Childhood Liver Cancer Treatment (PDQ®)

References

1. Czauderna P, Haeberle B, Hiyama E, et al.: The Children's Hepatic tumors International Collaboration (CHIC): Novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model. Eur J Cancer 52: 92-101, 2016. [PMC free article: PMC5141607] [PubMed: 26655560]
2. 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: 14752798]

References

1. López-Terrada D, Alaggio R, de Dávila MT, et al.: Towards an international pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium. Mod Pathol 27 (3): 472-91, 2014. [PubMed: 24008558]
2. Cho SJ, Ranganathan S, Alaggio R, et al.: Consensus classification of pediatric hepatocellular tumors: A report from the Children's Hepatic tumors International Collaboration (CHIC). Pediatr Blood Cancer : e30505, 2023. [PubMed: 37384428]

PRETEXT and POSTTEXT Group Definitions

The imaging grouping systems used to radiologically define the extent of liver involvement by the tumor are designated as the following:

• PRETEXT (PRE-Treatment EXTent of disease): The extent of liver involvement is defined before therapy.
• POSTTEXT (POST-Treatment EXTent of disease): The extent of liver involvement is defined in response to therapy.

PRETEXT

Major multicenter trial groups use PRETEXT as a central component of risk stratification schemes that guide treatment of hepatoblastoma. PRETEXT is based on the Couinaud eight-segment anatomical structure of the liver using cross-sectional imaging.

The PRETEXT system divides the liver into four parts, called sections. The left lobe of the liver consists of a lateral section (Couinaud segments I, II, and III) and a medial section (segment IV), whereas the right lobe consists of an anterior section (segments V and VIII) and a posterior section (segments VI and VII) (see Figure 1). PRETEXT groups were devised by the Société Internationale d’Oncologie Pédiatrique–Epithelial Liver Tumor Study Group (SIOPEL) for their first trial, SIOPEL-1,[2] and revised for the SIOPEL-3 trial in 2007.[3]

Figure 1. The liver is divided into four sections: the right posterior section, the right anterior section, the left medial section, and the left lateral section. Each section of the liver is further divided into segments: segments VI and VII make up the right posterior section, segments V and VIII make up the right anterior section, segment IV makes up the left medial section, and segments II and III make up the left lateral section. Segment I is found deep in the left side of the liver, in front of the inferior vena cava and behind the right, middle, and left hepatic veins.

PRETEXT group assignment I, II, III, or IV is determined by the number of uninvolved sections of the liver. PRETEXT is further described by annotation factors. Annotation factors include findings that are important for surgical management and evidence of tumor extension beyond the hepatic parenchyma of the major sections, including metastatic disease. For detailed descriptions of the PRETEXT groups, see Table 1. For descriptions of the annotation factors, see Table 2.

Annotation factors identify the extent of tumor involvement of the major vessels and its effect on venous inflow and outflow. These factors provide critical knowledge for the surgeon and can affect surgical outcomes. At one time, definitions of gross vascular involvement used by the Children's Oncology Group (COG) and major liver surgery centers in the United States differed from those used by SIOPEL and in Europe. These differences have been resolved, and the new definitions are being used in an international trial.[4]

Although PRETEXT can be used to predict tumor resectability, it has limitations. It can be difficult to distinguish real invasion beyond the anatomical border of a given hepatic section from compression and displacement by the tumor, especially at diagnosis. Additionally, it can be difficult to distinguish between vessel encroachment and involvement, particularly if imaging is inadequate. The PRETEXT group assignment has a moderate degree of interobserver variability. In a report using data from the SIOPEL-1 study, the preoperative PRETEXT group aligned with postoperative pathological findings only 51% of the time, with overstaging in 37% of patients and understaging in 12% of patients.[5]

Because distinguishing PRETEXT group assignment is difficult, central review of imaging is critical and is generally performed in all major clinical trials. For patients not enrolled in clinical trials, expert radiological review should be considered in questionable cases in which the PRETEXT group assignment affects choice of treatment.

Table

Table 1. Definitions of PRETEXT and POSTTEXT Groups^a .

Table

Table 2. Annotation Factors for Describing PRETEXT and POSTTEXT Groups^a.

Evans Surgical Staging for Childhood Liver Cancer

The COG/Evans staging system, based on operative findings and surgical resectability, was used for many years in the United States to group and determine treatment for children with liver cancer (see Table 3).[8-10] Currently, other risk stratification systems are predominantly used to classify patients and determine treatment strategy, although the Paediatric Hepatic International Tumour Trial (PHITT) uses the Evans system for patients with hepatocellular carcinoma. For more information, see Table 5.

Table

Table 3. Definition of Evans Surgical Staging .

References

1. Meyers AB, Towbin AJ, Geller JI, et al.: Hepatoblastoma imaging with gadoxetate disodium-enhanced MRI--typical, atypical, pre- and post-treatment evaluation. Pediatr Radiol 42 (7): 859-66, 2012. [PubMed: 22419052]
2. Brown J, Perilongo G, Shafford E, et al.: Pretreatment prognostic factors for children with hepatoblastoma-- results from the International Society of Paediatric Oncology (SIOP) study SIOPEL 1. Eur J Cancer 36 (11): 1418-25, 2000. [PubMed: 10899656]
3. Roebuck DJ, Aronson D, Clapuyt P, et al.: 2005 PRETEXT: a revised staging system for primary malignant liver tumours of childhood developed by the SIOPEL group. Pediatr Radiol 37 (2): 123-32; quiz 249-50, 2007. [PMC free article: PMC1805044] [PubMed: 17186233]
4. Towbin AJ, Meyers RL, Woodley H, et al.: 2017 PRETEXT: radiologic staging system for primary hepatic malignancies of childhood revised for the Paediatric Hepatic International Tumour Trial (PHITT). Pediatr Radiol 48 (4): 536-554, 2018. [PubMed: 29427028]
5. Aronson DC, Schnater JM, Staalman CR, et al.: Predictive value of the pretreatment extent of disease system in hepatoblastoma: results from the International Society of Pediatric Oncology Liver Tumor Study Group SIOPEL-1 study. J Clin Oncol 23 (6): 1245-52, 2005. [PubMed: 15718322]
6. Lovvorn HN, Ayers D, Zhao Z, et al.: Defining hepatoblastoma responsiveness to induction therapy as measured by tumor volume and serum alpha-fetoprotein kinetics. J Pediatr Surg 45 (1): 121-8; discussion 129, 2010. [PMC free article: PMC2852870] [PubMed: 20105591]
7. Venkatramani R, Stein JE, Sapra A, et al.: Effect of neoadjuvant chemotherapy on resectability of stage III and IV hepatoblastoma. Br J Surg 102 (1): 108-13, 2015. [PubMed: 25349947]
8. Ortega JA, Krailo MD, Haas JE, et al.: Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group. J Clin Oncol 9 (12): 2167-76, 1991. [PubMed: 1720452]
9. Douglass EC, Reynolds M, Finegold M, et al.: Cisplatin, vincristine, and fluorouracil therapy for hepatoblastoma: a Pediatric Oncology Group study. J Clin Oncol 11 (1): 96-9, 1993. [PubMed: 8380296]
10. Ortega JA, Douglass EC, Feusner JH, et al.: Randomized comparison of cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: A report from the Children's Cancer Group and the Pediatric Oncology Group. J Clin Oncol 18 (14): 2665-75, 2000. [PubMed: 10894865]

Surgery

Historically, complete surgical resection of the primary tumor has been essential for cure of malignant liver tumors in children.[2-6]; [7][Level of evidence C1] This approach continues to be the goal of definitive surgical procedures, which are often combined with chemotherapy. The surgeon performs a highly sophisticated liver resection in children and adolescents with primary liver tumors after the diagnosis is confirmed by pathological investigation of intraoperative frozen sections. While complete surgical resection is important for all liver tumors, it is especially important for hepatocellular carcinoma because curative chemotherapy is not available. In patients with advanced hepatoblastoma, postoperative complications are associated with worsened overall survival (OS).[8]

The three surgical options to treat primary pediatric liver cancer include the following:

• Initial surgical resection (alone or with adjuvant chemotherapy).
• Delayed surgical resection (with neoadjuvant chemotherapy).
• Orthotopic liver (cadaveric and living donor) transplant (most often with neoadjuvant chemotherapy).

The decision on which surgical approach to use (e.g., partial hepatectomy, extended resection, or transplant) depends on many factors, including the following:

• PRE-Treatment EXTent of disease (PRETEXT) group and POST-Treatment EXTent of disease (POSTTEXT) group.
• Size of the primary tumor.
• Presence of multifocal hepatic disease.
• Gross vascular involvement.
• Alpha-fetoprotein (AFP) levels.
• Whether preoperative chemotherapy is likely to convert an unresectable tumor into a resectable tumor.
• Whether hepatic disease meets surgical and histopathological criteria for orthotopic liver transplant.

Timing of the surgical approach is critical. Surgeons who have experience performing pediatric liver resections and transplants are involved early in the decision-making process to determine optimal timing and extent of resection.

Early involvement, preferably at diagnosis, with an experienced pediatric liver surgeon is especially important in patients with PRETEXT group III or IV or involvement of major liver vessels (positive annotation factors V [venous] or P [portal]).[9] Although vascular involvement was initially thought to be a contraindication to resection, experienced liver surgeons are sometimes able to successfully resect the tumor and avoid performing a transplant.[10-12]; [13][Level of evidence C1] Patients with vascular involvement and tumors that have been deemed nonresectable by the pediatric surgical expert should be referred to a transplant center to avoid unnecessary delays in evaluation and listing for transplant.

Intraoperative ultrasonography may result in further delineation of tumor extent and location and can affect intraoperative management.[14] Preoperative infusion of indocyanine green, a fluoroactive agent that is concentrated in the liver and retained by abnormal liver tumors, has also been used to provide visual intraoperative guidance to locate the tumor and assess proximity to surgical margins.[15,16]

If the tumor is determined to be unresectable, measures to reduce the tumor size to make a complete surgical resection possible need to be considered. These measures include preoperative intravenous chemotherapy, transarterial chemotherapy, or transarterial radioactive therapy. These efforts must be carefully coordinated with the surgical team to facilitate planning of resection. Prolonged chemotherapy can lead to unnecessary delays and, in rare cases, tumor progression. If the tumor can be completely excised by an experienced surgical team, less postoperative chemotherapy may be needed. Incomplete resection must be avoided because patients who undergo rescue transplants of incompletely resected tumors have an inferior outcome, compared with patients who undergo transplant as the primary surgical therapy.[17][Level of evidence C1] Accomplishing the appropriate surgery at resection is critical.

The approach taken by the Children's Oncology Group (COG) in North American clinical trials is to perform surgery initially when a complete resection can be done with a simple, negative-margin hemihepatectomy. The COG AHEP0731 (NCT00980460) trial studied the use of PRETEXT and POSTTEXT to determine the optimal approach and timing of surgery. POSTTEXT imaging grouping was performed after two and four cycles of chemotherapy to determine the optimal time for definitive surgery.[6,18] For more information, see the Tumor Stratification by Imaging section.

Chemotherapy

Chemotherapy regimens used in the treatment of hepatoblastoma and hepatocellular carcinoma are described in their respective sections. Chemotherapy has been much more successful in the treatment of hepatoblastoma than in the treatment of hepatocellular carcinoma.[6,28,42] For more information, see the sections on Treatment of Hepatoblastoma and Treatment of Hepatocellular Carcinoma.

The standard of care in the United States is preoperative chemotherapy when the tumor is unresectable and postoperative chemotherapy after complete resection, even if preoperative chemotherapy has already been given.[43] Preoperative chemotherapy has been shown to benefit children with hepatoblastoma. However, postoperative chemotherapy after definitive surgical resection or liver transplant has not been investigated in a randomized fashion.

Radiation Therapy

Radiation therapy, even in combination with chemotherapy, has not cured children with unresectable hepatic tumors. A study of 154 patients with hepatoblastoma showed that radiation therapy and/or second resection of positive margins may not be necessary in some patients with incompletely resected hepatoblastoma and microscopic residual tumor.[44] Although there is no standard indication, radiation therapy may have a role in the management of patients with incompletely resected hepatoblastomas.[45] Stereotactic body radiation therapy is a safe and effective alternative treatment that has been successfully used in adult patients with hepatocellular carcinoma who are unable to undergo liver ablation/resection.[46] This highly conformal radiotherapeutic technique, when available, may be considered on an individual basis in children with hepatocellular carcinoma.

Other Treatment Approaches

Other treatment approaches include the following:

• Transarterial chemoembolization (TACE): TACE is an image-guided, minimally invasive, nonsurgical procedure that is used to treat malignant lesions in the liver. The procedure uses a catheter to deliver both chemotherapy medication and embolization materials into the blood vessels that lead to the tumor. The arterial catheter route is image guided, most often via the hepatic artery, and perfusion of the tumor by the targeted artery may be confirmed by imaging before therapeutic injection. This procedure allows for the treatment of tumors that are not accessible with conventional surgery or radiation treatments. TACE has been used for patients with inoperable hepatoblastoma.[47-49] This procedure has also been used in a few children to successfully shrink tumors to permit resections.[48]
• Transarterial radioembolization (TARE): TARE is an image-guided, minimally invasive, nonsurgical procedure that delivers radiation therapy to treat tumors in the liver. This procedure delivers radioactive beads and blocks arterial flow within the tumor to keep the radiation inside the tumor. Glass or resin microspheres, coated most commonly with yttrium Y 90 (90Y), are delivered to the tumor via catheters placed in arteries that supply the tumor. Usually, the hepatic artery or its branches are used, but tumors may be partially supplied by parasitized surrounding vessels. Because of the risk of radiation delivery to the nearby lung, technetium Tc 99m microaggregated albumin imaging is performed with delivery via the catheter that is in place before the administration of radioactive beads to carefully measure radiation exposure to the lung. If calculations determine that lung exposure is unsafe, TARE is not pursued. TARE with 90Y has been used in children with hepatoblastoma (n = 2) and hepatocellular carcinoma (n = 2) who have unresectable tumors. After treatment with 90Y TARE, all tumors were completely resected.[50][Level of evidence C3]; [51][Level of evidence C2] This approach has also been used for palliation in children with hepatocellular carcinoma.[52] For more information, see Primary Liver Cancer Treatment.
• High-intensity focused ultrasonography (HIFU): HIFU is a noninvasive treatment for a wide range of tumors and diseases. HIFU uses an ultrasound transducer, similar to the ones used for diagnostic imaging, but with much higher energy. The transducer focuses sound waves to generate heat at a single point in the body and destroy the target tissue. The tissue can get as hot as 66°C in only 20 seconds. This process is repeated as many times as necessary until the target tissue is destroyed. Magnetic resonance imaging is used to plan the treatment and monitor the amount of heat in real time. A combination of chemotherapy followed by TACE and HIFU showed promising results in China for children with PRETEXT III and PRETEXT IV malignant liver tumors, some of whom had resectable tumors but did not undergo surgery because of parent refusal.[53]

References

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2. Czauderna P, Otte JB, Aronson DC, et al.: Guidelines for surgical treatment of hepatoblastoma in the modern era--recommendations from the Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL). Eur J Cancer 41 (7): 1031-6, 2005. [PubMed: 15862752]
3. Czauderna P, Mackinlay G, Perilongo G, et al.: Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 20 (12): 2798-804, 2002. [PubMed: 12065556]
4. Meyers RL, Czauderna P, Otte JB: Surgical treatment of hepatoblastoma. Pediatr Blood Cancer 59 (5): 800-8, 2012. [PubMed: 22887704]
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6. Murawski M, Weeda VB, Maibach R, et al.: Hepatocellular Carcinoma in Children: Does Modified Platinum- and Doxorubicin-Based Chemotherapy Increase Tumor Resectability and Change Outcome? Lessons Learned From the SIOPEL 2 and 3 Studies. J Clin Oncol 34 (10): 1050-6, 2016. [PubMed: 26811523]
7. Allan BJ, Wang B, Davis JS, et al.: A review of 218 pediatric cases of hepatocellular carcinoma. J Pediatr Surg 49 (1): 166-71; discussion 171, 2014. [PubMed: 24439603]
8. Becker K, Furch C, Schmid I, et al.: Impact of postoperative complications on overall survival of patients with hepatoblastoma. Pediatr Blood Cancer 62 (1): 24-8, 2015. [PubMed: 25251521]
9. D'Antiga L, Vallortigara F, Cillo U, et al.: Features predicting unresectability in hepatoblastoma. Cancer 110 (5): 1050-8, 2007. [PubMed: 17661341]
10. Lautz TB, Ben-Ami T, Tantemsapya N, et al.: Successful nontransplant resection of POST-TEXT III and IV hepatoblastoma. Cancer 117 (9): 1976-83, 2011. [PubMed: 21509775]
11. Fonseca A, Gupta A, Shaikh F, et al.: Extreme hepatic resections for the treatment of advanced hepatoblastoma: Are planned close margins an acceptable approach? Pediatr Blood Cancer 65 (2): , 2018. [PubMed: 28921939]
12. Fuchs J, Cavdar S, Blumenstock G, et al.: POST-TEXT III and IV Hepatoblastoma: Extended Hepatic Resection Avoids Liver Transplantation in Selected Cases. Ann Surg 266 (2): 318-323, 2017. [PubMed: 27501172]
13. Baertschiger RM, Ozsahin H, Rougemont AL, et al.: Cure of multifocal panhepatic hepatoblastoma: is liver transplantation always necessary? J Pediatr Surg 45 (5): 1030-6, 2010. [PubMed: 20438949]
14. Felsted AE, Shi Y, Masand PM, et al.: Intraoperative ultrasound for liver tumor resection in children. J Surg Res 198 (2): 418-23, 2015. [PubMed: 25940155]
15. Rossi G, Tarasconi A, Baiocchi G, et al.: Fluorescence guided surgery in liver tumors: applications and advantages. Acta Biomed 89 (9-S): 135-140, 2018. [PMC free article: PMC6502182] [PubMed: 30561406]
16. Shen Q, Liu X, Pan S, et al.: Effectiveness of indocyanine green fluorescence imaging in resection of hepatoblastoma. Pediatr Surg Int 39 (1): 181, 2023. [PubMed: 37061578]
17. 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: 14752798]
18. Venkatramani R, Stein JE, Sapra A, et al.: Effect of neoadjuvant chemotherapy on resectability of stage III and IV hepatoblastoma. Br J Surg 102 (1): 108-13, 2015. [PubMed: 25349947]
19. Vinayak R, Cruz RJ, Ranganathan S, et al.: Pediatric liver transplantation for hepatocellular cancer and rare liver malignancies: US multicenter and single-center experience (1981-2015). Liver Transpl 23 (12): 1577-1588, 2017. [PMC free article: PMC5725660] [PubMed: 28834194]
20. Guiteau JJ, Cotton RT, Karpen SJ, et al.: Pediatric liver transplantation for primary malignant liver tumors with a focus on hepatic epithelioid hemangioendothelioma: the UNOS experience. Pediatr Transplant 14 (3): 326-31, 2010. [PubMed: 20051026]
21. Malek MM, Shah SR, Atri P, et al.: Review of outcomes of primary liver cancers in children: our institutional experience with resection and transplantation. Surgery 148 (4): 778-82; discussion 782-4, 2010. [PubMed: 20728194]
22. Héry G, Franchi-Abella S, Habes D, et al.: Initial liver transplantation for unresectable hepatoblastoma after chemotherapy. Pediatr Blood Cancer 57 (7): 1270-5, 2011. [PubMed: 21910210]
23. Suh MY, Wang K, Gutweiler JR, et al.: Safety of minimal immunosuppression in liver transplantation for hepatoblastoma. J Pediatr Surg 43 (6): 1148-52, 2008. [PubMed: 18558198]
24. Zsíros J, Maibach R, Shafford E, et al.: Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study. J Clin Oncol 28 (15): 2584-90, 2010. [PubMed: 20406943]
25. Khan AS, Brecklin B, Vachharajani N, et al.: Liver Transplantation for Malignant Primary Pediatric Hepatic Tumors. J Am Coll Surg 225 (1): 103-113, 2017. [PubMed: 28232059]
26. Browne M, Sher D, Grant D, et al.: Survival after liver transplantation for hepatoblastoma: a 2-center experience. J Pediatr Surg 43 (11): 1973-81, 2008. [PubMed: 18970927]
27. Hamilton EC, Balogh J, Nguyen DT, et al.: Liver transplantation for primary hepatic malignancies of childhood: The UNOS experience. J Pediatr Surg : , 2017. [PubMed: 29108844]
28. McAteer JP, Goldin AB, Healey PJ, et al.: Surgical treatment of primary liver tumors in children: outcomes analysis of resection and transplantation in the SEER database. Pediatr Transplant 17 (8): 744-50, 2013. [PubMed: 23992390]
29. Reyes JD, Carr B, Dvorchik I, et al.: Liver transplantation and chemotherapy for hepatoblastoma and hepatocellular cancer in childhood and adolescence. J Pediatr 136 (6): 795-804, 2000. [PubMed: 10839879]
30. Boster JM, Superina R, Mazariegos GV, et al.: Predictors of survival following liver transplantation for pediatric hepatoblastoma and hepatocellular carcinoma: Experience from the Society of Pediatric Liver Transplantation (SPLIT). Am J Transplant 22 (5): 1396-1408, 2022. [PubMed: 34990053]
31. Otte JB: Should the selection of children with hepatocellular carcinoma be based on Milan criteria? Pediatr Transplant 12 (1): 1-3, 2008. [PubMed: 18086239]
32. de Ville de Goyet J, Meyers RL, Tiao GM, et al.: Beyond the Milan criteria for liver transplantation in children with hepatic tumours. Lancet Gastroenterol Hepatol 2 (6): 456-462, 2017. [PubMed: 28497761]
33. Khanna R, Verma SK: Pediatric hepatocellular carcinoma. World J Gastroenterol 24 (35): 3980-3999, 2018. [PMC free article: PMC6148423] [PubMed: 30254403]
34. Sevmis S, Karakayali H, Ozçay F, et al.: Liver transplantation for hepatocellular carcinoma in children. Pediatr Transplant 12 (1): 52-6, 2008. [PubMed: 18186889]
35. Faraj W, Dar F, Marangoni G, et al.: Liver transplantation for hepatoblastoma. Liver Transpl 14 (11): 1614-9, 2008. [PubMed: 18975296]
36. Pire A, Tambucci R, De Magnée C, et al.: Living donor liver transplantation for hepatic malignancies in children. Pediatr Transplant 25 (7): e14047, 2021. [PubMed: 34076944]
37. Feusner JH, Krailo MD, Haas JE, et al.: Treatment of pulmonary metastases of initial stage I hepatoblastoma in childhood. Report from the Childrens Cancer Group. Cancer 71 (3): 859-64, 1993. [PubMed: 8381705]
38. Zsiros J, Brugieres L, Brock P, et al.: Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study. Lancet Oncol 14 (9): 834-42, 2013. [PMC free article: PMC3730732] [PubMed: 23831416]
39. Meyers RL, Katzenstein HM, Krailo M, et al.: Surgical resection of pulmonary metastatic lesions in children with hepatoblastoma. J Pediatr Surg 42 (12): 2050-6, 2007. [PubMed: 18082706]
40. O'Neill AF, Towbin AJ, Krailo MD, et al.: Characterization of Pulmonary Metastases in Children With Hepatoblastoma Treated on Children's Oncology Group Protocol AHEP0731 (The Treatment of Children With All Stages of Hepatoblastoma): A Report From the Children's Oncology Group. J Clin Oncol 35 (30): 3465-3473, 2017. [PMC free article: PMC5648177] [PubMed: 28892430]
41. Yevich S, Calandri M, Gravel G, et al.: Reiterative Radiofrequency Ablation in the Management of Pediatric Patients with Hepatoblastoma Metastases to the Lung, Liver, or Bone. Cardiovasc Intervent Radiol 42 (1): 41-47, 2019. [PubMed: 30350173]
42. Weeda VB, Murawski M, McCabe AJ, et al.: Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma--results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience. Eur J Cancer 49 (12): 2698-704, 2013. [PubMed: 23683550]
43. Czauderna P, Lopez-Terrada D, Hiyama E, et al.: Hepatoblastoma state of the art: pathology, genetics, risk stratification, and chemotherapy. Curr Opin Pediatr 26 (1): 19-28, 2014. [PubMed: 24322718]
44. Schnater JM, Aronson DC, Plaschkes J, et al.: Surgical view of the treatment of patients with hepatoblastoma: results from the first prospective trial of the International Society of Pediatric Oncology Liver Tumor Study Group. Cancer 94 (4): 1111-20, 2002. [PubMed: 11920482]
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46. Wang PM, Chung NN, Hsu WC, et al.: Stereotactic body radiation therapy in hepatocellular carcinoma: Optimal treatment strategies based on liver segmentation and functional hepatic reserve. Rep Pract Oncol Radiother 20 (6): 417-24, 2015 Nov-Dec. [PMC free article: PMC4661347] [PubMed: 26696781]
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51. Whitlock RS, Loo C, Patel K, et al.: Transarterial Radioembolization Treatment as a Bridge to Surgical Resection in Pediatric Hepatocellular Carcinoma. J Pediatr Hematol Oncol 43 (8): e1181-e1185, 2021. [PubMed: 33769387]
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References

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Incidence

The annual incidence of hepatoblastoma in the United States has increased (more than doubled), from 0.8 (1975–1983) to 2.3 (2020) cases per 1 million children aged 19 years and younger.[1-3] The cause for this increase is unknown, but the improved survival of premature infants with very low birth weight, which is known to be associated with hepatoblastoma, may contribute.[4] In Japan, the risk of hepatoblastoma in children who weighed less than 1,000 g at birth is 15 times the risk in children with normal birth weight.[5] Other data have confirmed the high incidence of hepatoblastoma in premature infants with very low birth weight.[6] Attempts to identify factors resulting from treatment of infants born prematurely have not revealed any suggestive causation of the increased incidence of hepatoblastoma.[4]

The age of onset of liver cancer in children is related to tumor histology. Hepatoblastomas usually occur before the age of 3 years, and approximately 90% of malignant liver tumors in children aged 4 years and younger are hepatoblastomas.[7]

Risk Factors

Conditions associated with an increased risk of hepatoblastoma are described in Table 4.

Table

Table 4. Conditions Associated With an Increased Risk of Hepatoblastoma.

Genomics of Hepatoblastoma

Diagnosis

Prognosis and Prognostic Factors

Histology

Hepatoblastoma arises from precursors of hepatocytes and can have several morphologies, including the following:[80]

• Small cells that reflect neither epithelial nor stromal differentiation. It is critical to discriminate between small cell undifferentiated hepatoblastoma expressing SMARCB1 and rhabdoid tumor of the liver, which lacks the SMARCB1 gene and SMARCB1 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. For a more extensive discussion on the differences of these two diseases, see the Small cell undifferentiated histology hepatoblastoma and rhabdoid tumors of the liver section.
• Embryonal epithelial cells resembling the liver epithelium at 6 to 8 weeks of gestation.
• Well-differentiated fetal hepatocytes morphologically indistinguishable from normal fetal liver cells.

Most often the tumor consists of a mixture of epithelial hepatocyte precursors. About 20% of tumors have stromal derivatives such as osteoid, chondroid, and rhabdoid elements. Occasionally, neuronal, melanocytic, squamous, and enteroendocrine elements are found. The following histological subtypes have clinical relevance:

• Well-differentiated fetal (pure fetal) histology hepatoblastoma.
• Mixed fetal and embryonal epithelial cells.
• Small cell undifferentiated histology hepatoblastoma and rhabdoid tumors of the liver.

  • Small cell undifferentiated hepatoblastoma (SMARCB1 positive).
  • Rhabdoid tumor of liver (SMARCB1 negative).

Risk Stratification

There are significant differences among childhood cancer study groups in risk stratification used to determine treatment, making it difficult to compare results of the different treatments. Table 5 shows the variability in the definitions of risk groups.

Table

Table 5. A Comparison of the Use of PRETEXT in Risk Stratification Schemes for Hepatoblastoma^a,b.

International risk classification model

The CHIC group developed a novel risk stratification system for use in international clinical trials on the basis of prognostic features present at diagnosis. CHIC unified the disparate definitions and staging systems used by pediatric cooperative multicenter trial groups, enabling the comparison of studies conducted by heterogeneous groups in different countries.[63] Original detailed clinical patient data were extracted from eight published clinical trials using central review of imaging and histology, and prognostic factors were identified by univariate analysis.[58]

Based on the initial univariate analysis of the data combined with historical clinical treatment patterns and data from previous large clinical trials, five backbone groups were selected, which allowed for further risk stratification. Subsequent multivariate analysis on the basis of these backbone groups defined the following clinical prognostic factors: PRETEXT group (I, II, III, or IV), presence of metastasis (yes or no), and AFP (≤100 ng/mL). The backbone groups are as follows:[63]

• Backbone 1: PRETEXT I/II, not metastatic, AFP greater than 100 ng/mL.
• Backbone 2: PRETEXT III, not metastatic, AFP greater than 100 ng/mL.
• Backbone 3: PRETEXT IV, not metastatic, AFP greater than 100 ng/mL.
• Backbone 4: Any PRETEXT group, metastatic disease at diagnosis, AFP greater than 100 ng/mL.
• Backbone 5: Any PRETEXT group, metastatic or not, AFP less than or equal to 100 ng/mL at diagnosis.

Other diagnostic factors (e.g., age) were queried for each of the backbone categories, including the presence of at least one of the following PRETEXT annotations (defined as VPEFR+, see Table 2) or AFP less than or equal to 100 ng/mL:[63]

• V: Involvement of vena cava or all three hepatic veins, or both.
• P: Involvement of portal bifurcation or both right and left portal veins, or both.
• E: Extrahepatic contiguous tumor extension.
• F: Multifocal liver tumor.
• R: Tumor rupture at diagnosis.

An assessment of surgical resectability at diagnosis was added for PRETEXT I and II patients. Patients in each of the five backbone categories were stratified on the basis of backwards stepwise elimination multivariable analysis of additional patient characteristics, including age and presence or absence of PRETEXT annotation factors (V, P, E, F, and R). Each of these subcategories received one of four risk designations (very low, low, intermediate, or high). The result of the multivariate analysis was used to assign patients to very low-, low-, intermediate-, and high-risk categories, as shown in Figure 2. For example, the finding of an AFP level of 100 to 1,000 ng/mL was significant only among patients younger than 8 years in the backbone PRETEXT III group. The analysis enables prognostically similar risk groups to be assigned to the appropriate treatment groups on upcoming international protocols.[63]

Figure 2. Risk stratification trees for the Children’s Hepatic tumors International Collaboration—Hepatoblastoma Stratification (CHIC-HS). Very low-risk group and low-risk group are separated only by their resectability at diagnosis, which has been defined by international consensus as part of the surgical guidelines for the collaborative trial, Paediatric Hepatic International Tumour Trial (PHITT). Separate risk stratification trees are used for each of the four PRETEXT groups. AFP = alpha-fetoprotein. M = metastatic disease. PRETEXT = PRETreatment EXTent of disease.[63] Reprinted from The Lancet Oncology, Volume 18, Meyers RL, Maibach R, Hiyama E, Häberle B, Krailo M, Rangaswami A, Aronson DC, Malogolowkin MH, Perilongo G, von Schweinitz D, Ansari M, Lopez-Terrada D, Tanaka Y, Alaggio R, Leuschner I, Hishiki T, Schmid I, Watanabe K, Yoshimura K, Feng Y, Rinaldi E, Saraceno D, Derosa M, Czauderna P, Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration, Pages 122–131, Copyright (2017), with permission from Elsevier.

Treatment of Hepatoblastoma

Treatment options for newly diagnosed hepatoblastoma depend on the following:

• Whether the cancer is resectable at diagnosis.
• The tumor histology.
• How the cancer responds to chemotherapy.
• Whether the cancer has metastasized.

Cisplatin-based chemotherapy has resulted in a survival rate of more than 90% for children with PRETEXT and POST-Treatment EXTent (POSTTEXT) group I and II resectable disease before or after chemotherapy.[54,56,67]

Chemotherapy regimens used in the treatment of hepatoblastoma and their respective outcomes are described in Table 6. For information describing each stage, see the Tumor Stratification by Imaging section.

Table

Table 6. Outcomes for Hepatoblastoma Multicenter Trials^a.

Treatment of Progressive or Recurrent Hepatoblastoma

The prognosis for a patient with progressive or recurrent hepatoblastoma depends on several factors, including the following:[126]

• Site of recurrence.
• Previous treatment.
• Individual patient considerations.

Treatment options for progressive or recurrent hepatoblastoma include the following:

1. Surgical resection. In patients with hepatoblastoma that is completely resected at initial diagnosis, aggressive surgical treatment of isolated pulmonary metastases that develop in the course of the disease, in conjunction with an overall strategy that includes chemotherapy, may make extended DFS possible.[117,126,127]
   If possible, isolated metastases are resected completely in patients whose primary tumor is controlled.[128] A retrospective analysis of patients in the SIOPEL 1, 2, and 3 studies showed a 12% incidence of recurrence after complete remission by imaging and AFP levels. Outcome after recurrence was best if the tumor was amenable to surgery. Of patients who underwent chemotherapy and surgery, the 3-year EFS rate was 34%, and the OS rate was 43%.[126][Level of evidence C1]
   If all of the recurrent disease cannot be surgically removed, patients should consider enrolling in a clinical trial. Phase I and phase II clinical trials may be appropriate.
2. Chemotherapy. Analysis of survival after recurrence demonstrated that some patients treated with cisplatin/vincristine/fluorouracil could be salvaged with doxorubicin-containing regimens, but patients treated with doxorubicin/cisplatin could not be salvaged with vincristine/fluorouracil.[129] The addition of doxorubicin to vincristine/fluorouracil/cisplatin was clinically evaluated in the COG study AHEP0731 (NCT00980460).
   Combined vincristine/irinotecan and single-agent irinotecan have been used with some success.[123]; [122][Level of evidence C1]
   A review of COG phase I and II studies found no promising agents for relapsed hepatoblastoma.[130]
3. Liver transplant. Liver transplant should be considered for patients with nonmetastatic disease recurrence in the liver that is not amenable to resection.[71,98,101]
4. Percutaneous ablation. Percutaneous radiofrequency ablation has been used as an alternative to surgical resection of oligometastatic hepatoblastoma.[131][Level of evidence C1] Percutaneous ablation techniques may also be considered for palliation.[132]

Treatment Options Under Clinical Evaluation for Hepatoblastoma

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, see the ClinicalTrials.gov website.

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94. Hiyama E, Hishiki T, Watanabe K, et al.: Outcome and Late Complications of Hepatoblastomas Treated Using the Japanese Study Group for Pediatric Liver Tumor 2 Protocol. J Clin Oncol 38 (22): 2488-2498, 2020. [PubMed: 32421442]
95. Aronson DC, Weeda VB, Maibach R, et al.: Microscopically positive resection margin after hepatoblastoma resection: what is the impact on prognosis? A Childhood Liver Tumours Strategy Group (SIOPEL) report. Eur J Cancer 106: 126-132, 2019. [PubMed: 30528797]
96. Vasudevan SA, Meyers RL, Finegold MJ, et al.: Outcomes of children with well-differentiated fetal hepatoblastoma treated with surgery only: Report from Children's Oncology Group Trial, AHEP0731. J Pediatr Surg 57 (10): 251-256, 2022. [PMC free article: PMC9474653] [PubMed: 35810020]
97. Perilongo G, Maibach R, Shafford E, et al.: Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma. N Engl J Med 361 (17): 1662-70, 2009. [PubMed: 19846851]
98. Reyes JD, Carr B, Dvorchik I, et al.: Liver transplantation and chemotherapy for hepatoblastoma and hepatocellular cancer in childhood and adolescence. J Pediatr 136 (6): 795-804, 2000. [PubMed: 10839879]
99. Molmenti EP, Wilkinson K, Molmenti H, et al.: Treatment of unresectable hepatoblastoma with liver transplantation in the pediatric population. Am J Transplant 2 (6): 535-8, 2002. [PubMed: 12118897]
100. Czauderna P, Otte JB, Aronson DC, et al.: Guidelines for surgical treatment of hepatoblastoma in the modern era--recommendations from the Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL). Eur J Cancer 41 (7): 1031-6, 2005. [PubMed: 15862752]
101. Austin MT, Leys CM, Feurer ID, et al.: Liver transplantation for childhood hepatic malignancy: a review of the United Network for Organ Sharing (UNOS) database. J Pediatr Surg 41 (1): 182-6, 2006. [PubMed: 16410130]
102. Pham TA, Gallo AM, Concepcion W, et al.: Effect of Liver Transplant on Long-term Disease-Free Survival in Children With Hepatoblastoma and Hepatocellular Cancer. JAMA Surg 150 (12): 1150-8, 2015. [PubMed: 26308249]
103. Khan AS, Brecklin B, Vachharajani N, et al.: Liver Transplantation for Malignant Primary Pediatric Hepatic Tumors. J Am Coll Surg 225 (1): 103-113, 2017. [PubMed: 28232059]
104. Xianliang H, Jianhong L, Xuewu J, et al.: Cure of hepatoblastoma with transcatheter arterial chemoembolization. J Pediatr Hematol Oncol 26 (1): 60-3, 2004. [PubMed: 14707717]
105. 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: 10715298]
106. Aguado A, Dunn SP, Averill LW, et al.: Successful use of transarterial radioembolization with yttrium-90 (TARE-Y90) in two children with hepatoblastoma. Pediatr Blood Cancer 67 (9): e28421, 2020. [PubMed: 32603027]
107. Madanur MA, Battula N, Davenport M, et al.: Staged resection for a ruptured hepatoblastoma: a 6-year follow-up. Pediatr Surg Int 23 (6): 609-11, 2007. [PubMed: 17066271]
108. Aronson DC, Meyers RL: Malignant tumors of the liver in children. Semin Pediatr Surg 25 (5): 265-275, 2016. [PubMed: 27955729]
109. Venkatramani R, Stein JE, Sapra A, et al.: Effect of neoadjuvant chemotherapy on resectability of stage III and IV hepatoblastoma. Br J Surg 102 (1): 108-13, 2015. [PubMed: 25349947]
110. von Schweinitz D, Hecker H, Harms D, et al.: Complete resection before development of drug resistance is essential for survival from advanced hepatoblastoma--a report from the German Cooperative Pediatric Liver Tumor Study HB-89. J Pediatr Surg 30 (6): 845-52, 1995. [PubMed: 7545228]
111. Fuchs J, Cavdar S, Blumenstock G, et al.: POST-TEXT III and IV Hepatoblastoma: Extended Hepatic Resection Avoids Liver Transplantation in Selected Cases. Ann Surg 266 (2): 318-323, 2017. [PubMed: 27501172]
112. Hemming AW, Reed AI, Fujita S, et al.: Role for extending hepatic resection using an aggressive approach to liver surgery. J Am Coll Surg 206 (5): 870-5; discussion 875-8, 2008. [PubMed: 18471713]
113. Fonseca A, Gupta A, Shaikh F, et al.: Extreme hepatic resections for the treatment of advanced hepatoblastoma: Are planned close margins an acceptable approach? Pediatr Blood Cancer 65 (2): , 2018. [PubMed: 28921939]
114. de Freitas Paganoti G, Tannuri ACA, Dantas Marques AC, et al.: Extensive Hepatectomy as an Alternative to Liver Transplant in Advanced Hepatoblastoma: A New Protocol Used in a Pediatric Liver Transplantation Center. Transplant Proc 51 (5): 1605-1610, 2019. [PubMed: 31155201]
115. Katzenstein HM, Malogolowkin MH, Krailo MD, et al.: Doxorubicin in combination with cisplatin, 5-flourouracil, and vincristine is feasible and effective in unresectable hepatoblastoma: A Children's Oncology Group study. Cancer 128 (5): 1057-1065, 2022. [PMC free article: PMC9066555] [PubMed: 34762296]
116. Wang S, Yang C, Zhang J, et al.: First experience of high-intensity focused ultrasound combined with transcatheter arterial embolization as local control for hepatoblastoma. Hepatology 59 (1): 170-7, 2014. [PubMed: 23813416]
117. Meyers RL, Katzenstein HM, Krailo M, et al.: Surgical resection of pulmonary metastatic lesions in children with hepatoblastoma. J Pediatr Surg 42 (12): 2050-6, 2007. [PubMed: 18082706]
118. Karski EE, Dvorak CC, Leung W, et al.: Treatment of hepatoblastoma with high-dose chemotherapy and stem cell rescue: the pediatric blood and marrow transplant consortium experience and review of the literature. J Pediatr Hematol Oncol 36 (5): 362-8, 2014. [PubMed: 24577552]
119. Partrick DA, Bensard DD, Teitelbaum DH, et al.: Successful thoracoscopic lung biopsy in children utilizing preoperative CT-guided localization. J Pediatr Surg 37 (7): 970-3; discussion 970-3, 2002. [PubMed: 12077751]
120. Katzenstein HM, Rigsby C, Shaw PH, et al.: Novel therapeutic approaches in the treatment of children with hepatoblastoma. J Pediatr Hematol Oncol 24 (9): 751-5, 2002. [PubMed: 12468918]
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125. Habrand JL, Nehme D, Kalifa C, et al.: Is there a place for radiation therapy in the management of hepatoblastomas and hepatocellular carcinomas in children? Int J Radiat Oncol Biol Phys 23 (3): 525-31, 1992. [PubMed: 1319426]
126. Semeraro M, Branchereau S, Maibach R, et al.: Relapses in hepatoblastoma patients: clinical characteristics and outcome--experience of the International Childhood Liver Tumour Strategy Group (SIOPEL). Eur J Cancer 49 (4): 915-22, 2013. [PubMed: 23146961]
127. Shi Y, Geller JI, Ma IT, et al.: Relapsed hepatoblastoma confined to the lung is effectively treated with pulmonary metastasectomy. J Pediatr Surg 51 (4): 525-9, 2016. [PubMed: 26607968]
128. Matsunaga T, Sasaki F, Ohira M, et al.: Analysis of treatment outcome for children with recurrent or metastatic hepatoblastoma. Pediatr Surg Int 19 (3): 142-6, 2003. [PubMed: 12768314]
129. Malogolowkin MH, Katzenstein HM, Krailo M, et al.: Redefining the role of doxorubicin for the treatment of children with hepatoblastoma. J Clin Oncol 26 (14): 2379-83, 2008. [PMC free article: PMC4558624] [PubMed: 18467729]
130. Trobaugh-Lotrario AD, Meyers RL, Feusner JH: Outcomes of Patients With Relapsed Hepatoblastoma Enrolled on Children's Oncology Group (COG) Phase I and II Studies. J Pediatr Hematol Oncol 38 (3): 187-90, 2016. [PubMed: 26583620]
131. Yevich S, Calandri M, Gravel G, et al.: Reiterative Radiofrequency Ablation in the Management of Pediatric Patients with Hepatoblastoma Metastases to the Lung, Liver, or Bone. Cardiovasc Intervent Radiol 42 (1): 41-47, 2019. [PubMed: 30350173]
132. Liu B, Zhou L, Huang G, et al.: First Experience of Ultrasound-guided Percutaneous Ablation for Recurrent Hepatoblastoma after Liver Resection in Children. Sci Rep 5: 16805, 2015. [PMC free article: PMC4649467] [PubMed: 26578035]

Incidence

The annual incidence of hepatocellular carcinoma in the United States is 0.4 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] 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] However, the incidence of hepatocellular carcinoma in children has not increased. In several Asian countries, the incidence of hepatocellular carcinoma in children is 10 times higher than in North America. The high incidence appears to be related to the incidence of perinatally acquired hepatitis B virus (HBV), which can be prevented in most cases by vaccination and administration of hepatitis B immune globulin to the newborn child.[3]

Fibrolamellar carcinoma of the liver was thought to be a subtype of hepatocellular carcinoma. However, it is now recognized as a distinct cancer. For more information, see the Fibrolamellar Carcinoma section.

Risk Factors

Conditions associated with hepatocellular carcinoma are described in Table 7.

Table

Table 7. Conditions Associated With Hepatocellular Carcinoma.

Genomics of Hepatocellular Carcinoma

Diagnosis

For more information, see the Diagnosis section in the Hepatoblastoma section.

Prognosis and Prognostic Factors

Histology

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

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 of Progressive or Recurrent Hepatocellular Carcinoma

The prognosis for a patient with recurrent or progressive hepatocellular carcinoma is extremely poor.[50]

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.[25,35,36,51]
2. Radiofrequency ablation.
   In a retrospective single-institution study, ten children aged 6 to 17 years with recurrent hepatocellular carcinoma were treated with radiofrequency ablation. After one ablation, 14 of 15 target lesions had complete responses. None of these lesions progressed. The 1-year OS rate was 77.8%, and the 3-year OS rate was 44.4%.[52][Level of evidence C1]
3. 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 radiological progression were about 3 months longer than for patients who received a placebo.[53]

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, see the ClinicalTrials.gov website.

References

1. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed August 23, 2024.
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11. van Spronsen FJ, Bijleveld CM, van Maldegem BT, et al.: Hepatocellular carcinoma in hereditary tyrosinemia type I despite 2-(2 nitro-4-3 trifluoro- methylbenzoyl)-1, 3-cyclohexanedione treatment. J Pediatr Gastroenterol Nutr 40 (1): 90-3, 2005. [PubMed: 15625434]
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25. Austin MT, Leys CM, Feurer ID, et al.: Liver transplantation for childhood hepatic malignancy: a review of the United Network for Organ Sharing (UNOS) database. J Pediatr Surg 41 (1): 182-6, 2006. [PubMed: 16410130]
26. Vinayak R, Cruz RJ, Ranganathan S, et al.: Pediatric liver transplantation for hepatocellular cancer and rare liver malignancies: US multicenter and single-center experience (1981-2015). Liver Transpl 23 (12): 1577-1588, 2017. [PMC free article: PMC5725660] [PubMed: 28834194]
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33. Malek MM, Shah SR, Atri P, et al.: Review of outcomes of primary liver cancers in children: our institutional experience with resection and transplantation. Surgery 148 (4): 778-82; discussion 782-4, 2010. [PubMed: 20728194]
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35. Pham TA, Gallo AM, Concepcion W, et al.: Effect of Liver Transplant on Long-term Disease-Free Survival in Children With Hepatoblastoma and Hepatocellular Cancer. JAMA Surg 150 (12): 1150-8, 2015. [PubMed: 26308249]
36. Reyes JD, Carr B, Dvorchik I, et al.: Liver transplantation and chemotherapy for hepatoblastoma and hepatocellular cancer in childhood and adolescence. J Pediatr 136 (6): 795-804, 2000. [PubMed: 10839879]
37. Bilik R, Superina R: Transplantation for unresectable liver tumors in children. Transplant Proc 29 (7): 2834-5, 1997. [PubMed: 9365581]
38. Romano F, Stroppa P, Bravi M, et al.: Favorable outcome of primary liver transplantation in children with cirrhosis and hepatocellular carcinoma. Pediatr Transplant 15 (6): 573-9, 2011. [PubMed: 21797955]
39. McAteer JP, Goldin AB, Healey PJ, et al.: Surgical treatment of primary liver tumors in children: outcomes analysis of resection and transplantation in the SEER database. Pediatr Transplant 17 (8): 744-50, 2013. [PubMed: 23992390]
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42. Tohme S, Bou Samra P, Kaltenmeier C, et al.: Radioembolization for Hepatocellular Carcinoma: A Nationwide 10-Year Experience. J Vasc Interv Radiol 29 (7): 912-919.e2, 2018. [PubMed: 29843996]
43. Aguado A, Ristagno R, Towbin AJ, et al.: Transarterial radioembolization with yttrium-90 of unresectable primary hepatic malignancy in children. Pediatr Blood Cancer 66 (7): e27510, 2019. [PubMed: 30406959]
44. Schmid I, Häberle B, Albert MH, et al.: Sorafenib and cisplatin/doxorubicin (PLADO) in pediatric hepatocellular carcinoma. Pediatr Blood Cancer 58 (4): 539-44, 2012. [PubMed: 21922643]
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Incidence

Fibrolamellar carcinoma has a bimodal age distribution, most commonly arising in older adults as well as in adolescents and young adults. It can also arise in younger children and infants.[2,3] The Surveillance, Epidemiology, and End Results (SEER) Program reports an annual fibrolamellar carcinoma incidence of 0.2 cases per 1 million based on pathology reporting. However, clinical practice estimates are much higher, and tiered computational analysis of clinical data places this estimate five to eight times higher.[4] Unlike hepatoblastoma in children and hepatocellular carcinoma in adults, fibrolamellar carcinoma in adolescents and young adults is not clearly increasing in incidence over time.[3,5] Fibrolamellar carcinoma, unlike hepatocellular carcinoma, is not strongly associated with a history of cirrhosis, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection.[2]

Risk Factors

Carney complex is caused by heterozygous germline pathogenic variants in PRKAR1A and is an autosomal dominant genetic syndrome.[6] It is characterized by skin pigmentary abnormalities. It is also associated with cardiac, endocrine, cutaneous, and neural myxomatous tumors. Fibrolamellar carcinoma is observed, albeit rarely, in patients with Carney complex.[7] Fibrolamellar carcinoma arising in patients with Carney complex is negative for PRKACA rearrangements and instead shows loss of PRKAR1A protein expression.[7]

Diagnosis

Fibrolamellar carcinoma was first described as a distinct pathological entity by Edmonson in 1956. It is characterized by large cells with eosinophilic cytoplasm, central nuclei with vesiculated chromatin and prominent macronucleoli, along with dense bands of lamellar fibrosis that gives the tumor its name.[8]

Genomics of Fibrolamellar Carcinoma

Prognosis

Fibrolamellar carcinoma is not associated with cirrhosis of the liver. It was previously thought to confer a more favorable prognosis than hepatocellular carcinoma.[3,5,9] 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-to-stage and PRETEXT group–to–PRETEXT group, are the same as the outcomes of patients with conventional hepatocellular carcinomas.[10,11]; [12][Level of evidence C1]

Treatment of Fibrolamellar Carcinoma

Surgery is the standard of care for patients with radiographically localized fibrolamellar carcinoma. For patients with distant spread of disease, systemic therapy is based on the current treatments for pediatric or adult hepatocellular carcinoma, albeit with similarly poor effectiveness. For more information about the treatments used for fibrolamellar carcinoma, see the Treatment of Hepatocellular Carcinoma section.

Treatment Options Under Clinical Evaluation for Fibrolamellar 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, see the ClinicalTrials.gov website.

References

1. Honeyman JN, Simon EP, Robine N, et al.: Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science 343 (6174): 1010-4, 2014. [PMC free article: PMC4286414] [PubMed: 24578576]
2. Cruz O, Laguna A, Vancells M, et al.: Fibrolamellar hepatocellular carcinoma in an infant and literature review. J Pediatr Hematol Oncol 30 (12): 968-71, 2008. [PubMed: 19131794]
3. Eggert T, McGlynn KA, Duffy A, et al.: Fibrolamellar hepatocellular carcinoma in the USA, 2000-2010: A detailed report on frequency, treatment and outcome based on the Surveillance, Epidemiology, and End Results database. United European Gastroenterol J 1 (5): 351-7, 2013. [PMC free article: PMC4040774] [PubMed: 24917983]
4. Zack T, Losert KP, Maisel SM, et al.: Defining incidence and complications of fibrolamellar liver cancer through tiered computational analysis of clinical data. NPJ Precis Oncol 7 (1): 29, 2023. [PMC free article: PMC10034241] [PubMed: 36959495]
5. El-Serag HB, Davila JA, Petersen NJ, et al.: The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med 139 (10): 817-23, 2003. [PubMed: 14623619]
6. Stratakis CA: Carney Complex. In: Adam MP, Feldman J, Mirzaa GM, et al., eds.: GeneReviews. University of Washington, Seattle, 1993-2024, pp. Available online. Last accessed February 29, 2024.
7. Graham RP, Lackner C, Terracciano L, et al.: Fibrolamellar carcinoma in the Carney complex: PRKAR1A loss instead of the classic DNAJB1-PRKACA fusion. Hepatology 68 (4): 1441-1447, 2018. [PMC free article: PMC6151295] [PubMed: 29222914]
8. EDMONDSON HA: Differential diagnosis of tumors and tumor-like lesions of liver in infancy and childhood. AMA J Dis Child 91 (2): 168-86, 1956. [PubMed: 13282629]
9. Mayo SC, Mavros MN, Nathan H, et al.: Treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma: a national perspective. J Am Coll Surg 218 (2): 196-205, 2014. [PMC free article: PMC4596238] [PubMed: 24315886]
10. Czauderna P, Mackinlay G, Perilongo G, et al.: Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 20 (12): 2798-804, 2002. [PubMed: 12065556]
11. Katzenstein HM, Krailo MD, Malogolowkin MH, et al.: Fibrolamellar hepatocellular carcinoma in children and adolescents. Cancer 97 (8): 2006-12, 2003. [PubMed: 12673731]
12. Weeda VB, Murawski M, McCabe AJ, et al.: Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma--results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience. Eur J Cancer 49 (12): 2698-704, 2013. [PubMed: 23683550]

Incidence

Undifferentiated embryonal sarcoma of the liver (UESL) is a distinct clinical and pathological 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 are common. It may appear solid or cystic on imaging, frequently with central necrosis. Undifferentiated sarcomas, like small cell undifferentiated hepatoblastomas, should be examined for loss of SMARCB1 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 pathological features, but treatment differs between the two, as shown in Table 8.[1] For more information, see Childhood Rhabdomyosarcoma Treatment.

Table

Table 8. Diagnostic Differences Between Undifferentiated Embryonal Sarcoma of the Liver and Biliary Tract Rhabdomyosarcoma^a.

Histology

Distinctive histological features of UESL include 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.

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) rates of children with UESL appear to be substantially higher than 50% when combining reports, although all series are small and may have selection bias.[6]; [7-17][Level of evidence C1]

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 rate 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]

A retrospective study combined data from three European studies to identify 64 patients with UESL.[19][Level of evidence C1] The tumors were staged according to Intergroup Rhabdomyosarcoma Study (IRS) clinical grouping. Fourteen patients had IRS group I disease, 9 had IRS group II disease, 38 had IRS group III disease, and 4 had IRS group IV disease. A variety of chemotherapy regimens were used, with either neoadjuvant or adjuvant chemotherapy. Most regimens included alkylators and anthracyclines. Some patients also received radiation therapy. The 5-year event-free survival (EFS) rate was 89.1% (95% confidence interval [CI], 78.4%–94.6%), and the OS rate was 90.1% (95% CI, 79.3%–95.3%).

Treatment Options for UESL

UESL is rare. Only small series have been published regarding treatment.[20]

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]; [7-16,21][Level of evidence C1]

Evidence (surgical resection and chemotherapy):

1. The Italian and German Soft Tissue Sarcoma Cooperative Groups prospectively studied patients with UESL. Patients were treated with conservative surgery or 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 first complete remission, and one patient survived in third complete remission.
2. In a subset analysis from the Children's Oncology Group ARST0332 (NCT00346164) study, 39 patients with embryonal sarcoma of the liver were available for analysis. Patients underwent upfront (n = 23) or delayed (n = 16) resection and received adjuvant or neoadjuvant chemotherapy (dose-intensive ifosfamide/doxorubicin). Eight patients received radiation therapy.[22]

   • The 5-year EFS rate was 79% (95% CI, 65%–93%), and the 5-year OS rate was 95% (95% CI, 87%–100%).
3. 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 had stage I disease, and one patient had stage II disease. One patient received abdominal radiation for tumor rupture.[17][Level of evidence C1]

   • All patients were alive (range, 5–19 years), with EFS and OS rates of 100%.

Liver transplant has occasionally been used to successfully treat an otherwise unresectable primary tumor.[14,16,18,23]

Treatment Options Under Clinical Evaluation for UESL

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, see the ClinicalTrials.gov website.

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: 17378682]
2. Stocker JT: Hepatic tumors in children. Clin Liver Dis 5 (1): 259-81, viii-ix, 2001. [PubMed: 11218918]
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: 20925497]
4. Stringer MD, Alizai NK: Mesenchymal hamartoma of the liver: a systematic review. J Pediatr Surg 40 (11): 1681-90, 2005. [PubMed: 16291152]
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: 11779051]
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: 24142883]
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: 24210186]
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: 14694398]
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: 17390190]
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: 12378446]
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: 10591560]
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: 11815984]
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: 8402469]
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: 19231519]
15. Weitz J, Klimstra DS, Cymes K, et al.: Management of primary liver sarcomas. Cancer 109 (7): 1391-6, 2007. [PubMed: 17315167]
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: 23138115]
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. [PMC free article: PMC5073002] [PubMed: 27427850]
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. [PMC free article: PMC5333454] [PubMed: 27781381]
19. Guérin F, Martelli H, Rogers T, et al.: Outcome of patients with undifferentiated embryonal sarcoma of the liver treated according to European soft tissue sarcoma protocols. Pediatr Blood Cancer 70 (7): e30374, 2023. [PubMed: 37083216]
20. 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: 26925712]
21. 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: 25259441]
22. Spunt SL, Xue W, Gao Z, et al.: Embryonal sarcoma of the liver in pediatric and young adult patients: A report from Children's Oncology Group study ARST0332. Cancer 130 (15): 2683-2693, 2024. [PMC free article: PMC11260243] [PubMed: 38567652]
23. 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: 20005995]

Diagnosis

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 alpha-fetoprotein (AFP) levels in the reference range for age.[1]

Histology

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]

Prognosis

The prognosis of patients with infantile choriocarcinoma of the liver is often poor because of the instability at presentation from hemorrhage. A 2017 case report and literature review found 32 cases, with 6 long-term survivors. The authors emphasized the opportunity for early diagnosis and treatment of this very chemosensitive tumor.[3]

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.
3. Chemotherapy followed by liver transplant.

Initial surgical removal of the tumor mass may be difficult because of its friability and hemorrhagic tendency. Surgical removal of the primary tumor is often performed after neoadjuvant chemotherapy.[1]

Maternal gestational trophoblastic tumors are exquisitely sensitive to methotrexate. 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 the residual mass. Use of neoadjuvant methotrexate in infantile choriocarcinoma, although often resulting in a response, has not been uniformly successful.[1]

A case report of neoadjuvant chemotherapy followed by successful liver transplant highlights the opportunity for this therapy in children whose tumors remain unresectable after chemotherapy.[4]

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, see the ClinicalTrials.gov website.

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: 16206190]
2. Olson T, Schneider D, Perlman E: Germ cell tumors. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 6th ed. Lippincott Williams and Wilkins, 2011, pp 1045-1067.
3. Alsharif S, Karsou A: Infantile choriocarcinoma of the liver: case report and review of the literature. Oncol Cancer Case Rep 3 (1): 2017.
4. Hanson D, Walter AW, Dunn S, et al.: Infantile choriocarcinoma in a neonate with massive liver involvement cured with chemotherapy and liver transplant. J Pediatr Hematol Oncol 33 (6): e258-60, 2011. [PubMed: 21792032]

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 in the care of their 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)
• Andrea A. Hayes-Dixon, MD, FACS, FAAP (Howard University)
• Karen J. Marcus, MD, FACR (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)
• Michael V. Ortiz, MD (Memorial Sloan Kettering Cancer Center)
• 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.

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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]

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