sábado, 26 de octubre de 2019

Childhood Liver Cancer Treatment (PDQ®) 1/2 –Health Professional Version - National Cancer Institute

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

National Cancer Institute

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

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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:
Other, less common, histologies include the following:

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:
References
  1. López-Terrada D, Alaggio R, de Dávila MT, et al.: Towards an international pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium. Mod Pathol 27 (3): 472-91, 2014. [PUBMED Abstract]

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]
ENLARGEFigure 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 PathologyExit Disclaimer, 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 GroupsDefinitionImage
aAdapted from Roebuck et al.[3]
IOne section involved; three adjoining sections are tumor free.

ENLARGELiver 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.
IIOne or two sections involved; two adjoining sections are tumor free.

ENLARGELiver 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.
IIITwo or three sections involved; one adjoining section is tumor free.

ENLARGELiver 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.
IVFour sections involved.

ENLARGELiver 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 FactorsDefinition
CT = computed tomography; MRI = magnetic resonance imaging; HU = Hounsfield unit.
aAdapted from Roebuck et al.[3]
bAdditional details describing the annotation factors have been published.[4]
VbVenous involvement: Vascular involvement of the retrohepatic vena cava or involvement of all three major hepatic veins (right, middle, and left).
V0Tumor within 1 cm.
V1Tumor abutting.
V2Tumor compressing or distorting.
V3Tumor ingrowth, encasement, or thrombus.
PbPortal involvement: Vascular involvement of the main portal vein and/or both right and left portal veins.
P0Tumor within 1 cm.
P1Tumor abutting the main portal vein, the right and left portal veins, or the portal vein bifurcation.
P2Tumor compressing the main portal vein, the right and left portal veins, or the portal vein bifurcation.
P3Tumor 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.
EbExtrahepatic spread of disease. Any one of the following criteria is met:
E1Tumor crosses boundaries/tissue planes.
E2Tumor is surrounded by normal tissue more than 180 degrees.
E3Peritoneal 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.
MbDistant metastases. Any one of the following criteria is met:
M1One noncalcified pulmonary nodule ≥5 mm in diameter.
M2Two or more noncalcified pulmonary nodules, each ≥3 mm in diameter.
M3Pathologically proven metastatic disease.
CTumor involving the caudate.
FMultifocality. Two or more discrete hepatic tumors with normal intervening liver tissue.
NbLymph node metastases. Any one of the following criteria is met:
N1Lymph node with short-axis diameter of >1 cm.
N2Portocaval lymph node with short-axis diameter >1.5 cm.
N3Spherical lymph node shape with loss of fatty hilum.
RbTumor rupture. Free fluid in the abdomen or pelvis with one or more of the following findings of hemorrhage:
R1Internal complexity/septations within fluid.
R2High-density fluid on CT (>25 HU).
R3Imaging characteristics of blood or blood degradation products on MRI.
R4Heterogeneous fluid on ultrasound with echogenic debris.
R5Visible defect in tumor capsule OR tumor cells are present within the peritoneal fluid OR rupture diagnosed pathologically in patients who have received an upfront resection.

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).[11-13] 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 StageDefinition
Stage IThe tumor is completely resected.
Stage IIMicroscopic residual tumor remains after resection.
Stage IIIThere 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 IVThere 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.[13-15]
  • 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.[13,14,17-20] 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. [PUBMED Abstract]
  2. Brown J, Perilongo G, Shafford E, et al.: Pretreatment prognostic factors for children with hepatoblastoma-- results from the International Society of Paediatric Oncology (SIOP) study SIOPEL 1. Eur J Cancer 36 (11): 1418-25, 2000. [PUBMED Abstract]
  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. [PUBMED Abstract]
  4. Towbin AJ, Meyers RL, Woodley H, et al.: 2017 PRETEXT: radiologic staging system for primary hepatic malignancies of childhood revised for the Paediatric Hepatic International Tumour Trial (PHITT). Pediatr Radiol 48 (4): 536-554, 2018. [PUBMED Abstract]
  5. Aronson DC, Schnater JM, Staalman CR, et al.: Predictive value of the pretreatment extent of disease system in hepatoblastoma: results from the International Society of Pediatric Oncology Liver Tumor Study Group SIOPEL-1 study. J Clin Oncol 23 (6): 1245-52, 2005. [PUBMED Abstract]
  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. [PUBMED Abstract]
  7. Venkatramani R, Stein JE, Sapra A, et al.: Effect of neoadjuvant chemotherapy on resectability of stage III and IV hepatoblastoma. Br J Surg 102 (1): 108-13, 2015. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  10. Czauderna P, Mackinlay G, Perilongo G, et al.: Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 20 (12): 2798-804, 2002. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]

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.[2-6]; [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.[11-13]; [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]; [18-20][Level of evidence: 3iiA] A review of the world experience has documented a posttransplant survival rate of 70% to 80% for children with hepatoblastomas.[15,21-23] 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.[12,18-20,26]; [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.[32-35] 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.[42-44] 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 DisorderClinical Findings
Aicardi syndrome [7]Refer to the Aicardi syndrome section of this summary for more information.
Beckwith-Wiedemann syndrome [8,9]Refer to the Beckwith-Wiedemann syndrome and hemihyperplasia section of this summary for more information.
Familial adenomatous polyposis [10-12]Refer to the Familial adenomatous polyposis section of this summary for more information.
Glycogen storage diseases I–IV [13]Symptoms vary by individual disorder.
Low-birth-weight infants [3-5,14,15]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.[10-12,26] 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 beta-catenin 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.[30-32]
  • 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]
    ENLARGEChart 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 HepatologyExit Disclaimer, 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 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.[44][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.[45-49] 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.[50][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.[51]
    Orthotopic liver transplant is an additional treatment option for patients whose tumor remains unresectable after preoperative chemotherapy;[52,53] however, the presence of microscopic residual tumor at the surgical margin does not preclude a favorable outcome.[54,55] This may be due to the additional courses of chemotherapy that are administered before or after resection.[45,46,54]
    (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.[56] 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.[57]
    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 INI1 and may be considered rhabdoid tumors of the liver; all small cell undifferentiated hepatoblastomas are tested for loss of INI1 expression by immunohistochemistry.[58-63]
    Beta-hCG levels may also be elevated in children with hepatoblastoma or hepatocellular carcinoma, which may result in isosexual precocity in boys.[64,65]
  • 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.[58] 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.[62,66]

Histology

Hepatoblastoma arises from precursors of hepatocytes and can have several morphologies, including the following:[67]
  • Small cells that reflect neither epithelial nor stromal differentiation. It is critical to discriminate between small cell undifferentiated hepatoblastoma expressing INI1 and rhabdoid tumor of the liver, which lacks the INI1 gene and INI1 expression. Both diseases may share similar histology. Optimal treatment of rhabdoid tumor of the liver and small cell undifferentiated hepatoblastoma may require different approaches and different chemotherapy. (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

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:[47]
    • 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.[68,69]
  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).[70]
    • 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 [62,71] and is associated with AFP levels that are normal for age at presentation.[61,71]
Histologically, small cell undifferentiated hepatoblastoma is typified by a diffuse population of small cells with scant cytoplasm resembling neuroblasts.[72]
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/INI1 gene.[71,73]
  • Lack of INI1 expression. Lack of detection of INI1 by immunohistochemistry is characteristic of malignant rhabdoid tumors.[71]
  • Poor prognosis. A characteristic thought to be shared by small cell undifferentiated hepatoblastomas and malignant rhabdoid tumors is the poor prognosis associated with each.[62,71,74]
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 INI1 expression. (Refer to the AHEP1531 trial in the Treatment options under clinical evaluation for hepatoblastoma section of this summary for more information.) Patients with INI1-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 INI1/SMARCB1 by immunohistochemistry according to the practices at the institution.
If INI1 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 INI1 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.[71]
  • A single-institution study of seven children with small cell morphology liver tumors found that all retained expression of INI1. Six children survived, and one child died of complications from liver transplant.[75]
  • 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.[76]
  • In a single-institution study of six children with INI1-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.[77]
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.[71] Patients with stage I tumors appear to have increased risk of treatment failure when small cell elements are present.[78] 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.[78] Aggressive treatment for this histology was investigated in the completed COG AHEP0731 [NCT00980460] study, and all tumors were tested for INI1 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)GPOHJPLT (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.
aAdapted from Czauderna et al.[66]
bRefer to Table 2 for more information about the annotations used in PRETEXT.
cThe COG and PRETEXT definitions of vascular involvement differ.
Very low riskPRETEXT I or II; well-differentiated fetal histology; primary resection at diagnosis
Low risk/standard riskPRETEXT I or II of any histology with primary resection at diagnosisPRETEXT I, II, or IIIPRETEXT I, II, or IIIPRETEXT I, II, or III
Intermediate riskbPRETEXT II, III, or IV unresectable at diagnosis; or V+c, P+, E+; SCU histologyPRETEXT IV or any PRETEXT with rupture; or N1, P2, P2a, V3, V3a; or multifocal
High riskbAny PRETEXT with M+; AFP level <100 ng/mLAny PRETEXT; V+, P+, E+, M+; SCU histology; AFP level <100 ng/mL; tumor ruptureAny PRETEXT with V+, E+, P+, M+ or multifocalAny 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]
ENLARGEDiagram 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.43 Reprinted from The Lancet OncologyExit Disclaimer, 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.


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