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An 18-month-old child presented with a large hepatic mass. There was no evidence of genetic or metabolic liver disease. A partial hepatectomy (12.0 x 11.0 x 6.0 cm) revealed an 8.0 cm well-circumscribed lobulated tumor. Small satellite nodules were identified in the adjacent hepatic parenchyma. There was no cirrhosis.
Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2006, Case 3 and is a Hepatoblastoma.
Criteria for Diagnosis and Comments:
The tumor cells exhibit two distinct morphologic patterns. Most sections show small to intermediate sized tumor cells arranged in cords, ribbons and tubules. The cells have round or oval nuclei and small amount of cytoplasm (embryonal pattern). In other areas, the tumor cells are arranged in trabeculae and have moderate amounts of eosinophilic cytoplasm. This appearance closely resembles the fetal liver (fetal pattern). Scattered foci of extramedullary hematopoiesis are present. Mitotic figures are rare in both components. Although not seen in this example, lipid and/or glycogen in the tumor cells can lead to a clear cell appearance in the fetal areas. Both eosinophilic and clear cytoplasmic features often occur in the same tumor and result in a distinctive alternating pink and white appearance at low magnification. This constellation of histological features with embryonal and fetal patterns is characteristic of the epithelial subtype of hepatoblastoma.
Hepatoblastoma (HB) is the most common malignant liver tumor in children and comprises approximately 1% of the pediatric malignant neoplasms. Nearly 90% of cases occur between 6 months and 5 years. It can occasionally arise in older children, and very rarely in adults. The lesion has a male preponderance (2:1), but the incidence is similar in older cases. Associations with other congenital conditions such as Beckwith-Wiedemann syndrome, cleft palate, diaphragmatic hernia, Down syndrome, familial polyposis coli, hemihypertrophy, renal malformations, and other chromosomal abnormalities are noted in one-third of cases. An asymptomatic abdominal mass is the most common presentation, but nausea, vomiting, abdominal pain and rarely jaundice may be present. Serum AFP is nearly always elevated, and is a useful marker for tumor recurrence or metastasis after therapy.
HB occurs in a noncirrhotic liver, typically as a large, single mass with the majority of tumors arising in the right lobe. Bilateral disease may be present in one-third of patients. Different areas in the tumor can show different histological components necessitating adequate sampling for accurate diagnosis. The two morphologic subtypes of HB are the epithelial (55%) and the mixed epithelial-mesenchymal (45%). The epithelial type may show an embryonal pattern, fetal pattern, or a mixture of the two. Less common epithelial subtypes of HB include the small cell undifferentiated type and macrotrabecular type which together account for around 5% of cases. The small cell type resembles other small blue cell tumors like neuroblastoma, Ewing sarcoma, lymphoma and embryonal rhabdomyosarcoma. The identification of other typical patterns of HB helps in establishing the diagnosis. The macrotrabecular type forms wide trabeculae greater than 10 cells thick and can histologically mimic hepatocellular carcinoma.
The mixed epithelial-mesenchymal subtype is composed of admixed epithelial and mesenchymal components. In 80% of mixed tumors, the mesenchymal component is represented by immature fibrous tissue, osteoid and/or cartilage. The remaining 20% are mixed HB with teratoid features and show additional tissue types such as intestinal-type glandular elements, squamous epithelium, mucinous epithelium, melanin pigment, skeletal muscle or neural tissue. After chemotherapy, the majority of the epithelial component may undergo necrosis and the mesenchymal components, especially osteoid, appear prominent.
The tumor cells in HB express AFP in the embryonal and fetal components. Hepatocytic markers including Hep Par 1 and polyclonal CEA will stain the epithelial component, especially the fetal subtype. Hepatocytic cytokeratins (8 and 18) and biliary cytokeratins (7 and 19) can be variably positive. Focal neuroendocrine staining with chromogranin A has been reported in the embryonal, fetal, and osteoid components.
Prognosis is related to tumor stage and in stage 1 cases to histology. In contrast to other subtypes, the pure, well-differentiated fetal histologic subtype has an excellent outcome if completely resected at presentation. The 5-year survival for all histologic subtypes and stages is around 65%. Chemotherapy is often used preoperatively to reduce tumor size. Factors associated with an adverse outcome are age at presentation under one year, large tumor size, involvement of vital structures and certain histologic subtypes like small cell and macrotrabecular. Liver transplantation is an option for multifocal, bilobar or recurrent HB without extrahepatic extension. HB cells are usually show limited cytogenetic alterations, the most frequent being trisomy of chromosomes 2 and 20. LOH of maternal 11p15 seen in one-third of HB is characteristic of patients with Beckwith-Wiedemann syndrome, who are at increased risk for developing HB. Activation of Wnt/ -catenin signaling pathway is frequent as evidenced by abnormal nuclear localization of -catenin in majority of HB.
Undifferentiated embryonal sarcoma is a rare tumor that typically occurs in children 6-10 years old. It is the most common malignant mesenchymal hepatic tumor in children. It has been variously called as malignant mesenchymoma, fibromyxosarcoma and rhabdomyosarcoma of the liver. An abdominal mass and pain are common presenting features. Grossly, these tumors are large with cystic and solid areas, white gelatinous cut surface and areas of necrosis and hemorrhage. The tumor comprises a mixture of spindle and stellate cells embedded in a myxoid stroma. The tumor cells are large and have pleomorphic hyperchromatic nuclei; multinucleated tumor cells and brisk mitoses are common. PAS-diastase positive globules of various sizes can be present in the cytoplasm and in the stroma. The stroma is usually myxoid but some dense collagen can be present. Hematopoiesis is often noted and entrapped hepatocytes and/or ductules can be present at the periphery. Vimentin and bcl-2 are the only immunohistochemical markers that are consistently expressed, but neither is specific. Focal positive results are obtained with keratin, desmin and alpha-1 antitrypsin. Hep Par 1, S-100, myogenin and CD34 are negative. The prognosis is poor with 20% long-term survival in large series. The marked nuclear pleomorphism and absence of typical hepatoblastoma morphology makes the distinction from hepatoblastoma quite straightforward on morphological grounds alone.
Hepatocellular carcinoma (HCC) accounts for less than 0.5% of all pediatric malignant tumors, but is the second most common malignant liver tumor after HB. It is more frequent in older children and adolescents and rare in children less than 3 years. HCC often develops in the setting of preexisting chronic liver disease like hepatitis B, biliary atresia and metabolic conditions like hereditary tyrosinemia and glycogen storage disease type 1A. However, nearly two-thirds of pediatric HCC in western countries arise de novo in the absence of cirrhosis. HB with fetal and macrotrabecular patterns can be mistaken for HCC. The presence of embryonal or other patterns in other areas of the HB usually facilitates the diagnosis. The presence of preexisting chronic liver disease, macrotrabecular pattern and cytologic atypia favor HCC. The macrotrabecular variant of HB differs from HCC as it has minimal nuclear atypia and low mitotic activity. Unlike HB, HCC has a poor prognosis with less than 30% 5-year survival in most studies.
Hepatic adenoma is rare in children and usually occurs in the setting of glycogen storage diseases (types I, III, IV) and androgen use (treatment of Fanconi anemia). Pure fetal HB can closely resemble hepatic adenoma. The tumor cells tend to be smaller in HB and the alternating pink and white cytoplasmic staining pattern of fetal HB is not present in adenoma. Serum AFP is not elevated in adenoma. The clinical setting plays an important role in establishing the diagnosis, as distinction on morphologic grounds can be difficult.
Small cell undifferentiated histology in HB can be mistaken for other small round cell tumors. The presence of more typical areas of embryonal and/or fetal patterns is helpful in establishing a correct diagnosis. The presence of bile and immunohistochemical expression of cytokeratin supports the diagnosis of HB. Mixed HB with teratoid features should be distinguished from teratomas. Primary hepatic teratomas are exceedingly rare and lack the fetal and embryonal epithelial components of HB. Benign tumors like mesenchymal hamartoma and infantile hemangioendothelioma enter into the clinical and radiological differential diagnosis as they occur at the same age as HB. However, these neoplasms have distinctive pathologic features and do not enter into the histological differential diagnosis of HB.