martes, 16 de abril de 2019

Childhood Liver Cancer Treatment (PDQ®) 4/4 —Health Professional Version - National Cancer Institute

Childhood Liver Cancer Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute



Childhood Liver Cancer Treatment (PDQ®)–Health Professional Version



Hepatocellular Carcinoma

Incidence

The annual incidence of hepatocellular carcinoma in the United States is 0.8 cases per 1 million children between the ages of 0 and 14 years and 1.5 cases per 1 million adolescents aged 15 to 19 years.[1] Although the incidence of hepatocellular carcinoma in adults in the United States has steadily increased since the 1970s, possibly because of the increased frequency of chronic hepatitis C infection,[2] the incidence in children has not increased. In several Asian countries, the incidence of hepatocellular carcinoma in children is 10 times higher than the incidence in children in North America. The high incidence appears to be related to the incidence of perinatally acquired hepatitis B, which can be prevented in most cases by vaccination and administration of hepatitis B immune globulin to the newborn child.[3]
Fibrolamellar hepatocellular carcinoma, a subtype of hepatocellular carcinoma that is unrelated to cirrhosis, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection, generally occurs in adolescents and young adults, but has been reported in infants.[4]

Risk Factors

Conditions associated with hepatocellular carcinoma are described in Table 7.
Table 7. Conditions Associated With Hepatocellular Carcinoma
Associated DisorderClinical Findings
Alagille syndrome [5]Broad prominent forehead, deep set eyes, and small prominent chin. Abnormality of bile ducts leads to intrahepatic scarring.
Glycogen storage diseases I–IV [6]Symptoms vary by individual disorder.
Hepatitis B and C [7-9]Refer to the Hepatitis B and hepatitis C infection section of this summary for more information.
Progressive familial intrahepatic cholestasis [10,11]Symptoms of jaundice, pruritus, and failure to thrive begin in infancy and progress to portal hypertension and liver failure.
Tyrosinemia [12]First few months of life: failure to thrive, vomiting, jaundice.

Alagille syndrome

Alagille syndrome is an autosomal dominant genetic syndrome that is usually caused by a mutation in or deletion of the JAG1 gene. It involves the bile ducts of the liver, as well as the heart and blood vessels in the brain and kidney. Patients develop a characteristic facies.[5]

Hepatitis B and hepatitis C infection

In children, hepatocellular carcinoma is associated with perinatally acquired HBV, whereas in adults, it is associated with chronic HBV and HCV infection.[7-9] Widespread hepatitis B immunization has decreased the incidence of hepatocellular carcinoma in Asia.[3] Compared with adults, the incubation period from hepatitis virus infection to the genesis of hepatocellular carcinoma is extremely short in a small subset of children with perinatally acquired virus. Mutations in the met/hepatocyte growth factor receptor gene could be one mechanism that results in a shortened incubation period.[13]
Hepatitis C infection is associated with development of cirrhosis and hepatocellular carcinoma that takes decades to develop and is generally not seen in children.[9] Cirrhosis in children, compared with cirrhosis in adults, is much less commonly involved in the development of hepatocellular carcinoma, and is found in only 20% to 35% of children with hepatocellular carcinoma tumors.

Nonviral liver injury

Specific types of nonviral liver injury and cirrhosis that are associated with hepatocellular carcinoma in children include the following:
  • Tyrosinemia. Tyrosinemia patients are regularly screened for hepatocellular carcinoma, even if they are treated with nitisinone.[12] Nitisinone can prevent cirrhosis and decrease the incidence of hepatocellular carcinoma, especially when administered during infancy, after neonatal screening is used to diagnose tyrosinemia.[14] As of 2014, only a minority of state screening programs had adopted a highly recommended, new, more predictive newborn screen that is much more effective in newborn children aged 24 to 48 hours.[15]
    In an Iranian study, 36 children underwent liver transplant for tyrosinemia.[16] Twenty-two children had liver nodules greater than 10 cm, and in 20 children, the nodules were cirrhotic. Median age at transplant was 3.9 years. Five of 19 children older than 2 years had hepatocellular carcinoma, and no children younger than 2 years had hepatocellular carcinoma in the resected liver.
  • Aggressive familial intrahepatic cholestasis. Hepatocellular carcinoma may also arise in very young children with mutations in the bile salt export pump ABCB11, which causes progressive familial intrahepatic cholestasis.[10]

Genomics of Hepatocellular Carcinoma

Genomic abnormalities related to hepatocellular carcinoma include the following:
  • A first case of pediatric hepatocellular carcinoma was analyzed by whole-exome sequencing, which showed a higher mutation rate (53 variants) and the coexistence of CTNNB1 and NFE2L2 mutations.[17]
  • Fibrolamellar hepatocellular carcinoma is a rare subtype of hepatocellular carcinoma observed in older children. It is characterized by an approximately 400 kB deletion on chromosome 19 that results in production of a chimeric RNA coding for a protein containing the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in frame with PRKACA, the catalytic domain of protein kinase A.[18]
  • A rare, more aggressive subtype of childhood liver cancer (hepatocellular neoplasm, not otherwise specified, also termed transitional liver cell tumor) occurs in older children, and it has clinical and histopathological findings of both hepatoblastoma and hepatocellular carcinoma.
    TERT mutations were observed in two of four cases tested.[19] TERT mutations are also commonly observed in adults with hepatocellular carcinoma.[20]
To date, these genetic mutations have not been used to select therapeutic agents for investigation in clinical trials.

Diagnosis

Refer to the Diagnosis subsection in the Hepatoblastoma section of this summary for more information.

Prognosis and Prognostic Factors

The 5-year overall survival (OS) rate is 42% for children and adolescents with hepatocellular carcinoma.[1] The 5-year survival for hepatocellular carcinoma may be dependent on stage; in an intergroup chemotherapy study conducted in the 1990s, seven of eight stage I patients survived and less than 10% of stage III and IV patients survived.[1,21] An analysis of Surveillance, Epidemiology, and End Results (SEER) data found a 5-year OS rate of 24%, a 10-year rate of 23%, and a 20-year rate of 8% in patients aged 19 years and younger, suggesting improved outcome related to more recent treatment. In a multivariate analysis of the SEER data, surgical resection, localized tumor, and non-Hispanic ethnicity were all associated with improved outcome. Patients who had a complete surgical resection had an OS rate of 60%, compared with an OS rate of 0% for patients who had an incomplete resection.[22][Level of evidence: 3iiiA]
Factors affecting prognosis include the following:
  • Treatment-related factors:
    Cure of hepatocellular carcinoma requires gross tumor resection. However, hepatocellular carcinoma is often extensively invasive or multicentric, and less than 30% of tumors are resectable. Orthotopic liver transplant has been successful in selected children with hepatocellular carcinoma.[23,24]
  • PRE-Treatment EXTent of disease (PRETEXT) group (resectability) is also a prognostic factor (refer to the Risk Stratification section of this summary for more information).
  • Tumor histology:
    Refer to the Histology section of this summary for more information.

Histology

The cells of hepatocellular carcinoma are epithelial in appearance. Hepatocellular carcinoma commonly arises in the right lobe of the liver.

Fibrolamellar carcinoma

A distinctive histologic variant of hepatocellular carcinoma, termed fibrolamellar carcinoma, has been described in the livers of older children and young adults and, rarely, in infants.[4,25] This histology is characterized by a fusion transcript created by deletion of a 400 kb section of chromosome 19, which was found in 15 of 15 tumors that were tested.[18]
Fibrolamellar carcinoma is not associated with cirrhosis and was previously thought to be associated with an improved prognosis.[2,25,26] Unlike nonfibrolamellar hepatocellular carcinoma in adults, fibrolamellar hepatocellular carcinoma in older children and adults is not clearly increasing in incidence over time.[2,25] The improved outcomes of patients with fibrolamellar carcinoma in older studies may be related to a higher proportion of tumors being less invasive and more resectable in the absence of cirrhosis. However, the outcomes of patients with fibrolamellar carcinoma in recent prospective studies, when compared stage for stage and PRETEXT group to PRETEXT group, is not different from the outcomes of patients with conventional hepatocellular carcinomas.[27,28]; [29][Level of evidence: 3iiA]

Hepatocellular neoplasm, not otherwise specified (NOS)

Hepatocellular neoplasm, NOS is also known as transitional liver cell tumor. This tumor, with characteristics of both hepatoblastoma and hepatocellular carcinoma, is a rare neoplasm that is found in older children and adolescents, and has a putative intermediate position between hepatoblasts and more mature hepatocyte-like tumor cells. The tumor cells may vary in regions of the tumor between classical hepatoblastoma and obvious hepatocellular carcinoma. In the international consensus classification, these tumors are referred to as hepatocellular neoplasm, NOS.[30] The tumors are usually unifocal and may have central necrosis at presentation. Response to chemotherapy has not been rigorously studied but is felt to be much like that of hepatocellular carcinoma.[31]

Treatment of Hepatocellular Carcinoma

Treatment options for newly diagnosed hepatocellular carcinoma depend on the following:
  1. Whether the cancer is resectable at diagnosis.
  2. How the cancer responds to chemotherapy.
  3. Whether the cancer has metastasized.
  4. Whether the cancer is HBV related.

Treatment options for hepatocellular carcinoma that is resectable at diagnosis

Treatment options for hepatocellular carcinoma that is resectable at diagnosis include the following:
  1. Complete surgical resection of the primary tumor followed by chemotherapy.
  2. Chemotherapy followed by complete surgical resection of the primary tumor.[27]
  3. Complete surgical resection without chemotherapy.
Surgical resection and chemotherapy are the mainstays of treatment for resectable hepatocellular carcinoma.
Evidence (complete surgical resection followed by chemotherapy):
  1. Seven of eight patients with stage I hepatocellular carcinoma who were given adjuvant cisplatin-based chemotherapy survived disease free.[21]
  2. In a survey of childhood liver tumors treated before the consistent use of chemotherapy, only 12 of 33 patients with hepatocellular carcinoma who had complete excision of the tumor survived.[32] This suggests that treatment with adjuvant chemotherapy may benefit children with completely resected hepatocellular carcinoma.
  3. Cisplatin and doxorubicin may be administered as adjuvant therapy because these agents are active in the treatment of hepatocellular carcinoma.[27]
  4. In an analysis of SEER data for children and adolescents younger than 20 years diagnosed between 1976 and 2009, patients who underwent a complete resection had a 60% 5-year OS and those who did not have a complete resection had a 0% 5-year OS.[22][Level of evidence: 3iiiA]
Evidence (complete surgical resection without chemotherapy):
  1. In a single-institution retrospective report, 12 patients with stage I hepatocellular carcinoma were treated with surgery. Ten patients received no chemotherapy and two patients received a short course of chemotherapy based on oncologist preference.[33][Level of evidence: 3iiA]
    • All 12 patients are alive without evidence of disease at a median of 54 months.
Despite improvements in surgical techniques, chemotherapy delivery, and patient supportive care in the past 20 years, clinical trials of cancer chemotherapy have not shown improved survival rates for pediatric patients with hepatocellular carcinoma.[27] The International Childhood Liver Tumors Strategy Group (SIOPEL) studies in Europe have observed no improvement in 5-year OS since 1990. The only long-term survivors were patients whose tumors were resectable at diagnosis, which was less than 30% of children entered in the study.[34] However, some liver transplant studies (complete resection with transplant with or without neoadjuvant chemotherapy) have shown OS rates that are superior to the SIOPEL studies.[24,35-38]

Treatment options for nonmetastatic hepatocellular carcinoma that is not resectable at diagnosis

The use of neoadjuvant chemotherapy or transarterial chemoembolization (TACE) to enhance resectability or liver transplant, which may result in complete resection of tumor, is necessary for cure.
Treatment options for nonmetastatic hepatocellular carcinoma that is not resectable at diagnosis include the following:
  1. Chemotherapy followed by reassessment of surgical resectability. If the primary tumor is resectable, complete surgical resection.
  2. Chemotherapy followed by reassessment of surgical resectability. If the primary tumor remains unresectable:
    • Orthotopic liver transplant.
    • Temporizing TACE followed by complete resection or liver transplant.
    • TACE alone.
Evidence (chemotherapy followed by reassessment of surgical resectability and complete surgical resection of the primary tumor):
  1. In a prospective study of 41 patients who received preoperative cisplatin/doxorubicin chemotherapy, treatment resulted in some degree of decrease in tumor size, with a decrease in alpha-fetoprotein (AFP) levels in about 50% of patients. The responders had a superior tumor resectability and survival, although the OS was 28% and only those undergoing complete resection survived.[27]
Evidence (chemotherapy or TACE followed by reassessment of surgical resectability; treatment options for unresectable primary tumor after chemotherapy or TACE):
  1. Patients whose primary tumor remains unresectable after chemotherapy should be considered for orthotopic liver transplant. Liver transplant has been a successful therapy for children with unresectable hepatocellular carcinoma; survival is about 60%, with most deaths resulting from tumor recurrence.[23,38-41]
  2. A review of treatment for hepatocellular carcinoma in patients younger than 20 years reported to SEER revealed that 75% of patients underwent resection and 25% underwent liver transplant. The 5-year OS was 53.4% with resection and 85.3% with transplant, suggesting that the criteria for transplantation in hepatocellular carcinoma might be liberalized for overall patient benefit. This approach would benefit from prospective testing.[42]
  3. TACE followed by complete surgical resection of primary tumor may be an alternative to the use of chemotherapy followed by surgical resection.
    • Studies in adults in China suggest that repeated hepatic TACE before surgery may improve the outcome of subsequent hepatectomy.[43]
    • A meta-analysis found seven randomized trials that compared resection alone versus TACE followed by resection. There was no difference in 3-year event-free survival (EFS) and OS between the two groups, but the 5-year EFS and OS favored TACE followed by resection.[44]
If the primary tumor is not resectable after chemotherapy and the patient is not a transplant candidate, alternative treatment approaches used in adults include the following:
  • Sorafenib.
  • TACE.
  • Cryosurgery.
  • Intratumoral injection of alcohol.
  • Radiation therapy.
There are limited data on the use of these alternative treatment approaches in children.
Limited data from a European pilot study suggest that sorafenib was well tolerated in 12 newly diagnosed children and adolescents with advanced hepatocellular carcinoma when given in combination with standard chemotherapy of cisplatin and doxorubicin.[45] Additional study is needed to define its role in the treatment of children with hepatocellular carcinoma.
Cryosurgery, intratumoral injection of alcohol, and radiofrequency ablation can successfully treat small (<5 cm) tumors in adults with cirrhotic livers.[43,46,47] Some local approaches such as cryosurgery, radiofrequency ablation, and TACE that suppress hepatocellular carcinoma tumor progression are used as bridging therapy in adults to delay tumor growth while on a waiting list for cadaveric liver transplant.[48] In a pediatric study of eight patients with hepatocellular carcinoma, two patients died of progressive disease without transplant. Treatment with TACE stabilized disease in six patients, for a mean of 141 days to reach transplant.[49][Level of evidence: 3iiA] Five patients were alive at the end of the observation period, and one patient died of disease.(Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)

Treatment options for hepatocellular carcinoma with metastases at diagnosis

No specific treatment has proven effective for metastatic hepatocellular carcinoma in the pediatric age group.
In two prospective trials, cisplatin plus either vincristine/fluorouracil or continuous-infusion doxorubicin was ineffective in adequately treating 25 patients with metastatic hepatocellular carcinoma.[21,27] Occasional patients may transiently benefit from treatment with cisplatin/doxorubicin therapy, especially if the localized hepatic tumor shrinks adequately enough to allow resection of disease and the metastatic disease disappears or becomes resectable.

Treatment options for hepatitis B virus (HBV)–related hepatocellular carcinoma

Although HBV-related hepatocellular carcinoma is not common in children in the United States, nucleotide/nucleoside analog HBV inhibitor treatment improves postoperative prognosis in children and adults treated in China.[50]
Treatment options for HBV-related hepatocellular carcinoma include the following:
  1. Antiviral therapy.
Evidence (antiviral therapy):
  1. In a randomized controlled trial, 163 patients post–radical hepatectomy were evaluated for response to one of three antiviral treatments.[50]
    • Antiviral treatment significantly decreased hepatocellular carcinoma recurrence, with a hazard ratio (HR) of 0.48 (95% confidence interval [CI], 0.32–0.70), and hepatocellular carcinoma–related death, with an HR of 0.26 (95% CI, 0.14–0.50), in multivariate Cox analyses.
    • Patients who received antiviral treatment had significantly decreased early recurrence (HR, 0.41; 95% CI, 0.27–0.62) and improved liver function 6 months after surgery than did the control patients (P < .001).

Treatment options for progressive or recurrent hepatocellular carcinoma

The prognosis for a patient with recurrent or progressive hepatocellular carcinoma is extremely poor.[51]
Treatment options for progressive or recurrent hepatocellular carcinoma include the following:
  1. Chemoembolization temporization before transplant or immediate liver transplant, for those with isolated recurrence in the liver.[23,38,39,52]
  2. Phase I and phase II clinical trials may be appropriate and should be considered.
    • Treatment with sorafenib has resulted in improved progression-free survival in adults with advanced hepatocellular carcinoma. For adult patients who received sorafenib, the median survival and time to radiologic progression were about 3 months longer than for patients who received a placebo.[53] A phase II COG trial of single-agent sorafenib has been completed in children and the study results are pending.

Treatment options under clinical evaluation for hepatocellular carcinoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  • AHEP1531 (NCT03533582) (Cisplatin and Combination Chemotherapy in Treating Children and Young Adults with Hepatoblastoma or Liver Cancer After Surgery):
    This is the COG's participation in a large international trial (Pediatric Hepatic Malignancy International Therapeutic Trial [PHITT]) of treatment of all stages of hepatoblastoma and hepatocellular carcinoma in children.
    • Very low-risk hepatoblastoma is defined as either: 1) a well differentiated fetal mass completely resected at diagnosis, and these patients are treated with no chemotherapy; or 2) a non–well differentiated fetal mass or incompletely resected well differentiated fetal mass, and these patients are treated with two cycles of cisplatin chemotherapy.
    • Low-risk hepatoblastoma is defined as a PRETEXT I to III tumor without any positive VPEFR annotation factors (venous involvement, portal involvement, extrahepatic spread, multifocality, and tumor rupture). These patients are treated with two cycles of cisplatin chemotherapy and then undergo resection (if possible) followed by randomization between two and four more cycles of cisplatin. If the tumor is unresectable, the patient receives two more cycles of cisplatin chemotherapy, and the tumor's resectability is reassessed. If it is still unresectable, patients undergo liver transplant.
    • Intermediate-risk hepatoblastoma is defined as a PRETEXT I to III primary tumor with a positive VPEFR annotation factor but without metastasis. Patients are randomly assigned to either four 14-day cycles of cisplatin or four 21-day cycles of C5VD (cisplatin, fluorouracil, vincristine, and doxorubicin). Transplant teams are consulted early as needed. Patients in both arms then undergo resection and receive two more cycles of their assigned chemotherapy.
    • High-risk hepatoblastoma is defined as presence of distant metastasis or AFP less than 100 or age 8 years and older. All patients are treated with three cycles of induction chemotherapy per the SIOPEL-4 trial (dose-intensive cisplatin, doxorubicin, and carboplatin). The patients aged 8 years and older or with AFP less than 100 and those whose metastases have cleared receive three cycles of carboplatin and doxorubicin. Patients with metastases that have not cleared by end of induction are randomly assigned to receive either carboplatin/doxorubicin cycles alternating with carboplatin/etoposide for six cycles or carboplatin/doxorubicin alternating with vincristine/irinotecan for six cycles.
    • Hepatocellular carcinoma that is potentially resectable is treated with complete resection without any chemotherapy if the mass appears to derive from underlying liver disease. If the hepatocellular carcinoma appears to be de novo without underlying disease, it is treated with resection followed by four cycles of cisplatin/doxorubicin.
    • Patients with hepatocellular carcinoma that is metastatic or appears unresectable at diagnosis undergo consultation with interventional radiology and liver transplant services. Patients are then randomly assigned to receive either cisplatin/doxorubicin/sorafenib for three 21-day cycles or cisplatin/doxorubicin/sorafenib alternating with gemcitabine/oxaliplatin/sorafenib for four 14-day cycles. Responding patients continue chemotherapy for the same number of cycles (3 or 4); they receive the same chemotherapy regimen to which they were originally assigned.
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).
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  46. Zhou XD, Tang ZY: Cryotherapy for primary liver cancer. Semin Surg Oncol 14 (2): 171-4, 1998. [PUBMED Abstract]
  47. Lencioni RA, Allgaier HP, Cioni D, et al.: Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 228 (1): 235-40, 2003. [PUBMED Abstract]
  48. Lubienski A: Hepatocellular carcinoma: interventional bridging to liver transplantation. Transplantation 80 (1 Suppl): S113-9, 2005. [PUBMED Abstract]
  49. Weiss KE, Sze DY, Rangaswami AA, et al.: Transarterial chemoembolization in children to treat unresectable hepatocellular carcinoma. Pediatr Transplant 22 (4): e13187, 2018. [PUBMED Abstract]
  50. Yin J, Li N, Han Y, et al.: Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J Clin Oncol 31 (29): 3647-55, 2013. [PUBMED Abstract]
  51. Malogolowkin MH, Stanley P, Steele DA, et al.: Feasibility and toxicity of chemoembolization for children with liver tumors. J Clin Oncol 18 (6): 1279-84, 2000. [PUBMED Abstract]
  52. Otte JB, Pritchard J, Aronson DC, et al.: Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 42 (1): 74-83, 2004. [PUBMED Abstract]
  53. Llovet JM, Ricci S, Mazzaferro V, et al.: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359 (4): 378-90, 2008. [PUBMED Abstract]

Undifferentiated Embryonal Sarcoma of the Liver

Incidence

Undifferentiated embryonal sarcoma of the liver (UESL) is a distinct clinical and pathologic entity and accounts for 2% to 15% of pediatric hepatic malignancies.[1]

Diagnosis

UESL presents as an abdominal mass, often with pain or malaise, usually between the ages of 5 and 10 years. Widespread infiltration throughout the liver and pulmonary metastasis is common. It may appear solid or cystic on imaging, frequently with central necrosis.
Distinctive features are characteristic intracellular hyaline globules and marked anaplasia on a mesenchymal background.[2] Many UESL tumors contain diverse elements of mesenchymal cell maturation, such as smooth muscle and fat. Undifferentiated sarcomas, like small cell undifferentiated hepatoblastomas, should be examined for loss of INI1 expression by immunohistochemistry to help rule out rhabdoid tumor of the liver.
It is important to make the diagnostic distinction between UESL and biliary tract rhabdomyosarcoma because they share some common clinical and pathologic features but treatment differs between the two, as shown in Table 8.[1] (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.)
Table 8. Diagnostic Differences Between Undifferentiated Embryonal Sarcoma of the Liver and Biliary Tract Rhabdomyosarcomaa
 Undifferentiated Embryonal Sarcoma of the LiverBiliary Tract Rhabdomyosarcoma
aAdapted from Nicol et al.[1]
Age at DiagnosisMedian age 10.5 yMedian age 3.4 y
Tumor LocationOften arises in the right lobe of the liverOften arises in the hilum of the liver
Biliary ObstructionUnusualFrequent; jaundice is a common presenting symptom
TreatmentSurgery and chemotherapySurgery (usually biopsy only), radiation therapy, and chemotherapy

Histology

Distinctive histologic features are intracellular hyaline globules and marked anaplasia on a mesenchymal background.[2]
Strong clinical and histological evidence suggests that UESL can arise within preexisting mesenchymal hamartomas of the liver, which are large benign multicystic masses that present in the first 2 years of life.[1] In a report of 11 cases of UESL, 5 arose in association with mesenchymal hamartomas of the liver, and transition zones between the histologies were noted.[3] Many mesenchymal hamartomas of the liver have a characteristic translocation with a breakpoint at 19q13.4 and several UESLs have the same translocation.[4,5] Some UESLs arising from mesenchymal hamartomas of the liver may have complex karyotypes not involving 19q13.4.[4]

Prognosis and Prognostic Factors

The overall survival (OS) of children with UESL appears to be substantially better than 50% when combining reports, although all series are small and most may be selected to report successful treatment.[6]; [7][Level of evidence: 3iiA]; [8-17][Level of evidence: 3iiiA]
The Childhood Cancer Database, which does not provide central review of pathology or reliable details of nonsurgical treatment, reported on 103 children with UESL diagnosed between 1998 and 2012. The 5-year OS was 86% for all patients and 92% for those treated with combination surgery and chemotherapy. A multivariate analysis of the nonsurgical data revealed statistically significant poorer outcomes for patients with tumors larger than 15 cm. Seven of ten children who presented with metastases and ten of ten children who underwent orthotopic liver transplant survived at least 5 years, but details of their treatment were not presented.[18]

Treatment Options for Undifferentiated Embryonal Sarcoma of the Liver

UESL is rare. Only small series have been published regarding treatment.[19]
Treatment options for UESL include the following:
  • Surgical resection and chemotherapy.
  • Liver transplant, for unresectable tumors.
The generally accepted approach is resection of the primary tumor mass in the liver when possible.[18] Use of aggressive chemotherapy regimens seems to have improved the OS of patients with UESL. Neoadjuvant chemotherapy can be effective in decreasing the size of an unresectable primary tumor mass, resulting in resectability.[8-11] Most patients are treated with chemotherapy regimens used for pediatric rhabdomyosarcoma or Ewing sarcoma without cisplatin.[6]; [7,20][Level of evidence: 3iiA]; [8-16][Level of evidence: 3iiiA]
Evidence (surgical resection and chemotherapy):
  1. In the only prospective series treating patients with UESL, which came from the Italian and German Soft Tissue Sarcoma Cooperative Groups, patients were treated with (1) conservative surgery or (2) biopsy followed by neoadjuvant chemotherapy consisting of varying combinations of vincristine, cyclophosphamide, dactinomycin, doxorubicin, and ifosfamide. Disease evaluation, usually after four cycles of chemotherapy, was followed by second-look surgery when appropriate to try to remove residual primary tumor followed by additional and/or adjuvant chemotherapy.[12]
    • Ten of 17 patients survived in their first complete remission, and one patient survived in third complete remission.
  2. In a single-center retrospective report, five patients with UESL were treated with surgery and adjuvant chemotherapy consisting of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide. Four patients were stage I and one patient was stage II. One patient received abdominal radiation for tumor rupture.[17][Level of evidence: 3iiiA]
    • All patients are alive (range, 5–19 years), with 100% event-free survival and OS.
Liver transplant has occasionally been used to successfully treat an otherwise unresectable primary tumor.[14,16,18,21]

Treatment Options Under Clinical Evaluation for Undifferentiated Embryonal Sarcoma of the Liver

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
  • ARST1321 (NCT02180867) (Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Nonrhabdomyosarcoma Soft Tissue Sarcomas That Can be Removed by Surgery): This study will first determine the feasibility of adding a tyrosine kinase inhibitor in combination with radiation or chemotherapy (ifosfamide/etoposide) and radiation in pediatric and adult patients newly diagnosed with unresected, intermediate-risk and high-risk nonrhabdomyosarcomatous STS. Subsequently, this trial will compare the rates of near complete pathologic response (>90% necrosis) of: (1) preoperative pazopanib plus chemoradiation versus preoperative chemoradiation alone for potentially resectable (>5 cm), grade 3 intermediate-risk to high-risk chemotherapy-sensitive (i.e., histologies of undifferentiated sarcoma, synovial sarcoma, and embryonal sarcoma of the liver) adult and pediatric nonrhabdomyosarcomatous STS; and (2) pazopanib plus preoperative radiation therapy versus preoperative radiation therapy alone for potentially resectable, intermediate-risk to high-risk adult and pediatric nonrhabdomyosarcomatous STS.
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).
References
  1. Nicol K, Savell V, Moore J, et al.: Distinguishing undifferentiated embryonal sarcoma of the liver from biliary tract rhabdomyosarcoma: a Children's Oncology Group study. Pediatr Dev Pathol 10 (2): 89-97, 2007 Mar-Apr. [PUBMED Abstract]
  2. Stocker JT: Hepatic tumors in children. Clin Liver Dis 5 (1): 259-81, viii-ix, 2001. [PUBMED Abstract]
  3. Shehata BM, Gupta NA, Katzenstein HM, et al.: Undifferentiated embryonal sarcoma of the liver is associated with mesenchymal hamartoma and multiple chromosomal abnormalities: a review of eleven cases. Pediatr Dev Pathol 14 (2): 111-6, 2011 Mar-Apr. [PUBMED Abstract]
  4. Stringer MD, Alizai NK: Mesenchymal hamartoma of the liver: a systematic review. J Pediatr Surg 40 (11): 1681-90, 2005. [PUBMED Abstract]
  5. O'Sullivan MJ, Swanson PE, Knoll J, et al.: Undifferentiated embryonal sarcoma with unusual features arising within mesenchymal hamartoma of the liver: report of a case and review of the literature. Pediatr Dev Pathol 4 (5): 482-9, 2001 Sep-Oct. [PUBMED Abstract]
  6. Walther A, Geller J, Coots A, et al.: Multimodal therapy including liver transplantation for hepatic undifferentiated embryonal sarcoma. Liver Transpl 20 (2): 191-9, 2014. [PUBMED Abstract]
  7. Ismail H, Dembowska-Bagińska B, Broniszczak D, et al.: Treatment of undifferentiated embryonal sarcoma of the liver in children--single center experience. J Pediatr Surg 48 (11): 2202-6, 2013. [PUBMED Abstract]
  8. Chowdhary SK, Trehan A, Das A, et al.: Undifferentiated embryonal sarcoma in children: beware of the solitary liver cyst. J Pediatr Surg 39 (1): E9-12, 2004. [PUBMED Abstract]
  9. Baron PW, Majlessipour F, Bedros AA, et al.: Undifferentiated embryonal sarcoma of the liver successfully treated with chemotherapy and liver resection. J Gastrointest Surg 11 (1): 73-5, 2007. [PUBMED Abstract]
  10. Kim DY, Kim KH, Jung SE, et al.: Undifferentiated (embryonal) sarcoma of the liver: combination treatment by surgery and chemotherapy. J Pediatr Surg 37 (10): 1419-23, 2002. [PUBMED Abstract]
  11. Webber EM, Morrison KB, Pritchard SL, et al.: Undifferentiated embryonal sarcoma of the liver: results of clinical management in one center. J Pediatr Surg 34 (11): 1641-4, 1999. [PUBMED Abstract]
  12. Bisogno G, Pilz T, Perilongo G, et al.: Undifferentiated sarcoma of the liver in childhood: a curable disease. Cancer 94 (1): 252-7, 2002. [PUBMED Abstract]
  13. Urban CE, Mache CJ, Schwinger W, et al.: Undifferentiated (embryonal) sarcoma of the liver in childhood. Successful combined-modality therapy in four patients. Cancer 72 (8): 2511-6, 1993. [PUBMED Abstract]
  14. Okajima H, Ohya Y, Lee KJ, et al.: Management of undifferentiated sarcoma of the liver including living donor liver transplantation as a backup procedure. J Pediatr Surg 44 (2): e33-8, 2009. [PUBMED Abstract]
  15. Weitz J, Klimstra DS, Cymes K, et al.: Management of primary liver sarcomas. Cancer 109 (7): 1391-6, 2007. [PUBMED Abstract]
  16. Plant AS, Busuttil RW, Rana A, et al.: A single-institution retrospective cases series of childhood undifferentiated embryonal liver sarcoma (UELS): success of combined therapy and the use of orthotopic liver transplant. J Pediatr Hematol Oncol 35 (6): 451-5, 2013. [PUBMED Abstract]
  17. Mathias MD, Ambati SR, Chou AJ, et al.: A single-center experience with undifferentiated embryonal sarcoma of the liver. Pediatr Blood Cancer 63 (12): 2246-2248, 2016. [PUBMED Abstract]
  18. Shi Y, Rojas Y, Zhang W, et al.: Characteristics and outcomes in children with undifferentiated embryonal sarcoma of the liver: A report from the National Cancer Database. Pediatr Blood Cancer 64 (4): , 2017. [PUBMED Abstract]
  19. Techavichit P, Masand PM, Himes RW, et al.: Undifferentiated Embryonal Sarcoma of the Liver (UESL): A Single-Center Experience and Review of the Literature. J Pediatr Hematol Oncol 38 (4): 261-8, 2016. [PUBMED Abstract]
  20. Merli L, Mussini C, Gabor F, et al.: Pitfalls in the surgical management of undifferentiated sarcoma of the liver and benefits of preoperative chemotherapy. Eur J Pediatr Surg 25 (1): 132-7, 2015. [PUBMED Abstract]
  21. Kelly MJ, Martin L, Alonso M, et al.: Liver transplant for relapsed undifferentiated embryonal sarcoma in a young child. J Pediatr Surg 44 (12): e1-3, 2009. [PUBMED Abstract]

Infantile Choriocarcinoma of the Liver

Choriocarcinoma of the liver is a very rare tumor that appears to originate in the placenta during gestation and presents with a liver mass in the first few months of life. Metastasis from the placenta to maternal tissues occurs in many cases, necessitating beta-human chorionic gonadotropin (beta-hCG) testing of the mother. Infants are often unstable at diagnosis because of hemorrhage of the tumor.
Clinical diagnosis may be made without biopsy on the basis of tumor imaging of the liver associated with extremely high serum beta-hCG levels and normal alpha-fetoprotein (AFP) levels for age.[1]
Cytotrophoblasts and syncytiotrophoblasts are both present. The former are closely packed nests of medium-sized cells with clear cytoplasm, distinct cell margins, and vesicular nuclei. The latter are very large multinucleated syncytia formed from the cytotrophoblasts.[2]

Treatment Options for Infantile Choriocarcinoma of the Liver

Treatment options for infantile choriocarcinoma of the liver include the following:
  1. Surgical resection.[1]
  2. Chemotherapy followed by surgical resection.
Initial surgical removal of the tumor mass may be difficult because of its friability and hemorrhagic tendency. Often surgical removal of the primary tumor is performed after neoadjuvant chemotherapy.[1]
Maternal gestational trophoblastic tumors are exquisitely sensitive to methotrexate, and many women, including those with distant metastases, are cured with single-agent chemotherapy. Maternal and infantile choriocarcinoma both come from the same placental malignancy. The combination of cisplatin, etoposide, and bleomycin, as used in other pediatric germ cell tumors, has been effective in some patients and is followed by resection of residual mass. Use of neoadjuvant methotrexate in infantile choriocarcinoma, although often resulting in a response, has not been uniformly successful.[1]

Treatment Options Under Clinical Evaluation for Infantile Choriocarcinoma of the Liver

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).
References
  1. Yoon JM, Burns RC, Malogolowkin MH, et al.: Treatment of infantile choriocarcinoma of the liver. Pediatr Blood Cancer 49 (1): 99-102, 2007. [PUBMED Abstract]
  2. Olson T, Schneider D, Perlman E: Germ cell tumors. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams and Wilkins, 2011, pp 1045-1067.

Vascular Liver Tumors

Careful attention to the clinical history, physical exam, laboratory evaluation, and radiologic imaging is essential for an appropriate diagnosis of vascular liver tumors. If there is any doubt about the accuracy of the diagnosis, a biopsy should be performed.
The different diagnoses of vascular tumors of the liver include the following:

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Changes to This Summary (04/12/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Tumor Stratification by Imaging and Evans Surgical Staging for Childhood Liver Cancer
Revised Table 2 to update the annotation factor definitions.
Treatment Option Overview for Childhood Liver Cancer
Added text to state that radiofrequency ablation has also been used to treat oligometastatic hepatoblastoma when patients prefer to avoid surgical metastasectomy (cited Yevich et al. as reference 36 and level of evidence 3iiiB).
Hepatoblastoma
Added text to state that a careful compilation of published data on 1,370 children with (epi)genotyped Beckwith-Wiedemann syndrome demonstrated that the prevalence of hepatoblastoma was 4.7% in those with Beckwith-Wiedemann syndrome caused by chromosome 11p15 paternal uniparental disomy, less than 1% in the two types of alteration in imprinting control regions, and absent in CDKN1C mutation. The authors recommended that only children with Beckwith-Wiedemann syndrome caused by uniparental disomy be screened for hepatoblastoma using abdominal ultrasonography and alpha-fetoprotein levels every 3 months from age 3 months to 5 years (cited Mussa et al. as reference 25).
Added text to state that it is critical to discriminate between small cell undifferentiated hepatoblastoma expressing INI1 and rhabdoid tumor of the liver, which lacks the INI1gene and INI1 expression. Both diseases may share similar histology. Optimal treatment of rhabdoid tumor of the liver and small cell undifferentiated hepatoblastoma may require different approaches and different chemotherapy.
Added text about the ongoing international Pediatric Hepatic Malignancy International Treatment Trial.
Added text to state that if INI1 is maintained but small cell undifferentiated histology is present, the current literature suggests a worse outcome for these patients.
Added text about the results of the SIOPEL-4 trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma (added level of evidence 2Dii).
Added text to state that to date, the best outcomes for children with metastatic hepatoblastoma resulted from treatment with dose-dense cisplatin and doxorubicin, although significant toxicity was also noted.
Added text about the results of the SIOPEL-4 trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a subset of 39 patients with high-risk hepatoblastomas presenting with metastases.
Added text to state that percutaneous radiofrequency ablation has been used as an alternative to surgical resection of oligometastatic hepatoblastoma (cited Yevich et al. as reference 109 and level of evidence 3iiiB).
Revised text to state that percutaneous ablation techniques may also be considered for palliation or, in some cases, for curative therapy of oligometastatic disease.
Added text about the AHEP1531 trial as a treatment option under clinical evaluation for hepatoblastoma.
Hepatocellular Carcinoma
Added text to state that in a pediatric study of eight patients with hepatocellular carcinoma, two patients died of progressive disease without transplant. Treatment with transarterial chemoembolization stabilized disease in six patients, for a mean of 141 days to reach transplant. Five patients were alive at the end of the observation period, and one patient died of disease (cited Weiss et al. as reference 49 level of evidence 3iiA).
Added text about the AHEP1531 trial as a treatment option under clinical evaluation for hepatocellular carcinoma.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood liver cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Liver Cancer Treatment are:
  • Denise Adams, MD (Children's Hospital Boston)
  • Christopher N. Frantz, MD (Alfred I. duPont Hospital for Children)
  • Andrea A. Hayes-Jordan, MD, FACS, FAAP (University of North Carolina - Chapel Hill School of Medicine)
  • Karen J. Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
  • Stephen J. Shochat, MD (St. Jude Children's Research Hospital)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Liver Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/liver/hp/child-liver-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389232]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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  • Updated: April 12, 2019
Childhood Liver Cancer Treatment (PDQ®)—Health Professional Version - National Cancer Institute
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