eMedicine Specialties > Pediatrics: General Medicine > Oncology

Hepatocellular Carcinoma

Girindra G Raval, MD, Staff Physician, Department of Internal Medicine, University of Arkansas School of Medicine
Paulette Mehta, MD, MPH, Professor of Hematology/Oncology, Department of Internal Medicine, Co-Director of Fellowship Program, Medical Director of Hematology/Oncology at CAVHS, University Arkansas for Medical Sciences and Central Arkansas Veterans Hospital System

Updated: Feb 23, 2009

Introduction

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 hepatocellular carcinoma. 

The 2 pathological subtypes are classic hepatocellular carcinoma 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 hepatocellular carcinoma follow.

Pathophysiology

The pathophysiology of hepatocellular carcinoma is not clearly understood; however, underlying liver dysfunction, especially cirrhosis, is a predisposing condition. In contrast to adults, most pediatric hepatocellular carcinomas arise de-novo, without underlying liver abnormalities.¹ Karyotypic abnormalities are not common. Although children and adolescents are unlikely to have chronic liver disease, congenital liver disorders increase the chance of developing hepatocellular carcinoma. These findings are suggestive of a multihit model of malignant transformation in hepatic tissue.

Frequency

United States

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. This is the second most common hepatic malignancy in children after hepatoblastoma.

International

The international incidence is highly associated with endemic hepatitis B exposure such as Southeast Asia and sub-Saharan Africa. In China, aflatoxin exposure has been associated with the development of hepatocellular carcinoma 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 hepatocellular carcinoma; however, excluding environmental factors from these determinations is difficult. Because the condition is so rare in adolescents and children (0.5 cases per million population), ethnic data are not readily available for these age groups. Most studies of hepatocellular carcinoma 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. After congenital Hepatitis B infection the life time risk of developing hepatocellular carcinoma is 50% for men and 20% for women.

Age

The incidence is lower in infants and higher in children and adolescents. 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

History

Elements to ascertain include a prior history of hepatitis B or hepatitis C, chronic cirrhosis, or other diseases that tend to induce liver dysfunction. Co-infection with human immunodeficiency virus (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.

Most patients with hepatocellular carcinoma present with 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 hepatocellular carcinoma (eg, alpha-1 antitrypsin deficiency).

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. This is particularly true for bone pain at presentation.

Causes

Although no cause has been clearly elucidated, the risk factors for children and adolescents include a history of hepatitis B or C, alpha-1 antitrypsin deficiency, hereditary tyrosinemia, Gaucher disease, congenital biliary atresia, urea cycle defects, severe iron overload (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 because the risk of hepatocellular carcinoma 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.

Differential Diagnoses

Amebiasis
Hepatoblastoma

Other Problems to Be Considered

Capillary hemangioma
Cavernous hemangioma
Metastatic tumor from a nonhepatic primary site

Workup

Laboratory Studies

• Laboratory profile in hepatocellular carcinoma (HCC) should include serologies for hepatitis B and C and should evaluate the extent of hepatic dysfunction shown by the presence of altered liver function tests, 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. A serum sodium, calcium level should also be obtained , due to association of hypercalcemia and hyponatremia as part of the paraneoplastic syndrome secondary to excess production of parathyroid hormone–related protein (PTH-rP) and antidiuretic hormone (ADH).
• Vitamin B12–binding protein levels may be elevated in children with the fibrolamellar variant of hepatocellular carcinoma. 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 scanning. 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 hepatocellular carcinoma. Hepatocellular carcinoma has a typical radiographic appearance of increased dye uptake during the arterial phase.
• 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.
• Chest radiography 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 hepatocellular carcinoma is suspected and when imaging combined with AFP do not provide a conclusive diagnosis.
• 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. Seeding the biopsy tract with tumor during a needle biopsy is a concern. 
• If definitive tumor resection is planned, this biopsy should preferable be performed by the surgeon who is eventually going to perform the hepatectomy.

Histologic Findings

• Histologic examination of tumor tissue in children with classic hepatocellular carcinoma reveals 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 significantly elevated and rise and fall concomitantly with successful or unsuccessful disease control. Claims that the fibrolamellar variant is associated with a better prognosis compared with hepatocellular carcinoma have not been substantiated, and contradicting evidence is noted.¹

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 hepatocellular carcinoma draw on location, resectability, and response to any presurgical therapy given to the affected patient.
• The proposed staging system is as follows:
  • 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

Medical Care

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 hepatocellular carcinoma in at-risk patients. Patients with chronic hepatitis B have a relative risk for developing hepatocellular carcinoma that is 100-fold greater than that of uninfected persons. Currently, patients with chronic hepatitis B or C are recommended to have an annual a- fetoprotein level obtained. If the level is 29 ng/mL or more, continued surveillance is recommended at least annually.

Ultrasonography is also recommended at similar intervals for patients who are at risk. Suspicious lesions warrant biopsy; however, 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 because the chance of hepatocellular is virtually 100% in these cases.

Surgical Care

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 or chemotherapy.

Medication

Unfortunately, complete surgical resection of hepatocellular carcinoma (HCC) is possible in fewer than 30% of children at diagnosis. Hepatocellular carcinoma is only partially chemosensitive; thus, chemotherapy and radiation have limited efficacy as adjuvant or neoadjuvant therapy, although one or both are often used to temporarily control disease. In patients who are chemosensitive, chemotherapy may 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 (PLADO). Resectability rate and, hence, survival rate is higher among children who respond to neoadjuvant chemotherapy compared with children who do not.¹  

Alternative regimens include the following:

• Ifosfamide, carboplatin, and etoposide (ICE)
• 5-Fluorouracil in combination with vincristine, Adriamycin, and cyclophosphamide²
• Gemcitabine and carboplatin (recently gained acceptance as potentially active against hepatocellular carcinoma)

Recent trials in adults have demonstrated the efficacy of tyrosine kinase inhibitors like sorafenib in patient with locally advanced hepatocellular carcinoma. The efficacy and safety of these therapeutic measures in children remains to be determined.³

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 hepatocellular carcinoma warrants careful observation. Numerous reports associate hepatic coma with chemotherapy initiation.

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 is usually 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 patients. Although suggested doses are supplied, these doses widely vary among protocols, and the information cannot be used to design patient treatment plans.

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.

Dosing

Adult

25 mg/m² IV push or continuous infusion on days 1-3 (total dose 75 mg/m²/72 h

Pediatric

Administer as in adults

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

Contraindications

Documented hypersensitivity; severe heart failure, cardiomyopathy, impaired cardiac function, preexisting myelosuppression

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

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

Cisplatin (Platinol)

A planar, inorganic compound that interacts with DNA. The mechanism of action is to cause intrastrand crosslinks that interfere with replication.

Dosing

Adult

45 mg/m²/d IV infused over 4-6 h on days 1-2 (total dose 90 mg/m²/48 h)

Pediatric

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

Interactions

Increases toxicity of bleomycin and ethacrynic acid; cyclosporine may increase CNS toxicity

Contraindications

Documented hypersensitivity, preexisting renal insufficiency, myelosuppression, and hearing impairment

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

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 count and platelets is necessary
Patients must avoid exposure to ill contacts, seek care for fever or bleeding, and avoid contact sports

5-Fluorouracil (5FU; Adrucil)

Prodrug inhibits thymidine synthesis and is incorporated into RNA and DNA. Specific to the S phase of the cell cycle.

Dosing

Adult

15 mg/kg/d IV continuous infusion (over 24 h) for 5 consecutive d

Pediatric

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

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

Contraindications

Documented hypersensitivity; inherited deficiency of catabolic enzyme dihydropyrimidine dehydrogenase (associated with severe 5-FU toxicity); bone marrow suppression, serious infection

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

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 count is necessary
Patients must avoid exposure to ill contacts and seek care for fever or bleeding

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.

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).

Dosing

Adult

24-32 mg/d PO/IV

Pediatric

0.45 mg/kg/d; up to 24-32 mg/d PO/IV

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

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Headache occurs commonly; total daily dose should not exceed 8 mg/d for patients with severe liver failure

Follow-up

Further Inpatient Care

• Follow-up of patients with hepatocellular carcinomas (HCCs) varies. 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-month to 3-month intervals or sooner if clinically indicated.
• Grade III to grade IV mucositis, grade III to grade 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 - 55-60%
    • Groups III and IV - Less than 20%
  • Surgery is the mainstay of treatment in hepatocellular carcinoma; thus, factors like multifocal tumor, vascular invasion, and presence of metastatic disease, which preclude surgical resection, are important prognostic factors for survival.¹ 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.
  • Earlier claims for a better outcome of fibrolamellar versus hepatocellular carcinoma have not been substantiated.¹
• 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

Medicolegal Pitfalls

• Management of hepatocellular carcinoma (HCC) 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 is not expected to act as primary case manager.

References

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Keywords

hepatocellular carcinoma, hepatoma, HCC, fibrolamellar carcinoma, malignant hepatoma, hepatocarcinoma, liver cell carcinoma, liver disease, liver dysfunction, parenchymal cells, liver, tumor, cancer, cirrhosis, hepatitis B, hepatitis C, hemochromatosis, Gaucher disease, Gaucher's disease, biliary atresia, infantile cholestasis, glycogen-storage disease, cirrhosis, hepatitis B, hepatitis C, liver dysfunction, tyrosinemia, pleural effusions

Contributor Information and Disclosures

Author

Girindra G Raval, MD, Staff Physician, Department of Internal Medicine, University of Arkansas School of Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Paulette Mehta, MD, MPH, Professor of Hematology/Oncology, Department of Internal Medicine, Co-Director of Fellowship Program, Medical Director of Hematology/Oncology at CAVHS, University Arkansas for Medical Sciences and Central Arkansas Veterans Hospital System
Paulette Mehta, MD, MPH is a member of the following medical societies: American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, and American Society of Hematology
Disclosure: Nothing to disclose.

Medical Editor

Stephan A Grupp, MD, PhD, Director, Stem Cell Biology Program, Department of Pediatrics, Division of Oncology, Children's Hospital of Philadelphia; Associate Professor of Pediatrics, University of Pennsylvania
Stephan A Grupp, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland
Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and International Society for Experimental Hematology
Disclosure: Nothing to disclose.

CME Editor

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
Helen SL Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Senior Vice President, Children's National Medical Center (Center for Cancer and Blood Disorders); Director, Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Stuart Winter, MD, to the development and writing of this article.

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