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]

Tumor Stratification by Imaging

The main treatment goal for patients with liver cancer is surgical extirpation of the primary tumor. Therefore, the risk grouping depends heavily on factors determined by imaging that are related to safe surgical resection of the tumor, as well as the PRETEXT grouping. These imaging findings include the section or sections of the liver that are involved with the tumor and additional findings, termed annotation factors, that impact surgical decision making and prognosis.

Risk stratification of children with hepatoblastoma depends on the use of high-quality, cross-sectional imaging. Three-phase computed tomography scanning (noncontrast, arterial, and venous) or magnetic resonance imaging (MRI) with contrast agents are used for imaging. MRI with gadoxetate disodium, a gadolinium-based agent that is preferentially taken up and excreted by hepatocytes, is being used with increased frequency and may improve detection of multifocal disease.[1]

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

PRETEXT is used by the major multicenter trial groups as a central component of risk stratification schemes that define treatment of hepatoblastoma. PRETEXT is based on the Couinaud eight-segment anatomic 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 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, which is critical knowledge for the surgeon and can affect surgical outcomes. There were differences in the definitions of gross vascular involvement used by the COG and major liver surgery centers in the United States compared with SIOPEL definitions used in Europe. These differences have been resolved, and the new definitions are being used in an international trial that began in 2018.[4]

Although PRETEXT can be used to predict tumor resectability, there are limitations. The distinction between real invasion beyond the anatomical border of a given hepatic section and the compression and displacement by the tumor can be difficult, 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 published in 2005 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 1. Definitions of PRETEXT and POSTTEXT Groups^a

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PRETEXT and POSTTEXT Groups		Definition	Image
I		One section involved; three adjoining sections are tumor free.
II		One or two sections involved; two adjoining sections are tumor free.
III		Two or three sections involved; one adjoining section is tumor free.
IV		Four sections involved.

^aAdapted from Roebuck et al.[3]

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

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Annotation Factors		Definition
Vb		Venous involvement: Vascular involvement of the retrohepatic vena cava or involvement of all three major hepatic veins (right, middle, and left).
	V0		Tumor within 1 cm.
	V1		Tumor abutting.
	V2		Tumor compressing or distorting.
	V3		Tumor ingrowth, encasement, or thrombus.
Pb		Portal involvement: Vascular involvement of the main portal vein and/or both right and left portal veins.
	P0		Tumor within 1 cm.
	P1		Tumor abutting the main portal vein, the right and left portal veins, or the portal vein bifurcation.
	P2		Tumor compressing the main portal vein, the right and left portal veins, or the portal vein bifurcation.
	P3		Tumor ingrowth, encasement (>50% or >180 degrees), or intravascular thrombus within the main portal vein, the right and left portal veins, or the portal vein bifurcation.
Eb		Extrahepatic spread of disease. Any one of the following criteria is met:
	E1		Tumor crosses boundaries/tissue planes.
	E2		Tumor is surrounded by normal tissue more than 180 degrees.
	E3		Peritoneal nodules (not lymph nodes) are present so that there is at least one nodule measuring ≥10 mm or at least two nodules measuring ≥5 mm.
Mb		Distant metastases. Any one of the following criteria is met:
	M1		One noncalcified pulmonary nodule ≥5 mm in diameter.
	M2		Two or more noncalcified pulmonary nodules, each ≥3 mm in diameter.
	M3		Pathologically proven metastatic disease.
C		Tumor involving the caudate.
F		Multifocality. Two or more discrete hepatic tumors with normal intervening liver tissue.
Nb		Lymph node metastases. Any one of the following criteria is met:
	N1		Lymph node with short-axis diameter of >1 cm.
	N2		Portocaval lymph node with short-axis diameter >1.5 cm.
	N3		Spherical lymph node shape with loss of fatty hilum.
Rb		Tumor rupture. Free fluid in the abdomen or pelvis with one or more of the following findings of hemorrhage:
	R1		Internal complexity/septations within fluid.
	R2		High-density fluid on CT (>25 HU).
	R3		Imaging characteristics of blood or blood degradation products on MRI.
	R4		Heterogeneous fluid on ultrasound with echogenic debris.
	R5		Visible defect in tumor capsule OR tumor cells are present within the peritoneal fluid OR rupture diagnosed pathologically in patients who have received an upfront resection.

CT = computed tomography; MRI = magnetic resonance imaging; HU = Hounsfield unit.

^aAdapted from Roebuck et al.[3]

^bAdditional details describing the annotation factors have been published.[4]

Evans Surgical Staging for Childhood Liver Cancer (Historical)

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 used to classify patients and determine treatment strategy. For more information, see Table 5.

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 confirmation of the diagnosis 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 as to 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 potentially 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 for determining 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 for evaluation 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]

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.[16][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.[6,17] For more information, see the Tumor Stratification by Imaging and Evans Surgical Staging for Childhood Liver Cancer 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 hepatocellular carcinoma.[6,27,40] 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.[41] Treatment with preoperative chemotherapy has been shown to benefit children with hepatoblastoma; however, the use of 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.[42] Although there is no standard indication, radiation therapy may have a role in the management of patients with incompletely resected hepatoblastomas.[43] 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.[44] 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.[45-47] This procedure has also been used in a few children to successfully shrink tumors to permit resections.[46]
• 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. In a report of two patients with unresectable hepatoblastoma, complete remissions were achieved after treatment with TARE using 90Y resin beads, which successfully shrank the tumors and led to complete resections.[48][Level of evidence C3] This approach has also been used for palliation in children with hepatocellular carcinoma.[49] For more information, see Adult 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 within 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.[50]

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]
5. Aronson DC, Meyers RL: Malignant tumors of the liver in children. Semin Pediatr Surg 25 (5): 265-275, 2016. [PubMed: 27955729]
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. 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]
17. 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]
18. 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]
19. 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]
20. 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]
21. 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]
22. 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]
23. 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]
24. 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]
25. 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]
26. 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]
27. 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]
28. 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]
29. Otte JB: Should the selection of children with hepatocellular carcinoma be based on Milan criteria? Pediatr Transplant 12 (1): 1-3, 2008. [PubMed: 18086239]
30. 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]
31. Khanna R, Verma SK: Pediatric hepatocellular carcinoma. World J Gastroenterol 24 (35): 3980-3999, 2018. [PMC free article: PMC6148423] [PubMed: 30254403]
32. Sevmis S, Karakayali H, Ozçay F, et al.: Liver transplantation for hepatocellular carcinoma in children. Pediatr Transplant 12 (1): 52-6, 2008. [PubMed: 18186889]
33. Faraj W, Dar F, Marangoni G, et al.: Liver transplantation for hepatoblastoma. Liver Transpl 14 (11): 1614-9, 2008. [PubMed: 18975296]
34. 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]
35. 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]
36. 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]
37. 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]
38. 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]
39. 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]
40. 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]
41. 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]
42. 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]
43. 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]
44. 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]
45. 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]
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47. Hirakawa M, Nishie A, Asayama Y, et al.: Efficacy of preoperative transcatheter arterial chemoembolization combined with systemic chemotherapy for treatment of unresectable hepatoblastoma in children. Jpn J Radiol 32 (9): 529-36, 2014. [PubMed: 24923584]
48. 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]
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References

1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PMC free article: PMC4136455] [PubMed: 24853691]
2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed December 8, 2022.

Incidence

The annual incidence of hepatoblastoma in the United States has increased (more than doubled), from 0.8 (1975–1983) to 2.0 (2018) 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.

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 administered. Table 5 demonstrates the variability in the definitions of risk groups.

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.[64] 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.[50]

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:[64]

• 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:[64]

• 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.[64]

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 upcoming 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.[64] 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) I and II resectable disease before or after chemotherapy.[56,58,68]

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 and Evans Surgical Staging for Childhood Liver Cancer section.

Treatment of Progressive or Recurrent Hepatoblastoma

The prognosis for a patient with progressive or recurrent hepatoblastoma depends on several factors, including the following:[124]

• 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.[115,124,125]
   If possible, isolated metastases are resected completely in patients whose primary tumor is controlled.[126] A retrospective study of patients in SIOPEL studies 1, 2, and 3 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%.[124][Level of evidence C1]
   Enrollment in a clinical trial should be considered if all of the recurrent disease cannot be surgically removed. 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.[127] 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.[121]; [120][Level of evidence C1]
   A review of COG phase I and II studies found no promising agents for relapsed hepatoblastoma.[128]
3. Liver transplant. Liver transplant should be considered for patients with nonmetastatic disease recurrence in the liver that is not amenable to resection.[51,96,99]
4. Percutaneous ablation. Percutaneous radiofrequency ablation has been used as an alternative to surgical resection of oligometastatic hepatoblastoma.[129][Level of evidence C1] Percutaneous ablation techniques may also be considered for palliation.[130]

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.

The following are examples of national and/or institutional clinical trials that are 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 (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 patients receive no chemotherapy; or 2) a non–well-differentiated fetal mass or incompletely resected well-differentiated fetal mass, and 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, 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.
• 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 in a patient's tumor (refractory or recurrent). Children and adolescents aged 1 to 21 years are eligible for the trial.
  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 NCI website and ClinicalTrials.gov website.

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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 1.4 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 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.

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.[56]

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.[27,41,42,57]
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.[58]

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.

The following are examples of national and/or institutional clinical trials that are 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.

  • 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 (three or four). 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 in a patient's tumor (refractory or recurrent). Children and adolescents aged 1 to 21 years are eligible for the trial.
  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 NCI website and ClinicalTrials.gov website.

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56. 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]
57. 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]
58. Llovet JM, Ricci S, Mazzaferro V, et al.: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359 (4): 378-90, 2008. [PubMed: 18650514]

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 is 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.

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 appears to be substantially higher than 50% when combining reports, although all series are small and may have selection bias.[6]; [7][Level of evidence C1]; [8-17][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]

Treatment Options for UESL

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 C1]; [8-16][Level of evidence C1]

Evidence (surgical resection and chemotherapy):

1. The only prospective series to treat patients with UESL came from the Italian and German Soft Tissue Sarcoma Cooperative Groups. 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 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 event-free survival and OS rates of 100%.

Liver transplant has occasionally been used to successfully treat an otherwise unresectable primary tumor.[14,16,18,21]

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.

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 in a patient's tumor (refractory or recurrent). Children and adolescents aged 1 to 21 years are eligible for the trial.
  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 NCI website and 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. 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]
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: 25259441]
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: 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 normal alpha-fetoprotein (AFP) levels 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 case reports, 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, 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 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.

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 in a patient's tumor (refractory or recurrent). Children and adolescents aged 1 to 21 years are eligible for the trial.
  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 NCI website and 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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