AUTHOR INFORMATION

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Authored by Stuart S Winter, MD, Associate Professor, Department of Pediatrics, University of New Mexico Health Sciences Center

Stuart S Winter, MD, is a member of the following medical societies: American Association for Cancer Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, New Mexico Pediatric Society, Pediatric Oncology Group, and Society for Pediatric Research

Edited by Stephan A Grupp, MD, PhD, Director, Stem Cell Biology Program, Children's Hospital of Philadelphia; Assistant Professor, Department of Pediatrics, Division of Oncology, University of Pennsylvania; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland, CA; Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada; and Maureen Strafford, MD, Arnold P Gold Foundation Associate Professor, Departments of Anesthesiology and Pediatrics, Tufts University and Tufts-New England Medical Center

Author's Email:	Stuart S Winter, MD
Editor's Email:	Stephan A Grupp, MD, PhD

eMedicine Journal, April 13 2006, VOLUME 7, Number 4

INTRODUCTION

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Background: Hepatocellular carcinoma (HCC) is an aggressive hepatic neoplasm that most commonly affects adults. Nevertheless, children who are affected with biliary atresia, infantile cholestasis, glycogen storage diseases, and a wide array of cirrhotic diseases of the liver are predisposed to developing HCC. Most children have abdominal findings localized to the liver.

The 2 pathological subtypes are classic HCC and fibrolamellar carcinoma. Although surgical resection remains the mainstay of curative therapy, adjunctive chemotherapeutic and radiotherapeutic strategies are also helpful. The presenting signs and symptoms, epidemiology, biology, and current therapeutic strategies for HCC follow.

Pathophysiology: The pathophysiology of HCC is not understood clearly, but underlying liver dysfunction, especially cirrhosis, is a predisposing condition. Karyotypic abnormalities are not common. In adults, infectious or alcoholic cirrhosis and chronic hemochromatosis are highly associated with HCC. Although children and adolescents are unlikely to have chronic liver disease, congenital liver disorders increase the chance of developing HCC. These findings are suggestive of a multihit model of malignant transformation in hepatic tissue.

Frequency:

• In the US: Primary liver tumors are uncommon in children and adolescents, accounting for approximately 0.5-2% of all neoplasms in these age groups. Annual incidence in children is approximately 0.5 cases per million. Because of the low incidence of this tumor type in children, performing a meaningful study of the many epidemiological factors beyond those listed below is difficult

• Internationally: The international incidence is highly associated with endemic hepatitis B exposure. In China, aflatoxin exposure has been associated with the development of HCC in the fifth, sixth, and seventh decades of life.

Mortality/Morbidity: Morbidity and mortality directly correlate with surgical resectability of the primary tumor. Although chemotherapy and radiation control may improve in the clinical course, in selected patients, the overriding objective of these modalities is to render the tumor completely resectable. (See Surgical Care for details.)

Race: In older adults, race may play a role in the development of HCC, but it is difficult to exclude environmental factors from these determinations. Because the condition is so rare in adolescents and children (0.5 cases/million), ethnic data are not readily available for these age groups. Most studies of HCC have involved patients of Asian descent.

Sex: Because most congenital forms of liver dysfunction (eg, urea cycle defects, storage diseases, hereditary hemochromatosis) are inherited in an autosomal recessive manner, the female-to-male occurrence ratio in children and adolescents is equal.

Age: The patient is usually an older school-aged child or adolescent, often with no preexisting diagnosis of cirrhotic liver disease. In patients with underlying liver dysfunction, the likelihood of developing the condition increases with age.

CLINICAL

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History: Elements to ascertain include a prior history of hepatitis B or C, chronic cirrhosis, or other diseases that tend to induce liver dysfunction. Co-infection with HIV may further enhance a patient's risk for developing hepatocellular carcinoma (HCC). Most patients complain of abdominal pain, weight loss, and diminished appetite. In patients with a history of chronic liver disease, a change in routine symptoms may indicate the presence of a liver tumor.

• HCC usually presents as a slowly enlarging, right, upper-quadrant mass that may be found during a routine physical examination, brought to medical attention by the patient, or discovered by the patient’s parents.



• Many children also experience localized pain, nausea, vomiting, and weight loss. Nearly 25% of patients present with jaundice.



• In adults, chronic hepatitis secondary to alcohol exposure, infection with hepatitis, and hereditary hemochromatosis are predisposing factors. Aflatoxins and other environmental factors also are likely to play a role in the pathogenesis in adults. In comparison, children are far more likely to have inherited errors of metabolism, such as tyrosinemia or urea cycle enzymopathies. Liver diseases that cause cirrhosis increase risk for developing HCC.



• Children with biliary atresia, chronic cholestasis, or glycogen storage diseases are at increased risk.



• Symptoms can be masked in children with preexisting hepatic diseases, and, accordingly, a change in a chronic disease pattern merits careful consideration for the possibility of a new malignancy.

Physical: The physical examination often reveals abnormalities attributable to a hepatic tumor. In advanced cases, or when the primary tumor is large, the liver may be palpable below the right costal margin. In addition, deep palpation often reveals pain, especially over the location of the liver. Scleral icterus and other signs of jaundice are frequent. The patient's history also may indicate weight loss, the extent of which may be observed during the examination. In patients in whom metastatic disease to the lungs is in question, percussion of the lungs may reveal a difference in density, suggesting a pleural effusion. Other painful sites discovered on the examination should lead to radiographic imaging to determine the extent of malignant spread.

Causes: Although no cause has been elucidated clearly, the risk factors for children and adolescents include a history of hepatitis B or C, Gaucher disease, congenital biliary atresia, urea cycle defects, severe hemachromatosis (as occurs with thalassemia or sickle cell disease requiring chronic blood transfusion), or other forms of chronic cirrhosis or liver dysfunction. Acquired hepatitis C from blood product transfusions is an important risk factor, since the risk of HCC in patients with chronic hepatitis C and cirrhosis is highest (2-8% per year).

In areas of the world where hepatitis B or C are endemic, the incidence is likely to be proportionally increased in children and adolescents.

DIFFERENTIALS

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Amebiasis

Other Problems to be Considered:

Capillary hemangioma
Cavernous hemangioma
Metastatic tumor from a nonhepatic primary site

WORKUP

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Lab Studies:

• Laboratory profile should include serologies for hepatitis B and C and should evaluate the extent of hepatic dysfunction shown by the presence of coagulopathies or hyperammonemia. Tests for amebiasis and echinococcus may be helpful in patients who may have these diseases.



• Approximately 50% of patients demonstrate elevated a-fetoprotein (AFP) levels and, to a lesser extent, abnormal levels of beta human chorionic gonadotropin (b-hCG).



• These serum markers of fetal hepatocytic function are useful not only for diagnostic purposes, but also for monitoring tumor response to therapy.



• Rarely, polycythemia occurs because of extrarenal erythropoietin production by the malignantly transformed hepatocytes.



• Vitamin B12 binding protein levels may be elevated in children with the fibrolamellar variant of hepatocellular carcinoma (HCC). These levels may be followed as markers of disease burden.

Imaging Studies:

• Initial staging evaluation should include, but is not limited to, chest, abdomen, and pelvic CT scans. If surgical resection is anticipated, use MRI and magnetic resonance angiography (MRA) of the liver to best determine tumor margins and vasculature. Ultrasonography may be helpful to screen patients at high risk to develop HCC.



• Additional scans that may be helpful in the staging workup include a bone scan and MRI of the brain to determine the status of metastatic spread to the skeleton and neuraxis, respectively.



• The chest radiograph is an important tool to monitor pulmonary metastatic disease and, when appropriate, malignant pleural effusions.



• Because affected patients may have underlying hepatic dysfunction or deficits in liver function because of bulky tumor burden, deficiencies in coagulation function may occur. In this setting, deep venous thromboses may complicate the patient's course. If extremity swelling, edema, or pain is noted, venous Doppler studies may be performed to exclude the possibility of deep venous thromboses.

Procedures:

• Liver biopsy is the most important procedure to consider when HCC is suspected. Needle biopsies are generally not recommended, especially in the setting of cirrhosis, because overlooking the findings of malignantly transformed hepatocytes in a small specimen may be easy, and the diagnosis may be missed. If definitive tumor resection is possible, this procedure should be undertaken by a qualified surgeon.

• Histologic examination of tumor tissue in children with classic HCC shows large, polygonal cells with central nuclei, frequent mitotic figures, and, often, invasion into surrounding hepatic tissue or adjacent abdominal structures. Areas of hemorrhage and necrosis, which may complicate the interpretation of needle biopsy specimen, are common.

• A distinct histologic variation, termed fibrolamellar carcinoma, occurs with relatively high frequency in children and young adults. Tumor cells in this subtype are circumscribed characteristically by bundles of acellular collagen, creating either trabeculae or large nodules of tumor islands. Interestingly, in the fibrolamellar variant, levels of B12 binding protein are elevated significantly and rise and fall concomitantly with successful or unsuccessful disease control. The fibrolamellar variant is generally associated with a more favorable prognosis.

Staging:

• Although no staging system has been uniformly adopted, a staging method proposed by the Children’s Cancer Group and Southwest Oncology Group incorporates tumor bulk with surgical resection. The staging and classification for HCC draw upon location, resectability, and response to any presurgical therapy given to the affected patient.


• • Clinical group 1 - Complete resection of the tumor
  
  
  
  • Clinical group IIa - Completely resectable after presurgical irradiation and/or chemotherapy.
  
  
  
  • Clinical group IIb - Residual disease confined to either left or right lobes of the liver after presurgical irradiation or chemotherapy.
  
  
  
  • Clinical group III - Residual or unresectable tumor involves both left and right lobes of the liver
  
  
  
  • Clinical group IIIb - Regional node involvement
  
  
  
  • Clinical group IV - Distant metastatic spread (usually to the lungs and/or bone)
  
  
  

TREATMENT

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Medical Care:

Screening: Hepatocellular carcinoma (HCC) is most easily treated in its earliest stages of presentation. Because patients often present with advanced disease, for which treatment modalities are limited at best, recent emphasis has been placed on screening for HCC in at-risk patients. Patients with hepatitis B have a relative risk for developing HCC that is 100-fold greater than that of uninfected persons. Currently, patients with hepatitis B or C are recommended to have an annual a fetoprotein level drawn. If the level is 29 ng/mL or greater, continued surveillance is recommended at least annually. Ultrasonography is also recommended at similar intervals for patients who are at risk. Suspicious lesions require biopsy, but, in patients who are found to have a lesion larger than 2 cm and an a fetoprotein level in excess of 200 ng/mL, biopsy may not be necessary, as the chance of HCC is virtually 100% in these cases.

Surgical Care: Surgical resection must be undertaken by a surgeon familiar with liver tumor management. Underlying coagulation defects may complicate the surgery. Pathologic analysis that shows no remaining cells is the goal of resection. Although the liver is capable of regeneration, overly aggressive resection may predispose the patient to liver failure and death. Transarterial embolization and chemoembolization have been used with limited success.

Consultations: Management by a pediatric oncology healthcare team is required. This team should include individuals from the following areas of specialty: surgery, psychiatry, radiation oncology, infectious disease, metabolic disorders, diagnostic radiology, pharmacy, nursing specialists, and social work.

Diet: Vitamin K supplementation may help patients with a coagulation defect.

Activity: Activity depends on the overall health of the individual after surgery, chemotherapy, or radiation.

MEDICATION

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Unfortunately, complete surgical resection is possible in fewer than 30% of children at diagnosis. Chemotherapy and radiation have limited efficacy as adjuvant therapy, although one or both are often employed to control disease temporarily. Chemotherapy may also allow a meaningful reduction in tumor size before surgical control, in some cases rendering unresectable tumors resectable. Several combination chemotherapy regimens have been used.

One widely used regimen in children is doxorubicin and cisplatin.

Alternative regimens include the following:

• Ifosfamide, carboplatin, and etoposide (ICE)

• 5-Fluorouracil in combination with cisplatin and vincristine

• Gemcitabine and carboplatin (recently have gained acceptance as potentially being active against hepatocellular carcinoma [HCC])

Chemoembolization into isolated branches of the hepatic artery may benefit patients with nonmetastatic but unresectable or recurrent tumor. This is the more commonly used approach in adults, in whom systemic chemotherapy has had essentially no impact on disease-free survival.

Because the liver plays a key role in chemically inactivating many chemotherapeutic agents, the child with an underlying liver disease or extensive hepatic involvement with HCC warrants careful observation. A number of reports associate hepatic coma with chemotherapy initiation.

Drug Category: Antineoplastic agents -- Chemotherapy is used for tumor size reduction to allow for subsequent resection, in the setting of positive resection margins after surgery, and as palliation in the setting of advanced regional or metastatic disease.

When given postoperatively, chemotherapy usually is initiated approximately 4 weeks after surgery to allow liver regeneration. A minimum of 2 weeks should pass after surgery before administration of cytotoxic agents.

These drugs have achieved partial response rates in affected patients. Although suggested doses are supplied, these doses vary widely from among protocols, and the information cannot be used to design patient treatment plans.

Drug Name	Doxorubicin (Adriamycin, Rubex) -- An anthracycline antibiotic derived from Streptomyces peucetius susp caesius. Doxorubicin is a DNA-intercalating agent that interferes with DNA and RNA synthesis.
Adult Dose	25 mg/m2 IV push or continuous infusion on days 1-3 (total dose 75 mg/m2/72 h
Pediatric Dose	25 mg/m2 IV push or continuous infusion on days 1-3 (total dose 75 mg/m2/72 h)
Contraindications	Documented hypersensitivity; severe heart failure, cardiomyopathy, impaired cardiac function, preexisting myelosuppression
Interactions	May decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels of doxorubicin; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity of doxorubicin; cyclophosphamide increases cardiac toxicity of doxorubicin
Pregnancy	D - Unsafe in pregnancy
Precautions	Irreversible cardiac toxicity and grade III and IV myelosuppression may occur; mucositis; extravasation may result in severe local tissue necrosis; reduce dose in patients with impaired hepatic function

Drug Name	Cisplatin (Platinol) -- A planar, inorganic compound that interacts with DNA. The mechanism of action is to cause intrastrand crosslinks that interfere with replication.
Adult Dose	45 mg/m2/d IV infused over 4-6 h on days 1-2 (total dose 90 mg/m2/48 h)
Pediatric Dose	20-40 mg/m2/d IV for 5 d Alternative: 90-100 mg/m2 IV as a single dose Requires prehydration and should be administered with 0.45% NaCl, potassium chloride, and mannitol
Contraindications	Documented hypersensitivity, preexisting renal insufficiency, myelosuppression, and hearing impairment
Interactions	Increases toxicity of bleomycin and ethacrynic acid; cyclosporine may increase CNS toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	May produce significant nephrotoxicity and ototoxicity; CrCl and audiologic evaluation must be performed at baseline and during the course of therapy to monitor renal function and hearing; other primary toxic effects include nausea, vomiting (highly emetogenic), myelosuppression, electrolyte disturbances; rare toxic effects include metallic taste, peripheral neuropathy, hepatotoxicity, and secondary leukemia; close monitoring of CBC and platelets is necessary Patients must avoid exposure to ill contacts, seek care for fever or bleeding, and avoid contact sports

Drug Name	5-Fluorouracil (5FU; Adrucil) -- Prodrug inhibits thymidine synthesis and is incorporated into RNA and DNA. Specific to the S phase of the cell cycle.
Adult Dose	15 mg/kg/d IV continuous infusion (24 h) for 5 consecutive d
Pediatric Dose	500 mg/m2 IV push as single dose or qd for 5 d; or 800-1200 mg/m2 continuous IV infusion over 24–120 h No guidelines available for modifying dose in patients with hepatic or renal dysfunction
Contraindications	Documented hypersensitivity; inherited deficiency of catabolic enzyme dihydropyrimidine dehydrogenase (associated with severe 5-FU toxicity); bone marrow suppression, serious infection
Interactions	Increased risk of bleeding with anticoagulants, NSAIDs, platelet inhibitors, thrombolytic agents; enhanced bone marrow toxicity with other immunosuppressive agents Clearance delayed and toxicity increased by thymidine competing for enzyme that catabolizes 5-FU; intracellular activation and incorporation into RNA increased by methotrexate
Pregnancy	D - Unsafe in pregnancy
Precautions	Toxic effects exacerbated by impairments in liver function Dose-limiting toxic effects include leukopenia and thrombocytopenia, severe diarrhea, stomatitis, and dysphagia; local ulceration if extravasation occurs; other common toxic effects include proctitis, nausea and vomiting, partial loss of nails, hypopigmentation, and immunosuppression; severe mucositis can lead to infection, dehydration, and poor nutritional status; close monitoring of CBC is necessary Patients must avoid exposure to ill contacts and seek care for fever or bleeding

Drug Category: Antiemetics -- Antineoplastic induced vomiting is stimulated through the chemoreceptor trigger zone (CTZ), which then stimulates the vomiting center (VC) in the brain. Increased activity of central neurotransmitters, dopamine in CTZ, or acetylcholine in VC appears to be a major mediator for inducing vomiting. Following administration of antineoplastic agents, serotonin (5-HT) is released from enterochromaffin cells in the GI tract. With serotonin release and subsequent binding to 5-HT3–receptors, vagal neurons are stimulated and transmit signals to the VC, resulting in nausea and vomiting.

Antineoplastic agents may cause nausea and vomiting so intolerable that patients may refuse further treatment. Some antineoplastic agents are more emetogenic than others. Prophylaxis with antiemetic agents before and following cancer treatment is often essential to ensure administration of the entire chemotherapy regimen.

The 5-HT antagonists are highly effective at controlling cisplatin-induced nausea.

Drug Name	Ondansetron (Zofran) -- Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin).
Adult Dose	24-32 mg/d PO/IV
Pediatric Dose	0.45 mg/kg/d; up to 24-32 mg/d PO/IV
Contraindications	Documented hypersensitivity
Interactions	Although there is potential for CYP-450 inducers (eg, barbiturates, rifampin, carbamazepine, phenytoin) to change half-life and clearance of ondansetron, dosage adjustment usually is not required
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Headache occurs commonly; total daily dose should not exceed 8 mg/d for patients with severe liver failure

FOLLOW-UP

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Further Inpatient Care:

• Follow-up of the patient is varied. For the child who requires only surgery, only good postoperative management of the surgical site and assessment of liver function tests may be required. If the a-fetoprotein or B12 binding protein levels are abnormal, these markers of tumor burden, in addition to previously abnormal imaging studies, necessitate close follow-up monitoring. Patients with abnormal scans also require follow-up monitoring, usually at 2- to 3-month intervals or sooner if clinically indicated.



• Grade III to IV mucositis, grade III to IV myelosuppression, febrile neutropenia, anorexia, and cachexia most likely occur in the patient who receives chemotherapy. These problems require hospitalization and management by a team of individuals who are versed in the toxicities of high-dose chemotherapy.

Prognosis:

• Survival


• • The 5-year survival rates for patients undergoing multiagent therapy and surgical resection are as follows:
    • Group I - Approximately 85-90%

    • Group II - Between 55 and 60%

    • Groups III and IV - Less than 20%
  
  
  
  • The major determinants of prognostic significance are the number of liver segments involved with tumor and the presence of metastatic disease. Liver transplantation may play a role in the treatment of children with advanced disease; however, survival rates have not exceeded 30% at 2 years follow-up, and distant metastatic disease precludes this therapeutic strategy.
  
  
  
  • Although chemotherapeutic and radiotherapeutic modalities are associated with numerous toxicities, even a temporary reduction in tumor size can greatly enhance a child’s quality of life by alleviating tumor-associated pain and hepatic dysfunction.
  
  
  
• Future directions


• • Identification in a young patient requires a careful evaluation for a preexisting underlying liver disorder. With careful staging and adjuvant therapy, many patients can be treated with intent-to-cure, especially if localized disease is identified in the initial staging workup.
  
  
  
  • This disease awaits a well-organized clinical trial to best determine which chemotherapeutic agents, duration of therapy, and use of radiation might best benefit affected children. The formation of the Children’s Oncology Group within the United States suggests that a clinical trial specifically designed to answer these questions may be forthcoming.
  
  
  

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Management requires a multidisciplinary team of specialists versed in the complexities of pediatric cancer. Although formal management is undertaken by the pediatric oncology team, the primary care physician is encouraged to help when possible but would not be expected to act as primary case manager.

TEST QUESTIONS

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CME Question 1: Which environmental and personal pathogen increases a patient's chances of developing hepatocellular carcinoma (HCC)?

A: Long-term heavy metal exposure in a southern Colorado mining town
B: Long-term exposure to electromagnetic radiation from an electric blanket in northern Wisconsin
C: Endemic hepatitis B and positive serologic tests for hepatitis B S Ag and hepatitis B Core Ab
D: Hereditary spherocytosis with a prolonged period of neonatal jaundice, resulting in phototherapy and discontinuation of breastfeeding
E: All of the above can increase a patient's chances of developing HCC.

The correct answer is C: Even in young people, chronic hepatitis increases the risk of developing HCC.

CME Question 2: What is the most common marker of disease in hepatocellular carcinoma (HCC)?

A: a-Fetoprotein in classic hepatocellular carcinoma
B: B12-binding protein in classic hepatocellular carcinoma
C: The carcinoembryonic antigen (CEA)
D: The serum total and direct bilirubin levels
E: None of the above

The correct answer is A: The a-fetoprotein level is elevated in approximately 50% of patients with hepatocellular carcinoma. The B12-binding protein is helpful only in the fibrolamellar variant of HCC.

Pearl Question 1 (T/F): The intestinal tract is the most common site of metastatic disease in hepatocellular carcinoma (HCC).

The correct answer is False: The liver, lungs, and bones are the most common sites of metastatic disease in HCC.

Pearl Question 2 (T/F): Complete surgical resection is the therapeutic modality most likely to achieve a cure in patients affected with hepatocellular carcinoma (HCC).

The correct answer is True: Surgical resection with margins free of tumor is most likely to achieve a cure.

Pearl Question 3 (T/F): The annual incidence of HCC in children and adolescents is roughly 0.5 cases per million.

The correct answer is True: Primary liver tumors are uncommon in children and adolescents, accounting for approximately 0.5-2% of all neoplasms in these age groups. The annual incidence of HCC in children is about 0.5 cases per million. Because of the low incidence of this tumor type in children, performing a meaningful study of the many epidemiological factors beyond those listed below is difficult.

Pearl Question 4 (T/F): The best way to prevent hepatocellular carcinoma (HCC) is by thorough hand washing when traveling in developing countries.

The correct answer is False: The best ways to prevent HCC are vaccination against hepatitis, education regarding the hazards of chronic alcohol exposure, and any other means of preventing chronic cirrhosis.

BIBLIOGRAPHY

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• Morita K, Okabe I, Uchino J, et al: The proposed Japanese TNM classification of primary liver carcinoma in infants and children. Jpn J Clin Oncol 1983 Jun; 13(2): 361-9[Medline].
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• Paradinas FJ, Melia WM, Wilkinson ML, et al: High serum vitamin B12 binding capacity as a marker of the fibrolamellar variant of hepatocellular carcinoma. Br Med J (Clin Res Ed) 1982 Sep 25; 285(6345): 840-2[Medline].
• Ringe B, Wittekind C, Bechstein WO, et al: The role of liver transplantation in hepatobiliary malignancy. A retrospective analysis of 95 patients with particular regard to tumor stage and recurrence. Ann Surg 1989 Jan; 209(1): 88-98[Medline].
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• Vaillo A, Rodriguez-Recio FJ, Gutierrez-Martin A, et al: Fine needle aspiration cytology of clear cell carcinoma of the gallbladder with hepatic infiltration: a case report. Acta Cytol 2004 Jul-Aug; 48(4): 560-4[Medline].
• Winter SS, Rose E, Katz R: Hyperammonemia after chemotherapy in an adolescent with hepatocellular carcinoma. J Pediatr Gastroenterol Nutr 1997 Nov; 25(5): 537-40[Medline].
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