, 5-fluorouracil (5-FU), and doxorubicin have had little impact on the progression of this disease. Complete surgical resection or transplantation is often the only chance for cure. Newer therapeutic strategies have included chemoembolization, intra-arterial chemotherapy, and intraoperative cryotherapy.
The use of sorafenib (Nexavar), a novel tyrosine kinase inhibitor of angiogenesis, has shown some benefit in clinical trials and has been approved for HCC in adults by the US Food and Drug Administration (FDA). 
The overall survival rate remains poor, with a recent Surveillance, Epidemiology, and End-Results (SEER) database review showing 5-, 10-, and 20-year survival rates of 24%, 23%, and 8%, respectively.  Children with initially resectable disease have a much better prognosis than those who present with advanced or disseminated disease.
Other primary liver tumors include undifferentiated sarcoma, biliary rhabdomyosarcoma, angiosarcoma, and rhabdoid tumors.
Hepatic metastases are more common in the pediatric population than primary tumors and may arise from various primary malignancies, including neuroblastoma, Wilms tumor, rhabdomyosarcoma, rhabdoid tumor, non-Hodgkin lymphoma, and adrenal cortical carcinoma. The role of surgical resection of these lesions is extremely limited. 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. The resection of hepatic metastases is feasible in selected cases, and anatomic hepatectomy is associated with better local control compared with wedge resection. 
Complete surgical resection of malignant hepatic tumors is considered a key part of attempt at cure.  Planning a major hepatic resection begins with adequate imaging studies to ensure resectability. Doppler ultrasonography used in combination with MRI provides valuable information regarding the vascular and biliary anatomy. The PRETEXT system was developed by the International Society of Pediatric Oncology on Childhood Liver Tumors (SIOPEL) group to identify suitable candidates for primary resection.  This system is being adopted internationally to provide a universal language for surgeons and will be helpful for those who see such cases infrequently.
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. Surgical resection has seen applications of newer technology. Intraoperative ultrasonography has been widely applied to determine the exact location of the tumor relative to the vessels. Once deemed resectable, the resection is marked out, and various tools may then be used to perform the resection; electrocautery, bipolar devices such as LigaSure, and argon beam coagulation for hemostasis have been used. See the images below.
Laparoscopic and robotic resections of both benign and malignant liver tumors have been described. Their role in standard practice is still being defined.
Unresectability is usually determined by involvement of hilar structures or all hepatic veins, multicentricity, and invasion of inferior vena cava (IVC) or portal vein. Centrally located tumors are, by definition, more likely unresectable.
The most frequently performed procedure is a right hepatectomy (60%) because hepatoblastomas (HBs) 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 4 is resected. At completion, only segments 2 and 3 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 is then transected after vascular isolation of the resected segments. An extended left hepatectomy includes removal of all or most of segments 5 and 8.
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 ultrasonography, chest radiography, and serial α -fetoprotein (AFP) level measurements, generally at 3-month to 6-month intervals.
Hepatic Transplantation For Malignancy
Orthotopic liver transplantation was first described in 1968 by Starzl.  Hepatoblastoma (HB) now constitutes an indication for 3% of all pediatric liver transplantations. Additionally, successful transplantation has been used for hepatocellular carcinoma (HCC) and benign lesions such as diffuse hepatic hemangiomas. The main indication for transplantation is nonmetastatic, unresectable lesions.  Transplantation may also be used in selected cases of tumor recurrence but is much less successful when used for salvage therapy. In addition, liver transplantation may be an option in children with unresectable primary tumors, without metastatic disease, after neoadjuvant chemotherapy and pulmonary metastasectomy, if necessary. Rarely, transplantation is an option for benign lesions that have resulted in significant organ compromise with no other effective therapeutic modality. 
The survival rate after liver transplantation in children with malignant tumors (ie, HB and HCC) at a single center has been reported as 91% at 1 year and 5 years and 82% at 14 years, respectively.  More generally, the 5-year survival rate for patients transplanted for HB is 70%.
The role of liver transplantation for HCC is more controversial. The criteria currently used to evaluate adult transplant candidates may not be applicable for pediatric patients. Because no good medical therapy for pediatric HCC has been identified, liver transplantation should be carefully evaluated as front-line therapy.
A study of the United Network for Organ Sharing (UNOS) database reported 135 patients undergoing 135 transplants for HB and 43 transplants for HCC with 1-year, 5-year, and 10-year survival of 79%, 69%, and 66% for HB, respectively, and 86%, 63%, and 58% for HCC, respectively.  The primary cause of death for both groups was metastatic disease.
The availability of donor organs has increased with the use of split-liver grafting and other "technical variant" techniques, along with living-related liver transplant techniques. Prognosis in terms of graft and patient survival appear to be the same between full-size liver and technical variant liver transplants; however, morbidity following transplant appears to be higher in those patients who receive technical variant grafts.  Generally, preoperative and postoperative chemotherapy are recommended, in addition to postoperative immunosuppression.
Liver transplantation for hepatic hemangioma has been studied in 59 patients in Europe with 1-year, 5-year, and 10-year patient survival rates of 93%, 83%, and 72%, respectively. Extrahepatic disease and lymph node involvement did not prove to be contraindications. 
Early failure of liver transplant (< 30 d) is usually due to vascular complications or primary nonfunction. Late failure is usually more a result of infection, posttransplant lymphoproliferative disease, chronic rejection, biliary complications, or recurrence of malignant disease. These failures may warrant retransplantation. The predictors of success after retransplantation remain unknown.
Bcl-2 appears to play a role in the anti-apoptotic mechanisms of some hepatoblastoma (HB) subtypes. This gene may serve as a target for future gene-directed therapy. 
The Wnt signaling and mutations in the beta-catenin gene have been shown to be present in HB specimens. A better understanding of these pathways may lead to targeted therapies.