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Liver and intrahepatic bile ducts - tumor

Other malignancies

Hepatoblastoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 9 January 2013, last major update February 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
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● Malignant liver neoplasm almost exclusively in infants, composed exclusively of immature hepatocytic elements (WHO)
● Most common primary liver tumor in children (50% of liver malignancies in children)
● Existence in adults is controversial (J Hepatol 2012;56:1392)

General
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● Can be congenital; 90% occur by age of 5 years, 70% by age of 2 years; 2/3 male, prevalence of 1 per 120,000 (1 per million children under age 15 years)
● Associated with familial colonic polyposis (APC gene, 500x risk), glycogen storage disease, hemihypertrophy (Beckwith-Wiedemann syndrome), Li-Fraumeni syndrome, low birth weight infants, Simpson-Golabi-Behmel syndrome, trisomy 18, Wilm’s tumor; not associated with cirrhosis
● Also associated with adenomatoid transformation of Bowman’s capsular epithelium in kidney
● Metastases to adrenal glands, bone marrow, brain, lung, lymph nodes (regional)
● Variable virilization due to hCG production by multinucleated giant cells
● Laboratory: thrombocytosis (Arch Dis Child 1993;69:171), elevated serum AFP (75%)
● Note: diagnosis difficult on needle biopsy; must sample generously

Staging
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Based on Children’s Cancer Study Group:
Stage I: completely resected
Stage II: microscopic residual disease only
Stage III: gross residual disease or positive lymph nodes or spilled tumor
Stage IV: metastases

Note: can also stage using TNM

Prognostic factors
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● Stage, age and sex
● Favorable: presence of osteoid
● Unfavorable: small cell / undifferentiated (Pediatr Blood Cancer 2009;52:328) and macrotrabecular patterns, increased mitotic activity; also AFP level < 100, nuclear beta catenin staining, low p27 / kip1, high cyclin D1, 4q deletions

Treatment
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● Preoperative chemotherapy and surgery; resect lung metastases; liver transplant if unresectable
● Long term survival now 60-70% with most recurrences detected within 3 years

Gross description
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● Usually right lobe
● Usually solid, variegated, tan-green, solitary (70%), variable hemorrhage and cysts
● Mean 10 cm (range 3-20 cm), well-circumscribed; often partially encapsulated
● May be calcified or ossified in prominent mesenchymal component

Micro description
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● Epithelial and mesenchymal elements in varying proportions and at variable stages of differentiation
● Pseudocapsule, canaliculi with bile formation, cords 2-3 cells thick with alternating light and dark pattern due to glycogen and fat
● Cells smaller than normal hepatocytes
● Extramedullary hematopoiesis common in fetal and embryonal subtypes
● Usually no pleomorphism, no intranuclear inclusions, no hyaline globules, rare / no tumor giant cells, no mitotic figures and no associated cirrhosis
● Rare rhabdoid cells


Epithelial type (56%)

General
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Fetal pattern (31%):
● Tumor cells in trabeculae 2-3 cells thick (resembling fetal liver), separated by sinusoids lined by CD34+ endothelial cells
● Tumor cells are same size or smaller than in non-neoplastic liver
● Distinct cell membranes, uniform, polyhedral, slightly higher nuclear / cytoplasmic ratio, inconspicuous nucleoli and may contain bile
● Minimal pleomorphism, no / rare mitotic figures
● Have “dark” and “light” foci related to amount of glycogen and fat
● Extramedullary hematopoiesis common; no portal tracts, bile ducts or ductules at the periphery
● Reduced reticulin, rare mitosis
● Cholangoblastic if ductular differentiation (CK7/19 positive) prominent
● Crowded fetal type: crowded cells and 2+ mitotic figures/10 hpf

Embryonal pattern (19%):
● Sheets, ribbons, rosettes, papillary patterns or trabeculae of variable thickness with immature appearance, discohesive small cells with poorly defined cell borders, basophilic cytoplasm, high N/C ratio, prominent nucleoli, coarse chromatin and increased mitotic figures
● Extramedullary hematopoiesis, necrosis and vascular lakes are common; no fat, glycogen or bile

Macrotrabecular pattern (3%):
● Frequent trabeculae > 10 cells thick throughout the tumor, variable cytologic features

Small cell undifferentiated / anaplastic pattern (3%):
● Most primitive form
● Definition: 70%+ small cell areas; however, even small foci should be reported becaues associated with poor prognosis
● Discohesive sheets of small uniform keratin+ cells with minimal cytoplasm, indistinct cell borders, oval hyperchromatic nuclei, variable prominent nucleoli and increased mitotic figures (Mod Pathol 2003;16:930)
● Resembles small cell carcinoma at other sites
● May have mucoid stroma, hyalinized septae; bile
● Loss of INI1 associated with rhabdoid phenotype

Gross images
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Epithelial hepatoblastoma


Patient with trisomy 18

Micro images
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Cholangioblastic pattern


Fetal pattern


Fetal pattern in patient with trisomy 18


Macrotrabecular pattern


Mixed fetal and embryonal patterns


Small cell pattern


Mixed epithelial mesenchymal type (44%)

General
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● Mixture of fetal / epithelial and mesenchymal cell types
● Teratoid (34%) or not (10%)
● Mesenchymal component has spindle-oval cells with minimal cytoplasm, frequent osteoid, fibrous septa, myxoid zones, hemorrhage and necrosis
● Teratoid features are keratinized squamous epithelium, intestinal epithelial, skeletal muscle, mature bone and cartilage, melanin and neuroectodermal structures

Micro images
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Mixed pattern


Post-chemotherapy treatment effect

Positive stains
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● Alpha fetoprotein (negative in small cell type), chromogranin (fetal, epithelial subtypes, usually focal), CK8/18 (fetal, epithelial subtypes), CK19 (embryonal subtypes)
● Also EMA, HepPar1 (negative in small cell type), polyclonal CEA (canalicular pattern), vimentin
● Variable hCG, occasional HMB45 and melanin
● Beta catenin (nuclear) in small cell and embryonal types, Delta-like protein (DLK), glypican-3 (negative in small cell type), glutamine synthase

Negative stains
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● CD45 / LCA, desmin and neurofilament

Molecular description
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● Gain of Xq in 60%, gain of Xp in 43%, also trisomy 2q (2q+) and trisomy 20, 1p-, 2q-, 4q-, 4q+
● Fetal type usually diploid, embryonal often aneuploid (Hum Pathol 2003;34:864)
● Deletion or translocation of 22q in small cell type (Front Biosci (Elite Ed) 2012;4:1287); also FOXG1 overexpression (Hum Pathol 2007;38:400), Yin Yang 1 (YY1) protein (Virchows Arch 2011;458:453), SERPINB3 overexpression (Eur J Cancer 2012;48:1219)

Electron microscopy description
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● Immature hepatocytes

Differential diagnosis
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Hepatocellular carcinoma - resembles macrotrabecular variant of hepatoblastoma, uncommon in children, larger more pleomorphic tumor cells, no extramedullary hematopoiesis

Metastatic tumors: more common than hepatoblastoma, primary tumor cells should not resemble hepatocytes
Lymphoma
● Neuroblastoma
Rhabdomyosarcoma
Teratoma
Undifferentiated sarcoma
● Wilms’ tumor
Yolk sac tumor: rare yolk sac cells may be present in hepatoblastoma

End of Liver and intrahepatic bile ducts - tumor > Other malignancies > Hepatoblastoma


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