(<100) and predict adverse outcomes with poor response to chemotherapy.215 The majority of

hepatoblastoma tumors are epithelial with mixed embryonal and fetal patterns (67%), and 21% of these

have mesenchymal components.213,216 Hepatoblastoma tumors secrete interleukin 1β that induces IL-6

production, enhancing hepatocyte growth factor.217 There is evidence that hepatocyte growth factor is

secreted postoperatively and functions as a growth factor for hepatoblastoma tumor cells.218

Presentation, Diagnosis, and Staging

Children with hepatoblastoma present with an asymptomatic abdominal mass or abdominal swelling.

Systemic symptoms such as weight loss, failure to thrive, or anorexia may indicate advanced disease.

Jaundice and biliary obstruction does not typically occur in patients with hepatoblastoma. Distant

metastases are present in approximately 20% of patients at diagnosis and the most common site is

lungs.219 Ultrasound and cross-sectional imaging (three-phase CT scan or MRI with EOVIST) will define

segmental extension of the tumor within the liver and assess for distant metastases (Fig. 105-11). The

majority of hepatoblastoma tumors are located in the right lobe of the liver (up to 70%). The tumor

appears as a solid mass with low attenuation. On MRI, the lesion appears as low intensity on T1

-

weighted images and high intensity on T2

-weighted images. There is no evidence that MRI is superior to

CT scan for diagnosis or surveillance of hepatoblastoma. It is important to distinguish central venous

structures and to evaluate the liver for multifocal disease. Chest CT scan is obtained to evaluate for lung

metastases. Anemia and thrombocytosis are common in children with hepatoblastoma and are likely

related to cytokine secretion by tumor cells. AFP is elevated in approximately 90% of patients with

hepatoblastoma and is a useful clinical marker for monitoring tumor responsiveness and recurrence.

Interpretation of AFP may be difficult because the protein is expressed in the fetus and commonly

remains elevated in normal neonates and infants up to 6 months of age. AFP may also be elevated in

patients with hepatitis, hepatocellular carcinoma (HCC), and germ cell tumors. A high serum cholesterol

level is also detected in 50% to 60% of children with hepatoblastoma.

Table 105-9 Relative Risk of Death for Histologic Subtypes of Hepatoblastomaa

Figure 105-11. Abdominal CT scan with right hepatic lobe hepatoblastoma displacing normal hepatic vasculature and

parenchyma.

Staging is based on the COG hepatoblastoma staging system (Table 105-10). This system is a

postsurgical staging system that is based on outcome of the primary operation before the administration

of chemotherapy.220 Stage I (22%) is complete resection with clear margins. Stage II (0.5%) is complete

gross resection with microscopic residual disease at the margins. Stage III (53%) is grossly positive

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margins, biopsy only at diagnosis, nodal involvement, or tumor spill. Stage IV disease (23%) is

metastatic tumor at diagnosis.221

Table 105-10 Children’s Oncology Group Staging for Hepatoblastoma

Figure 105-12. The Liver Tumor Study Group of the International Society of Pediatric Oncology (SIOP) SIOPEL-1 pretreatment

extent of disease grouping system, PRETEXT groups I–IV. L, left; R, right. (From Schnater JM, Aronson DC, Plaschkes J, et al.

Surgical view of the treatment of patients with hepatoblastoma: results from the first prospective trial of the International Society

of Pediatric Oncology Liver Tumor Study Group (SIOPEL-1). Cancer 2002;94(4):1111–1120, with permission.)

PRETEXT (pretreatment extent of disease) grouping is used internationally in combination with COG

stage to stratify patients on the basis of the tumor’s radiographic characteristics prior to treatment.222

PRETEXT describes the anatomic involvement and Couinaud hepatic segments affected by the tumor

and can be applied to patients who have not yet had operations (Fig. 105-12).223 PRETEXT divides the

liver into four parts termed sectors. The left lobe is divided into a lateral sector (segments 2 and 3) and

a medial sector (segment 4). The right lobe is divided into an anterior sector (segments 5 and 8) and a

posterior sector (segments 6 and 7). PRETEXT is further annotated by V (venous involvement), P

(portal vascular involvement), E (extrahepatic involvement), M (distant metastatic disease), C (caudate

lobe), F (multifocal), and R (rupture prior to diagnosis) categories. Imaging is obtained after every two

cycles of chemotherapy, where POST-TEXT (posttreatment of disease) is then used to reassess anatomy.

The COG utilizes COG stage, PRETEXT, histology, and AFP at diagnosis to determine risk for therapy

assignment and for clinical trial standards. In general, excellent prognosis is expected for stage I tumors

completely resected at diagnosis with pure fetal histology. Poor prognosis is associated with PRETEXT

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IV, metastatic tumors, AFP less than 100, and tumors with small cell undifferentiated histology.216

Treatment

8 Complete surgical resection is the mainstay of curative therapy for hepatoblastoma. Completely

resected tumors have significantly improved survival outcomes compared with all other hepatoblastoma

patients. The tumor may present as large bulky disease with mass effect on surrounding abdominal

structures. The umbilical fissure is typically not involved. If the tumor appears resectable, conventional

resection is performed. If the mass is judged unresectable at diagnosis, incisional biopsy is performed

and the patient is treated with chemotherapy prior to conventional resection. A complete preoperative

evaluation is necessary to assess full extent of disease, PRETEXT grouping, and to determine a safe

surgical plan that will achieve the highest survival outcomes. In the United States, tumor resection at

diagnosis whenever possible is the preferred standard. This is based on the notion that a subset of

patients may be spared toxicity of unnecessary neoadjuvant chemotherapy and that tumors have

capacity to become resistant to prolonged chemotherapy.220,224 The COG currently determines surgical

resectability based on PRETEXT grouping. Primary resection is recommended for localized PRETEXT 1

or PRETEXT 2 tumors with >1-cm radiographic margin on the middle hepatic vein, without vena cava

or contralateral portal venous invasion.220 Neoadjuvant chemotherapy is recommended for PRETEXT III

or IV tumors and for multicentric tumors with central venous invasion. Patients with pulmonary

metastases also receive chemotherapy upfront. Tumor volume and AFP measurements may be utilized

to monitor tumor responsiveness after each cycle. Minimal benefit is may be seen by prolonging

induction therapy after cycle 2; therefore, tailoring exposure to response may help reduce toxic

effects.225

Conventional liver resection is safe and effective in children with hepatoblastoma, and surgical

techniques have been optimized in the last three decades.226,227 An anatomic resection is recommended

and is most often required. As much as 85% of hepatic parenchyma may be safely removed in children

with full regeneration expected despite postoperative chemotherapy.228 Mortality from liver resection

in children should be low (0% to 3%) with technical advances such as the Cavitron Ultrasonic Surgical

Aspirator (CUSA; Cooper Lasersonics, Santa Clara, CA) and metallic clip applicators for hemostasis

while dividing liver parenchyma. The surgical principles include a generous incision with wide exposure

using bilateral subcostal incision. Dissection of the hilum with identification and isolation of the ductal

and vascular structures of the segment of resection is critical. Hepatic arterial and portal venous inflow

is obstructed or ligated, allowing demarcation of the resection plane. This allows the operation to

proceed with minimal blood loss. Intraoperative Doppler ultrasound is often utilized to aid in locating

major venous structures traversing the tumor and for ensuring adequate resection margins of at least 1

cm.

Chemotherapy improves resectability of hepatoblastoma and improves prognosis in nearly all cases.

Currently most patients diagnosed with hepatoblastoma receive chemotherapy either before or after

resection of the primary tumor. Based on results from the Pediatric Oncology Group/Children’s Cancer

Study Group studies INT-0098 and P9645, patients with completely resected well-differentiated fetal

histology (WDF or pure fetal histology) tumors and low mitotic activity may be treated exclusively with

surgery alone.229 Children with WDF histology tumors comprise 7% of hepatoblastoma cases and have

100% event-free survival. Most hepatoblastoma tumors are sensitive to cisplatin-based chemotherapy

and overall survival increased from 30% to 70% with the addition of cisplatin.230 The COG currently

recommends cisplatin, 5-fluorouracil, and vincristine for all low-risk tumors (non–well differentiated

fetal histologic subtypes). Low-risk patients are patients with completely grossly resected tumors

(stages I and II, PRETEXT I or II) without any small cell undifferentiated histology elements and who

do not have a low diagnostic AFP (<100). This group can expect 5-year event-free survival and overall

survival of 84% and 96%, respectively.216 Intermediate-risk patients (PRETEXT II, III, or IV) are

patients with gross residual disease or grossly resected disease with small cell undifferentiated histology

(without metastases) and without low diagnostic AFP (<100). Those with high-risk tumors are any

patients with metastatic disease and low diagnostic AFP level of <100. Patients with intermediate-risk

and high-risk tumors are currently treated with cisplatin, 5-fluorouracil, vincristine, and doxorubicin.

The COG is currently determining the efficacy of the addition of doxorubicin to intermediate and highrisk patients and for patients with minimal radiographic response to standard therapy. Depending on

risk group protocol, patients will receive two to six cycles of cisplatin, 5-fluorouracil, vincristine with or

without doxorubicin prior to primary resection or transplantation. Outcomes for patients with

hepatoblastoma after surgical resection and chemotherapy were documented in INT-0098 with 5-year

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event-free survivals for stages I, II, III, and IV of 91%, 100%, 64%, and 25%, respectively.230 Overall

survivals were similar. The subsets of patients with stage III or IV disease who were able to have

complete tumor resection and were tumor-free after induction chemotherapy had 5-year event-free

survival of 83%. The role of radiotherapy in hepatoblastoma has not been defined because of the risk of

hepatic toxicity and low hepatic tolerance to radiation in children. There may be a role for focal

radiotherapy up to 45 Gy in patients with incomplete resection or microscopic residual disease.231

Liver transplantation has become a promising treatment option for children with unresectable

hepatoblastoma without metastatic disease after neoadjuvant chemotherapy.232 Liver transplantation

has improved overall survival in children with large or multifocal unresectable hepatoblastoma.233,234

Tumors with extensive major vessel involvement or multifocal disease should be referred to centers that

have pediatric liver transplant expertise.220 Primary transplantation is also recommended for multifocal

PRETEXT IV tumors despite apparent clearance after chemotherapy because of the risk of persistent

microscopic disease.235 If after four cycles of chemotherapy, the tumor remains unresectable by

conventional liver resection, liver transplantation is recommended. These are typically POSTTEXT IV or

POSTTEXT III with major vascular involvement that would jeopardize blood supply to the contralateral

lobe.236 A review of the United Network for Organ Sharing (UNOS) database revealed that overall 1-, 5-

, and 10-year graft survival was 71%, 61%, and 58% for patients receiving liver transplant for

hepatoblastoma. Overall 1-, 5-, and 10-year patient survival was 79%, 69%, and 66%.237 Other series

have reported similar success.234 The primary cause of death was metastatic and relapsed disease. For

transplantation eligibility, patients with hepatoblastoma must not have any active extrahepatic or

metastatic sites that have not cleared with surgery or chemotherapy. Patients with lung metastases are

not excluded from transplantation if the lung disease is clear after neoadjuvant chemotherapy. It is

critical to correctly identify patients who will benefit from primary liver transplant prior to attempts at

conventional resection because liver transplant after incomplete tumor resection or hepatic relapse has

had disappointing results, with reported survival for “rescue” transplant of only 40%.238

The COG and other large international cooperative groups are investigating novel therapeutic

strategies. COG AHEP-0731 is a COG study that is randomizing patients with metastatic disease to

receive a novel upfront window design of vincristine, irinotecan, vincristine, irinotecan, and

temsirolimus prior to standard cisplatin, 5-fluorouracil, vincristine, and doxorubicin therapy.239

Chemotherapeutic intensification by dosing and duration has had promising preliminary results and may

be beneficial in patients with high-risk hepatoblastoma. The expanding roles of antibodies and T

lymphocytes as anticancer therapy for pediatric solid tumors may also hold promise as novel treatment

agents for hepatoblastoma.240

Hepatocellular Carcinoma

HCC occurs more commonly in older children and is similar in histopathology to the disease in adults.

HCC accounts for less than 0.5% of pediatric tumors and is the second most common malignant liver

mass in children after hepatoblastoma. Risk factors and preexisting liver diseases for HCC include

cirrhosis, type 1 glycogen storage disease, autoimmune hepatitis, and primary sclerosing cholangitis.220

Areas endemic for hepatitis B have higher incidences of HCC in children. HCC is rare in infancy and

there is a slight male predominance. HCC tumors are classified as either epithelial variant (75%)

fibrolamellar (15%), and rarely poorly differentiated or clear cell.241 Differences in outcome or

treatment response among children with different histologic subtypes of HCC have not been confirmed.

The fibrolamellar subtype is seen more often in younger children and rarely occurs with cirrhosis. The

most common presenting symptom is hepatomegaly and abdominal pain although HCC is often

indistinguishable from hepatoblastoma on physical examination, imaging, and laboratory values. The

diagnostic workup mirrors hepatoblastoma and diagnosis is confirmed by histopathologic examination

of tumor biopsy or resection. HCC is more likely to have multifocal nodules with intrahepatic venous

and lymphatic spread. More than one-third of patients have lung metastases at diagnosis. The PRETEXT

grouping system is utilized for risk assessment and to determine resectability. PRETEXT III and

PRETEXT IV are the most common categories at presentation in patients with HCC.

As reported by the Intergroup Pediatric Oncology Group Study 8945/CCG 8881, 17% of patients

diagnosed with HCC had stage 1 disease, none had stage 2 disease, 54% had stage 3 disease, and 28%

had stage 4 disease.221 It is not clear whether AFP levels can be used to predict outcome in HCC

similarly to hepatoblastoma as study results have not been consistent.221 The overall event-free survival

for children with HCC at 5 years was 19%. Stage 1 disease had the best outcome compared to stage 3

and 4 diseases. The 5-year event-free survival for stage 1, 3, and 4 diseases was 88%, 8%, and 0%,

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respectively.221 Overall survival was similar to event-free survival for each disease stage. Complete

surgical resection or transplantation has the highest potential for cure in children with HCC.

Unfortunately, fewer than 20% of patients with HCC have tumors that are resectable at diagnosis and

multifocal tumors are common. In contrast to hepatoblastoma, HCC tumors are generally unresponsive

to chemotherapy and outcomes for patients with stage 3 disease and higher are dismal. Transplantation

is reserved for patients with localized tumor without any evidence of metastatic disease at presentation

because of high risk of pulmonary metastatic relapse.220 The guidelines for liver transplantation in HCC

are largely derived from the adult experience using the Milan criteria (not more than three tumors,

smaller than 3 cm in size, or single tumor smaller than 5 cm in size).242 The COG studies on liver

tumors and hepatoblastoma include children with HCC and treatment regimens have generally been the

same. Treatment protocols for HCC currently consist of cisplatin, vincristine, doxorubicin, and 5-

fluorouracil in multiple combinations. Compared to hepatoblastoma, these agents are not as effective in

HCC, and patients generally remain with poor prognosis.230 The majority of patients do not undergo

postinduction surgery or liver transplantation because of the presence of either unresectable or

metastatic disease.

Alternative approaches for local control have demonstrated some benefit in children with HCC.

Hepatic arterial chemoembolization in patients with refractory and unresectable disease requires

cooperative group study but has been shown to be well-tolerated and may be effective in inducing

surgical resectability in select cases of HCC.243

References

1. Foucher ES, Stiller C, Lacour B, et al. International classification of childhood cancer. Cancer

2005;103(7):1457–1467.

2. Linet MS, Ries LA, Smith MA, et al. Cancer surveillance series: recent trends in childhood cancer

incidence and mortality in the United States. J Natl Cancer Inst 1999;91(12):1051–1058.

3. Stiller CA, Parkin DM. International variations in the incidence of neuroblastoma. Int J Cancer

1992;52(4):538–543.

4. Ries LG, Reichman ME, Lewis DR, et al. Cancer survival and incidence from the Surveillance,

Epidemiology, and End Results (SEER) Program. Oncologist 2003;8:541–552.

5. Young JL Jr, Miller RW. Incidence of malignant tumors in U.S. children. J Pediatr 1975;86(2):254–

258.

6. Hamrick S, Olshan AF, Neglia JP, et al. Association of pregnancy history and birth characteristics

with neuroblastoma: a report from the Children’s Cancer Group and the Pediatric Oncology Group.

Paediatr Perinat Epidemiol 2001;15(4):328–337.

7. Olshan AF, Smith J, Cook MN, et al. Hormone and fertility drug use and the risk of neuroblastoma:

a report from the Children’s Cancer Group and the Pediatric Oncology Group. Am J Epidemiol

1999;150(9):930–938.

8. Olshan AF, Bunin GR, Teschke K, et al. Neuroblastoma and parental occupation. Cancer Causes

Control 1999;10:539–549.

9. Yang Q, Olshan AF, Bondy ML, et al. Parental smoking and alcohol consumption and risk of

neuroblastoma. Cancer Epidemiol Biomarkers Prev 2000;9(9):967–972.

10. Buck GM, Michalek AM, Chen CJ, et al. Perinatal factors and risk of neuroblastoma. Paediatr Perinat

Epidemiol 2001;15(1):47–53.

11. Maris JM, Chatten J, Meadows AT, et al. Familial neuroblastoma: a three generation pedigree and

a further association with Hirschsprung disease. Med Pediatr Oncol 1997;28(1):1–5.

12. Kushner BH, Hajdu SI, Helson L. Synchronous neuroblastoma and von Recklinghausen’s disease: a

review of the literature. J Clin Oncol 1985; 3:117–120.

13. Stovroff M, Dykes F, Teague WG. The complete spectrum of neurocristopathy in an infant with

congenital hypoventilation, Hirschsprung’s disease, and neuroblastoma. J Pediatr Surg

1995;30(8):1218–1221.

14. Knudson SR Jr, Strong LC. Mutation and cancer: neuroblastoma and pheochromocytoma. Am J Hum

Genet 1972;24(5):514–532.

15. Maris JM, Kyemba SM, Rebbeck TR, et al. Molecular genetic analysis of familial neuroblastoma.

Eur J Cancer 1997;33(12):1923–1928.

3106

16. Mossé YP, Laudenslager M, Longo L, et al. Identification of ALK as a major familial neuroblastoma

predisposition gene. Nature 2008;455(7215):930–935.

17. Janoueix-Lerosey I, Lequin D, Brugières L, et al. Somatic and germline activating mutations of the

ALK kinase receptor in neuroblastoma. Nature 2008;455(7215):967–970.

18. George RE, Sanda T, Hanna M, et al. Activating mutations in ALK provide a therapeutic target in

neuroblastoma. Nature 2008;455(7215):975–978.

19. Capasso M, Devoto M, Hou C, et al. Common variations in BARD1 influence susceptibility to highrisk neuroblastoma. Nat Genet 2009;41(6):718–723.

20. Maris JM, Mossé YP, Bradfield JP, et al. Chromosome 6p22 locus associated with clinically

aggressive neuroblastoma. N Engl J Med 2008;358(24):2585–2593.

21. Diskin SJ, Hou C, Glessner JT, et al. Copy number variation at 1q21.1 associated with

neuroblastoma. Nature 2009;459(7249):987–991.

22. Pugh TJ, Morozova O, Attiyeh EF, et al. The genetic landscape of high-risk neuroblastoma. Nat

Genet 2013;45(3):279–284.

23. London WB, Castleberry RP, Matthay KK, et al. Evidence for an age cutoff greater than 365 days

for neuroblastoma risk group stratification in the Children’s Oncology Group. J Clin Oncol

2005;23(27):6459–6465.

24. Peuchmaur M, d’Amore ES, Joshi VV, et al. Revision of the International Neuroblastoma Pathology

Classification: confirmation of favorable and unfavorable prognostic subsets in

ganglioneuroblastoma, nodular. Cancer 2003;98(10):2274–2281.

25. Look AT, Hayes FA, Nitschke R, et al. Cellular DNA content as a predictor of response to

chemotherapy in infants with unresectable neuroblastoma. N Engl J Med 1984;311(4):231–235.

26. Brodeur GM, Seeger RC, Schwab M, et al. Amplification of N-myc in untreated human

neuroblastomas correlates with advanced disease stage. Science 1984;224(4653):1121–1124.

27. Seeger RC, Brodeur GM, Sather H. Association of multiple copies of the N-myc oncogene with rapid

progression of neuroblastomas. N Engl J Med 1985;313(18):1111–1116.

28. Nakagawara A, Ikeda K, Tsuda T, et al. N-myc oncogene amplification and prognostic factors of

neuroblastoma in children. J Pediatr Surg 1987; 22(10):895–898.

29. Weiss WA. Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J

1997;16(11):2985–2995.

30. Schweigerer L, Breit S, Wenzel A, et al. Augmented MYCN expression advances the malignant

phenotype of human neuroblastoma cells: evidence for induction of autocrine growth factor

activity. Cancer Res 1990;50(14):4411–4416.

31. Cohn SL, London WB, Huang D, et al. MYCN expression is not prognostic of adverse outcome in

advanced-stage neuroblastoma with nonamplified MYCN. J Clin Oncol 2000;18(21):3604–3613.

32. Klein R, Jing SQ, Nanduri V, et al. The trk proto-oncogene encodes a receptor for nerve growth

factor. Cell 1991;65(1):189–197.

33. Brodeur GM, Nakagawara A, Yamashiro DJ, et al. Expression of TrkA, TrkB and TrkC in human

neuroblastomas. J Neurooncol 1997;31(1–2):49–56.

34. Lucarelli E, Kaplan D, Thiele CJ. Activation of trk-A but not trk-B signal transduction pathway

inhibits growth of neuroblastoma cells. Eur J Cancer 1997;33(12):2068–2070.

35. Schleiermacher G, Michon J, Ribeiro A, et al. Segmental chromosomal alterations lead to a higher

risk of relapse in infants with MYCN-non-amplified localised unresectable/disseminated

neuroblastoma (a SIOPEN collaborative study). Br J Cancer 2011;105(12):1940–1948.