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

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

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:

References

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]

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 Exit 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]

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. — Table 1. Definitions of PRETEXT and POSTTEXT Groupsa

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. — Table 1. Definitions of PRETEXT and POSTTEXT Groupsa

PRETEXT and POSTTEXT Groups	Definition	Image
aAdapted from Roebuck et al.[3]
I	One section involved; three adjoining sections are tumor free.	ENLARGE
II	One or two sections involved; two adjoining sections are tumor free.	ENLARGE
III	Two or three sections involved; one adjoining section is tumor free.	ENLARGE
IV	Four sections involved.	ENLARGE

Table 2. Annotation Factors For Describing PRETEXT and POSTTEXT Groupsa

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

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 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.[13-15]
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

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]
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]
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]
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]
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]
Lovvorn HN 3rd, 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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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.
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]