Hepatic Tumors

Abstract

This chapter describes the current diagnosis, staging, and treatment of hepatic tumors. The most common pediatric hepatic tumor is hepatoblastoma. While hepatocarcinomas are usually seen in adults, they do present in children. With the advent of effective chemotherapy significant improvement in survival for patients with hepatoblastoma has occurred, although the treatment of hepatocarcinoma still remains a challenge. Coordination of chemotherapy and surgery is needed. In hepatic tumors, surgery and chemotherapy are essential, with liver transplantation as an accepted surgical option.

Keywords

Hepatoblastoma, hepatocarcinoma, pure fetal histology, α-fetoprotein, human chorionic gonadotropin, PRETEXT

Primary hepatic neoplasms are rare and account for only 1–2% of all childhood cancers. Hepatoblastoma accounts for approximately two-thirds of liver tumors in children. Hepatoblastoma and hepatocellular carcinoma (HCC) are the two most common malignancies that arise de novo in the liver. Table 30.1 lists the most prevalent malignant and benign liver tumors in children.

Table 30.1

Malignant and Benign Liver Tumors in Children

Malignant	Benign
Hepatoblastoma	Hemangioma
Hepatocellular carcinoma	Hemangioendothelioma
Rhabdomyosarcoma	Angiomyolipoma
Undifferentiated embryonal sarcoma	Hamartoma
Angiosarcoma	Biliary cyst
Mesenchymal (mixed)	Adenoma
Sarcoma	Teratoma
Rhabdoid tumor	Myofibroblastic tumor
Yolk sac tumor
Leiomyosarcoma

Incidence

Table 30.2 lists the demographic features associated with hepatoblastoma and HCC. Hepatoblastoma occurs primarily in young children, with 80% of cases reported before 3 years of age. The incidence of hepatoblastoma has increased over the last 25 years. The cause for this increase is unknown, but increased survival of very-low-birth-weight infants may be a contributing factor. The association between the development of hepatoblastoma and low birth weight has been well documented.

Table 30.2

Demographic Features Associated with Hepatoblastoma and Hepatocellular Carcinoma in Children

Host factor	Hepatoblastoma	Hepatocellular carcinoma
Incidence
White males	1.4 per million	0.5 per million
African American males	0.9 per million	0.0 per million
White females	0.5 per million	0.9 per million
African American females	0.0 per million	0.0 per million
Median age	1 year	12 years
Male:female ratio	1.7:1.0	1.0:1.1

Epidemiology

The etiology of hepatoblastoma and HCC is unknown. Certain disorders increase the risk of liver cancer (see Table 30.3 ). Congenital anomalies which have been reported with hepatoblastoma include:

•

Hemihyperplasia syndromes (formerly hemihypertrophy) including Beckwith–Wiedemann syndrome.
•

Meckel’s diverticulum.
•

Congenital absence of adrenal gland.
•

Congenital absence of kidney.
•

Umbilical hernia.

Table 30.3

Disorders Associated with Increased Risk of Hepatoblastoma and Hepatocellular Carcinoma

Hepatoblastoma	Hepatocellular carcinoma
Low-birth-weight infant Von Gierke disease Congenital cystathioninuria and hemihyperplasia Maternal use of hormonal therapy Exposure to metals such as in welding and soldering fumes Beckwith–Wiedemann syndrome Li–Fraumeni syndrome Trisomy 18 Fetal alcohol syndrome Gardner syndrome ^a Type I glycogen storage disease Prader–Willi syndrome	Familial cholestatic cirrhosis of childhood Ataxia telangiectasia Biliary cirrhosis due to bile duct atresia Cirrhosis following giant cell hepatitis Chronic carrier of hepatitis B virus Hereditary tyrosinemia Androgen therapy Methotrexate therapy α ₁-Antitrypsin deficiency Fanconi anemia Type 1 glycogen storage disease Neurofibromatosis Soto syndrome ^b Familial adenomatous polyposis (FAP) Hepatoblastoma Alagille syndrome Wilms’ tumor with liver metastases treated with hepatic radiation

Hepatoblastoma

Hepatocellular carcinoma

Low-birth-weight infant
Von Gierke disease
Congenital cystathioninuria and hemihyperplasia
Maternal use of hormonal therapy
Exposure to metals such as in welding and soldering fumes
Beckwith–Wiedemann syndrome
Li–Fraumeni syndrome
Trisomy 18
Fetal alcohol syndrome
Gardner syndrome ^a
Type I glycogen storage disease
Prader–Willi syndrome

Familial cholestatic cirrhosis of childhood
Ataxia telangiectasia
Biliary cirrhosis due to bile duct atresia
Cirrhosis following giant cell hepatitis
Chronic carrier of hepatitis B virus
Hereditary tyrosinemia
Androgen therapy
Methotrexate therapy
α ₁-Antitrypsin deficiency
Fanconi anemia
Type 1 glycogen storage disease
Neurofibromatosis
Soto syndrome ^b
Familial adenomatous polyposis (FAP)
Hepatoblastoma
Alagille syndrome
Wilms’ tumor with liver metastases treated with hepatic radiation

a Gardner syndrome, a variant of familial adenomatous polyposis, is an autosomal syndrome associated with deletions on the long arm of chromosome 5. It is characterized by colonic polyps that undergo malignant change and benign and malignant extracolonic lesions. Tumors frequently associated with Gardner syndrome include carcinoma of the ampulla of Vater, papillary carcinoma of the thyroid, and, in children, hepatoblastoma. The childhood malignancies often precede the appearance of other manifestations by several years.

b A rare genetic disorder characterized by excessive physical growth during the first 2–3 years of life. They tend to be larger at birth. May have mild mental retardation, delayed development, and hypotonia.

Patients with Beckwith–Wiedemann syndrome and isolated hemihyperplasia should be screened every 3 months for hepatoblastoma with measurements of α-fetoprotein (AFP) tumor markers and abdominal ultrasounds until age 7 years. Though there is an association between hepatoblastoma and familial adenomatous polyposis (FAP), hepatoblastoma occurs in less than 1% of members of families with FAP. Screening in these families is controversial, but in children with APC gene (adenomatous polyposis coli) mutations it may be warranted.

Hepatic tumors have a wide geographic variation in incidence:

1.

They are the third most common abdominal cancer in Japan.
2.

They are seen more frequently in Asian and African children.

The geographic variation is thought to reflect the etiologic role of environmental conditions.

Pathology

Hepatic tumors are divided into two major histologic types: hepatoblastoma and HCC. Other less frequent liver tumors include transitional liver cell tumor, undifferentiated embryonal sarcoma of liver, and infantile choriocarcinoma. The pathologic classifications for hepatoblastoma and HCC are as follows:

1.

Hepatoblastoma.
- a.
  
  Epithelial type.
  - i.
    
    Embryonal pattern.
  - ii.
    
    Pure fetal pattern.
  - iii.
    
    Macrotrabecular type.
  - iv.
    
    Small cell undifferentiated type or anaplastic
- b.
  
  Mixed epithelial and mesenchymal type.
2.

HCC.
3.

Fibrolamellar HCC (a histologic variant of HCC and has a similar prognosis when adjusted for stage).

Clinical Features

The most common sign of primary liver malignancy is an upper abdominal mass or generalized abdominal enlargement. Table 30.4 outlines the clinical features of the various pathologic types of hepatic tumors. Table 30.5 shows the frequency of signs and symptoms at diagnosis in children with hepatoblastoma and HCC. The clinical manifestations are similar in both.

Table 30.4

Clinical Features of the Various Pathological Types of Hepatic Tumors

Feature	Hepatoblastoma	Hepatocellular carcinoma	Fibrolamellar variant
Usual age of presentation	0–3 year	5–18 year	10–20 year
Associated congenital anomalies	Dysmorphic features	Metabolic	None
	Hemihyperplasia
	Beckwith–Wiedemann syndrome
Advanced disease at presentation	40%	70%	10%
Usual site of origin	Right lobe	Right lobe, multifocal	Right lobe
Abnormal liver function tests	15–30%	30–50%	Rare
Jaundice	5%	25%	Absent
Elevated AFP	60–70%	50%	10%
Positive hepatitis B serology	Absent	Present in some	Absent
Abnormal B12-binding protein	Absent	Absent	Present
Chromosomal abnormalities	11p15.5, 18, 17p13 occasional loss of heterozygosity	17q11.2, 20p12, 11q22-23 rare presence of TP53 mutation	Not reported
Distinctive radiographic appearance	None	None	None
Pathology hepatocytes	Fetal and/or embryonal cells + mesenchymal component	Large pleomorphic tumor cells and tumor giant cells	Eosinophilic with dense fibrous stroma