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Background
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 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 birthMale predominance of 1.5:1 to 2:1 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 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 patients75% of APC gene related tumors occur in males
LABORATORY/RADIOLOGIC/
OTHER TESTSCHARACTERIZATION Radiographs CT scan and MRI CT shows calcifications in >50% of cases Laboratory Markers 70% of cases 50% Elevated in up to 90%
Parallels the course of the disease and returns to normal following tumor resection
Re-elevates with tumor recurrenceElevated in 10/59 patients Elevated in 20-25% 60% mildly elevated
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION General 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 appearanceVARIANTS
HISTOLOGICAL TYPES CHARACTERIZATION RELATIVE FREQUENCY General Broadly divided into epithelial and mixed epithelial and mesenchymal types EPITHELIAL 56% 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 network31% Smaller, darker staining cells with scant basophilic cytoplasm
Acinar or tubular pattern
May have better prognosis if fetal pattern is>75% of tumor19% Contain trabeculae more than 10 cells in thickness in a repetitive pattern within the tumor 3% 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% Immature mesenchymal tissue usually cellular spindle cells
Foci of osteoid and cartilaginous material34% 10% VARIANTS
SPECIAL STAINS/IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION Immunoperoxidase Positive for:
AFP
CK19 (small cell and embyronal areas)
CK18 (fetal)
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 prognosisOther poor prognostic factors include:
Multiple lobes
Embryonal histology
AFP levels <100 or >1,000,000 ng/ml
Multifocal disseminationp27/KIP1
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 cavaMultiple resections and chemotherapy/radiation therapy may be successful in treating pulmonary and brain metastases over a prolonged period
Treatment Surgical removal
If smaller tumor, a lobectomy may be performed
Larger tumors may require preoperative chemotherapy to facillitate resectionAbout 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
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.
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 tumorIII 24% 65-68% Gross residual or
Nodal involvement or
Spilled tumorIV 29% 0-27% Metastatic disease
Last Updated 4/25/2002
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