Pediatric Hepatoblastoma Workup

Updated: Sep 15, 2017
  • Author: Jennifer Reikes Willert, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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Workup

Laboratory Studies

Diagnostic evaluation of a child in whom a liver tumor is suggested should include the following:

  • CBC count with differential should be obtained.

    • Normochromic normocytic anemia is often present.

    • Thrombocytosis may be present. In a study by Ortega et al, 60% of patients had platelet counts greater than 500 X 109/L, and 12% had platelet counts greater than 1000 X 109/L. [20]

  • Liver enzyme levels are moderately elevated in 15-30% of patients.

  • α -fetoprotein (AFP) is a major serum protein synthesized by fetal liver cells, yolk sacs, and the GI tract. AFP is found in high concentrations in fetal serum and in children with hepatoblastoma, hepatocellular carcinoma, germ cell tumors, or teratocarcinoma. The tumor's ability to synthesize AFP reflects its fetal origin. Embryonal tumors produce less AFP than fetal tumors.

    • Levels of AFP in hepatoblastoma are often as high as 100,000-300,000 mcg/mL. Ortega et al found AFP levels elevated for age in 97% of patients. [20]

    • The half-life of AFP is 4-9 days, and levels usually fall to within reference range within 4-6 weeks following resection.

    • Other causes of elevated AFP levels include viral hepatitis, cirrhosis, inflammatory bowel disease, and yolk sac tumors.

    • Although elevated AFP levels are not specific for hepatoblastoma, they provide an excellent marker for response to therapy, disease progression, and detection of recurrent disease.

    • Rarely, a hepatoblastoma can recur as a non–AFP-secreting tumor with metastases, even if the initial tumor was AFP secreting.

    • Interpretation of AFP levels can be difficult because hepatoblastoma tends to occur within the first 2 years of life. Reference range AFP levels are comparatively high at birth and even higher in premature infants, which can complicate interpretation of this value. By age 1 year, adult levels of 3-15 mcg/mL have been reached.

    • Data from the German Cooperative Pediatric Liver Tumor Study showed that both very low (< 100 ng/L) and very high (>1,000,000 ng/L) AFP levels are associated with poorer prognosis than intermediate AFP levels. [27]

    • Laboratory-specific and age-specific AFP values should be used.

    • Baseline testing of glomerular filtration rate (GFR) or creatinine clearance should be performed before cisplatin administration; follow-up studies are needed periodically to assess nephrotoxicity.

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Imaging Studies

See the list below:

  • Abdominal radiography

    • Plain abdominal films reveal a right upper quadrant abdominal mass.

    • Calcification is seen in approximately 6% of hepatic masses and 12% of hemangiomas.

  • Ultrasonography

    • Abdominal ultrasonography allows assessment of tumor size and anatomy, which helps in surgical planning.

    • The mass usually appears hyperechoic on abdominal ultrasound images, which is particularly useful in determining vascular involvement (vessels have lower attenuation than surrounding parenchyma).

    • Baseline echocardiography is needed before anthracycline (doxorubicin) administration; follow-up studies are needed to assess cardiotoxicity.

  • CT scanning

    • CT scanning of the abdomen using contrast reveals patchy enhancement.

    • CT scanning reveals involvement of nearby structures. Regional lymph nodes are almost never involved.

    • CT scanning of the chest is warranted to assess for pulmonary metastases.

  • MRI: This is believed to be superior to CT scanning but does not necessarily add to the anatomic detail seen on CT scans.

  • Radionuclide bone scanning: This is recommended to evaluate for bone metastases when a patient is symptomatic.

  • Positron emission tomography (PET) scanning: Studies support a potential role for PET scanning at diagnosis and for follow-up evaluation in hepatoblastoma. [28]

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Other Tests

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  • A baseline audiology evaluation is needed before cisplatin or carboplatin administration; follow-up studies are needed to assess ototoxicity.

  • A baseline cardiology evaluation is needed for any child receiving anthracycline; the child should be monitored every 1-2 years thereafter.

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Procedures

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  • Pathologic diagnosis: Before commencing therapy, surgical diagnosis must be made. Surgical resection is the usual manner in which material for pathologic assessment is obtained. Open biopsy is performed when complete surgical resection is not possible. Needle biopsy is not recommended because these lesions usually are highly vascular.

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Histologic Findings

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  • Standardizing criteria for histologic classification of hepatoblastoma has been suggested because of the significant variation in the current medical literature. Particular attention to the subtypes of this tumor and direct correlation with clinical outcomes is increasingly being incorporated into all major protocols internationally. [29]

  • Six histologic variants of hepatoblastoma have been described, as follows:

    • Epithelial type

      • Fetal pattern (fetal components are shown in the image below)

        Fetal components of hepatoblastoma. Hematoxylin an Fetal components of hepatoblastoma. Hematoxylin and eosin stain. Image courtesy of Denise Malicki, MD.
      • Embryonal and fetal pattern (as is shown in the image below)

        Embryonal hepatoblastoma. Hematoxylin and eosin st Embryonal hepatoblastoma. Hematoxylin and eosin stain. Image courtesy of Denise Malicki, MD.
      • Macrotrabecular pattern

      • Small cell undifferentiated pattern

    • Mixed epithelial and mesenchymal type

      • With teratoid features

      • Without teratoid features

  • Pure epithelial tumors account for approximately 56% of cases; they contain varying amounts of fetal cells, embryonal cells, or both. Within this group, purely fetal tumors account for 31% of hepatoblastomas; embryonal tumors account for 19% of hepatoblastomas; and macrotrabecular tumors and small cell undifferentiated types each account for 3% of hepatoblastomas. The remaining 44% of hepatoblastomas are mixed tumors containing primitive mesenchymal tissue and specialized derived components, such as myofibroblastic, chondroid, and osteoid tissues in addition to epithelial elements. Mixed tumors may express teratoid features. Teratoid hepatoblastomas are admixed with various heterologous structures of epithelial or mesenchymal origin.

  • Fetal cells are smaller than normal hepatocytes and have low nuclear-to-cytoplasmic (N/C) ratios and infrequent mitoses; cells form slender cords. Embryonal cells have a higher N/C ratio and more mitoses; they resemble early ducts of embryonal liver. Extramedullary hematopoiesis can be associated with mixed tumors. In tumors that have been completely resected, pure fetal histologic (PFH) results (with a 92% rate of disease-free survival) are associated with better prognosis than other histologic types, which have an overall disease-free survival rate of 57%. The absence of mitoses is a good prognostic sign. In advanced disease in which tumors cannot be completely resected, PFH results do not predict a better outcome.

  • Special stains, molecular studies, and evaluation of the Wnt, notch and hedgehog (Hh) pathways can also be helpful in differentiating subtypes of hepatoblastoma.

  • INI1 testing helps differentiate hepatoblastoma from a more aggressive variant that mimics rhabdoid tumor.

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Staging

Staging of hepatoblastoma is based on degree of surgical resection, histologic evaluation, and presence of metastatic disease. The system cited here is based on the work of von Schweinitz et al. [30]

  • Stage I

    • The tumor is completely resectable via wedge resection or lobectomy.

    • The tumor has PFH results.

    • The AFP level is within reference range within 4 weeks of surgery.

  • Stage IIA

    • The tumor is completely resectable.

    • The tumor has histologic results other than PFH (UH).

  • Stage IIB

    • The tumor is completely resectable.

    • AFP findings are negative at time of diagnosis (ie, no marker to follow).

  • Stage IIC

    • The tumor is completely resected or rendered completely resectable by initial radiotherapy or chemotherapy or microscopic residual disease is present.

    • The AFP level is elevated 4 weeks after resection.

  • Stage III (any of the following)

    • The tumor is initially unresectable but is confined to one lobe of liver.

    • Gross residual disease is present after surgery.

    • Tumor ruptures or spills preoperatively or intraoperatively.

    • Regional lymph nodes are involved.

  • Stage IV: Distant bone or lung metastasis is present.

European groups have also developed a staging system through SIOPEL-1; the system uses the predictive value of pretreatment extent of disease (PRETEXT) in order to stage patients and determine which therapy is most appropriate. [21] Using this system, physicians are able to refer higher risk patients for evaluation by liver transplant teams earlier with improved outcomes. These groups also advocate for chemotherapy treatment of lung metastases followed by surgical resection, with attempts for negative surgical margins providing optimal outcomes.

Which staging regimen is preferred among the Children’s Cancer Group (CCG) staging, Pediatric Oncology Group (POG) staging, and the European group staging is still actively discussed. However, for comparability reasons, following one staging regimen has been suggested, and international collaboration with consistency is ideal for this rare tumor.

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