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2010—March Case of the Month

Posted March 2, 2010

CLINICAL SUMMARY: LIVER  

CAP Foundation March 2010 Online Case of the Month

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After reading the summary, try answering the three related multiple-choice questions below.

A previously healthy, 14-year-old boy presented with a one-year history of intermittent fever and the recent onset of severe right-sided abdominal pain. A CT scan revealed a 15.0 cm liver mass. Serum alpha-fetoprotein was markedly elevated. Subsequent neoadjuvant chemotherapy was followed by hemihepatectomy, which revealed a well circumscribed, 15.0 x 14.0 x 9.0 cm mass with tan-brown cut surface and several foci of hemorrhage.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2007, Case 4 and is a hepatoblastoma.

Criteria for Diagnosis and Comments: Histologically, the tumor is relatively monomorphic and composed of thin trabeculae of small cuboidal cells that resemble developing fetal liver. Hemorrhage and necrosis is focally present, but most of the tumor is histologically viable. Mitotic figures are rare, and most cells have moderate amounts of eosinophilic cytoplasm. Scattered foci of extramedullary hematopoiesis are present. This histologic pattern is characteristic of the pure fetal epithelial subtype of hepatoblastoma, which accounts for about one third of cases.

Hepatoblastoma comprises approximately 1% of pediatric malignancies, but it is the most common malignant liver tumor in children. Nearly two-thirds of cases occur in the first two years of life and 90% by five years of age. It is very rare in older children and adults. An abdominal mass is the most common presentation. Other clinical symptoms include nausea, vomiting, abdominal pain, and rarely jaundice. Serum alpha-fetoprotein is typically elevated, which provides a useful marker for clinical follow-up. Approximately one-third of cases show other congenital conditions, including cleft palate, Down syndrome, Beckwith-Wiedemann syndrome, diaphragmatic hernia, familial adenomatous polyposis coli, and various other chromosomal anomalies. Prognosis is mostly related to tumor histology, stage and surgical resectability. The 5-year survival for all histologic subtypes and stages is around 65%. The pure, well-differentiated fetal histologic subtype has an excellent outcome if completely resected at presentation. Neoadjuvant chemotherapy may be utilized to reduce tumor size prior to surgery. Age at presentation under one year, large tumor size, involvement of vital structures and small cell or macrotrabecular histologic subtypes are associated with adverse outcome. Liver transplantation remains an option for multifocal, bilobar or recurrent hepatoblastoma without extrahepatic extension.

Hepatoblastoma occurs as a large, single mass in a noncirrhotic liver. Different areas in the tumor can show different histological components, and the morphologic variants of hepatoblastoma include the epithelial and the mixed epithelial-mesenchymal subtypes. The former may show an embryonal pattern, fetal pattern, or a mixture of the two. Less common are the small cell undifferentiated and macrotrabecular types, in which the identification of other typical patterns of hepatoblastoma helps in establishing the diagnosis. The macrotrabecular type can mimic hepatocellular carcinoma histologically. The mixed epithelial-mesenchymal subtype is composed of admixed epithelial and mesenchymal components, including immature fibrous tissue, osteoid or cartilage. Mixed hepatoblastomas can also show teratoid features and show 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 appear prominent. The embryonal and fetal components in hepatoblastoma express alpha-fetoprotein. Hepatocytic markers such as HepPar-1, polyclonal CEA, hepatocytic cytokeratins 8 and 18, and biliary cytokeratins 7 and 19 will stain the epithelial component. Focal neuroendocrine staining has been reported.

Cytogenetic alterations are limited, the most frequent being trisomy 2 and 20. The characteristic feature of patients with Beckwith-Wiedemann syndrome (loss of heterozygosity of maternal 11p15) is seen in one-third of hepatoblastoma. Activation of Wnt/ß-catenin signaling pathway is frequent, and an association with familial adenomatous polyposis has been described.

Hepatic adenoma is rare in children and usually occurs in the setting of glycogen storage diseases or androgen use. Pure fetal hepatoblastoma can closely resemble hepatic adenoma, and distinction on morphologic grounds can be difficult. The tumor cells of hepatoblastoma tend to be smaller than native liver hepatocytes and adenoma cells may be larger than native liver hepatocytes. The alternating eosinophilic and clear cytoplasmic staining pattern of fetal hepatoblastoma is not present in adenoma. Most importantly, serum alpha-fetoprotein is not elevated in adenoma.

Hepatocellular carcinoma accounts for less than 0.5% of all pediatric malignant tumors, but is the second most common malignant liver tumor after hepatoblastoma. It is more frequent in older children and adolescents. Unlike hepatocellular carcinoma in adults, nearly two-thirds of pediatric hepatocellular carcinoma in western countries arise in the absence of cirrhosis. Hepatoblastoma with fetal and macrotrabecular patterns can be mistaken for hepatocellular carcinoma, but the presence of embryonal or other patterns in hepatoblastoma usually facilitates the diagnosis. The macrotrabecular variant of hepatoblastoma differs from hepatocellular carcinoma as it has minimal nuclear atypia and low mitotic activity.

Undifferentiated embryonal sarcoma of the liver 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. The stroma is usually myxoid but some dense collagen can be present. Vimentin and bcl-2 are the only immunohistochemical markers that are consistently expressed in undifferentiated embryonal sarcoma, but are non-specific. Marked nuclear pleomorphism and absence of typical hepatoblastoma components help to make the distinction from hepatoblastoma.

Small cell undifferentiated histology in hepatoblastoma can be mistaken for other small round cell tumors. The presence of typical histologic hepatoblastoma patterns and immunohistochemical expression of cytokeratin is helpful in establishing the diagnosis of small cell undifferentiated hepatoblastoma. Mixed hepatoblastoma with teratoid features should be distinguished from teratomas. Primary hepatic teratomas are exceedingly rare and lack the fetal and embryonal epithelial components of hepatoblastoma. Mesenchymal hamartoma enters into the clinical and radiological differential diagnosis as it occurs in the same age group as hepatoblastoma. However, mesenchymal hamartoma is a benign mass composed of mesenchyme, bile ducts, hepatocyte cords, and variably sized cysts. Hepatocytes are considered a “passive” component of mesenchymal hamartoma, in contrast to the proliferative neoplastic hepatocytes in hepatoblastoma.

Supplementary Questions For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
Which of the entities is the most common pediatric liver tumor? A.  Hepatic adenoma
B.  Hepatoblastoma
C.  Hepatocellular carcinoma
D.  Mesenchymal hamartoma of the liver
E.  Undifferentiated embryonal sarcoma of the liver
In which of the entities is serum alpha-fetoprotein elevated essentially in all cases? A.  Hepatic adenoma
B.  Hepatoblastoma
C.  Hepatocellular carcinoma
D.  Mesenchymal hamartoma of the liver
E.  Undifferentiated embryonal sarcoma of the liver
Which of the above entities may have histologic features that overlap with small round cell tumors of childhood? A.  Hepatic adenoma
B.  Hepatoblastoma
C.  Hepatocellular carcinoma
D.  Mesenchymal hamartoma of the liver
E.  Undifferentiated embryonal sarcoma of the liver

References

  1. Anthony P. Tumours and tumour-like lesions of the liver and biliary tract. In: MacSween R, Anthony P, Scheuer P, Burt AD, eds. et al. Pathology of the Liver, 4th edition. Edinburgh, NY: Churchill Livingstone; 2002:741-743.
  2. Emre S, McKenna GJ. Liver tumors in children. Pediatr Transplant. 2004;8(6):632-638.
  3. Schnater JM, Kohler SE, Lamers WH, et al. Where do we stand with hepatoblastoma&363; Cancer. 2003;98(4):668-678.
  4. Stocker J. Hepatoblastoma. Semin Diagn Pathol. 1994;11(2):136-143.
  5. Buendia MA. Genetic alterations in hepatoblastoma and hepatocellular carcinoma: common and distinctive aspects. Med Pediatr Oncol. 2002;39(5):530-535.
  6. Stocker JT, Husain AN, Dehner LP, Chandra RS. In: Stocker JT, Dehner LP, eds. Pediatric Pathology. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:756-881.
  7. Stocker JT and Schmidt D. Hepatoblastoma. In: Hamilton SR, Aaltonen LA, eds. World Health Organization Classification of Tumours. Pathology and genetics: Tumours of the digestive system. 1st edition. Lyon, France: IARC Press; 2000:184-189.

Author:
2007
Hagen Blaszyk, MD
Surgical Pathology Committee
University of Vermont College of Medicine
Burlington, VT