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.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/Immunohistochemistry/Electron Microscopy Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION INCIDENCE
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
SEX (M:F) Male predominance of 1.5:1 to 2:1 GEOGRAPHY No racial predominance
DISEASE ASSOCIATIONS CHARACTERIZATION 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 Cystothionuria 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) Hemihypertrophy Heterotopic lung tissue Heterozygous alpha-1-antitrypsin deficiency HIV or HBV infection Horseshoe kidney Hypoglycemia Inguinal hernia Isosexual precocity Maternal use of clomiphene citrate and Pergonal Meckel's diverticulum Oral contraceptive, mother or patient Osteoporosis 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
PATHOGENESIS CHARACTERIZATION APC GENE MUTATIONS 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.
CHARACTERIZATION Radiographs CT scan and MRI CT shows calcifications in >50% of cases Laboratory Markers Anemia 70% of cases Thrombocytosis 50% 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 Bilirubin 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
HISTOLOGICAL TYPES CHARACTERIZATION RELATIVE FREQUENCY General Broadly divided into epithelial and mixed epithelial and mesenchymal types EPITHELIAL 56% Epithelial-Fetal
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
31% Fetal-Embryonal Smaller, darker staining cells with scant basophilic cytoplasm
Acinar or tubular pattern
May have better prognosis if fetal pattern is>75% of tumor
19% Macrotrabecular 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
34% With teratoid features 10% VARIANTS
CHARACTERIZATION Immunoperoxidase Positive for:
CK19 (small cell and embyronal areas)
Hep Par 1
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
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 - +/-
PROGNOSIS AND TREATMENT CHARACTERIZATION 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:
AFP levels <100 or >1,000,000 ng/ml
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 METASTASIS
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
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.
Liver cell adenoma
Staging (CCSG-Children's Cancer Study Group)
STAGE RELATIVE FREQUENCY % OVERALL SURVIVAL CHARACTERIZATION 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
IV 29% 0-27% Metastatic disease
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Last Updated 6/3/2003
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