OVERVIEW: What every practitioner needs to know Are you sure your patient has a liver neoplasm? What are the typical findings for this disease?

Liver tumors represent approximately 1% of all childhood cancers resulting in 100-150 new cases diagnosed in the United States in children each year.

Hepatoblastoma is the most common malignant tumor of the liver, typically occurs in the first few years of life, and accounts for two thirds of all liver cancer in children. Hepatocellular carcinoma is the second most common tumor and typically occurs in the second decade of life. Surgical resection is typically required as part of curative therapy for primary liver neoplasms. A variety of benign tumors also can occur with clinical suspicion based on the age at presentation, history, and characterisitic radiographic findings.

Liver tumors, whether benign or malignant, do not have a pathognomonic presentation. The key to diagnosis is the age of the patient, the radiographic appearance, and the level of the tumor marker alpha fetoprotein.

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The most common presentation is an asymptomatic mass. Patients may also present with abdominal pain, nausea, vomiting, weight loss, and/or fever.

Underlying liver dysfunction and associated jaundice or ascites are extremely rare as primary presenting features and are usually present only when hepatocellular carcinoma develops in a patient with a history of underlying liver disease.

Metastatic disease from other pediatric malignancies is more common than primary liver cancers and should always be considered.

Benign hemangiomas may present with Kassabach-Merritt syndrome, i.e., hemangiomas associated with varying degrees of consumptive coagulpathy and cardiac dysfunction.

What other disease/condition shares some of these symptoms?

Primary liver tumors are relatively rare, with metastatic lesions from other malignancies occurring more commonly; such malignancies must therefore be considered in the differential diagnosis.

The vast majority of liver tumors do not have clinical evidence of liver dysfunction and there is not a pathognomonic presentation.

What caused this disease to develop at this time?

The cause of most liver tumors is unknown. Hepatoblastoma can develop in patients with a history of premature birth, hemihypertrophy, Beckwith-Wiedemann syndrome, familial polyposis (mutations on chromsome 5q), or precocious puberty.

Hepatocellular carcinoma should be considered in patients with cirrhosis, galactosemia, tyrosinemia, glycogen storage disease or alpha-1 antitrypsin deficiency. Hepatitis B and hepatitis C are the most common etiologic agents worldwide in endemic areas but are observed much less often in the United States.

Hepatoblastoma has been observed with increased incidence in children with fetal alcohol syndrome, as well as with maternal use of birth control pills, a history of parental smoking, amd parental job exposure to certain metals, petroleum porducts, pigments, and paints.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Serum alpha fetoprotein (AFP) is the most helpful laboratory test in the work-up of pediatric liver tumors. Elevation of the AFB level is usually indicative of a malignancy and is usually seen in the majority of hepatoblastomas and about half of hepatocellular carcinomas.

A low AFB concentration can be seen in very small primary hepatoblastomas with low tumor burden. In contrast, a low AFB concentration may also be indicative of hepatoblastoma of small cell undifferentiated histologic type, which is associated with a poor outcome.

Normal AFP levels can be seen in any type of hepatocelluar carcinoma but are always observed in the fibrolamellar variant. Vitamin B12 binding protein levels can be elevated in fibrolamellar hepatocellular carcinoma.

A normal AFB level should cause one to consider other malignant histologic types such as rhabdoid tumor and undifferentiated sarcoma.

The rate of decline of the AFB level has been shown to correlate with disease outcome. Routine determination of AFB levels after the completion of therapy is helpful in surveillance of disease recurrence and can limit the need for radiographic studies after therapy for patients with increasing AFB levels.

Thrombocytosis and anemia can be observed but are nonspecific findings.

Would imaging studies be helpful? If so, which ones?

Abdominal ultrasonography is typically the first test performed to confirm the presence of a mass.

Computed tomography (CT) and magnetic resonance imaging are both very helpful. CT may be more common merely because it is used most often to evaluate the lungs, which are the most common site of disease metastases.

Angiography may be helpful in guiding surgical approaches.

The role of positron emission tomography is not yet established.

Benign tumors such as hemangioma and focal nodular hyperplasia have fairly typical radiographic appearances.

Confirming the diagnosis

Biopsy to establish a histopathologic diagnosis is required in any patient with a suspected malignancy because pathologic variants are associated with distinct outcomes and are used to guide risk-based therapy. Benign tumors with characteristic findings of radiologic studies may be followed closely and without biopsy in some cases.

If you are able to confirm that the patient has this disease, what treatment should be initiated?

The foundation for curative therapy in any pediatric malignancy is surgical resection of the primary tumor. In patients who undergo resection, there is no clear survival advantage to patients who have their tumors removed at diagnosis compared with those who undergo a delayed resection. However, patients who are not able to have a primary resection at diagnosis typically receive a longer chemotherapy course than do patients who can undergo a first-line resection. Therefore, primary surgical resection is associated with less acute and long-term toxicity.

In essence, then, the tumor should be removed as soon as it can be done safely. Maximal tumor is typically observed within the first 3 to 4 cycles of chemotherapy, and so additional cycles are not expected to increase the potential for resection.

Any patient with hepatoblastoma or hepatocellular carcinoma who is unable to have the tumor resected at diagnosis should have a consultation with a liver transplant surgeon as soon as possible to proceed to potential transplantation in as expeditious manner as possible without the need for extra toxic cycles of chemotherapy while undergoing a delayed liver transplant evaluation.

Cisplatin and doxorubin are the two most active agents against hepatoblastoma, but their cumulative use is limited by the potential for hearing loss and cardiac toxicity, respectively.

Radiation therapy does not have an established role in the primary treatment of hepatoblastoma or hepatocellular carcinoma but is sometimes used in palliative situations.

The past 2 decades have failed to identify any new agents with efficacy against hepatoblastoma, although current studies are being evaluated. Chemotherapy has been used in the treatment of hepatocellular carcinoma but with very modest results which almost never render an initially resectable tumor operable. There is no clearly established regimen for rhabdoid tumors of the liver. Undifferentiated sarcomas are typically treated as other sarcomas with chemotherapy and radiation.

What are the adverse effects associated with each treatment option?

Cisplatin is can be associated with significant nausea and vomiting, renal toxicity and electrolyte wasting, and hearing loss. Doxorubicin may cause myelosuppression, mucositis, and cumulative dose-dependent cardiotoxicity.

What are the possible outcomes of liver neoplasms?

Hepatoblastoma that can be resected is typically very curable. Certain biologic and pathologic features may either positively or adversely affect prognosis.

What is the evidence?

Tomlinson, GE, Finegold, MJ, Pizzo, PA, Poplack, DG. “Tumors of the liver”. 2002. pp. 847-64.

Weinberg, A, Finegold, M. “Primary hepatic tumors of childhood”. Hum Pathol. vol. 14. 1983. pp. 512-37.

Ongoing controversies regarding etiology, diagnosis, treatment

Some controversy exists among the international community on the optimal chemotherapy drugs to be used as well as the timing of surgery. The Children’s Oncology Group has favored first-line resection when possible, which results in lower cumulative dosing of chemotherapy. Conversely, European approaches have advocated for chemotherapy followed by resection to decrease surgical morbidity. Most importantly, recent efforts are actively under way to develop a unified international consensus for the treatment and management of pediatric liver tumors.