Pediatric Liver Tumors 

Updated: Jan 18, 2022
Author: Arun A Rangaswami, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK) 

Overview

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 renal tumors, such as Wilms tumor. The incidence of primary malignant liver tumors per year is approximately 1.5 per million children in the United States. This yields a relative low rate for hepatic tumors (1.3% of all pediatric malignancies in children under the age of 19 years of age). Of these malignant tumors, hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the most common and account for over two thirds of all hepatic neoplasms. Benign liver tumors include hepatocellular adenomas (HCAs), 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.[1]

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 with Doppler 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 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 Tumors

Benign lesions in children represent 30% of hepatic tumors and are most commonly vascular in origin (eg, hemangiomas, hemangioendotheliomas).[2]

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 the images below). A female predilection for hemangioendothelioma is noted, with a female-to-male ratio of 4.3:1 to 2:1.

CT scan appears of a hemangioendothelioma. Note th CT scan appears of a hemangioendothelioma. Note the contrast enhancement around the periphery.
Intraoperative view during resection of a localize Intraoperative view during resection of a localized hemangioendothelioma.

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.[3] 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.[3]

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.[4] 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.[7] 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.[12]

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

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.[13] 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.[3] 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.[3]

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.[3]

Typical appearance of a mesenchymal hamartoma duri Typical appearance of a mesenchymal hamartoma during resection.
Gross image of the mesenchymal hamartoma specimen Gross image of the mesenchymal hamartoma specimen after resection.
Intraoperative image of a mesenchymal hamartoma. Intraoperative image of a mesenchymal hamartoma.

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.[3]

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.

Enhanced axial CT scan through the liver in the ar Enhanced axial CT scan through the liver in the arterial phase in a 38-year-old woman referred for gallbladder scanning. The mass demonstrates intense enhancement. Image courtesy of Dr Ali Nawaz Khan, MBBS.

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.[3] Open biopsy may be required for definitive diagnosis in rare circumstances, especially if observation is considered (see the image below).

Intraoperative image of a focal nodular hyperplasi Intraoperative image of a focal nodular hyperplasia (FNH).

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]

CT scan revealing hepatic adenoma arising from the CT scan revealing hepatic adenoma arising from the left lobe of the liver.
Intraoperative image demonstrating an hepatic aden Intraoperative image demonstrating an hepatic adenoma.
 

Malignant Tumors

Hepatoblastoma

Hepatoblastoma (HB) is the most common primary hepatic malignancy in childhood, accounting for two thirds of all pediatric liver tumors in patients under the age of 20.[17] . For reasons that are unclear, the incidence of HB appears to be increasing at a rate of 4% per year in North America and 2.5% per year in the European Union.[17]  There seems to be a slight predilection for males, with some studies citing a male to female ratio of 1.5:1. An increased incidence of HB is seen in children born prematurely or with a birthweight under 1 kg. 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.[18, 19]

Associated laboratory finding abnormalities include an elevated α-fetoprotein (AFP) level and thrombocytosis. The diagnosis of a liver mass presenting in the first several months of life may be challenging as the AFP level may be physiologically elevated and therefore may obscure the diagnosis and burden of disease. In children and young adults, hepatoblastoma is almost never associated with chronic liver disease.  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.[20] In addition, an increased incidence of HB is associated with trisomy 18, trisomy 21, Aicardi syndrome, Li-Fraumeni syndrome, Goldenhar syndrome, type 1a glycogen storage disease (von Gierke disease), and familial adenomatous polyposis.[21, 22, 23]  For some of these conditions, recommended screening is with quarterly AFP measurement and abdominal ultrasound scans. 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, which carries importance with respect to candidacy for up-front surgical resection. CT scanning of the abdomen and chest is used to assess resectability and evaluate for the presence of pulmonary metastasis (see the images below), although MRI using the hepatobiliary-specific contrast agent, Eovist, may have added benefit in identifying multifocal lersions. Hepatic angiography or MRI angiography may be helpful preoperatively to determine resectability because these modalities delineate the vascular anatomy more precisely.

CT scan of a hepatoblastoma amenable to surgical r CT scan of a hepatoblastoma amenable to surgical resection.
CT scan showing a hepatoblastoma present in multip CT scan showing a hepatoblastoma present in multiple liver segments that is not amenable to surgical resection at the time of presentation.

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.[24] 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.[25]

HB histologic subtypes may impact on prognosis. In one series, the small cell undifferentiated (SCUD) subtype demonstrated 50% survival in compared with those that had fetal and embryonal histology (30% survival).[1]  However, a recent analysis by the Children's Oncology Group (COG) conducted on a more contemporary dataset asserts that this is not the case.[26]  COG has also shown that complete resection of stage I patients with well differentiated pure fetal histology are cured with surgery alone and require no chemotherapy.

Multiple staging systems are used worldwide. Historically, in COG, staging of HB followed the Evans surgical guidelines. Here, stage I denotes a completely resected tumor; stage II represents resection with microscopic residual disease; stage III denotes unresectable tumor, resection with gross residual disease, or positive lymph nodes; and stage IV connotes distant metastases. COG followed these staging guidelines for protocols up to and including the AHEP0731 Trial (NCT#00980460), which enrolled patients between 2009 and 2020. These historical COG protocols used a risk stratification that incorporated Evans stages as well as AFP, as follows:

  • Very low risk - Stage I with well differentiated pure fetal histology (≤ 2 mitoses per 10 HPF)

  • Low risk - Completely resected lesions with negative margins and favorable histology (crowded fetal and fetal/ embryonal)

  • Intermediate risk - Unresected lesions without metastases or resected lesions with unfavorable biology

  • High risk - Metastatic disease or AFP level of less than 100 ng/mL at diagnosis

More recently, HB staging has evolved to incorporate the Pre-Treatment Extent of Disease (PRETEXT) system, which depends on the number of adjacent liver sectors involved. Tumors are staged from PRETEXT I to IV, along with annotation factors for hepatic and portal venous involvement, extra-abdominal extension, focality, rupture, and metastases. These annotation factors have been associated with poorer prognosis. The PRETEXT 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 hepatic sectors incorporate the 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 focality, preoperative tumor rupture, distant metastasis, lymph node involvement, caudate lobe involvement, and portal, hepatic, and inferior vena cava (IVC) involvement.

Based on the tumor location, the patient is placed in one of 4 categories: PRETEXT stage I if 3 adjoining sectors are free; PRETEXT stage 2 if 2 adjoining sectors free; PRETEXT III if one sector is free; and PRETEXT IV if no sectors are free of tumor (see the images below). Both staging systems directly correlate with patient survival.[27]

Sectors of the liver with tumor location based on Sectors of the liver with tumor location based on the International Society of Pediatric Oncology on Childhood Liver Tumors (SIOPEL) study.
Sectors of the liver with tumor location based on Sectors of the liver with tumor location based on the International Society of Pediatric Oncology on Childhood Liver Tumors (SIOPEL) study.

The 5-year survival rates based on the COG Evans 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 International Childhood Liver Tumor Strategy Group (SIOPEL) PRETEXT staging are as follows:

  • PRETEXT I - 100%

  • PRETEXT II - 91%

  • PRETEXT III - 68%

Complete surgical resection remains the goal of current therapy for HB for cure. Historically, two main strategies for approaching resection of the tumor were utilized. In the United States, the bias was towards early resection of tumor at diagnosis. Proponents of this therapy argued 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 advocated neoadjuvant therapy in all patients, based upon their belief that primary systemic chemotherapy reduced the size of the tumor and may allow for easier complete resection and lower morbidity.[3]  The divergent approaches to staging and risk stratification described above, as well as the overall rarity of HB, challenged harmonization of these therapeutic approaches.

In an effort to develop a unified approach to risk-based therapy assignment, the Children’s Hepatic Tumors International Collaboration (CHIC) performed an analysis of 1605 children treated in eight multicenter HB trials over 25 years. This revealed that the most prognostic factors were PRETEXT group, age (younger than 3 years, 3-7 years, and 8 years and older), AFP (< 100 and 101-1000 ng/mL), and presence of PRETEXT annotation factors.[11, 12]  Data from the CHIC analysis showed that the risk of adverse prognostic events increases continuously with age.[12]  This has been suggested to correlate with biologic characteristics that may be more aggressive in older patients.

Risk stratification based on the factors identified by the CHIC analysis is now being used in the open Pediatric Hepatic International Tumor Trial (PHITT) (designated COG AHEP1731 in North America) for patients with newly diagnosed HB. This trial is actively enrolling patients in North America, Europe, and Japan. An effort to validate the CHIC risk stratification system using more contemporary trials is underway in CHIC currently.[28, 29]  The PHITT trial bridges the divergent approaches in COG and SIOPEL by offering up-front resection and therapy reduction in patients with smaller (PRETEXT I and II) tumors, while continuing to offer preoperative chemotherapy in patients with larger tumors or annotation factor positivity.

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, and distant metastases. Isolated pulmonary metastases that persist after neoadjuvant chemotherapy may be treated with pulmonary metastasectomy.[30] 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 HB 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 2 cycles of chemotherapy, and then to 20% after 4 cycles.[31, 32]

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 high 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 (OLT) is an option if no evidence of regional or distant metastases is noted or when metastatic disease has been surgically removed.[33]  For patients with HB with pulmonary metastasis, OLT is permissible as long as metastases are cleared by preoperative chemotherapy (as demonstrated by cross-sectional imaging) or by surgical removal of all metastatic disease.[33]

Through the years, several cooperative groups, including the German Society for Paediatric Haematology and Oncology (GPOH), Japanese Children’s Cancer Group (JCCG), SIOPEL, and COG, have followed different protocols for treating HB, using a combination of cisplatin-based chemotherapy and surgical resection or liver transplantation. With these strategies, cure rates for low-stage/low-risk HB now reach 90%. Specifically, the COG AHEP0731 trial has shown that stage I and II non-pure fetal or small-cell undifferentiated HB can be treated with up-front surgical resection and with 2 adjuvant cycles of cisplatin, 5-fluorouracil, and vincristine, with a 5-year event-free survival of 88%. Intermediate-risk patients were treated with 6 cycles of cisplatin, 5-fluorouracil, vincristine, and doxorubicin, with surgical resection or liver transplant ideally performed with 2 or more cycles remaining. The results will soon be available, pending publication.

The SIOPEL 3 trial determined that therapy to reduction to cisplatin alone (versus cisplatin with doxorubicin) achieved equivalent rates of complete resection and event-free survival and overall survival in children with standard-risk HB (PRETEXT III or less with elevated AFP at diagnosis and no extrahepatic disease). Of note, this cohort of patients is not directly comparable to the AHEP1531 intermediate-risk cohort. Unfortunately, high-risk patients with PRETEXT IV and metastatic HB continue to have the worst prognoses, with, at best, 76% 3-year event-free survival and 83% overall survival when treated with the SIOPEL 4 pilot protocol consisting of intensive treatment with cisplatin, carboplatin, and doxorubicin.[34, 35, 36, 37]  The efficacy of this regimen is being validated in PHITT.

The timing of surgery has not historically been standardized across the international consortia. Whereas groups in the United States have prioritized attempts at up-front resection when possible, the SIOPEL group traditionally gave chemotherapy to all patients at diagnosis. The general approach has been to follow the response to neoadjuvant chemotherapy after every 2 cycles in order to determine the optimal timing of surgical resection or referral for liver transplant. Patients with large tumors that are PRETEXT IV or that significantly involve the portal, all three hepatic veins, or the IVC are usually deemed unresectable and are considered for transplant. In addition, for patients with multifocal tumors, several small studies have shown a superior outcome when these patients are treated with liver transplant rather than surgical resection.[34]

Liver transplantation has become an important part of treatment in unresectable HB. Since 2012, the United Network for Organ Sharing (UNOS) has automatically assigned all patients with a diagnosis of HB to status 1B, which has significantly reduced wait times for liver transplant. Nonetheless, not all patients with unresectable disease are eligible for liver transplant. For instance, patients with metastatic disease must have all metastatic sites cleared in order to be eligible for liver transplant. Therefore, persistent metastatic disease in the setting of an unresectable primary liver tumor presents a particularly difficult therapeutic challenge, which highlights the need for novel approaches for salvage therapy.[38]

Along with developing a standardized risk stratification protocol through the CHIC initiative, the international groups have now combined efforts to initiate the PHITT trial for patients with newly diagnosed HB and HCC. For low-risk patients who cannot undergo up-front resection but who are able to have their tumors resected after 2 cycles of cisplatin, the PHITT investigators will test whether therapy can be reduced from 4 postoperative cycles, which was traditionally used in the SIOPEL protocols, to 2 cycles, as has been used in COG AHEP0731. For intermediate disease, PHITT compares patients treated with cisplatin monotherapy, as has been the standard in Europe, to patients treated with cisplatin, 5-FU, vincristine, doxorubicin, as has been the standard in the United States. Finally, for high-risk disease, the PHITT study will use the SIOPEL 4 high risk induction regimen, and for patients with metastatic disease, will randomize to treatment with carboplatin/etoposide or vincristine/irinotecan alternating with standard cisplatin/doxorubicin consolidation treatment. 

Beyond chemotherapy, the timing of surgery has not historically been standardized across the different international groups treating HB. Whereas groups in North America and Japan have prioritized attempts at up-front resection when possible (low Evans and PRETEXT stage tumors), the SIOPEL group traditionally gave chemotherapy to all patients at diagnosis. The general approach has been to follow response to neoadjuvant chemotherapy after every 2 cycles in order to determine the optimal timing of surgical resection or referral for liver transplant.

Another major effort in the treatment of HB has been in reducing the toxicities associated with chemotherapy. As cisplatin is associated with hearing loss in greater than 50% of children with HB, with up to 16% of patients requiring hearing aids, efforts have been underway to reduce treatment-associated toxicity. The SIOPEL 6 study evaluated the use of sodium thiosulfate in reducing hearing loss associated with treatment of standard risk HB with cisplatin monotherapy. Among a total of 109 patients who were randomized to receive either cisplatin only or cisplatin and sodium thiosulfate, 63% of patients who received cisplatin developed grade 1 or higher hearing loss, as compared with only 33% of patients who received sodium thiosulfate in addition to cisplatin.[39]

AFP is considered an early marker for recurrence, and elevated levels should prompt thorough investigation. The survival rate has steadily improved over the past 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 for patients with HCC.[40]

Hepatocellular carcinoma

Pediatric hepatocellular carcinoma (HCC) is a rare malignancy that constitutes 0.5-1.0% of all childhood tumors, with an incidence of 0.8-1.5 per million in the United States. As with adult HCC, disease extent and unresectability are associated with an inferior prognosis.[41]  Unfortunately, fewer than 20% of pediatric patients are considered eligible for up-front resection.[42]  As compared with HB, the most common pediatric primary hepatic malignancy, the overall prognosis for pediatric HCC patients is significantly worse. This is postulated to be secondary to an inferior response to chemotherapy and an inability to achieve surgical resectability. 

Historically, approaches to treating pediatric HCC patients have largely mirrored those for HB, as patients were previously enrolled in studies accruing both histologies. For this reason, and the fact that an estimated 80% of pediatric HCC cases arise in the context of a normal liver without a backdrop of cirrhosis, the treatment of pediatric HCC has largely diverged from the approach to the adult counterpart.  

Studies from the Children’s Oncology Group (COG), the International Childhood Liver Tumour Strategy Group (SIOPEL), and the Japanese Pediatric Liver Tumor group (JPLT) utilizing HB-specific chemotherapy regimens have shown response rates to preoperative chemotherapy as high as 50%. Nevertheless, the power of these studies is hampered by relatively small numbers of patients, and overall survival remains low at 24% at 5 years and 8% at 20 years.[43]

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.[3]

Resection of a hepatocellular carcinoma of the rig Resection of a hepatocellular carcinoma of the right lobe.

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 resectability 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).[44]

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.[45] 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

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.[46]

 

Surgical Techniques

Complete surgical resection of malignant hepatic tumors is considered a key part of attempt at cure.[47] 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.[27] 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.

Intraoperative ultrasonography used to assess rese Intraoperative ultrasonography used to assess resectability of a right lobe hepatoblastoma.
The lesion to resect is marked out. The lesion to resect is marked out.
Electrocautery is useful for dissecting through th Electrocautery is useful for dissecting through the liver capsule and parenchyma.
Bipolar cautery may be useful in sealing blood ves Bipolar cautery may be useful in sealing blood vessels and hepatic ducts.
Argon beam coagulation is used to assist with hemo Argon beam coagulation is used to assist with hemostasis of the raw hepatic parenchyma.

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.[48] 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.[49] 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.[50]

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.[51] 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.[52] 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.[53] 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.[54]

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.[51]

 

Future Therapies

Despite the strides made in treating localized hepatoblastoma (HB), metastatic and relapsed or refractory disease remain challenging to treat. Indeed, the approach to treatment in the setting of relapse is not standardized, although salvage chemotherapy regimens often include combinations of ifosfamide, carboplatin, etoposide, high dose cyclophosphamide, vincristine, and/or irinotecan. Advances in understanding the biology of HB have led to the development of new targeted treatments.

There is much interest in targeting the Wnt pathway in HB given its apparent central role in pathogenesis. The challenge to developing inhibitors of the Wnt pathway lies in the fact that the oncogenic mutations in HB are commonly in the downstream effector, beta-catenin, which has proven more difficult to target than upstream components of the Wnt pathway. A high-throughput assay for inhibitors of the interaction between beta-catenin and the transcription factor Tcf4 revealed several compounds with promise for disrupting this part of the pathway. In recent years, Wnt targeting agents have been tested in other cancers in which aberrant Wnt activation is implicated, including colon cancer and germ cell tumors, although many remain at the preclinical stage.

Preclinical studies have revealed several additional pathways that may be targeted. A chemical inhibitor screen performed on orthotopic patient-derived xenografts revealed trametinib, a MEK inhibitor, and NVP-BKM120, a PI3-kinase inhibitor, as drugs that inhibited the growth of HB. Volasertib, a PLK1 inhibitor, was identified in a chemical screen for agents that inhibited growth of HB but not normal hepatocytes. In another recent study, olaparib, a PARP1 inhibitor, was found to block the growth of HB cell lines and patient-derived xenografts. In models of HB induced by beta-catenin and YAP activation, inhibition of the mTOR pathway with rapamycin reduces tumor growth. Finally, the PIM kinases have also been implicated in HB tumorigenesis, and targeting these kinases with RNA interference or a small molecule inhibitor, AZD1208, blocked tumor cell growth in vitro and in mice .

Modulators of apoptosis comprise another avenue for therapy. For instance, MDM4 interacts with the tumor suppressor p53 and represses its transcriptional activity. Treatment of HB cells with either the MDM4 inhibitor, NSC207895 (XI-006), or a dual MDM2/MDM4 stapled peptide inhibitor, ATSP-7041, resulted in cytotoxic and antiproliferative effects in conjunction with upregulation of p53. In addition, preclinical data have also shown overexpression of Bcl-2 and Bcl-xL in HB cell lines and have demonstrated that inhibition with a small-molecular inhibitor induced apoptosis and enhanced the cytotoxic effects of chemotherapeutic agents (58610). Indeed, there is an open phase 1 study of the Bcl-2 inhibitor venetoclax on relapsed or refractory malignancies, which is open for patients with solid tumors, although so far there have been no published clinical data, including on patients with HB.

Moving into the clinic, several COG phase 1 studies testing agents such as Aurora kinase inhibitors and pazopanib, a multi-receptor tyrosine kinase inhibitor, have included patients with HB with some response. However, the number of patients in each of these studies has been low, and it remains difficult to conclude how effective these agents are against HB.

Immunotherapy agents comprise another promising avenue of treatment being tested. Currently, there is an open trial testing CAR-T cells to GPC3, a cell surface protein that is upregulated in HB. Alternatively, codrituzumab, a humanized antibody against GPC3, is also being tested in trials against refractory and relapsed extracranial solid tumors including HB. In addition, CAR-T cells targeting AFP are another avenue of therapy that has shown promise in preclinical studies. Finally, immune checkpoint inhibition has also been proposed as a potential therapy. Although the majority of HBs have a low overall tumor mutational burden, there has been success reported in treating relapsed HB with a high tumor mutational burden with pembrolizumab, a humanized monoclonal antibody targeting PD-1.[55, 56, 57, 58, 59, 60, 61, 62, 63, 64]