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Childhood Liver Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

Childhood Liver Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

General Information About Childhood Liver Cancer

Liver cancer is a rare malignancy in children and adolescents and is divided into the following two major histologic subgroups:

  • Hepatoblastoma.
    • Well-differentiated fetal (pure fetal) histology .
    • Small cell undifferentiated histology hepatoblastoma and rhabdoid tumors of the liver.
  • Hepatocellular carcinoma.

Other, less common, histologies include the following:

  • Undifferentiated embryonal sarcoma of the liver.
  • Infantile choriocarcinoma of the liver.
  • Vascular liver tumors.
  • Biliary rhabdomyosarcoma (refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information).

Cellular Classification of Childhood Liver Cancer

Liver tumors are rare in children. Their diagnoses may be challenging, in part, because of the lack of consensus regarding a classification system. Systematic central histopathological review of these tumors performed as part of pediatric collaborative therapeutic protocols has allowed the identification of histologic subtypes with distinct clinical associations. As a result, histopathology has been incorporated within the Children's Oncology Group (COG) protocols and, in the United States, as a risk-stratification parameter used for patient management.

The COG Liver Tumor Committee sponsored an International Pathology Symposium in 2011 to discuss the histopathology and classification of pediatric liver tumors (hepatoblastoma, in particular) to develop an International Pediatric Liver Tumors Consensus Classification that would be required for international collaborative projects. The results of this international classification for pediatric liver tumors have been published.[1] This standardized, clinically meaningful classification will allow the integration of new biological parameters and tumor genetics within a common pathologic language in order to help improve future patient management and outcome.

For information on the histology of each childhood liver cancer subtype, refer to the following sections of this summary:

  • Hepatoblastoma.
  • Hepatocellular carcinoma.
  • Undifferentiated embryonal sarcoma of the liver.
  • Infantile choriocarcinoma of the liver.
  • Vascular liver tumors.

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.

Tumor Stratification by Imaging and Evans Surgical Staging for Childhood Liver Cancer

Historically, the four major study groups (International Childhood Liver Tumors Strategy Group [previously known as Société Internationale d'Oncologie Pédiatrique–Epithelial Liver Tumor Study Group (SIOPEL)], Children's Oncology Group [COG], Gesellschaft für Pädiatrische Onkologie und Hämatologie [Society for Paediatric Oncology and Haematology], and Japanese Study Group for Pediatric Liver Tumors) have had disparate risk stratification categories, making it difficult to compare outcomes across continents. All groups are now using the PRE-Treatment EXTent of tumor (PRETEXT) grouping system as part of the risk stratification.

Tumor Stratification by Imaging

The primary treatment goal for patients with liver cancer is surgical extirpation of the primary tumor. Therefore, the risk grouping designed 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 are termed annotation factors.

The use of high-quality, cross-sectional imaging to evaluate children with hepatoblastoma is of paramount importance because the risk stratification that defines treatment is very dependent on imaging analysis. 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]

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

  • 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 and POSTTEXT Group Definitions

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) (refer to Figure 1). PRETEXT groups were devised by the SIOPEL for their first trial, SIOPEL-1 [2] and revised for SIOPEL-3 in 2007.[3]

Figure showing 4 sections of the liver: the right posterior section, the right anterior section, the left medial section, and the left lateral section. The boundaries of each section are defined by the right hepatic vein, the middle hepatic vein, and the umbilical fissure/ligamentum teres. Also shown are 8 anatomic segments (I-VIII), each corresponding to a specific section of the liver.
Figure 1. PRETEXT is distinct from Couinaud 8-segment (I–VIII) anatomic division of the liver. PRETEXT defines 4 'Sections'. Boundaries of each section defined by the right and middle hepatic veins, and umbilical fissure. Reprinted by permission from Copyright Clearance Center: Springer Nature, Modern Pathology, Towards an international pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium, Dolores López-Terrada, Rita Alaggio, Maria T de Dávila, et al., Copyright © 2013.

PRETEXT group assignment I, II, III, or IV is determined by the number of contiguous uninvolved sections of the liver. PRETEXT is further described by annotation factors, defined as V, P, E, M, C, F, N, or R, depending on extension of tumor beyond the hepatic parenchyma of the major sections (refer to Table 1 for detailed descriptions of the PRETEXT groups and Table 2 for descriptions of the annotation factors).

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 in the definitions to be used in an international trial that begins in 2018.[4]

Although PRETEXT can be used to predict tumor resectability, there are limitations. The distinction between real invasion beyond the anatomic border of a given hepatic section and the compression and displacement by the tumor can be very difficult, especially at diagnosis. Additionally, distinguishing between vessel encroachment and involvement can be difficult, particularly if inadequate imaging is obtained. The PRETEXT group assignment has a moderate degree of interobserver variability, and in a report published in 2005 using data from the SIOPEL-1 study, the preoperative PRETEXT group agreed with postoperative pathologic 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 on clinical trials, expert radiologic review should be considered in questionable cases in which the PRETEXT group assignment affects choice of treatment.

The POSTTEXT is determined after chemotherapy. It has been shown that the greatest chemotherapy response, measured as decreases in tumor size and alpha-fetoprotein (AFP) level, occurs after the first two cycles of chemotherapy.[6,7] Also, a study that evaluated surgical resectability after two versus four cycles of chemotherapy showed that many tumors may be resectable after two cycles.[6]

Table 1. Definitions of PRETEXT and POSTTEXT Groupsa
PRETEXT and POSTTEXT Groups Definition Image
a Adapted from Roebuck et al.[3]
I One section involved; three adjoining sections are tumor free.
Liver PRETEXT I; drawing shows two livers. Dotted lines divide each liver into four vertical sections of about the same size. In the first liver, cancer is shown in the section on the far left. In the second liver, cancer is shown in the section on the far right.
II One or two sections involved; two adjoining sections are tumor free.
Liver PRETEXT II; drawing shows five livers. Dotted lines divide each liver into four vertical sections that are about the same size. In the first liver, cancer is shown in the two sections on the left. In the second liver, cancer is shown in the two sections on the right. In the third liver, cancer is shown in the far left and far right sections. In the fourth liver, cancer is shown in the second section from the left. In the fifth liver, cancer is shown in the second section from the right.
III Two or three sections involved; one adjoining section is tumor free.
Liver PRETEXT III; drawing shows seven livers. Dotted lines divide each liver into four vertical sections that are about the same size. In the first liver, cancer is shown in three sections on the left. In the second liver, cancer is shown in the two sections on the left and the section on the far right. In the third liver, cancer is shown in the section on the far left and the two sections on the right. In the fourth liver, cancer is shown in three sections on the right. In the fifth liver, cancer is shown in the two middle sections. In the sixth liver, cancer is shown in the section on the far left and the second section from the right. In the seventh liver, cancer is shown in the section on the far right and the second section from the left.
IV Four sections involved.
Liver PRETEXT IV; drawing shows two livers. Dotted lines divide each liver into four vertical sections that are about the same size. In the first liver, cancer is shown across all four sections. In the second liver, cancer is shown in the two sections on the left and spots of cancer are shown in the two sections on the right.
Table 2. Annotation Factors For Describing PRETEXT and POSTTEXT Groupsa
Annotation Factors Definition
CT = computed tomography; MRI = magnetic resonance imaging; HU = Hounsfield unit.
a Adapted from Roebuck et al.[3]
b Additional details describing the annotation factors have been published.[4]
Vb Venous involvement: Vascular involvement of the retrohepatic vena cava or involvement ofall 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/orboth 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 capsuleOR tumor cells are present within the peritoneal fluidOR rupture diagnosed pathologically in patients who have received an upfront resection.

Hepatoblastoma prognosis by PRETEXT group and annotation factor

The Children's Hepatic tumor International Collaboration (CHIC) analyzed survival in a collaborative database of 1,605 patients with hepatoblastoma treated on eight separate multicenter clinical trials, with central review of all tumor imaging and histologic details.[8] Patients who underwent orthotopic liver transplant are included in all of the international study results.[9]

Survival at 5 years, unrelated to annotation factors, was found to be the following:

  • 90% for PRETEXT I.
  • 83% for PRETEXT II.
  • 73% for PRETEXT III.
  • 52% for PRETEXT IV.

When each annotation factor was examined separately, regardless of the PRETEXT group or other annotation factors present in each patient, the 5-year overall survival (OS) was found to be the following:

  • 51% for positive V (involvement all three hepatic veins and/or inferior vena cava).
  • 49% for positive P (involvement both right and left portal veins).
  • 53% for positive E (contiguous extrahepatic tumor).
  • 52% for positive F (multifocal).
  • 51% for positive R (tumor rupture).
  • 41% for positive M (distant metastasis).

Hepatocellular carcinoma prognosis by PRETEXT group and annotation factor

The 5-year OS by PRETEXT group for hepatocellular carcinoma in SIOPEL-1 was found to be the following:[10]

  • 44% for PRETEXT I.
  • 44% for PRETEXT II.
  • 22% for PRETEXT III.
  • 8% for PRETEXT IV.

Evans Surgical Staging for Childhood Liver Cancer (Historical)

The COG/Evans staging system is based on operative findings and surgical resectability and has been used for many years in the United States to group children with liver cancer. This staging system was used to determine treatment in past years (refer to Table 3).[11,12,13] Currently, other risk stratification systems are used to classify patients and determine treatment strategy (refer to Table 5 for more information).

Table 3. Definition of Evans Surgical Staging
Evans Surgical Stage Definition
Stage I The tumor is completely resected.
Stage II Microscopic residual tumor remains after resection.
Stage III There are no distant metastases and at least one of the following is true: (1) the tumor is either unresectable or the tumor is resected with gross residual tumor; (2) there are positive extrahepatic lymph nodes.
Stage IV There is distant metastasis, regardless of the extent of liver involvement.

Hepatoblastoma prognosis by Evans surgical stage

Stages I and II

Approximately 20% to 30% of children with hepatoblastoma are stage I or II. Prognosis varies depending on the subtype of hepatoblastoma:

  • Patients with well-differentiated fetal (previously termed pure fetal) histology tumors (4% of hepatoblastomas) have a 3- to 5-year OS rate of 100% with minimal or no chemotherapy, whether PRETEXT I, II, or III.[13,14,15]
  • Patients with non–well-differentiated fetal histology, non–small cell undifferentiated stage I and II hepatoblastomas have a 3- to 4-year OS rate of 90% to 100% with adjuvant chemotherapy.[13,14]
  • If any small cell undifferentiated elements are present in patients with stage I or II hepatoblastoma, the 3-year survival rate is 40% to 70%.[14,16]

Stage III

Approximately 50% to 70% of children with hepatoblastoma are stage III. The 3- to 5-year OS rate for children with stage III hepatoblastoma is less than 70%.[13,14]

Stage IV

Approximately 10% to 20% of children with hepatoblastoma are stage IV. The 3- to 5-year OS rate for children with stage IV hepatoblastoma varies widely, from 20% to approximately 60%, based on published reports.[13,14,17,18,19,20] Postsurgical stage IV is equivalent to any PRETEXT group with annotation factor M.[8,21,22]

Hepatocellular carcinoma prognosis by Evans surgical stage

Stage I

Children with stage I hepatocellular carcinoma have a good outcome.[23]

Stage II

Stage II is too rarely seen to predict outcome.

Stages III and IV

Stages III and IV are usually fatal.[10,24]

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.
  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.
  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.
  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.
  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.
  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.
  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.
  8. 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.
  9. 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.
  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.
  11. 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.
  12. 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.
  13. 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.
  14. Meyers RL, Rowland JR, Krailo M, et al.: Predictive power of pretreatment prognostic factors in children with hepatoblastoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 53 (6): 1016-22, 2009.
  15. Malogolowkin MH, Katzenstein HM, Meyers RL, et al.: Complete surgical resection is curative for children with hepatoblastoma with pure fetal histology: a report from the Children's Oncology Group. J Clin Oncol 29 (24): 3301-6, 2011.
  16. De Ioris M, Brugieres L, Zimmermann A, et al.: Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: the SIOPEL group experience. Eur J Cancer 44 (4): 545-50, 2008.
  17. Pritchard J, Brown J, Shafford E, et al.: Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: a successful approach--results of the first prospective study of the International Society of Pediatric Oncology. J Clin Oncol 18 (22): 3819-28, 2000.
  18. Perilongo G, Brown J, Shafford E, et al.: Hepatoblastoma presenting with lung metastases: treatment results of the first cooperative, prospective study of the International Society of Paediatric Oncology on childhood liver tumors. Cancer 89 (8): 1845-53, 2000.
  19. Perilongo G, Shafford E, Maibach R, et al.: Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Paediatric Oncology--SIOPEL 2. Eur J Cancer 40 (3): 411-21, 2004.
  20. 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.
  21. Katzenstein HM, Furman WL, Malogolowkin MH, et al.: Upfront window vincristine/irinotecan treatment of high-risk hepatoblastoma: A report from the Children's Oncology Group AHEP0731 study committee. Cancer 123 (12): 2360-2367, 2017.
  22. 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.
  23. Douglass E, Ortega J, Feusner J, et al.: Hepatocellular carcinoma (HCA) in children and adolescents: results from the Pediatric Intergroup Hepatoma Study (CCG 8881/POG 8945). [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-1439, 420, 1994.
  24. Katzenstein HM, Krailo MD, Malogolowkin MH, et al.: Hepatocellular carcinoma in children and adolescents: results from the Pediatric Oncology Group and the Children's Cancer Group intergroup study. J Clin Oncol 20 (12): 2789-97, 2002.

Treatment Option Overview for Childhood Liver Cancer

Many of the improvements in survival in childhood cancer have been made using new therapies that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare potentially better therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment and comparing the results with those previously obtained with standard therapy.

Because of the relative rarity of cancer in children, all children with liver cancer should be considered for entry onto a clinical trial when one is available. Treatment planning by a multidisciplinary team of cancer specialists with experience treating tumors of childhood is required to determine and implement optimal treatment.[1]

Surgery

Historically, complete surgical resection of the primary tumor has been required to cure malignant liver tumors in children.[2,3,4,5,6]; [7][Level of evidence: 3iiiA] This approach continues to be the goal of definitive surgical procedures, which are often combined with chemotherapy. In patients with advanced hepatoblastoma, postoperative complications are associated with worsened overall survival.[8]

There are three ways in which surgery is used to treat primary pediatric liver cancer:

  • Initial surgical resection (alone or followed by chemotherapy).
  • Delayed surgical resection (preceded by chemotherapy).
  • Orthotopic liver (cadaveric and living donor) transplant (most often preceded by chemotherapy).

The timing of the surgical approach is critical. For this reason, 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. Also, the rarity of liver tumors in children has resulted in limited experience and exposure of surgeons to these procedures. In some cases, the patient may need to be referred to another institution for surgery or, more commonly, for liver transplant. Consultation with the surgeon should occur shortly after diagnosis.

In children and adolescents with primary liver tumors, the surgeon has to be prepared to perform a highly sophisticated liver resection 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 true for hepatocellular carcinoma because curative chemotherapy is not available. Intraoperative ultrasonography may result in further delineation of tumor extent and location and can affect intraoperative management.[9]

If the tumor is determined to be unresectable and preoperative chemotherapy is to be administered, it is very important to frequently consult with the surgical team concerning the timing of resection, as 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.

Early involvement with an experienced pediatric liver surgeon is especially important in patients with PRE-Treatment EXTent of disease (PRETEXT) group III or IV or involvement of major liver vessels (positive annotation factors V [venous] or P [portal]).[10] 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.[11,12,13]; [14][Level of evidence: 3iiA] Accomplishing the appropriate surgery at resection is critical. Margin-negative resection is imperative 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.[15][Level of evidence: 3iiiA]

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

  • 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 histopathologic criteria for orthotopic liver transplantation.

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 accomplished with a simple, negative-margin hemihepatectomy. The COG study AHEP0731 (NCT00980460) has studied the use of PRETEXT and POSTTEXT to determine the optimal approach and timing of surgery. POSTTEXT imaging grouping is performed after two and four cycles of chemotherapy to determine the optimal time for definitive surgery (refer to the Tumor Stratification by Imaging and Evans Surgical Staging for Childhood Liver Cancer section of this summary for more information).[6,16]

Orthotopic liver transplant

Liver transplants have been associated with significant success in the treatment of children with unresectable hepatic tumors.[17]; [18,19,20][Level of evidence: 3iiA] A review of the world experience has documented a posttransplant survival rate of 70% to 80% for children with hepatoblastomas.[15,21,22,23] Intravenous vascular invasion, positive lymph nodes, and contiguous extrahepatic spread did not have a significant adverse effect on outcome. It has been suggested that adjuvant chemotherapy after transplant may decrease the risk of tumor recurrence but its use has not been studied definitively in a randomized clinical trial.[24]

Evidence (orthotopic liver transplant):

  1. The United Network for Organ Sharing (UNOS) database was queried for all patients younger than 18 years old with a primary malignant liver tumor who underwent an orthotopic liver transplant between 1987 and 2012 (N = 544). The patients were diagnosed with hepatoblastoma (n = 376, 70%), hepatocellular carcinoma (n = 84, 15%), and other (n = 84, 15%). Patients with hepatocellular carcinoma were older, more often hospitalized at the time of transplant, and more likely to receive a cadaveric organ than were patients with hepatoblastoma.
    1. Five-year patient survival was 73% and graft survival was 74% for the entire cohort, with most deaths resulting from malignancy. On multivariate analysis, independent predictors of 5-year patient and graft survival included the following:[25]
      1. Diagnosis.
        • For the study period of 1987 to 2012, the 5-year patient survival rate was 76% and the graft survival was 77% for hepatoblastoma; the survival rate was 63% and graft survival rate was 63% for hepatocellular carcinoma.
        • For the study period of 2009 to 2012, the 3-year patient survival rate was 84% and the graft survival rate was 84% for hepatoblastoma; the survival rate was 85% and graft survival rate was 85% for hepatocellular carcinoma.
      2. Transplant era.
        • The death rate by hazard ratio was 1.0 for the period before 2002, 0.72 for the period of 2002 to 2009, and 0.54 for the period of 2009 to 2012.
      3. Medical condition at transplant.
        • For hepatoblastoma patients, the survival rate by hazard ratio was 1.0 for hospitalized patients versus 1.81 for not hospitalized patients at the time of transplant. For hepatocellular carcinoma patients, the survival rate by hazard ratio was 1.0 for hospitalized patients versus 1.92 for not hospitalized patients.
        • Patients hospitalized in the intensive care unit did not fare worse.
  2. A report of 149 patients with hepatocellular carcinoma younger than 21 years who underwent transplants between 1987 and 2015 utilized detailed data collected at all U.S. pediatric transplant centers by the U.S. Scientific Registry of Transplant Recipients.[17]
    • One-year graft survival was about 85%, which did not differ from the survival for hepatoblastoma or biliary atresia. Survival continued to decline over time, from 85% at 1 year, 52% at 5 years, and 43% at 10 years, which was a more dramatic decline than what was seen for hepatoblastoma or biliary atresia.
    • The survival after transplant did not differ from that of adults who underwent transplant for hepatocellular carcinoma.
    • Of the hepatocellular carcinoma patients, 22 had hepatocellular carcinoma diagnosed after transplant for medical cirrhotic disease such as tyrosinemia. They had a superior outcome, but it was not statistically significant compared with the rest of the 149 patients.
  3. A review of the Surveillance, Epidemiology, and End Results (SEER) database and numerous single-institution series have reported results similar to the UNOS database study described above.[12,18,19,20,26]; [23][Level of evidence: 3iiA]
  4. In a three-institution study of children with hepatocellular carcinoma, the overall 5-year disease-free survival rate was approximately 60%.[27]

Application of the Milan criteria for UNOS selection of recipients of deceased donor livers is controversial.[28,29] The Milan criteria for liver transplantation are directed toward adults with cirrhosis and hepatocellular carcinoma. The criteria do not apply to children and adolescents with hepatocellular carcinoma, especially those without cirrhosis. Living-donor liver transplant is more common in children and the outcome is similar to those undergoing cadaveric liver transplant.[30,31] In hepatocellular carcinoma, gross vascular invasion, distant metastases, lymph node involvement, tumor size, and male sex were significant risk factors for recurrence. Because of the poor prognosis in patients with hepatocellular carcinoma, liver transplant should be considered for disorders such as tyrosinemia and familial intrahepatic cholestasis early in the course, before the development of liver failure and malignancy.

Surgical resection for metastatic disease

Surgical resection is often recommended, but the rate of cure in children with hepatoblastoma has not been fully determined. Resection of metastases, when possible, is often recommended, including the areas of locally invasive disease (e.g., diaphragm) and isolated brain metastases. Resection of pulmonary metastases should be considered if the number of metastases is limited.[32,33,34,35] In an American study of 20 patients who presented with pulmonary metastases, only nine patients underwent surgical resection. The timing of pulmonary resection in relation to definitive resection of the primary tumor varied (two patients before, five patients simultaneously, and two patients after primary resection). Eight of the nine patients survived. Of 20 children with relapse restricted to the lungs, all patients received salvage chemotherapy, 13 had pulmonary surgery, 8 had metastasectomy, and 5 had biopsy only. Of these patients, only 4 of 13 were long-term survivors, two of whom presented with stage I disease and two of whom presented with stage IV disease.[34] Radiofrequency ablation has also been used to treat oligometastatic hepatoblastoma when patients prefer to avoid surgical metastasectomy.[36][Level of evidence: 3iiiB]

Chemotherapy

Chemotherapy regimens used in the treatment of hepatoblastoma and hepatocellular carcinoma are described in their respective sections (refer to the Treatment of Hepatoblastoma and the Treatment of Hepatocellular Carcinoma sections of this summary for more information). Chemotherapy has been much more successful in the treatment of hepatoblastoma than in hepatocellular carcinoma.[6,26,37]

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.[38] 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. Although there is no standard indication, radiation therapy may have a role in the management of incompletely resected hepatoblastoma.[39] However, 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.[40] Stereotactic body radiation therapy is a safe and effective alternative treatment that has been successfully used in hepatocellular carcinoma in adults who are unable to undergo liver ablation/resection.[41] 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.[42,43,44] TACE has also been used in a few children to successfully shrink tumors to permit resections.[43]
  • Transarterial radioembolization (TARE): TARE is an image-guided, minimally invasive, nonsurgical procedure that delivers radiation therapy to treat tumors in the liver. The principle of the procedure is to deliver radioactive beads and block 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 a catheter placed to treat the tumor; this imaging is done to calculate whether an unsafe amount of radiation will be delivered to the lung by the procedure. TARE with 90Y resin beads has been used for palliation in children with hepatocellular carcinoma.[45] (Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)
  • 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. MRI 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.[46]

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[47] Children and adolescents with cancer should be referred to medical centers that have multidisciplinary teams of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

  • Primary care physicians.
  • Pediatric surgeons and transplant surgeons.
  • Radiation oncologists.
  • Pediatric medical oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
  • Child life professionals.
  • Psychologists.

(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer have been outlined by the American Academy of Pediatrics.[48] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[47] Childhood and adolescent cancer survivors require close monitoring because late effects of therapy may persist or develop months or years after treatment. (Refer to Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

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Hepatoblastoma

Incidence

The annual incidence of hepatoblastoma in the United States appears to have doubled, from 0.8 (1975–1983) to 1.6 (2002–2009) cases per 1 million children aged 19 years and younger.[1,2] The cause for this increase is unknown, but the increasing survival of very low-birth-weight premature infants, which is known to be associated with hepatoblastoma, may contribute.[3] In Japan, the risk of hepatoblastoma in children who weighed less than 1,000 g at birth is 15 times the risk in normal birth-weight children.[4] Other data have confirmed the high incidence of hepatoblastoma in very low-birth-weight premature infants.[5] Attempts to identify factors resulting from treatment of infants born prematurely have not revealed any suggestive causation of the increased incidence of hepatoblastoma.[3]

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.[6]

Risk Factors

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

Table 4. Conditions Associated With Hepatoblastoma
Associated Disorder Clinical Findings
Aicardi syndrome[7] Refer to the Aicardi syndromesection of this summary for more information.
Beckwith-Wiedemann syndrome[8,9] Refer to the Beckwith-Wiedemann syndrome and hemihyperplasiasection of this summary for more information.
Familial adenomatous polyposis[10,11,12] Refer to the Familial adenomatous polyposissection of this summary for more information.
Glycogen storage diseases I–IV[13] Symptoms vary by individual disorder.
Low-birth-weight infants[3,4,5,14,15] Preterm and small-for-gestation-age neonates.
Simpson-Golabi-Behmel syndrome[16] Macroglossia, macrosomia, renal and skeletal abnormalities, and increased risk of Wilms tumor.
Trisomy 18, other trisomies[17] Trisomy 18: Microcephaly and micrognathia, clenched fists with overlapping fingers, and failure to thrive. Most patients (>90%) die in the first year of life.

Aicardi syndrome

Aicardi syndrome is presumed to be an X-linked condition reported exclusively in females, leading to the hypothesis that a mutated gene on the X chromosome causes lethality in males. The syndrome is classically defined as agenesis of the corpus callosum, chorioretinal lacunae, and infantile spasms, with a characteristic facies. Additional brain, eye, and costovertebral defects are often found.[7]

Beckwith-Wiedemann syndrome and hemihyperplasia

The incidence of hepatoblastoma is increased 1,000-fold to 10,000-fold in infants and children with Beckwith-Wiedemann syndrome.[9,18] The risk of hepatoblastoma is also increased in patients with hemihyperplasia, previously termed hemihypertrophy, a condition that results in asymmetry between the right and left side of the body when a body part grows faster than normal.[19,20]

Beckwith-Wiedemann syndrome is most commonly caused by epigenetic changes and is sporadic. The syndrome may also be caused by genetic mutations and be familial. Either mechanism can be associated with an increased incidence of embryonal tumors, including Wilms tumor and hepatoblastoma.[9] The expression of both IGFR2 alleles and ensuing increased expression of insulin-like growth factor 2 (IGF-2) has been implicated in the macrosomia and embryonal tumors seen in patients with Beckwith-Wiedemann syndrome.[9,21] When sporadic, the types of embryonal tumors associated with Beckwith-Wiedemann syndrome have frequently also undergone somatic changes in the Beckwith-Wiedemann syndrome locus and IGF-2.[22,23] The genetics of tumors in children with hemihyperplasia have not been clearly defined.

To detect abdominal malignancies at an early stage, all children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia are screened regularly for multiple tumor types by abdominal ultrasonography.[20] Screening using alpha-fetoprotein (AFP) levels has also been quite helpful in the early detection of hepatoblastoma in these children.[24] Because the hepatoblastomas that are discovered early are small, it has been suggested to minimize the use of adjuvant therapy after surgery.[18] However, a careful compilation of published data on 1,370 children with (epi)genotyped Beckwith-Wiedemann syndrome demonstrated that the prevalence of hepatoblastoma was 4.7% in those with Beckwith-Wiedemann syndrome caused by chromosome 11p15 paternal uniparental disomy, less than 1% in the two types of alteration in imprinting control regions, and absent in CDKN1C mutation.[25] The authors recommended that only children with Beckwith-Wiedemann syndrome caused by uniparental disomy be screened for hepatoblastoma using abdominal ultrasonography and AFP levels every 3 months from age 3 months to 5 years.

Familial adenomatous polyposis

There is an association between hepatoblastoma and familial adenomatous polyposis (FAP); children in families that carry the APC gene have an 800-fold increased risk of hepatoblastoma. However, hepatoblastoma has been reported to occur in less than 1% of FAP family members, so screening for hepatoblastoma in members of families with FAP using ultrasonography and AFP levels is controversial.[10,11,12,26] However, one study of 50 consecutive children with apparent sporadic hepatoblastoma reported that five children (10%) had APC germline mutations.[26]

Current evidence cannot rule out the possibility that predisposition to hepatoblastoma may be limited to a specific subset of APC mutations. Another study of children with hepatoblastoma found a predominance of the mutation in the 5' region of the gene, but some patients had mutations closer to the 3' region.[27] This preliminary study provides some evidence that screening children with hepatoblastoma for APC mutations and colon cancer may be appropriate.

In the absence of APC germline mutations, childhood hepatoblastomas do not have somatic mutations in the APC gene; however, hepatoblastomas frequently have mutations in the CTNNB1 gene, the function of which is closely related to APC.[28]

Screening children predisposed to hepatoblastoma

An American Association for Cancer Research publication suggested that all children with more than a 1% risk of developing hepatoblastoma be screened. This includes patients with Beckwith-Wiedemann, hemihyperplasia, Simpson-Golabi-Behmel, and trisomy 18 syndromes. Screening is by abdominal ultrasound and alpha-fetoprotein determination every 3 months from birth (or diagnosis) through the fourth birthday, which will identify 90% to 95% of hepatoblastomas that develop in these children.[29]

Genomics of Hepatoblastoma

Genomic abnormalities related to hepatoblastoma include the following:

  • Hepatoblastoma mutation frequency, as determined by three groups using whole-exome sequencing, was very low (approximately three variants per tumor) in children younger than 5 years.[30,31,32]
  • Hepatoblastoma is primarily a disease of WNT pathway activation. The primary mechanism for WNT pathway activation is CTNNB1 activating mutations/deletions involving exon 3. CTNNB1 mutations have been reported in 70% of cases.[30] Rare causes of WNT pathway activation include mutations in AXIN1, AXIN2, and APC (APC seen only in cases associated with familial adenomatosis polyposis coli).[33]
  • The frequency of NFE2L2 mutations in hepatoblastoma specimens was reported to be 4 of 62 tumors (7%) in one study [31] and 5 of 51 specimens (10%) in another study.[30]

    Similar mutations have been found in many types of cancer, including hepatocellular carcinoma. These mutations render NFE2L2 insensitive to KEAP1-mediated degradation, leading to activation of the NFE2L2-KEAP1 pathway, which activates resistance to oxidative stress and is believed to confer resistance to chemotherapy.

  • Somatic mutations were identified in other genes related to regulation of oxidative stress, including inactivating mutations in the thioredoxin-domain containing genes, TXNDC15 and TXNDC16.[31]
  • Figure 2 shows the distribution of CTNNB1, NFE2L2, and TERT mutations in hepatoblastoma.[30]
    Chart showing the distribution of CTNNB1, APC, NFE2L2, and TERT mutations for hepatoblastoma.
    Figure 2. Mutational status and functional relevance of NFE2L2 in hepatoblastoma. Clinicopathological characteristics and the mutational status of the CTNNB1, APC, and NFE2L2 genes, as well as the TERT promoter region are color-coded and depicted in rows for each tumor of our cohort of 43 hepatoblastoma (HB) patients and four transitional liver cell tumour (TLCT) patients and 4 HB cell lines. Reprinted from Journal of Hepatology, Volume 61 (Issue 6), Melanie Eichenmüller, Franziska Trippel, Michaela Kreuder, Alexander Beck, Thomas Schwarzmayr, Beate Häberle, Stefano Cairo, Ivo Leuschner, Dietrich von Schweinitz, Tim M. Strom, Roland Kappler, The genomic landscape of hepatoblastoma and their progenies with HCC-like features, Pages 1312–1320, Copyright 2014, with permission from Elsevier.

To date, these genetic mutations have not been used to select therapeutic agents for investigation in clinical trials.

Diagnosis

Biopsy

A biopsy of a pediatric liver tumor is always indicated to secure the diagnosis of a liver tumor, with the exception of the following circumstances:

  • Infantile hepatic hemangioma. Biopsy is not indicated in infantile hemangioma of the liver with classic findings on magnetic resonance imaging (MRI). If the diagnosis is in doubt after high-quality imaging, a confirmatory biopsy is done.
  • Focal nodular hyperplasia. Biopsy may not be indicated or may be delayed in focal nodular hyperplasia with classic features on MRI using hepatocyte-specific contrast agent. If the diagnosis is in doubt, a confirmatory biopsy is done.
  • Children's Oncology Group (COG) surgical guidelines (AHEP0731 [NCT00980460] appendix) recommend tumor resection at diagnosis without preoperative chemotherapy in children with PRE-Treatment EXTent of disease (PRETEXT) group I tumors and PRETEXT group II tumors with greater than 1 cm radiographic margin on the vena cava and middle hepatic and portal veins. Therefore, biopsy is not usually recommended in this circumstance.
  • Infantile hepatic choriocarcinoma. In infantile hepatic choriocarcinoma, which can be diagnosed by imaging and markedly elevated beta-human chorionic gonadotropin (beta-hCG), chemotherapy without biopsy is often indicated.[34]

Tumor markers

The AFP and beta-hCG tumor markers are very helpful in the diagnosis and management of liver tumors. Although AFP is elevated in most children with hepatic malignancy, it is not pathognomonic for a malignant liver tumor.[35] The AFP level can be elevated with either a benign tumor or a malignant solid tumor. AFP is very high in neonates and steadily falls after birth. The half-life of AFP is 5 to 7 days, and by age 1 year, it should be less than 10 ng/mL.[36]

Prognosis and Prognostic Factors

The 5-year overall survival (OS) rate for children with hepatoblastoma is 70%.[37,38] Neonates with hepatoblastoma have outcomes comparable to older children up to age 5 years.[39]

Individual childhood cancer study groups have attempted to define the relative importance of a variety of prognostic factors present at diagnosis and in response to therapy.[40,41] A collaborative group consisting of four study groups (International Childhood Liver Tumors Strategy Group [SIOPEL], COG, Gesellschaft für Pädiatrische Onkologie und Hämatologie [GPOH], and Japanese Study Group for Pediatric Liver Tumor [JPLT]), termed Childhood Hepatic tumor International Collaboration (CHIC), have retrospectively combined data from eight clinical trials (N = 1,605) conducted between 1988 and 2010. The CHIC published a univariate analysis of the effect of clinical prognostic factors present at the time of diagnosis on event-free survival (EFS).[42,43] The analysis confirmed many of the findings described below. The statistically significant adverse factors included the following:[42]

  • Higher PRETEXT group.
  • Positive PRETEXT annotation factors:
    • V: Involvement all three hepatic veins and/or intrahepatic inferior vena cava.
    • P: Involvement of both left and right portal veins.
    • E: Contiguous extrahepatic tumor extensions (e.g., diaphragm, adjacent organs).
    • F: Multifocal tumors.
    • R: Tumor rupture.
    • M: Distant metastases, usually lung.
  • Low AFP level (<100 ng/mL or 100–1,000 ng/mL to account for infants with elevated AFP levels).[43]
  • Older age. Patients aged 3 to 7 years have a worse outcome in the PRETEXT IV group.[42] Patients aged 8 years and older have a worse outcome than do younger patients in all PRETEXT groups. In a subsequent report from the CHIC group, risk of an event increased in continuous fashion with advancing age throughout all age cohorts.[44][Level of evidence: 3iiA] Increasing age attenuated the effect of other risk factors, including metastasis, AFP level less than 100 ng/mL, tumor rupture, and the presence of one annotation factor.

    In contrast, in the SIOPEL-2 and -3 studies, infants younger than 6 months had PRETEXT, annotation factors, and outcomes similar to that of older children undergoing the same treatment.[45][Level of evidence: 3iiA]

In contrast, sex, prematurity, birth weight, and Beckwith-Wiedemann syndrome had no effect on EFS.[42]

A multivariate analysis of these prognostic factors has been published to help develop a new risk group classification for hepatoblastoma.[43] This classification was used to generate a risk stratification schema to be used in international clinical trials. (Refer to the International risk classification model section of this summary for more information.)

Other studies of factors affecting prognosis observed the following:

  • PRETEXT group: In SIOPEL studies, having a low PRETEXT group at diagnosis (PRETEXT I, II, and III tumors) is a good prognostic factor, whereas PRETEXT IV is a poor prognostic factor.[42] (Refer to the Tumor Stratification by Imaging and Evans Surgical Staging for Childhood Liver Cancer section of this summary for more information.)
  • Tumor stage: In COG studies, stage I tumors that were resected at diagnosis and tumors with well-differentiated fetal histology have a good prognosis. These tumors are treated differently than tumors of other stages and histologies.[42]
  • Treatment-related factors:

    Chemotherapy: Chemotherapy often decreases the size and extent of hepatoblastoma, allowing complete resection.[46,47,48,49,50] Favorable response of the primary tumor to chemotherapy, defined as either a 30% decrease in tumor size by Response Evaluation Criteria In Solid Tumors (RECIST) or 90% or greater decrease in AFP levels, predicted the resectability of the tumor; in turn, this favorable response predicted overall survival among all CHIC risk groups treated with neoadjuvant chemotherapy on the JPLT-2 Japanese national clinical trial.[51][Level of evidence: 2A]

    Surgery: Cure of hepatoblastoma requires gross tumor resection. Hepatoblastoma is most often unifocal and thus, resection may be possible. If a hepatoblastoma is completely removed, most patients survive, but because of vascular or other involvement, less than one-third of patients have lesions amenable to complete resection at diagnosis.[42] Thus, it is critically important that a child with probable hepatoblastoma be evaluated by a pediatric surgeon; the surgeon should be experienced in the techniques of extreme liver resection with vascular reconstruction and have access to a liver transplant program. In advanced tumors, surgical treatment of hepatoblastoma is a demanding procedure. Postoperative complications in high-risk patients decrease the rate of overall survival.[52]

    Orthotopic liver transplant is an additional treatment option for patients whose tumor remains unresectable after preoperative chemotherapy;[53,54] however, the presence of microscopic residual tumor at the surgical margin does not preclude a favorable outcome.[55,56] This may be due to the additional courses of chemotherapy that are administered before or after resection.[46,47,55]

    (Refer to Table 6 for more information on outcomes associated with specific chemotherapy regimens.)

  • Tumor marker–related factors:

    Ninety percent of children with hepatoblastoma and two-thirds of children with hepatocellular carcinoma exhibit the serum tumor marker AFP, which parallels disease activity. The level of AFP at diagnosis and rate of decrease in AFP levels during treatment are compared with the age-adjusted normal range. Lack of a significant decrease in AFP levels with treatment may predict a poor response to therapy.[57] In an exploratory study of 34 children with hepatoblastoma, the rate of decrease in AFP and tumor volume, but not in RECIST I measurements, following two courses of treatment after diagnosis was predictive of EFS and OS.[58]

    Absence of elevated AFP levels at diagnosis (AFP <100 ng/mL) occurs in a small percentage of children with hepatoblastoma and appears to be associated with very poor prognosis, as well as with the small cell undifferentiated variant of hepatoblastoma.[42] Some of these variants do not express SMARCB1 and may be considered rhabdoid tumors of the liver; all small cell undifferentiated hepatoblastomas are tested for loss of SMARCB1 expression by immunohistochemistry.[59,60,61,62,63,64]

    Beta-hCG levels may also be elevated in children with hepatoblastoma or hepatocellular carcinoma, which may result in isosexual precocity in boys.[65,66]

  • Tumor histology:

    Refer to the Histology section of this summary for more information.

Other variables have been suggested as poor prognostic factors, but the relative importance of their prognostic significance has been difficult to define. In the SIOPEL-1 study, a multivariate analysis of prognosis after positive response to chemotherapy showed that only one variable, PRETEXT, predicted OS, while metastasis and PRETEXT predicted EFS.[59] In an analysis of the intergroup U.S. study from the time of diagnosis, well-differentiated fetal histology, small cell undifferentiated histology, and AFP less than 100 ng/mL were prognostic in a log rank analysis. PRETEXT was prognostic among patients designated group III, but not group IV.[63,67]

Histology

Hepatoblastoma arises from precursors of hepatocytes and can have several morphologies, including the following:[68]

  • 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. (Refer to the Small cell undifferentiated histology hepatoblastoma and rhabdoid tumors of the liver section of this summary for a more extensive discussion of the differences between small cell undifferentiated hepatoblastoma and rhabdoid tumor of the liver.)
  • 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 two histologic subtypes have clinical relevance:

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

Well-differentiated fetal (pure fetal) histology hepatoblastoma

An analysis of patients with initially resected hepatoblastoma tumors (before receiving chemotherapy) has suggested that patients with well-differentiated fetal (previously termed pure fetal) histology tumors have a better prognosis than do patients with an admixture of more primitive and rapidly dividing embryonal components or other undifferentiated tissues. Studies have reported the following:

  1. A study of patients with hepatoblastoma and well-differentiated fetal histology tumors observed the following:[48]
    • The survival rate was 100% for patients who received four doses of single-agent doxorubicin. This suggested that patients with well-differentiated fetal histology tumors might not need chemotherapy after complete resection.[69,70]
  2. In a COG study (COG-P9645), 16 patients with well-differentiated fetal histology hepatoblastoma with two or fewer mitoses per 10 high-power fields were not treated with chemotherapy. Retrospectively, their PRETEXT groups were group I (n = 4), group II (n = 6), and group III (n = 2).[71]
    • Survival was 100% with no chemotherapy given.
    • All 16 patients entered on this study were alive with no evidence of disease at a median follow-up of 4.9 years (range, 9 months to 9.2 years).

Thus, complete resection of a well-differentiated fetal hepatoblastoma may preclude the need for chemotherapy.

Small cell undifferentiated histology hepatoblastoma and rhabdoid tumors of the liver

Small cell undifferentiated hepatoblastoma is an uncommon hepatoblastoma variant that represents several percent of all hepatoblastomas. It tends to occur at a younger age (6–10 months) than do other cases of hepatoblastoma [63,72] and is associated with AFP levels that are normal for age at presentation.[62,72]

Histologically, small cell undifferentiated hepatoblastoma is typified by a diffuse population of small cells with scant cytoplasm resembling neuroblasts.[73]

Small cell undifferentiated hepatoblastoma may be difficult to distinguish from malignant rhabdoid tumor of the liver, which has been conflated with small cell undifferentiated hepatoblastoma in past studies. They can be distinguished by the following characteristic abnormalities:

  • Chromosomal abnormalities. These abnormalities in rhabdoid tumors include translocations involving a breakpoint on chromosome 22q11 and homozygous deletion at the chromosome 22q12 region that harbors the SMARCB1 gene.[72,74]
  • Lack of SMARCB1 expression. Lack of detection of SMARCB1 by immunohistochemistry is characteristic of malignant rhabdoid tumors.[72]
  • Poor prognosis. A characteristic thought to be shared by small cell undifferentiated hepatoblastomas and malignant rhabdoid tumors is the poor prognosis associated with each.[63,72,75]

The ongoing international Pediatric Hepatic Malignancy International Treatment Trial (PHITT) designates any childhood liver tumor as rhabdoid tumor of the liver if it contains cells that lack SMARCB1 expression. (Refer to the AHEP1531 trial in the Treatment options under clinical evaluation for hepatoblastoma section of this summary for more information.) Patients with SMARCB1-negative tumors, which are presumed to be related to rhabdoid tumors, may not be entered on the international trial, which addresses treatment of hepatoblastoma that includes small cell undifferentiated histology, hepatocellular carcinoma, and hepatic malignancy of childhood NOS, but not rhabdoid tumor of the liver. In this trial, all patients with histology as assessed by the institutional pathologist consistent with pure small cell undifferentiated hepatoblastoma are required to have testing for SMARCB1 by immunohistochemistry according to the practices at the institution.

If SMARCB1 is maintained but small cell undifferentiated histology is present, the current literature suggests a worse outcome for these patients. However, because small cell undifferentiated hepatoblastoma and rhabdoid tumor of the liver have not been discriminated in past studies, some of the prognostic features attributed to the former may have been contributed in part by the latter. Published studies of prognostic features related to small cell undifferentiated histology include the following:

  • In 2009, the results of a study of 11 young children with low AFP levels and small cell morphology were reported. Ten children died of disease progression, and one child died of complications. Six of six children tested were SMARCB1 negative, but only one child had any rhabdoid morphology. This finding suggests that many or all liver tumors with small cell morphology and very low AFP levels in young children may be rhabdoid tumors of the liver. These tumors have a poor prognosis that is associated with the driver mutation.[72]
  • A single-institution study of seven children with small cell morphology liver tumors found that all retained expression of SMARCB1. Six children survived, and one child died of complications from liver transplant.[76]
  • A study of 23 liver tumors from the Kiel tumor bank found 12 tumors with small cell morphology. Nine tumors had malignant rhabdoid tumor classic histology, and two tumors had mixed small cell and rhabdoid histologies. Outcomes were not provided, but it was noted that rhabdoid brain tumors had small cell, not classic, rhabdoid histology.[77]
  • In a single-institution study of six children with SMARCB1-negative liver tumors, two children with small cell morphology died. The remaining four children with classic rhabdoid histology were not treated with cisplatin-based therapy; three children survived, and one child died from complications of transplant.[78]

The outcomes of the CHIC trial of childhood liver tumors may clarify some of the questions regarding these different histologic and genetic findings.

Patients with small cell undifferentiated hepatoblastoma whose tumors are unresectable have an especially poor prognosis.[72] Patients with stage I tumors appear to have increased risk of treatment failure when small cell elements are present.[79] For this reason, completely resected tumors composed of well-differentiated fetal histology or of mixed fetal and embryonal cells must have a thorough histologic examination as small foci of undifferentiated small cell histology indicates a need for aggressive chemotherapy.[79] Aggressive treatment for this histology was investigated in the completed COG AHEP0731 [NCT00980460] study, and all tumors were tested for SMARCB1 expression by immunohistochemistry. In this study, hepatoblastoma that would otherwise be considered very low or low risk was upgraded to intermediate risk if any small cell undifferentiated elements were found (refer to Table 5 for more information).

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.

Table 5. A Comparison of the Use of PRETEXT in Risk Stratification Schemes for Hepatoblastomaa,b
​ COG (AHEP-0731) SIOPEL (SIOPEL-3, -3HR, -4, -6) GPOH JPLT (JPLT-2 and -3)
AFP = alpha-fetoprotein; COG = Children's Oncology Group; GPOH = Gesellschaft für Pädiatrische Onkologie und Hämatologie (Society for Paediatric Oncology and Haematology); JPLT = Japanese Study Group for Pediatric Liver Tumor; PRETEXT = PRE-Treatment EXTent of disease; SCU = small cell undifferentiated; SIOPEL = International Childhood Liver Tumors Strategy Group.
a Adapted from Czauderna et al.[67]
b Refer to Table 2for more information about the annotations used in PRETEXT.
c The COG and PRETEXT definitions of vascular involvement differ.
Very low risk PRETEXT I or II; well-differentiated fetal histology; primary resection at diagnosis
Low risk/standard risk PRETEXT I or II of any histology with primary resection at diagnosis PRETEXT I, II, or III PRETEXT I, II, or III PRETEXT I, II, or III
Intermediate riskb PRETEXT II, III, or IV unresectable at diagnosis; or V+c, P+, E+; SCU histology PRETEXT IV or any PRETEXT with rupture; or N1, P2, P2a, V3, V3a; or multifocal
High riskb Any PRETEXT with M+; AFP level <100 ng/mL Any PRETEXT; V+, P+, E+, M+; SCU histology; AFP level <100 ng/mL; tumor rupture Any PRETEXT with V+, E+, P+, M+ or multifocal Any PRETEXT with M1 or N2; or AFP level <100 ng/mL

International risk classification model

The Children's Hepatic tumors International Collaboration (CHIC) 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.[43] 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.[42]

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 was performed on the basis of these backbone groups; the groups were defined according to the following clinical prognostic factors: AFP (≤100 ng/mL), PRETEXT group (I, II, III, or IV), and presence of metastasis (yes or no). The backbone groups are as follows:[43]

  • 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+, refer to Table 2) or AFP less than or equal to 100 ng/mL:[43]

  • 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 3. 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.[43]

Diagram showing risk stratification trees for the Children's Hepatic tumors International Collaboration—Hepatoblastoma Stratification (CHIC-HS).
Figure 3. 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. 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.[47,49,60]

Chemotherapy regimens used in the treatment of hepatoblastoma and their respective outcomes are described in Table 6. (Refer to the Tumor Stratification by Imaging and Evans Surgical Staging for Childhood Liver Cancer section of this summary for information describing each stage.)

Table 6. Outcomes for Hepatoblastoma Multicenter Trialsa
Study Chemotherapy Regimen Number of Patients Outcomes
AFP = alpha-fetoprotein; C5V = cisplatin, fluorouracil (5-FU), and vincristine; CARBO = carboplatin; CCG = Children's Cancer Group; CDDP = cisplatin; CITA = pirarubicin-cisplatin; COG = Children's Oncology Group; DOXO = doxorubicin; EFS = event-free survival; GPOH = Gesellschaft für Pädiatrische Onkologie und Hämatologie (Society for Paediatric Oncology and Haematology); HR = high risk; IFOS = ifosfamide; IPA = ifosfamide, cisplatin, and doxorubicin; JPLT = Japanese Study Group for Pediatric Liver Tumor; LR = low risk; NR = not reported; OS = overall survival; PLADO = cisplatin and doxorubicin; POG = Pediatric Oncology Group; PRETEXT = PRE-Treatment EXTent of disease; SIOPEL = International Childhood Liver Tumors Strategy Group; SR = standard risk; SUPERPLADO = cisplatin, doxorubicin, and carboplatin; THP = tetrahydropyranyl-adriamycin (pirarubicin); VP = vinorelbine and cisplatin; VPE+ = venous, portal, and extrahepatic involvement; VP16 = etoposide.
a Adapted from Czauderna et al.[67]and Meyers et al.[80]
b Study closed early because of inferior results in the CDDP/CARBO arm.
INT0098 (CCG/POG) 1989–1992 C5V vs. CDDP/DOXO Stage I/II: 50 4-Year EFS/OS:
I/II = 88%/100% vs. 96%/96%
Stage III: 83 III = 60%/68% vs. 68%/71%
Stage IV: 40 IV = 14%/33% vs. 37%/42%
P9645 (COG) b 1999–2002 C5V vs. CDDP/CARBO Stage I/II: Pending publication 1-Year EFS:
I/II: Pending publication
Stage III: 38 III/IV: C5V = 51%; CDDP/CARBO = 37%
Stage IV: 50
AHEP0731 (COG) 2010–2014[81][Level of evidence: 3iiA] LR: C5V (2 cycles) LR (stage I/II): 49 5-year EFS: 88%;5-year OS: 91%
HB 94 (GPOH) 1994–1997 I/II: IFOS/CDDP/DOXO Stage I: 27 4-Year EFS/OS:
I = 89%/96%
Stage II: 3 II = 100%/100%
III/IV: IFOS/CDDP/DOXO + VP/CARBO Stage III: 25 III = 68%/76%
Stage IV: 14 IV = 21%/36%
HB 99 (GPOH) 1999–2004 SR: IPA SR: 58 3-Year EFS/OS:
SR = 90%/88%
HR: CARBO/VP16 HR: 42 HR = 52%/55%
SIOPEL-2 1994–1998 SR: PLADO PRETEXT I: 6 3-Year EFS/OS:
SR: 73%/91%
PRETEXT II: 36
PRETEXT III: 25
HR: CDDP/CARBO/DOXO PRETEXT IV: 21 HR: IV = 48%/61%
Metastases: 25 HR: metastases = 36%/44%
SIOPEL-3 1998–2006 SR: CDDP vs. PLADO SR: PRETEXT I: 18 3-Year EFS/OS:
SR: CDDP = 83%/95%; PLADO = 85%/93%
PRETEXT II: 133
PRETEXT III: 104
HR: SUPERPLADO HR: PRETEXT IV: 74 HR: Overall = 65%/69%
VPE+: 70
Metastases: 70 Metastases = 57%/63%
AFP <100 ng/mL: 12
SIOPEL-4 2005–2009 HR: Block A: Weekly; CDDP/3 weekly DOXO; Block B: CARBO/DOXO PRETEXT I: 2 3-Year EFS/OS:
All HR = 76%/83%
PRETEXT II: 17
PRETEXT III: 27
PRETEXT IV: 16 HR: IV = 75%/88%
Metastases: 39 HR: Metastases = 77%/79%
JPLT-1 1991–1999 I/II: CDDP(30)/THP-DOXO Stage I: 9 5-Year EFS/OS:
I = NR/100%
Stage II: 32 II = NR/76%
III/IV: CDDP(60)/THP-DOXO Stage IIIa: 48 IIIa = NR/50%
Stage IIIb: 25 IIIb = NR/64%
Stage IV: 20 IV = NR/77%
JPLT-2 1999–2010 I: Low-dose CDDP-pirarubicin PRETEXT I–IV: 212 5-Year EFS/OS:
I = NR/100%
II–IV: CITA II = NR/89%
III = NR/93%
IV = NR/63%
Metastases: High dose chemotherapy + stem cell transplant Metastases = 32%

Treatment options for hepatoblastoma that is resectable at diagnosis

Approximately 20% to 30% of children with hepatoblastoma have resectable disease at diagnosis. COG surgical guidelines (AHEP0731 [NCT00980460] appendix) recommend tumor resection at diagnosis without preoperative chemotherapy in children with PRETEXT I tumors and PRETEXT II tumors with greater than 1 cm radiographic margin on the vena cava and middle hepatic and portal veins.

Prognosis varies depending on the histologic subtype, as follows:

  • Patients with well-differentiated fetal histology (4% of hepatoblastomas) have a 3- to 5-year OS rate of 100% with minimal or no adjuvant chemotherapy.[48,63,71]
  • Patients with non–well-differentiated fetal histology, non–small cell undifferentiated hepatoblastomas have a 3- to 4-year OS rate of 90% to 100% with adjuvant chemotherapy.[48,49,60,63,82]
  • If any small cell undifferentiated elements are present, the 3-year survival rate is 40% to 70%.[62,63]

Treatment options for hepatoblastoma resectable at diagnosis showing non–well-differentiated fetal histology include the following:

  1. Resection followed by two to four cycles of chemotherapy.

Re-resection of positive microscopic margins may not be necessary. Conclusive evidence is lacking for tumors with resection at diagnosis compared with those with positive microscopic margins resected after preoperative chemotherapy.

Evidence (gross surgical resection [with or without microscopic margins] and postoperative chemotherapy):

  1. Gross surgical excision with or without microscopic margins has been followed by four courses of combination chemotherapy with cisplatin, vincristine, and fluorouracil or cisplatin and doxorubicin or cisplatin alone.[47,48,49,60]

    Second resection of positive margins and/or radiation therapy may not be necessary in patients with incompletely resected hepatoblastoma whose residual tumor is microscopic and who receive subsequent chemotherapy.[55,64]

  2. In the COG AHEP0731 (NCT00980460) trial, 49 of 51 patients with stage I or stage II hepatoblastoma (without pure fetal histology) received two cycles of adjuvant chemotherapy consisting of cisplatin, fluorouracil, and vincristine.[81][Level of evidence: 3iiA]
    • The 5-year EFS rate was 88%, and the 5-year OS rate was 91%.
    • This outcome is comparable to the outcomes for children treated with four cycles after initial resection, and to the outcomes for children treated with two cycles of neoadjuvant chemotherapy before resection followed by two cycles of chemotherapy after resection.
  3. There is no reliable data for local recurrence risk in patients with a positive microscopic margin status who were resected at diagnosis.[50] SIOPEL studies suggest that in patients who received preoperative chemotherapy, positive microscopic margin did not increase risk of local recurrence.[55,60,64]; [83][Level of evidence: 3iiiA]
    • In a European study conducted between 1990 and 1994, 11 patients had tumor found at the surgical margins after hepatic resection and two patients died, neither of whom had a local recurrence. None of the 11 patients underwent a second resection and only one patient received radiation therapy postoperatively. All of the patients were treated with four courses of cisplatin and doxorubicin before surgery and received two courses of postoperative chemotherapy.[55]
    • In another European study of high-risk hepatoblastoma, 11 patients had microscopic residual tumor remaining after initial surgery and received two to four postoperative cycles of chemotherapy with no additional surgery. Of these 11 patients, 9 survived.[64]
    • In the SIOPEL-2 study, 13 of 13 patients with microscopic positive resection margins survived.[60]
    • An unplanned retrospective study of the SIOPEL-2 and SIOPEL-3 trials found that after four courses of cisplatin for standard-risk patients and seven courses of cisplatin alternating with doxorubicin/carboplatin for high-risk patients, resection was performed where imaging suggested it would be safe. Of the 431 children treated in these trials, 58 patients had positive microscopic tumor margins, and 371 patients were in complete remission. There were no statistically significant differences in the rates of local recurrence, EFS, or OS between the two groups.[83][Level of evidence: 3iiiA]
  4. A randomized clinical trial demonstrated comparable efficacy with postoperative cisplatin/vincristine/fluorouracil and cisplatin/doxorubicin in the treatment of hepatoblastoma.[48]
    • Although outcome was nominally higher for the children who received cisplatin/doxorubicin, this difference was not statistically significant.
    • The combination of cisplatin/vincristine/fluorouracil was significantly less toxic than the doses of cisplatin/doxorubicin, to which it was compared.

Results of chemotherapy clinical trials are described in Table 6.

Treatment options for hepatoblastoma of well-differentiated fetal (pure fetal) histology resectable at diagnosis include the following:

  1. Complete surgical resection followed by watchful waiting or chemotherapy.[71]

Evidence (complete surgical resection followed by watchful waiting or chemotherapy):

  1. In the COG prospective clinical trial (INT0098), nine children with stage I (completely resected) well-differentiated fetal histology and fewer than two mitoses per high-power field were treated with adjuvant doxorubicin for four cycles.[48]
    • At a median follow-up of 5.1 years, the EFS and OS were 100% for all nine children.
  2. In the COG P9645 (NCT00003994) study, 16 patients with stage I (completely resected) tumor had well-differentiated fetal histology and received no adjuvant chemotherapy. In a retrospective PRETEXT classification of 21 of these 25 patients with adequate data, PRETEXT I, II, and III were found in 7, 10, and 4 patients, respectively.[71]
    • The EFS and OS were 100% for patients with stage I well-differentiated fetal histology, including one patient who had a second surgery to address a positive tumor margin.
  3. Treatment of a small focus of undifferentiated small cell histology within an otherwise well-differentiated fetal histology tumor with aggressive chemotherapy has been reported in the following small series suggesting the importance of a thorough histologic examination of apparent well-differentiated fetal histology.[79]

    A retrospective study of 16 patients with well-differentiated fetal histology treated at multiple institutions had complete surgical resections, but also had elements of (or, in some case, predominance of) small cell histology found in the resected tumor.[79]

    • Despite receiving postoperative chemotherapy, 10 of 16 patients recurred, and 5 of these patients died of hepatoblastoma.

Treatment options for hepatoblastoma that is not resectable or not resected at diagnosis

Approximately 70% to 80% of children with hepatoblastoma have tumors that are not resected at diagnosis. COG surgical guidelines (AHEP0731 [NCT00980460] appendix) recommend biopsy without an attempt to resect the tumor at diagnosis in children with PRETEXT II tumors with less than 1 cm radiographic margin on the vena cava and middle hepatic vein and in all children with PRETEXT III and IV tumors.

Tumor rupture at presentation, resulting in major hemorrhage that can be controlled by transcatheter arterial embolization or partial resection to stabilize the patient, does not preclude a favorable outcome when followed by chemotherapy and definitive surgery.[84]

Treatment options for hepatoblastoma that is not resectable or is not resected at diagnosis include the following:

  1. Chemotherapy followed by reassessment of surgical resectability and complete surgical resection.
  2. Chemotherapy followed by reassessment of surgical resectability and orthotopic liver transplant.[49,53,85,86,87,88,89,90]
  3. Transarterial chemoembolization (TACE). TACE may be used to improve resectability before definitive surgical approaches.[91,92]

In recent years, almost all children with hepatoblastoma have been treated with chemotherapy, and in European centers, children with resectable hepatoblastoma are treated with preoperative chemotherapy, which may reduce the incidence of surgical complications at the time of resection.[49,55,60] Treatment with preoperative chemotherapy has been shown to benefit children with hepatoblastoma. In contrast, an American intergroup study of treatment of children with hepatoblastoma encouraged resection at the time of diagnosis for all tumors amenable to resection without undue risk. The study (COG-P9645) did not treat children with stage I tumors of well-differentiated fetal histology with preoperative or postoperative chemotherapy unless they developed progressive disease.[71] In this study, most patients with PRETEXT III and all PRETEXT IV tumors were treated with chemotherapy before resection or transplant.

Patients whose tumors remain unresectable after chemotherapy should be considered for liver transplant.[49,53,85,86,87,88,89] In the presence of features predicting unresectability, early coordination with a pediatric liver transplant service is critical.[61] In the COG AHEP0731 (NCT00980460) study, early referral (i.e., based on imaging done after the second cycle of chemotherapy) to a liver specialty center with liver transplant capability was recommended for patients with POSTTEXT III tumors with positive V or P and POSTTEXT IV tumors with positive F.

Evidence (chemotherapy followed by reassessment of surgical resectability and complete surgical resection):

  1. In the SIOPEL-1 study, preoperative chemotherapy (doxorubicin and cisplatin) was given to all children with hepatoblastoma with or without metastases. After chemotherapy, and excluding those who underwent a liver transplant (<5% of patients), complete resection was performed.[49]
    • The chemotherapy was well tolerated.
    • Complete resection was obtained in 87% of children.
    • This strategy resulted in an OS rate of 75% at 5 years after diagnosis.
  2. Identical results were seen in a follow-up international study (SIOPEL-2).[60]
  3. The SIOPEL-3 study compared cisplatin alone with cisplatin and doxorubicin in patients with preoperative standard-risk hepatoblastoma. Standard risk was defined as tumor confined to the liver and not involving more than three sectors.[82][Level of evidence:1iiA]
    • The rates of resection were similar for the cisplatin (95%) and cisplatin/doxorubicin (93%) groups.
    • The OS rates were also similar for the cisplatin (95%) and cisplatin/doxorubicin (93%) groups.
  4. In a pilot study, SIOPEL-3HR, cisplatin alternating with carboplatin/doxorubicin was administered in a dose-intensive fashion to high-risk patients with hepatoblastoma.[64]
    • In 74 patients with PRETEXT IV tumors, 22 of whom also had metastases, 31 became resectable and 26 underwent transplant. The 3-year OS of this group was 69% (± 11%).
    • Of the 70 patients with metastases enrolled in the trial, the 3-year EFS rate was 56% and the OS rate was 62%. Of patients with lung metastases, 50% were able to achieve complete remission of metastases with chemotherapy alone (without lung surgery).
  5. SIOPEL-4 (NCT00077389) was a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Surgical removal of all remaining tumor lesions after chemotherapy was performed if feasible (including liver transplant and metastasectomy, if needed). Patients whose tumors were resected or whose livers were transplanted after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors remained unresectable after three cycles of chemotherapy received two cycles of very intensive carboplatin and doxorubicin before surgery. The primary tumor masses were identified as PRETEXT II (27%), III (44%), and IV (26%).[56][Level of evidence: 2Dii]
    • Ninety-seven percent of patients (60 of 61) had a partial response with chemotherapy.
    • Eighty-five percent of patients (53) underwent complete macroscopic resection; tumor was microscopically present in five patients, all of whom are disease-free survivors.
    • Two patients died postoperatively.
    • There were 37 partial hepatectomies and 16 liver transplants.
    • The study had a total of 62 high-risk patients; 74% of patients (62%–84%) underwent resection. The 3-year disease-free survival (DFS) was 76% (95% CI, 65%–87%), and the 3-year OS was 83% (95% CI, 73%–93%).
    • Of the 16 PRETEXT IV patients, 11 were downstaged after chemotherapy—6 patients to PRETEXT III, 4 patients to PRETEXT II, and 1 patient to PRETEXT I. Twelve tumors became resectable; of these, four patients underwent a partial hepatectomy and eight patients underwent a liver transplant. For patients who presented with PRETEXT IV disease, the 3-year DFS was 73% (95% CI, 51%–96%), and the 3-year OS was 80% (95% CI, 60%–100%).
  6. In approximately 75% of children and adolescents with initially unresectable hepatoblastoma, tumors can be rendered resectable with cisplatin-based preoperative chemotherapy, and 60% to 65% will survive disease-free.[93]
  7. A combination of ifosfamide, cisplatin, and doxorubicin followed by postinduction resection has also been used in the treatment of advanced-stage disease.[94]

In the United States, unresectable tumors have been treated with chemotherapy before resection or transplant.[46,47,48,71] On the basis of radiographic imaging, most stage III and IV hepatoblastomas are rendered resectable after two cycles of chemotherapy.[95] Some centers have also used extended resection of selected POSTTEXT III and IV tumors rather than liver transplant.[61,96,97,98,99]

Chemotherapy followed by TACE followed by high-intensity focused ultrasound showed promising results in China for PRETEXT III and IV patients with hepatoblastoma, some of whom were resectable but did not undergo surgical resection because of parent refusal.[100]

Treatment options for hepatoblastoma with metastases at diagnosis

The outcomes of patients with metastatic hepatoblastoma at diagnosis are poor, but long-term survival and cure is possible.[46,47,48] Survival rates at 3 to 5 years range from 20% to 79%.[56,64,101,102] To date, the best outcomes for children with metastatic hepatoblastoma resulted from treatment with dose-dense cisplatin and doxorubicin, although significant toxicity was also noted (SIOPEL-4 [NCT00077389] trial).[56][Level of evidence: 2Dii]

Treatment options for hepatoblastoma with metastases at diagnosis include the following:

  1. Chemotherapy followed by reassessment of surgical resectability.
    • If the primary tumor and extrahepatic disease (usually pulmonary nodules) are resectable after chemotherapy, surgical resection followed by additional chemotherapy.
    • If extrahepatic metastatic disease is in complete remission after chemotherapy and/or surgical resection of lung nodule but the primary tumor remains unresectable, orthotopic liver transplant.
    • If extrahepatic metastatic disease is not resectable or the patient is not a transplant candidate, additional chemotherapy, TACE, or radiation therapy.

The standard combination chemotherapy regimen in North America is four courses of cisplatin/vincristine/fluorouracil [48] or doxorubicin/cisplatin [49,71,101] followed by attempted complete tumor resection. If the tumor is completely removed, two postoperative courses of the same chemotherapy are usually given. Study results for different chemotherapy regimens have been reported (refer to Table 6 for more information).

High-dose chemotherapy with stem cell rescue does not appear to be more effective than standard multiagent chemotherapy.[103]

Evidence (chemotherapy to treat metastatic disease at diagnosis):

  1. A subset of 39 patients presenting with metastases were entered on the SIOPEL-4 (NCT00077389) trial, a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Patients whose tumors were resected or livers transplanted after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors were unresectable after three cycles of chemotherapy received two additional cycles of very intensive carboplatin and doxorubicin before surgery.[56][Level of evidence: 2Dii]
    • After three cycles of chemotherapy, there was a complete response (only in the metastases) in 20 of 39 patients and a partial response in 18 of 39 patients. Nineteen of the patients who achieved a complete response were alive without disease 3 years after diagnosis.
    • Of the patients who achieved a partial response, seven patients underwent metastasectomy near the time of resection or liver transplant, with an OS of 100%. An additional seven patients with residual small pulmonary nodules underwent resection without metastasectomy; of those, six patients did well and one patient recurred.
    • Two patients with initial metastases eventually recurred.
    • Liver transplant, rather than resection alone, was needed to treat 7 of the 39 patients who presented with metastases.
    • For the subset of 39 patients presenting with metastases, the 3-year DFS was 77% (95% CI, 63%–90%), and the OS was 79% (95% CI, 66%–92%).

In patients with resected primary tumors, any remaining pulmonary metastasis is surgically removed, if possible.[101] A review of patients treated on a U.S. intergroup trial suggested that resection of metastasis may be done at the time of resection of the primary tumor.[102][Level of evidence: 3iiA]

If extrahepatic disease is in complete remission after chemotherapy, and the primary tumor remains unresectable, an orthotopic liver transplant may be performed.[56,64,71,94]

The outcome results are discrepant for patients with lung metastases at diagnosis who undergo orthotopic liver transplant after complete resolution of lung disease in response to pretransplant chemotherapy. Some studies have reported favorable outcomes for these groups,[56,64,89,94] while others have noted high rates of hepatoblastoma recurrence.[53,85,88,91] All of these studies are limited by small patient numbers; additional study is needed to better define outcomes for this subset of patients. Recent clinical trials have resulted in few pulmonary recurrences in children who underwent liver transplants and presented with metastatic disease.[56,64,104]

If extrahepatic disease is not resectable after chemotherapy or the patient is not a transplant candidate, alternative treatment approaches include the following:

  • Nonstandard chemotherapy agents. Nonstandard chemotherapy agents such as irinotecan, high-dose cisplatin/etoposide, or continuous-infusion doxorubicin have been used.[105,106,107]; [108][Level of evidence: 3iiA]
  • TACE.[92,109]
  • Radiation therapy.[110]

Treatment options for progressive or recurrent hepatoblastoma

The prognosis for a patient with progressive or recurrent hepatoblastoma depends on several factors, including the following:[111]

  • 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 appropriate chemotherapy, may make extended disease-free survival possible.[102,111,112]

    If possible, isolated metastases are resected completely in patients whose primary tumor is controlled.[113] 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. Outcome after recurrence was best if the tumor was amenable to surgery. Of patients who underwent chemotherapy and surgery, the 3-year EFS was 34%, and the OS was 43%.[111][Level of evidence: 3iiA] Percutaneous radiofrequency ablation has been used as an alternative to surgical resection of oligometastatic hepatoblastoma.[114][Level of evidence: 3iiiB]

    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 and should be considered.

  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.[115] Addition of doxorubicin to vincristine/fluorouracil/cisplatin is under clinical evaluation in the COG study AHEP0731 [NCT00980460]. Combined vincristine/irinotecan and single-agent irinotecan have been used with some success.[108]; [107][Level of evidence: 3iiiA]

    A review of COG phase I and II studies found no promising agents for relapsed hepatoblastoma.[116]

  3. Liver transplant. Liver transplant should be considered for patients with nonmetastatic disease recurrence in the liver that is not amenable to resection.[53,85,88]
  4. Percutaneous ablation. Percutaneous ablation techniques may also be considered for palliation.[117]

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, refer to 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 these patients are treated with no chemotherapy; or 2) a non–well differentiated fetal mass or incompletely resected well differentiated fetal mass, and these patients are treated with two cycles of cisplatin chemotherapy.
    • Low-risk hepatoblastoma is defined as a PRETEXT I to III tumor without any positive VPEFR annotation factors (venous involvement, portal involvement, extrahepatic spread, multifocality, and tumor rupture). These patients are treated with two cycles of cisplatin chemotherapy and then undergo resection (if possible) followed by randomization between two and four more cycles of cisplatin. If the tumor is unresectable, the patient receives two more cycles of cisplatin chemotherapy, and the tumor's resectability is reassessed. If it is still unresectable, patients undergo liver transplant.
    • Intermediate-risk hepatoblastoma is defined as a PRETEXT I to III primary tumor with a positive VPEFR annotation factor but without metastasis. Patients are randomly assigned to either four 14-day cycles of cisplatin or four 21-day cycles of C5VD (cisplatin, fluorouracil, vincristine, and doxorubicin). Transplant teams are consulted early as needed. Patients in both arms then undergo resection and receive two more cycles of their assigned chemotherapy.
    • High-risk hepatoblastoma is defined as presence of distant metastasis or AFP less than 100 or age 8 years and older. All patients are treated with three cycles of induction chemotherapy per the SIOPEL-4 trial (dose-intensive cisplatin, doxorubicin, and carboplatin). The patients aged 8 years and older or with AFP less than 100 and those whose metastases have cleared receive three cycles of carboplatin and doxorubicin. Patients with metastases that have not cleared by end of induction are randomly assigned to receive either carboplatin/doxorubicin cycles alternating with carboplatin/etoposide for six cycles or carboplatin/doxorubicin alternating with vincristine/irinotecan for six cycles.
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

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  105. 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.
  106. Palmer RD, Williams DM: Dramatic response of multiply relapsed hepatoblastoma to irinotecan (CPT-11). Med Pediatr Oncol 41 (1): 78-80, 2003.
  107. Qayed M, Powell C, Morgan ER, et al.: Irinotecan as maintenance therapy in high-risk hepatoblastoma. Pediatr Blood Cancer 54 (5): 761-3, 2010.
  108. Zsíros J, Brugières L, Brock P, et al.: Efficacy of irinotecan single drug treatment in children with refractory or recurrent hepatoblastoma--a phase II trial of the childhood liver tumour strategy group (SIOPEL). Eur J Cancer 48 (18): 3456-64, 2012.
  109. Sue K, Ikeda K, Nakagawara A, et al.: Intrahepatic arterial injections of cisplatin-phosphatidylcholine-Lipiodol suspension in two unresectable hepatoblastoma cases. Med Pediatr Oncol 17 (6): 496-500, 1989.
  110. 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.
  111. 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.
  112. 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.
  113. 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.
  114. 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.
  115. 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.
  116. 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.
  117. 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.

Hepatocellular Carcinoma

Incidence

The annual incidence of hepatocellular carcinoma in the United States is 0.8 cases per 1 million children between the ages of 0 and 14 years and 1.5 cases per 1 million adolescents aged 15 to 19 years.[1] Although the incidence of hepatocellular carcinoma in adults in the United States has steadily increased since the 1970s, possibly because of the increased frequency of chronic hepatitis C infection,[2] the incidence in children has not increased. In several Asian countries, the incidence of hepatocellular carcinoma in children is 10 times higher than the incidence in children in North America. The high incidence appears to be related to the incidence of perinatally acquired hepatitis B, which can be prevented in most cases by vaccination and administration of hepatitis B immune globulin to the newborn child.[3]

Fibrolamellar hepatocellular carcinoma, a subtype of hepatocellular carcinoma that is unrelated to cirrhosis, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection, generally occurs in adolescents and young adults, but has been reported in infants.[4]

Risk Factors

Conditions associated with hepatocellular carcinoma are described in Table 7.

Table 7. Conditions Associated With Hepatocellular Carcinoma
Associated Disorder Clinical Findings
Alagille syndrome[5] Broad prominent forehead, deep set eyes, and small prominent chin. Abnormality of bile ducts leads to intrahepatic scarring.
Glycogen storage diseases I–IV[6] Symptoms vary by individual disorder.
Hepatitis B and C[7,8,9] Refer to the Hepatitis B and hepatitis C infectionsection of this summary for more information.
Progressive familial intrahepatic cholestasis[10,11] Symptoms of jaundice, pruritus, and failure to thrive begin in infancy and progress to portal hypertension and liver failure.
Tyrosinemia[12] First few months of life: failure to thrive, vomiting, jaundice.

Alagille syndrome

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

Hepatitis B and hepatitis C infection

In children, hepatocellular carcinoma is associated with perinatally acquired HBV, whereas in adults, it is associated with chronic HBV and HCV infection.[7,8,9] Widespread hepatitis B immunization has decreased the incidence of hepatocellular carcinoma in Asia.[3] Compared with adults, the incubation period from hepatitis virus infection to the genesis of hepatocellular carcinoma is extremely short in a small subset of children with perinatally acquired virus. Mutations in the MET gene could be one mechanism that results in a shortened incubation period.[13]

Hepatitis C infection is associated with development of cirrhosis and hepatocellular carcinoma that takes decades to develop and is generally not seen in children.[9] Cirrhosis in children, compared with cirrhosis in adults, is much less commonly involved in the development of hepatocellular carcinoma, and is found in only 20% to 35% of children with hepatocellular carcinoma tumors.

Nonviral liver injury

Specific types of nonviral liver injury and cirrhosis that are associated with hepatocellular carcinoma in children include the following:

  • Tyrosinemia. Tyrosinemia patients are regularly screened for hepatocellular carcinoma, even if they are treated with nitisinone.[12] Nitisinone can prevent cirrhosis and decrease the incidence of hepatocellular carcinoma, especially when administered during infancy, after neonatal screening is used to diagnose tyrosinemia.[14] As of 2014, only a minority of state screening programs had adopted a highly recommended, new, more predictive newborn screen that is much more effective in newborn children aged 24 to 48 hours.[15]

    In an Iranian study, 36 children underwent liver transplant for tyrosinemia.[16] Twenty-two children had liver nodules greater than 10 cm, and in 20 children, the nodules were cirrhotic. Median age at transplant was 3.9 years. Five of 19 children older than 2 years had hepatocellular carcinoma, and no children younger than 2 years had hepatocellular carcinoma in the resected liver.

  • Aggressive familial intrahepatic cholestasis. Hepatocellular carcinoma may also arise in very young children with mutations in the ABCB11 gene (encodes bile salt export pump protein), which causes progressive familial intrahepatic cholestasis.[10]

Genomics of Hepatocellular Carcinoma

Genomic abnormalities related to hepatocellular carcinoma include the following:

  • A first case of pediatric hepatocellular carcinoma was analyzed by whole-exome sequencing, which showed a higher mutation rate (53 variants) and the coexistence of CTNNB1 and NFE2L2 mutations.[17]
  • One study investigated pediatric nonfibrolamellar hepatocellular carcinoma tumors (N = 15) using multiple analytic tools. These tumors were found to frequently carry alterations in a subset of genes that are commonly mutated in adult hepatocellular carcinoma, including CTNNB1 and TERT, but the molecular mechanisms of the mutations are different; the TP53 mutation was rare in this pediatric hepatocellular carcinoma cohort. Pediatric hepatocellular carcinoma that arose in the background of underlying metabolic disease had fewer mutations and a distinct molecular profile; typical driver mutations were lacking in this group of patients.[18]
  • Fibrolamellar hepatocellular carcinoma is a rare subtype of hepatocellular carcinoma observed in older children. It is characterized by an approximately 400 kB deletion on chromosome 19 that results in production of a chimeric RNA coding for a protein containing the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in frame with PRKACA, the catalytic domain of protein kinase A.[19]
  • A rare, more aggressive subtype of childhood liver cancer (hepatocellular neoplasm, not otherwise specified, also termed transitional liver cell tumor) occurs in older children, and it has clinical and histopathological findings of both hepatoblastoma and hepatocellular carcinoma.

    TERT mutations were observed in two of four cases tested.[20]TERT mutations are also commonly observed in adults with hepatocellular carcinoma.[21]

To date, these genetic mutations have not been used to select therapeutic agents for investigation in clinical trials.

Diagnosis

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

Prognosis and Prognostic Factors

The 5-year overall survival (OS) rate is 42% for children and adolescents with hepatocellular carcinoma.[1] The 5-year survival for hepatocellular carcinoma may be dependent on stage; in an intergroup chemotherapy study conducted in the 1990s, seven of eight stage I patients survived and less than 10% of stage III and IV patients survived.[1,22] An analysis of Surveillance, Epidemiology, and End Results (SEER) data found a 5-year OS rate of 24%, a 10-year rate of 23%, and a 20-year rate of 8% in patients aged 19 years and younger, suggesting improved outcome related to more recent treatment. In a multivariate analysis of the SEER data, surgical resection, localized tumor, and non-Hispanic ethnicity were all associated with improved outcome. Patients who had a complete surgical resection had an OS rate of 60%, compared with an OS rate of 0% for patients who had an incomplete resection.[23][Level of evidence: 3iiiA]

Factors affecting prognosis include the following:

  • Treatment-related factors:

    Cure of hepatocellular carcinoma requires gross tumor resection. However, hepatocellular carcinoma is often extensively invasive or multicentric, and less than 30% of tumors are resectable. Orthotopic liver transplant has been successful in selected children with hepatocellular carcinoma.[24,25]

  • PRE-Treatment EXTent of disease (PRETEXT) group (resectability) is also a prognostic factor (refer to the Risk Stratification section of this summary for more information).
  • Tumor histology:

    Refer to the Histology section of this summary for more information.

Histology

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

Fibrolamellar carcinoma

A distinctive histologic variant of hepatocellular carcinoma, termed fibrolamellar carcinoma, has been described in the livers of older children and young adults and, rarely, in infants.[4,26] This histology is characterized by a fusion transcript created by deletion of a 400 kb section of chromosome 19, which was found in 15 of 15 tumors that were tested.[19]

Fibrolamellar carcinoma is not associated with cirrhosis and was previously thought to be associated with an improved prognosis.[2,26,27] Unlike nonfibrolamellar hepatocellular carcinoma in adults, fibrolamellar hepatocellular carcinoma in older children and adults is not clearly increasing in incidence over time.[2,26] The improved outcomes of patients with fibrolamellar carcinoma in older studies may be related to a higher proportion of tumors being less invasive and more resectable in the absence of cirrhosis. However, the outcomes of patients with fibrolamellar carcinoma in recent prospective studies, when compared stage for stage and PRETEXT group to PRETEXT group, is not different from the outcomes of patients with conventional hepatocellular carcinomas.[28,29]; [30][Level of evidence: 3iiA]

Hepatocellular neoplasm, not otherwise specified (NOS)

Hepatocellular neoplasm, NOS is also known as transitional liver cell tumor. This tumor, with characteristics of both hepatoblastoma and hepatocellular carcinoma, is a rare neoplasm that is found in older children and adolescents, and has a putative intermediate position between hepatoblasts and more mature hepatocyte-like tumor cells. The tumor cells may vary in regions of the tumor between classical hepatoblastoma and obvious hepatocellular carcinoma. In the international consensus classification, these tumors are referred to as hepatocellular neoplasm, NOS.[31] The tumors are usually unifocal and may have central necrosis at presentation. Response to chemotherapy has not been rigorously studied but is felt to be much like that of hepatocellular carcinoma.[32]

Treatment of Hepatocellular Carcinoma

Treatment options for newly diagnosed hepatocellular carcinoma depend on the following:

  1. Whether the cancer is resectable at diagnosis.
  2. How the cancer responds to chemotherapy.
  3. Whether the cancer has metastasized.
  4. Whether the cancer is HBV related.

Treatment options for hepatocellular carcinoma that is resectable at diagnosis

Treatment options for hepatocellular carcinoma that is resectable at diagnosis include the following:

  1. Complete surgical resection of the primary tumor followed by chemotherapy.
  2. Chemotherapy followed by complete surgical resection of the primary tumor.[28]
  3. Complete surgical resection without chemotherapy.

Surgical resection and chemotherapy are the mainstays of treatment for resectable hepatocellular carcinoma.

Evidence (complete surgical resection followed by chemotherapy):

  1. Seven of eight patients with stage I hepatocellular carcinoma who were given adjuvant cisplatin-based chemotherapy survived disease free.[22]
  2. In a survey of childhood liver tumors treated before the consistent use of chemotherapy, only 12 of 33 patients with hepatocellular carcinoma who had complete excision of the tumor survived.[33] This suggests that treatment with adjuvant chemotherapy may benefit children with completely resected hepatocellular carcinoma.
  3. Cisplatin and doxorubicin may be administered as adjuvant therapy because these agents are active in the treatment of hepatocellular carcinoma.[28]
  4. In an analysis of SEER data for children and adolescents younger than 20 years diagnosed between 1976 and 2009, patients who underwent a complete resection had a 60% 5-year OS and those who did not have a complete resection had a 0% 5-year OS.[23][Level of evidence: 3iiiA]

Evidence (complete surgical resection without chemotherapy):

  1. In a single-institution retrospective report, 12 patients with stage I hepatocellular carcinoma were treated with surgery. Ten patients received no chemotherapy and two patients received a short course of chemotherapy based on oncologist preference.[34][Level of evidence: 3iiA]
    • All 12 patients are alive without evidence of disease at a median of 54 months.

Despite improvements in surgical techniques, chemotherapy delivery, and patient supportive care in the past 20 years, clinical trials of cancer chemotherapy have not shown improved survival rates for pediatric patients with hepatocellular carcinoma.[28] The International Childhood Liver Tumors Strategy Group (SIOPEL) studies in Europe have observed no improvement in 5-year OS since 1990. The only long-term survivors were patients whose tumors were resectable at diagnosis, which was less than 30% of children entered in the study.[35] However, some liver transplant studies (complete resection with transplant with or without neoadjuvant chemotherapy) have shown OS rates that are superior to the SIOPEL studies.[25,36,37,38,39]

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

The use of neoadjuvant chemotherapy or transarterial chemoembolization (TACE) to enhance resectability or liver transplant, which may result in complete resection of tumor, is necessary for cure.

Treatment options for nonmetastatic hepatocellular carcinoma that is not resectable at diagnosis include the following:

  1. Chemotherapy followed by reassessment of surgical resectability. If the primary tumor is resectable, complete surgical resection.
  2. Chemotherapy followed by reassessment of surgical resectability. If the primary tumor remains unresectable:
    • Orthotopic liver transplant.
    • Temporizing TACE followed by complete resection or liver transplant.
    • TACE alone.

Evidence (chemotherapy followed by reassessment of surgical resectability and complete surgical resection of the primary tumor):

  1. In a prospective study of 41 patients who received preoperative cisplatin/doxorubicin chemotherapy, treatment resulted in some degree of decrease in tumor size, with a decrease in alpha-fetoprotein (AFP) levels in about 50% of patients. The responders had a superior tumor resectability and survival, although the OS was 28% and only those undergoing complete resection survived.[28]

Evidence (chemotherapy or TACE followed by reassessment of surgical resectability; treatment options for unresectable primary tumor after chemotherapy or TACE):

  1. Patients whose primary tumor remains unresectable after chemotherapy should be considered for orthotopic liver transplant. Liver transplant has been a successful therapy for children with unresectable hepatocellular carcinoma; survival is about 60%, with most deaths resulting from tumor recurrence.[24,39,40,41,42]
  2. A review of treatment for hepatocellular carcinoma in patients younger than 20 years reported to SEER revealed that 75% of patients underwent resection and 25% underwent liver transplant. The 5-year OS was 53.4% with resection and 85.3% with transplant, suggesting that the criteria for transplantation in hepatocellular carcinoma might be liberalized for overall patient benefit. This approach would benefit from prospective testing.[43]
  3. TACE followed by complete surgical resection of primary tumor may be an alternative to the use of chemotherapy followed by surgical resection.
    • Studies in adults in China suggest that repeated hepatic TACE before surgery may improve the outcome of subsequent hepatectomy.[44]
    • A meta-analysis found seven randomized trials that compared resection alone versus TACE followed by resection. There was no difference in 3-year event-free survival (EFS) and OS between the two groups, but the 5-year EFS and OS favored TACE followed by resection.[45]

If the primary tumor is not resectable after chemotherapy and the patient is not a transplant candidate, alternative treatment approaches used in adults include the following:

  • Sorafenib.
  • TACE.
  • Cryosurgery.
  • Intratumoral injection of alcohol.
  • Radiation therapy.

There are limited data on the use of these alternative treatment approaches in children.

Limited data from a European pilot study suggest that sorafenib was well tolerated in 12 newly diagnosed children and adolescents with advanced hepatocellular carcinoma when given in combination with standard chemotherapy of cisplatin and doxorubicin.[46] Additional study is needed to define its role in the treatment of children with hepatocellular carcinoma.

Cryosurgery, intratumoral injection of alcohol, and radiofrequency ablation can successfully treat small (<5 cm) tumors in adults with cirrhotic livers.[44,47,48] Some local approaches such as cryosurgery, radiofrequency ablation, and TACE that suppress hepatocellular carcinoma tumor progression are used as bridging therapy in adults to delay tumor growth while on a waiting list for cadaveric liver transplant.[49] In a pediatric study of eight patients with hepatocellular carcinoma, two patients died of progressive disease without transplant. Treatment with TACE stabilized disease in six patients, for a mean of 141 days to reach transplant.[50][Level of evidence: 3iiA] Five patients were alive at the end of the observation period, and one patient died of disease.(Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)

Treatment options for hepatocellular carcinoma with metastases at diagnosis

No specific treatment has proven effective for metastatic hepatocellular carcinoma in the pediatric age group.

In two prospective trials, cisplatin plus either vincristine/fluorouracil or continuous-infusion doxorubicin was ineffective in adequately treating 25 patients with metastatic hepatocellular carcinoma.[22,28] Occasional patients may transiently benefit from treatment with cisplatin/doxorubicin therapy, especially if the localized hepatic tumor shrinks adequately enough to allow resection of disease and the metastatic disease disappears or becomes resectable.

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

Although HBV-related hepatocellular carcinoma is not common in children in the United States, nucleotide/nucleoside analog HBV inhibitor treatment improves postoperative prognosis in children and adults treated in China.[51]

Treatment options for HBV-related hepatocellular carcinoma include the following:

  1. Antiviral therapy.

Evidence (antiviral therapy):

  1. In a randomized controlled trial, 163 patients post–radical hepatectomy were evaluated for response to one of three antiviral treatments.[51]
    • Antiviral treatment significantly decreased hepatocellular carcinoma recurrence, with a hazard ratio (HR) of 0.48 (95% confidence interval [CI], 0.32–0.70), and hepatocellular carcinoma–related death, with an HR of 0.26 (95% CI, 0.14–0.50), in multivariate Cox analyses.
    • Patients who received antiviral treatment had significantly decreased early recurrence (HR, 0.41; 95% CI, 0.27–0.62) and improved liver function 6 months after surgery than did the control patients (P < .001).

Treatment options for progressive or recurrent hepatocellular carcinoma

The prognosis for a patient with recurrent or progressive hepatocellular carcinoma is extremely poor.[52]

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.[24,39,40,53]
  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.[54] A phase II COG trial of single-agent sorafenib has been completed in children and the study results are pending.

Treatment options under clinical evaluation for hepatocellular carcinoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  • AHEP1531 (NCT03533582) (Cisplatin and Combination Chemotherapy in Treating Children and Young Adults with Hepatoblastoma or Liver Cancer After Surgery):

    This is the COG's participation in a large international trial (Pediatric Hepatic Malignancy International Therapeutic Trial [PHITT]) of treatment of all stages of hepatoblastoma and hepatocellular carcinoma in children.

    • Hepatocellular carcinoma that is potentially resectable is treated with complete resection without any chemotherapy if the mass appears to derive from underlying liver disease. If the hepatocellular carcinoma appears to be de novo without underlying disease, it is treated with resection followed by four cycles of cisplatin/doxorubicin.
    • Patients with hepatocellular carcinoma that is metastatic or appears unresectable at diagnosis undergo consultation with interventional radiology and liver transplant services. Patients are then randomly assigned to receive either cisplatin/doxorubicin/sorafenib for three 21-day cycles or cisplatin/doxorubicin/sorafenib alternating with gemcitabine/oxaliplatin/sorafenib for four 14-day cycles. Responding patients continue chemotherapy for the same number of cycles (3 or 4); they receive the same chemotherapy regimen to which they were originally assigned.
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

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  43. 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.
  44. Zhang Z, Liu Q, He J, et al.: The effect of preoperative transcatheter hepatic arterial chemoembolization on disease-free survival after hepatectomy for hepatocellular carcinoma. Cancer 89 (12): 2606-12, 2000.
  45. Yu T, Xu X, Chen B: TACE combined with liver resection versus liver resection alone in the treatment of resectable HCC: a meta-analysis. Chinese-German J Clin Oncol 12 (11): 532-6, 2013.
  46. 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.
  47. Zhou XD, Tang ZY: Cryotherapy for primary liver cancer. Semin Surg Oncol 14 (2): 171-4, 1998.
  48. Lencioni RA, Allgaier HP, Cioni D, et al.: Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 228 (1): 235-40, 2003.
  49. Lubienski A: Hepatocellular carcinoma: interventional bridging to liver transplantation. Transplantation 80 (1 Suppl): S113-9, 2005.
  50. Weiss KE, Sze DY, Rangaswami AA, et al.: Transarterial chemoembolization in children to treat unresectable hepatocellular carcinoma. Pediatr Transplant 22 (4): e13187, 2018.
  51. Yin J, Li N, Han Y, et al.: Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J Clin Oncol 31 (29): 3647-55, 2013.
  52. 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.
  53. 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.
  54. Llovet JM, Ricci S, Mazzaferro V, et al.: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359 (4): 378-90, 2008.

Undifferentiated Embryonal Sarcoma of the Liver

Incidence

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

Diagnosis

UESL presents as an abdominal mass, often with pain or malaise, usually between the ages of 5 and 10 years. Widespread infiltration throughout the liver and pulmonary metastasis is common. It may appear solid or cystic on imaging, frequently with central necrosis.

Distinctive features are characteristic intracellular hyaline globules and marked anaplasia on a mesenchymal background.[2] Many UESL tumors contain diverse elements of mesenchymal cell maturation, such as smooth muscle and fat. Undifferentiated sarcomas, like small cell undifferentiated hepatoblastomas, should be examined for loss of 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 pathologic features but treatment differs between the two, as shown in Table 8.[1] (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.)

Table 8. Diagnostic Differences Between Undifferentiated Embryonal Sarcoma of the Liver and Biliary Tract Rhabdomyosarcomaa
​ Undifferentiated Embryonal Sarcoma of the Liver Biliary Tract Rhabdomyosarcoma
a Adapted from Nicol et al.[1]
Age at Diagnosis Median age 10.5 y Median age 3.4 y
Tumor Location Often arises in the right lobe of the liver Often arises in the hilum of the liver
Biliary Obstruction Unusual Frequent; jaundice is a common presenting symptom
Treatment Surgery and chemotherapy Surgery (usually biopsy only), radiation therapy, and chemotherapy

Histology

Distinctive histologic features are intracellular hyaline globules and marked anaplasia on a mesenchymal background.[2]

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

Prognosis and Prognostic Factors

The overall survival (OS) of children with UESL appears to be substantially better than 50% when combining reports, although all series are small and most may be selected to report successful treatment.[6]; [7][Level of evidence: 3iiA]; [8,9,10,11,12,13,14,15,16,17][Level of evidence: 3iiiA]

The Childhood Cancer Database, which does not provide central review of pathology or reliable details of nonsurgical treatment, reported on 103 children with UESL diagnosed between 1998 and 2012. The 5-year OS was 86% for all patients and 92% for those treated with combination surgery and chemotherapy. A multivariate analysis of the nonsurgical data revealed statistically significant poorer outcomes for patients with tumors larger than 15 cm. Seven of ten children who presented with metastases and ten of ten children who underwent orthotopic liver transplant survived at least 5 years, but details of their treatment were not presented.[18]

Treatment Options for Undifferentiated Embryonal Sarcoma of the Liver

UESL is rare. Only small series have been published regarding treatment.[19]

Treatment options for UESL include the following:

  • Surgical resection and chemotherapy.
  • Liver transplant, for unresectable tumors.

The generally accepted approach is resection of the primary tumor mass in the liver when possible.[18] Use of aggressive chemotherapy regimens seems to have improved the OS of patients with UESL. Neoadjuvant chemotherapy can be effective in decreasing the size of an unresectable primary tumor mass, resulting in resectability.[8,9,10,11] Most patients are treated with chemotherapy regimens used for pediatric rhabdomyosarcoma or Ewing sarcoma without cisplatin.[6]; [7,20][Level of evidence: 3iiA]; [8,9,10,11,12,13,14,15,16][Level of evidence: 3iiiA]

Evidence (surgical resection and chemotherapy):

  1. In the only prospective series treating patients with UESL, which came from the Italian and German Soft Tissue Sarcoma Cooperative Groups, patients were treated with (1) conservative surgery or (2) biopsy followed by neoadjuvant chemotherapy consisting of varying combinations of vincristine, cyclophosphamide, dactinomycin, doxorubicin, and ifosfamide. Disease evaluation, usually after four cycles of chemotherapy, was followed by second-look surgery when appropriate to try to remove residual primary tumor followed by additional and/or adjuvant chemotherapy.[12]
    • Ten of 17 patients survived in their first complete remission, and one patient survived in third complete remission.
  2. In a single-center retrospective report, five patients with UESL were treated with surgery and adjuvant chemotherapy consisting of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide. Four patients were stage I and one patient was stage II. One patient received abdominal radiation for tumor rupture.[17][Level of evidence: 3iiiA]
    • All patients are alive (range, 5–19 years), with 100% event-free survival and OS.

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

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

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

  • ARST1321 (NCT02180867) (Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Nonrhabdomyosarcoma Soft Tissue Sarcomas That Can be Removed by Surgery): This study will first determine the feasibility of adding a tyrosine kinase inhibitor in combination with radiation or chemotherapy (ifosfamide/etoposide) and radiation in pediatric and adult patients newly diagnosed with unresected, intermediate-risk and high-risk nonrhabdomyosarcomatous STS. Subsequently, this trial will compare the rates of near complete pathologic response (>90% necrosis) of: (1) preoperative pazopanib plus chemoradiation versus preoperative chemoradiation alone for potentially resectable (>5 cm), grade 3 intermediate-risk to high-risk chemotherapy-sensitive (i.e., histologies of undifferentiated sarcoma, synovial sarcoma, and embryonal sarcoma of the liver) adult and pediatric nonrhabdomyosarcomatous STS; and (2) pazopanib plus preoperative radiation therapy versus preoperative radiation therapy alone for potentially resectable, intermediate-risk to high-risk adult and pediatric nonrhabdomyosarcomatous STS.
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the 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.
  2. Stocker JT: Hepatic tumors in children. Clin Liver Dis 5 (1): 259-81, viii-ix, 2001.
  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.
  4. Stringer MD, Alizai NK: Mesenchymal hamartoma of the liver: a systematic review. J Pediatr Surg 40 (11): 1681-90, 2005.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  15. Weitz J, Klimstra DS, Cymes K, et al.: Management of primary liver sarcomas. Cancer 109 (7): 1391-6, 2007.
  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.
  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.
  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.
  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.
  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.
  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.

Infantile Choriocarcinoma of the Liver

Choriocarcinoma of the liver is a very rare tumor that appears to originate in the placenta during gestation and presents with a liver mass in the first few months of life. Metastasis from the placenta to maternal tissues occurs in many cases, necessitating beta-human chorionic gonadotropin (beta-hCG) testing of the mother. Infants are often unstable at diagnosis because of hemorrhage of the tumor.

Clinical diagnosis may be made without biopsy on the basis of tumor imaging of the liver associated with extremely high serum beta-hCG levels and normal alpha-fetoprotein (AFP) levels for age.[1]

Cytotrophoblasts and syncytiotrophoblasts are both present. The former are closely packed nests of medium-sized cells with clear cytoplasm, distinct cell margins, and vesicular nuclei. The latter are very large multinucleated syncytia formed from the cytotrophoblasts.[2]

Treatment Options for Infantile Choriocarcinoma of the Liver

Treatment options for infantile choriocarcinoma of the liver include the following:

  1. Surgical resection.[1]
  2. Chemotherapy followed by surgical resection.

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

Maternal gestational trophoblastic tumors are exquisitely sensitive to methotrexate, and many women, including those with distant metastases, are cured with single-agent chemotherapy. Maternal and infantile choriocarcinoma both come from the same placental malignancy. The combination of cisplatin, etoposide, and bleomycin, as used in other pediatric germ cell tumors, has been effective in some patients and is followed by resection of residual mass. Use of neoadjuvant methotrexate in infantile choriocarcinoma, although often resulting in a response, has not been uniformly successful.[1]

Treatment Options Under Clinical Evaluation for Infantile Choriocarcinoma of the Liver

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the 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.
  2. Olson T, Schneider D, Perlman E: Germ cell tumors. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams and Wilkins, 2011, pp 1045-1067.

Vascular Liver Tumors

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

The different diagnoses of vascular tumors of the liver include the following:

  • Benign tumors.
    • Focal congenital hemangiomas (refer to the Congenital Hemangiomas section of the PDQ summary on Childhood Vascular Tumors Treatment for more information).
    • Multiple or diffuse infantile hemangiomas (refer to the Infantile Hemangioma section of the PDQ summary on Childhood Vascular Tumors Treatment for more information).
  • Malignant tumors.
    • Epithelioid hemangioendothelioma (refer to the Epithelioid Hemangioendothelioma section of the PDQ summary on Childhood Vascular Tumors Treatment for more information).
    • Angiosarcoma (refer to the Angiosarcoma of the Soft Tissue section of the PDQ summary on Childhood Vascular Tumors Treatment for more information).

Current Clinical Trials

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

Changes to This Summary (11 / 25 / 2020)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

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

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Liver Cancer Treatment are:

  • Denise Adams, MD (Children's Hospital Boston)
  • Christopher N. Frantz, MD (Alfred I. duPont Hospital for Children)
  • Andrea A. Hayes-Jordan, MD, FACS, FAAP (University of North Carolina - Chapel Hill School of Medicine)
  • Karen J. Marcus, MD, 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)
  • Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

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

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Liver Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/liver/hp/child-liver-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389232]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

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

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Last Revised: 2020-11-25

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