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This is the most common hepatocellular tumor of children. If untreated, these tumors are fatal within two years. These tumors may present with an enlarged abdomen with a firm enlarged liver in the right upper quadrant. Less frequent symptoms include weight loss, anorexia, nausea, jaundice, and vomiting.


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Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/Immunohistochemistry/Electron Microscopy  
Differential Diagnosis  
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0.2/100,000 children in United States below <14 years

1.5% of all childhood malignancies <5 years of age

AGE RANGE-MEDIAN 90% occur within first 5 years
68% occur in first 2 years
4% occur at birth
Male predominance of 1.5:1 to 2:1
No racial predominance


Absence of left adrenal gland  
Aicardi's syndrome  
Alcohol embryopathy  
Beckwith-Wiedemann syndrome  
Beckwith-Wiedemann syndrome with opsoclonus, myoclonus  
Bilateral talipes  
Budd-Chiari syndrome  
Cleft palate, macroglossia, dysplasia of ear lobes  
Down's syndrome, malrotation of colon, pectum excavatum, intrathoracic kidney, single coronary artery  
Duplicated ureters  
Fetal hydrops  
Familial polyposis coli  
Gardner's syndrome  
Goldenhar's syndrome (oculoauriculovertebral dysplasia, absence of portal vein)  
Heterotopic lung tissue  
Heterozygous alpha-1-antitrypsin deficiency  
HIV or HBV infection  
Horseshoe kidney  
Inguinal hernia  
Isosexual precocity  
Maternal use of clomiphene citrate and Pergonal  
Meckel's diverticulum  
Oral contraceptive, mother or patient  
Persistent ductus arteriosus  
Prader-Willi syndrome  
Renal dysplasia  
Right-sided diaphragmatic hernia  
Schnizel-Geidion syndrome  
Synchronous Wilm's tumor  
Trisomy 18  
Type 1a glycogen storage disease  
Umbilical hernia  
Very low birth weight  


Link to familial adenomatous polyposis

APC mutations in 8 patients with tumor arising in seven FAP kindreds
Genetic alterations detected in APC gene in 9/13 hepatoblastoma cases in nonfamilial adenomatous polyposis patients

75% of APC gene related tumors occur in males


Hypermethylation of the p16 Gene and Lack of p16 Expression in Hepatoblastoma.

Shim YH, Park HJ, Choi MS, Kim JS, Kim H, Kim JJ, Jang JJ, Yu E.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine (Y-HS, YMK, MSC, JSK, EY).


Mod Pathol 2003 May;16(5):430-6 Abstract quote

Hepatoblastoma is the most frequent pediatric liver tumor that develops mostly in young children. Abnormal regulation of cell cycle regulatory genes including p16 has been described, displaying no p16 mRNA and p16 protein in hepatoblastomas. The inactivation of p16, leading to the disruption of cell cycle control is involved in many types of human malignancies. However, the mechanism of the p16 inactivation in hepatoblastomas has not yet been elucidated.

In this present study, we examined the methylation status of the p16 gene promoter by using methylation-specific PCR in 24 cases of hepatoblastomas and in 20 cases of corresponding non-neoplastic liver tissue. Aberrant methylation of 5' CpG islands of p16 was present in 12 of 24 (50.0%) cases of hepatoblastoma.

Clinicopathologic parameters were not associated with the methylation status of p16. To correlate the methylation status of p16 with the expression of p16, immunohistochemical staining was done in tumors and non-neoplastic liver tissue. All non-neoplastic liver tissues displayed moderate, but heterogeneous immunoreactivity for p16. Eight of 12 (66.6%) methylation-positive hepatoblastomas showed a complete lack of immunoreactivity for p16. The other 4 methylation-positive hepatoblastomas had heterogeneous immunoreactivity. Nine of 12 (75.0%) unmethylated cases of hepatoblastoma displayed diffuse immunoreactivity, whereas 3 cases of unmethylated hepatoblastoma were not immunostained for p16.

Our data indicate that the hypermethylation of p16 is a major mechanism of the transcriptional repression of p16 in hepatoblastomas, and we suggest that the inactivation of p16, leading to the lack of p16, may play an important role in the tumorigenesis of hepatoblastomas.



CT scan and MRI CT shows calcifications in >50% of cases
Laboratory Markers  
70% of cases
Alpha-fetoprotein (AFP)
Elevated in up to 90%
Parallels the course of the disease and returns to normal following tumor resection
Re-elevates with tumor recurrence
Serum cholesterol
Elevated in 10/59 patients
Elevated in 20-25%
Alkaline phosphatase
60% mildly elevated



Single mass in 80% of cases
Right lobe in 57%
Left lobe in 15%
Both lobes in 27%

Diameter ranges from 5-22 cm
Weight from 150-1400 grams
Hemorrhage and necrosis common with mixed epithelial-mesenchymal tumors showing a more variegated appearance


General Broadly divided into epithelial and mixed epithelial and mesenchymal types  

Polygonal tumor cells with round to medium-sized nuclei and moderate eosinophilic cytoplasm

Low power light and dark pattern
Smaller than normal liver cells resembling fetal hepatocytes
Cords with glycogen or fat
Diminished reticulin network

Smaller, darker staining cells with scant basophilic cytoplasm
Acinar or tubular pattern
May have better prognosis if fetal pattern is>75% of tumor
Contain trabeculae more than 10 cells in thickness in a repetitive pattern within the tumor 3%
Small cell undifferentiated (anaplastic)
Uniform population of cells lacking evidence of stromal or epithelial differentiation. 3%
MIXED EPITHELIAL AND MESENCHYMAL TYPES Epithelial pattern with mixed mesenchymal elements including bone, cartilage, skeletal muscle, and fibrous tissue 44%
Mixed epithelial-mesenchymal without teratoid features
Immature mesenchymal tissue usually cellular spindle cells
Foci of osteoid and cartilaginous material
With teratoid features


Immunoperoxidase Positive for:
CK19 (small cell and embyronal areas)
CK18 (fetal)
Hep Par 1


TUMOR Patient Age Serum AFP Cell Size Reticulin Stain Light/Dark cells Nodularity
Hepatoblastoma, fetal type <2-3 yrs + < or normal Focally absent + +
Adenoma >10 yrs - normal or > Intact - +/-


Prognostic Factors

Key is determining resectability of tumor
Histologic subtype not as important but small cell type may have worse prognosis

Other poor prognostic factors include:
Multiple lobes
Embryonal histology
AFP levels <100 or >1,000,000 ng/ml
Multifocal dissemination


Distinct patterns of p27/KIP 1 gene expression in hepatoblastoma and prognostic implications with correlation before and after chemotherapy.

Brotto M, Finegold MJ.

Department of Pathology, Texas Children's Hospital, Houston, TX.

Hum Pathol 2002 Feb;33(2):198-205 Abstract quote

Over the past 3 years, numerous studies have examined the diagnostic and prognostic significance of p27/Kip1 expression in various tumors. Almost all studies report decreased p27 expression in more aggressive tumors. Information about morphologic changes due to chemotherapy in hepatoblastoma (Hbs) is limited, and so is information about distinct patterns of p27 gene expression.

Twenty-nine hepatoblastomas were evaluated for possible prognostic correlation between p27 expression in different histotypes of hepatoblastoma, changes during chemotherapy, and outcome. These observations should prompt prospective randomized studies designed to investigate the predictive role of p27 expression in different Hbs histotypes. Patients were treated according to the Children's Cancer Group and Pediatric Oncology Group protocols, which included initial surgery before chemotherapy wherever possible.

Follow-up ranged from 1 to 133 months. The results show that primary well-differentiated fetal tumors without mitotic activity are strongly p27 positive. The embryonal pattern displays a variable p27 protein expression pattern, with focal positivity between completely negative zones; p27 is positive where the mitotic activity is low or absent and negative where the mitogenic activity is high. The vast majority of small undifferentiated cell components are p27 negative. p27 protein expression is downregulated after chemotherapy in the remaining fetal well-differentiated component of Hbs.

Although this may imply selection of a more aggressive clone, all patients with this histology were cured in this series. Aggressiveness and ultimate prognosis for incompletely resected tumors after chemotherapy remain indeterminate.

SURVIVAL See staging below
RECURRENCE 10/33 patients of stage I disease with 6 having pulmonary involvementdr

Lungs most frequent, present in 10-20% of initial diagnosis
Bone, brain, eye, and ovaries
May extend into hepatic vessels and inferior vena cava

Multiple resections and chemotherapy/radiation therapy may be successful in treating pulmonary and brain metastases over a prolonged period


Surgical removal
If smaller tumor, a lobectomy may be performed
Larger tumors may require preoperative chemotherapy to facillitate resection

About 40-60% are considered surgically unresectable at inital discovery but preoperative chemotherapy can downsize these tumors to resectability in 85% of cases

Chemotherapy utilizes cisplatin and adriamycin by continuous IV infusion

Analysis of treatment outcome for children with recurrent or metastatic hepatoblastoma.

Matsunaga T, Sasaki F, Ohira M, Hashizume K, Hayashi A, Hayashi Y, Mugishima H, Ohnuma N.

Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Pediatr Surg Int 2003 May 24; Abstract quote

For better total survival rate of children with hepatoblastoma, the therapeutic strategy for recurrent or metastatic hepatoblastoma should be improved. From 1991 to 1999, 134 cases of hepatoblastoma were treated by surgery and combination chemotherapy of cisplatin (CDDP) and THP-Adriamycin (THP-ADR) based on the JPLT-1 protocol. In 114 non-metastatic cases, 90 primary liver tumors were resected completely by partial hepatectomy, but 12 recurrences were observed in the liver (4 cases) and the lungs (8 cases).

Distant metastases on the diagnosis were observed in 20 cases. The treatment outcome of these 12 recurrent and 20 metastatic tumors was analyzed. In four recurrent liver tumors, surgical resection was performed in all four cases, and all the patients were alive and well. In eight recurrent lung tumors, surgical resection was performed completely in six cases with unilateral lung disease, and five of the six patients were alive and well.

In stage IV tumors, the survival rate of the patients having primary tumors within two hepatic sections was significantly higher than that of the patients having primary tumors over three hepatic sections. Active surgical intervention to lung metastases and a more intensive chemotherapy to facilitate complete resection of primary hepatic tumor could improve survival rate of children with refractory hepatoblastoma.

Surgical resection and chemotherapy improve survival rate for patients with hepatoblastoma.

Carceller A, Blanchard H, Champagne J, St-Vil D, Bensoussan AL.

Division of Pediatrics, General Surgery, and Hemato-Oncology, Ste-Justine Hospital, Montreal, Quebec, Canada.

J Pediatr Surg 2001 May;36(5):755-9 Abstract quote

BACKGROUND: The authors reviewed retrospectively their experience in 30 children with hepatoblastoma (HB). Despite an increased trend in the incidence of HB during the last 2 decades, an encouraging cure rate has been achieved with complete resection of the tumor and chemotherapy before or after surgery with cisplatin plus doxorubicin (Adriamycin) or cisplatin plus vincristine plus 5-Fluorouracil.

RESULTS: There were 10 female and 20 male patients. For the period from 1963 to 1980 there were 8 patients, and for the period from 1981 to 1998 there were 22 patients. Their mean age at surgery was 16 months (range, 3.5 months to 5.5 years). Tumors were localized to the right lobe in 10 (42%), to the left lobe in 7 (29%), and in both lobes in 7 (29%) of the resected patients. Tumors were greater than 10 cm in size in 16 (67%) of these patients. Twenty-four patients (80%), underwent liver resection before or after chemotherapy. One patient (3%) with an unresectable tumor received chemotherapy and a liver transplant. In 5 patients (17%) the hepatic involvement was too extensive for resection. The types of resection performed were right lobectomy in 7, left lobectomy in 6, right trisegmentectomy in 8, left trisegmentectomy in 2, and middle hepatectomy in 1. The overall survival rate for 35 years of the study was 60% (18 of 30). With the association of surgery and chemotherapy (1981 through 1998) survival rate is 82% (14 of 17). Overall median follow-up in our study is 8 years (range, 2.5 to 24 years).

CONCLUSIONS: There has been a dramatic improvement in the results of treatment of hepatoblastoma. Formerly, only 25% to 30% of patients were cured, whereas today, with combination of chemotherapy and surgery, 75% to 80% may be cured.

Tumors of the Liver and Intrahepatic Bile Ducts. Atlas of Tumor Pathology Third Series Fascicle 31. AFIP 2001.

Commonly Used Terms

Liver cell adenoma

Staging (CCSG-Children's Cancer Study Group)

I 38% 100% Complete resection
II 9% 75-80% Microscopic residual
Negative nodal involvement
No spilled tumor
III 24% 65-68% Gross residual or
Nodal involvement or
Spilled tumor
IV 29% 0-27% Metastatic disease

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Last Updated 6/3/2003

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