There are two standard surgical staging systems for pediatric liver tumors. The International Society of Pediatric Oncology Epithelial Liver Tumor Group (SIOPEL) uses a presurgical-based (PRETEXT) staging system, while the Children's Oncology Group (COG) uses a postsurgical-based staging system. The SIOPEL presurgical staging system is used with neoadjuvant chemotherapy followed by definitive surgery, while the COG staging system is based on the findings at time of operation, whenever possible.
Both staging systems are used in the United States, although initial resection of PRETEXT 1 and 2 hepatoblastomas are routinely undertaken in the United States. In a retrospective comparison of the two staging systems at diagnosis using data from patients entered on a North American randomized trial, both staging systems predicted outcome. The presurgical PRETEXT staging system may add prognostic information compared with postsurgical staging alone. The European PRETEXT staging system can also be used to restage patients after surgery, which has been termed POSTTEXT staging. The COG is investigating the use of PRETEXT/POSTTEXT stage before and after chemotherapy to determine the optimal surgical approach (COG-AHEP0731).
Presurgical Staging for Hepatoblastoma and Hepatocellular Carcinoma
The European PRETEXT staging system for hepatoblastoma categorizes the primary tumor based on extent of liver involvement at diagnosis. In Europe, all children with hepatoblastoma are treated with chemotherapy prior to attempted resection of the primary tumor. The liver tumors are staged by interpretation of computerized tomography or ultrasound with or without additional imaging by magnetic resonance. The presence or absence of metastases is noted, but it does not alter the PRETEXT stage. Tumor involvement of the vena cava, hepatic veins, and portal vein, and extrahepatic extension are also noted.
The imaged liver is divided into four sectors and involvement of each sector with tumor is determined. Stage increases and prognosis decreases as the number of liver sectors radiologically involved with tumor increases from one to four.[2,3] Experienced radiologist review is important because it may be difficult to discriminate between real invasion beyond the anatomic border of a given sector and displacement of the anatomic border.[3,4] Revisions and radiologic examples of the PRETEXT staging system were published in 2007.
PRETEXT stage 1
- Tumor involves only one liver sector; three adjoining liver sectors are free of tumor.
PRETEXT stage 2
- Tumor involves one or two liver sectors; two adjoining liver sectors are free of tumor.
PRETEXT stage 3
- Tumor involves three liver sectors and one liver sector is free of tumor or tumor involves two liver sectors and two nonadjoining liver sectors are free of tumor.
PRETEXT stage 4
- Tumor involves all four liver sectors; there is no liver sector free of tumor.
Any stage may have involvement of:
- V—Vena cava or all three hepatic veins.
- P—Main portal or portal bifurcation vein.
- E—Extrahepatic contiguous.
- M—Distant metastatic.
Hepatoblastoma and hepatocellular carcinoma prognosis by PRETEXT stage
The PRETEXT staging system has a moderate degree of interobserver variability, and the preoperative PRETEXT stage agrees with postoperative pathologic findings only 51% of the time, with overstaging in 37% of patients and understaging in 12% of patients.
The 5-year overall survival (OS) in the first international study of hepatoblastoma, in which the study protocol called for treatment of children with preoperative doxorubicin and cisplatin chemotherapy and included children with metastasis, was as follows:
The second international study compared 3-year OS among hepatoblastoma patients by PRETEXT stage absent of extrahepatic disease. The 3-year OS was as follows:
- 100% for PRETEXT stage 1.
- 95% for PRETEXT stage 2.
- 84% for PRETEXT stage 3.
- 61% for PRETEXT stage 4.
The study also prospectively analyzed OS in patients by the presence of intraabdominal extrahepatic disease without distant metastasis (OS, 58%) and distant metastases (OS, 44%). Patients who underwent orthotopic liver transplant are included in all of the international study results. The COG is investigating prospective staging of hepatoblastoma patients using the PRETEXT system to determine the timing of surgery and the timing of early notification of liver transplant centers (COG-AHEP0731).
The 5-year OS for PRETEXT staged hepatocellular carcinoma was as follows:
- 44% for PRETEXT stage 1.
- 44% for PRETEXT stage 2.
- 22% for PRETEXT stage 3.
- 8% for PRETEXT stage 4.
Postsurgical Staging for Childhood Liver Cancer
A staging system based on operative findings and surgical resectability has been used in the United States to group children with liver cancer. This staging system is used to determine treatment.[11-13]
Hepatoblastoma prognosis by postsurgical stage
Stages I and II
In stage I hepatoblastoma, the tumor is completely resected.
In stage II hepatoblastoma, microscopic residual tumor remains after resection.
Approximately 20% to 30% of children with hepatoblastoma are stage I or II. Prognosis varies depending on the subtype of hepatoblastoma:
- Pure fetal histology (4% of hepatoblastomas) have a 3- to 5-year OS rate of 100% with minimal or no chemotherapy.[1,13,14]
- Non–pure 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.[1,6,8,13,15]
- If any small cell undifferentiated elements are present in stage I or II hepatoblastoma, the 3-year survival rate is 40% to 70%.[1,16]
In stage III hepatoblastoma, there are no distant metastases and one of the following is true:
- The tumor is either unresectable or the tumor is resected with gross residual tumor.
- There are positive lymph nodes.
Stage IV (distant metastases)
In stage IV hepatoblastoma, there is distant metastasis regardless of the extent of liver involvement.
Approximately 10% to 20% of children with hepatoblastoma are stage IV. The 3- to 5-year OS rate for children with stage IV hepatoblastoma vary widely based on published reports, from 20% to approximately 60%.[1,6-8,13,17]
Hepatocellular carcinoma prognosis by postsurgical stage of disease at diagnosis
Treatment Options Under Clinical Evaluation: COG Hepatoblastoma Risk Groups
The COG study COG-AHEP0731 (Combination Chemotherapy in Treating Children With Newly Diagnosed Hepatoblastoma) incorporates the following risk groups:
- Very low risk
- Stage I tumor with pure fetal histology and an alpha-fetoprotein (AFP) level greater than 100 ng/ml.
- Low risk
- Stage I and II tumors and no small cell undifferentiated elements and an AFP level greater than 100 ng/ml.
- Intermediate risk
- Gross residual disease or unresectable disease.
- Grossly resected disease with small cell undifferentiated elements.
- No metastases.
- AFP level must be greater than 100 ng/ml.
- High risk
- Any patient with metastases.
- Any patient with initial AFP level less than 100 ng/ml, regardless of stage.
- 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]
- 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]
- 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]
- Roebuck DJ, Olsen Ø, Pariente D: Radiological staging in children with hepatoblastoma. Pediatr Radiol 36 (3): 176-82, 2006. [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]
- 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]
- 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]
- 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]
- Perilongo G, Maibach R, Shafford E, et al.: Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma. N Engl J Med 361 (17): 1662-70, 2009. [PUBMED 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]
- 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]
- 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]