Hepatoblastomas are the most common liver tumors in infants and children. Overall, 90% of cases are diagnosed before the age of 5 years.¹ There is a modest male predominance with about a male to female ratio of 2:1.¹ Clinical findings at presentation are nonspecific but can include a palpable abdominal mass, abdominal pain, weight loss, and jaundice.² A variety of paraneoplastic findings have also been reported, and the most common are anemia and thrombocytosis. Rarely, hepatoblastomas produce human chorionic gonadotropin and lead to virilization and precocious puberty.³ Patients do not have underlying chronic liver disease. Hepatoblastomas rarely have been reported in adults, though many of these cases are somewhat suspect, not being sufficiently well documented to rule out other potential mimics.

The etiology of hepatoblastomas is unknown, but there is a strong association with prematurity and low birth weight, especially <1,500 g. Hepatoblastomas are also associated with several clinical syndromes including familial adenomatosis polyposis⁴ and the Beckwith-Wiedemann syndrome.⁵

A marked elevation in serum α fetoprotein (AFP) is noted in >90% of cases and is an important tool in the diagnostic workup. However, elevated serum AFP levels are not specific to hepatoblastoma because they can be seen in other benign and malignant liver tumors, including mesenchymal hamartomas⁶ and hepatocellular carcinomas. Also of note, a small subset of hepatoblastomas (2% to 4%) has normal or mildly elevated serum AFP levels (<100 ng/mL).⁷ This group of tumors has a worse prognosis, in most cases because of an association with the more aggressive small cell undifferentiated morphology.

Hepatoblastomas are well-circumscribed and usually solitary lesions (Fig. 25.1), but they can be multifocal. The background liver is noncirrhotic, but there can be a rim of inflamed and fibrotic background liver at the tumor-nontumor interface. The cut surface of the tumor has a variegated appearance, reflecting the different components of the tumor. The epithelial components tend to be tan brown in color, whereas the mesenchymal areas tend to be more grey-white in color. Areas of necrosis, hemorrhage, and cystic degeneration can be encountered, especially in cases with neoadjuvant therapy. Adequate tumor sampling is critical for proper tumor evaluation, allowing the identification of the various epithelial and mesenchymal components. Per standardized protocol, at least one section per centimeter of tumor diameter should be submitted.⁸

Hepatoblastomas display a wide variety of histologic patterns, including various combinations of epithelial as well as mixed epithelial and mesenchymal components. By definition, an epithelial component is needed for the diagnosis. Most hepatoblastomas (70%) are purely epithelial, while the remaining cases have both epithelial and mesenchymal components. Hepatoblastomas are currently subclassified into the following subtypes⁸:

1. Hepatoblastoma, pure fetal with low mitotic activity (≤2 mitoses/10 high-power fields)

2. Hepatoblastoma, pure fetal, mitotically active (>2 mitoses/10 high-power fields)

3. Hepatoblastoma, epithelial type, pleomorphic fetal

4. Hepatoblastoma, epithelial type, embryonal

5. Hepatoblastoma, epithelial type, macrotrabecular

6. Hepatoblastoma, epithelial type, small cell undifferentiated

7. Hepatoblastoma, epithelial type, cholangioblastic

8. Hepatoblastoma, mixed epithelial type (combination of any or all of the above components)

9. Hepatoblastoma, mixed epithelial and mesenchymal components

a. Without teratoid features

b. With teratoid features

The fetal pattern is the most common type of epithelium, being found in 80% to 90% of cases, either alone or in combination with other types of epithelium. Overall, about one-third of hepatoblastomas are composed solely of fetal type epithelium. In contrast, the embryonal pattern is present in 30% of cases, where it is almost always admixed with fetal type epithelium. The other epithelial types are seen in 5% of cases or less and are also typically admixed with other epithelial subtypes.

Hepar-1 and Arginase are typically positive in fetal and embryonal patterns, but negative in the small cell undifferentiated pattern. β-Catenin is normally expressed as membranous staining in benign hepatocytes and bile ducts. Two abnormal patterns of β-catenin expression are found in hepatoblastomas: nuclear staining (Fig. 25.14) or diffuse cytoplasmic staining. Abnormal nuclear expression is best seen in the embryonal pattern. The fetal pattern can show only focal or patchy β-catenin nuclear staining. Glypican-3 can be positive in any of the patterns. INI-1 immunostain should be performed on hepatoblastomas with a small cell undifferentiated morphology because loss of INI-1 expression can be seen in a subset of cases.⁹ Cases with INI-1 loss typically require more aggressive chemotherapy. The main molecular finding in hepatoblastomas is mutations involving exon 3 of the CTNNB1 gene (β-catenin). The majority of mutations are deletions and these lead to nuclear accumulation of β-catenin protein and aberrant activation of the Wnt signaling pathway. Neither the genetic changes nor nuclear accumulation of β-catenin is specific for hepatoblastoma, being found in other tumors of the liver including conventional hepatocellular carcinoma.

Two staging systems are currently used for hepatoblastomas: the first is the COG system and the second is the PRETEXT (pretreatment extent of disease) staging system. The COG system is a postsurgical staging system adopted by the American Children Oncology Group that recommends surgical resection as the initial treatment (Table 25.1). The PRETEXT system is a preoperative or pretreatment staging system and is based on pretreatment imaging findings to determine the size, site, and extent of disease. This system is helpful to determine risk stratification, monitor response to chemotherapy, and predicts surgical respectability. In this system, the liver is divided into four segments, and each segment is evaluated for involvement by the tumor. This system has four categories (PRETEXT I, II, III, and IV) depending on the number of segments involved by the tumor (Fig. 25.15).

Approximately 20% of hepatoblastomas are metastatic at the time of initial diagnosis.¹⁰ The lungs are the most common site of metastases.¹¹ Hepatoblastomas developing in utero may metastasize to the placenta.¹² The recurrence rate of hepatoblastomas after complete remission is about 10%.¹³ The median time to relapse after initial diagnosis is about 12 months. The major risk factors for recurrence of hepatoblastoma are as
follows: PRETEXT IV, metastases at presentation, older age at diagnosis, low AFP level, the presence of vascular involvement, and the presence of a small cell undifferentiated component.¹⁴ The most common sites of recurrence are liver, lungs, peritoneum, and brain.¹⁴

Malignant rhabdoid tumors are rare, but can be primary to the liver. In the largest studies to date, the median age of presentation was 8 months and mean age was 2 years.¹⁹ There is modest male predominance. Patients present with nonspecific findings that can include palpable abdominal masses, hepatomegaly, fever, anorexia, vomiting, and lethargy. Common laboratory findings include anemia, thrombocytopenia, and elevated liver enzyme levels. Serum AFP levels are normal or minimally activated. Spontaneous tumor rupture occurs in up to 20% of cases.²⁰ Sixty percent of patients have metastatic disease at the time of presentation.¹⁹

The tumors are typically very large and frequently involve multiple lobes of the liver. Tumors have variegated lobulated cut surfaces, with areas of hemorrhage, necrosis, calcifications, and sometimes large areas of cystic degeneration.

Malignant rhabdoid tumors are epithelioid malignant neoplasms with predominantly solid and thick trabecular growth patterns, but there can be spindled or pseudoacinar morphology. The neoplastic cells are large, round to polygonal, and discohesive with abundant dense eosinophilic cytoplasm (Fig. 25.16). They have round vesicular nuclei that are eccentrically located in the cell cytoplasm, along with prominent nucleoli. In a subset of cases, the cytoplasm contains distinctive round hyaline filamentous perinuclear inclusions that push the nucleus to the edge of the cell. Extensive areas of necrosis are common and can elicit a reactive lymphohistiocytic infiltrate and myxoid stromal changes.

The most important stain is INI-1, which is a very sensitive and specific marker for the diagnosis of malignant rhabdoid tumor. The loss of nuclear INI-1 expression by immunohistochemical stain results from mutations/deletions in the SMARCB1/INI-1. Markers of epithelial differentiation are frequently positive. The majority
of tumors are positive for pancytokeratin (AE1/AE3, OSCAR), CK8 (low molecular weight keratin), and epithelial membrane antigen (EMA). The extent of keratin expression varies from focal or patchy to diffuse staining. Vimentin can show strong paranuclear expression. Of note, these tumors do not express markers of skeletal muscle differentiation such as myogenin or myo-D1. Glypican-3 is positive in two-third of cases,²¹,²² but more specific markers of hepatic differentiation are negative, including HePar1 and Arginase. Other markers such as S-100, NSE, synaptophysin, SMA, CD34, and CD99 can show variable nonspecific immunostaining.