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
Figure 25.1 Hepatoblastoma gross features. The cut sur face has variegated appearance; periphery of the tumor is tan brown, while central areas are greyish. Areas of necrosis and hemorrhage are also seen.
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.
Small cell undifferentiated
The small cell undifferentiated subtype is composed of discohesive sheets, nests, and clusters of small cells that resemble the cells of neuroblastoma or other small round blue cell tumors. Sometimes, the clusters of cells are embedded in a myxoid matrix. This subtype typically lacks well-defined acini, trabeculae, or rosette/pseudogland formation. The cells demonstrate very high nuclear-cytoplasmic ratios, scant cytoplasm, relatively fine nuclear chromatin, and inconspicuous nucleoli (Fig. 25.2
). This subtype frequently displays numerous mitotic figures. Immunostains for INI-1 should also be performed because loss of INI-1 has been reported in some cases with small cell undifferentiated histology.9
Small cell undifferentiated hepatoblastomas usually have normal or mildly elevated serum AFP levels.9
This subgroup of hepatoblastomas has a more aggressive behavior and worse survival.9
Per current Children’s Oncology Group (COG) protocol, specimens with any percentage of small cell undifferentiated histology may require more extensive therapy, and the presence and percent of tumor (estimated to nearest 10%) with small cell undifferentiated morphology should be included in the pathology report.
Figure 25.2 Small cell undifferentiated component. The cells have scant cytoplasm, high nuclear-cytoplasmic ratio, and fine nuclear chromatin.
Figure 25.3 Embryonal pattern. Rosettes or pseudogland formation is noted. The cells have basophilic appearance with relatively high nuclear-cytoplasmic ratio.
The embryonal pattern has small basophilic epithelial cells with angulated nuclei and relatively high nuclear-cytoplasmic ratios. The tumor cells mostly show a solid growth pattern but also have scattered areas of rosettes or pseudogland formation (Fig. 25.3
). The embryonal pattern is only rarely seen in isolation, in most cases being found with the fetal pattern. This makes the fetal pattern easier to see because the basophilic embryonal cells are juxtaposed to more eosinophilic fetal cells (Fig. 25.4
). Extramedullary hematopoiesis can be present (Fig. 25.5
). The tumor cells of the embryonal pattern can sometimes resemble the tumor cells in the small cell undifferentiated pattern. However, the tumor cells in the embryonal pattern have a more basophilic appearance at low power, slightly bigger nuclei, and have more cytoplasm.
The fetal pattern is the most common histologic pattern in hepatoblastomas. The fetal type epithelium is more mature appearing than the tumor cells of the small cell undifferentiated or the embryonal patterns. The fetal growth pattern shows bland-appearing tumor cells with moderate amounts of eosinophilic cytoplasm. The cells have recognizable hepatocyte differentiation (Fig. 25.6
). In some areas, the tumor cells will show clear cell change because of glycogen accumulation. The tumor cells grow as solid sheets or thin trabeculae (2 to 3 cells thick) and can show a “light and dark pattern” because of patchy glycogen accumulation (Fig. 25.7
). These alternating light and dark zones can be further highlighted by periodic acid-Schiff (PAS) stains, but are not specific for hepatoblastoma.
Hepatoblastomas that are composed entirely of tumor cells showing a fetal morphology are further divided into those with low mitotic activity (previously called well-differentiated fetal hepatoblastomas), and mitotically active hepatoblastomas (previously called “crowded fetal hepatoblastoma”), using a cutoff of less than or equal to 2 mitoses per 10 high-power fields (40×). The pure fetal hepatoblastoma with low mitotic activity has a favorable prognosis. Complete surgical resection with negative margins is curative, and no adjuvant chemotherapy is required. Pure fetal hepatoblastoma, mitotically active, has more than 2 mitoses per 10 high power fields (40×) (Fig. 25.8
) and has less favorable prognosis.
Figure 25.4 Embryonal pattern with fetal pattern. A basophilic appearing embryonal component (upper right) is juxtaposed to eosinophilic fetal component.
Figure 25.5 Extramedullary hematopoiesis. Immature hematopoietic elements seen in hepatoblastoma.
Figure 25.6 Fetal component. The more mature appearing tumor cells grow as thin trabeculae (2-3 cells thick) and have eosinophilic cytoplasm.
Figure 25.7 Fetal component. Alternating light (clear cells) and dark zones are seen.
The pleomorphic pattern is uncommon. It is not a primitive appearing growth pattern, but instead demonstrates definite hepatocellular differentiation that can resemble adult type hepatocellular carcinomas. The tumor cells in the pleomorphic pattern show
more striking nuclear atypia than the fetal growth pattern. There is moderate nuclear pleomorphism with coarse, basophilic chromatin, and prominent nucleoli (Fig. 25.9
Figure 25.8 Fetal component, mitotically active. Four mitotic figures are seen (40×).
Figure 25.9 Pleomorphic pattern. The cells have moderate degree of nuclear pleomorphism with prominent nucleoli.
Figure 25.10 Macrotrabecular pattern. The tumor is growing in thick trabeculae.
Figure 25.11 Cholangioblastic pattern. Malignant gland-like structures are seen.
The macrotrabecular pattern is rare, being found in <5% of cases. The individual tumor cells usually have a fetal morphology. This subtype is defined by its distinctive growth pattern, characterized by very thick, broad trabeculae (>10 cells thick, Fig. 25.10
). This pattern of thick trabeculae can be nicely highlighted by a CD34 immunostain. The macrotrabecular pattern is almost always seen admixed with other patterns.
The cholangioblastic pattern is very rare, but can be more evident in treated cases. The tumor shows scattered small duct-like structures, usually in a loose mesenchymal background. Sometimes, the findings can resemble a benign reactive ductular proliferation. In most cases, there is sufficient cytological atypia to confidently recognize the cells as neoplastic. The location of the duct-like structures can be another useful clue: tumor-nontumor interface versus deeper in the tumor (Fig. 25.11
), the latter location making a benign ductular proliferation unlikely. Immunohistochemistry for β-catenin can be helpful, as strong diffuse nuclear β-catenin expression indicates malignant process.
About 20% to 40% of hepatoblastomas have a mesenchymal component. The mesenchymal components show various morphologies, but are mostly a mixture of undifferentiated spindle cells and osteoid formation (Fig. 25.12
). Rarely, teratoid components are found, which include endodermal derivatives (squamous, glandular, mucinous epithelium, etc.) and neuroectodermal derivatives such as neuroglial elements or melanin-containing cells (Fig. 25.13
Figure 25.12 Mesenchymal component. Undifferentiated spindle cell areas are seen as well as an osteoid component.
Figure 25.13 Melanin. This hepatoblastoma had aggregates of melanin producing cells (right side of image) scattered throughout the tumor.
Figure 25.14 β-Catenin immunostain. Nuclear β-catenin expression is noted.
Immunohistochemical and molecular findings
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
Figure 25.15 PRETEXT staging. The liver is divided into four sections with boundaries being the right and middle hepatic veins and the umbilical fissure. Stage 1 disease is defined by three contiguous disease-free sections of the liver; Stage 2 by two contiguous disease-free sections of the liver; Stage 3 by one disease-free sections of the liver; Stage 4 disease involving all sections of the liver. When hepatoblastomas are multifocal, additional combinations are possible but are not illustrated for Stages II and III.
Metastasis and recurrence
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