A small cell undifferentiated component is present in some hepatoblastomas as small clusters of cells and can rarely be the sole pattern seen in the tumor (mostly in infants). The small cell undifferentiated pattern is composed of small basophilic blastemal-type cells characterized by a very high nuclear-to-cytoplasmic ratio, scant cytoplasm, relatively fine nuclear chromatin, and inconspicuous nucleoli (Fig. 14.2). The tumor cells grow in large solid sheets or with slightly nested patterns. The tumor cells are often poorly cohesive and mitotic activity is high. The small cell undifferentiated epithelium can be intimately admixed with other epithelial types and may be confused with “blastemal” or plump spindle cell areas.

Tumors that are composed largely of the small cell undifferentiated pattern need to be carefully examined for histological features of rhabdoid tumor, which can benefit from different chemotherapy. Immunostaining for INI-1, discussed further below, is critical in this distinction. Otherwise typical hepatoblastomas with small clusters of the small cell undifferentiated pattern tend to have retained INI-1 staining in all of the components and do not have tumor cells with typical rhabdoid morphology.

Epithelial hepatoblastomas with fetal or embryonal histology should be searched carefully for small clusters of the small cell undifferentiated pattern, as this increases their risk for aggressive behavior. However, recognizing small clusters of the small cell undifferentiated pattern can be challenging in practice, as they have histological overlap with the embryonal pattern. One helpful approach is to compare the cytology with published images or known study sets. Cytology findings can also be helpful, as the tumor cells in the small cell undifferentiated pattern have round or oval nuclei, finely dispersed chromatin, and inconspicuous nuclei. In contrast, the embryonal pattern tends to have more angulated and basophilic nuclei and can have somewhat more prominent nucleoli. The embryonal pattern also commonly has slightly bigger cells with more cytoplasm. Brisk mitotic activity can be seen in either morphology but is often more striking in the embryonal pattern. Finally, extensive sampling is very helpful in resected specimens, as most cases with foci of the small cell undifferentiated pattern will also have more obvious areas of the embryonal and fetal patterns, which are useful for comparison. There are currently no validated immunostains that can help in this distinction, but an INI-1 stain should be performed to ensure there is retained INI-1 nuclear staining.

The embryonal pattern has recognizable hepatocellular differentiation but consists of atypical, small, basophilic epithelial cells, with high nuclear-to-cytoplasmic ratios, and angulated nuclei (Fig. 14.3). The tumor cells grow in a predominantly solid pattern but there can be frequent formation of rosettes or pseudoglands (Fig. 14.4). This pattern essentially always coexists with the fetal pattern and can often be recognized at low power as distinct basophilic areas. Extramedullary hematopoiesis may be seen in association with either fetal or embryonal patterns (Fig. 14.5).

The fetal pattern (Fig. 14.6) represents the most common histologic component of hepatoblastomas and is present in most cases. This pattern is formed by a proliferation of generally bland-appearing hepatocytes. The fetal type hepatocytes have moderate amounts of eosinophilic cytoplasm and can also have varying degrees of glycogen accumulation that causes the classic “light and dark pattern” at low power examination (Fig. 14.7). A PAS stain further accentuates this pattern but is not needed for diagnosis. Also of note, this “light and dark pattern,” while distinctive, is not specific for hepatoblastoma and can sometimes be seen in hepatocellular carcinomas. The tumor cells grow in solid sheets or as thin trabeculae (2–3 cells thick), closely resembling fetal liver. They have finely dispersed chromatin and inconspicuous nucleoli. Mitotic activity is variable. For hepatoblastomas with pure fetal morphology and mitotic counts of less than 2 per high-power field, complete surgical resection is curative and additional chemotherapy is not necessary. The diagnosis of pure fetal hepatoblastoma with low mitotic counts requires complete resection and extensive sampling of the tumor. If there are more than two mitoses in ten high-power fields, the prognosis is worse and the hepatoblastoma is classified as the “crowded fetal type” or the more preferred designation of “Hepatoblastoma, fetal type, mitotically active” (Fig. 14.8).

The pleomorphic pattern is uncommon. The epithelium can be either fetal or embryonal type but has significantly increased atypical nuclear features (Fig. 14.9). The atypia includes moderate to marked nuclear pleomorphism, coarser chromatin than seen in the usual fetal or embryonal epithelium, and prominent nucleoli. Some cases can be difficult to reliably distinguish from hepatocellular carcinoma, especially if the sample is small and the age or clinical findings are not typical for hepatoblastoma.

The macrotrabecular pattern (Fig. 14.10) is seen in a minority of cases (approximately 5 % of hepatoblastomas). The tumor shows a distinctive growth pattern with very thick trabecular architecture (>10 cells thick). The cytological features are otherwise identical to other epithelial subtypes, most commonly fetal or pleomorphic. A CD34 immunostain shows a distinctive pattern, outlining the thickened trabeculae (Fig. 14.11). Of note, hepatoblastomas with only a macrotrabecular pattern are essentially indistinguishable from adult hepatocellular carcinomas (see also Chap. 7), which can also have a similar growth pattern, high serum AFP levels, and similar cytology. Thus, a diagnosis of the macrotrabecular pattern of hepatoblastoma is made most confidently when sections show other areas of more typical hepatoblastoma. If only the macrotrabecular pattern is seen on a biopsy, then histology itself does not reliably separate these two possibilities. If other findings such as age or underlying liver disease are not informative, then the best approach is to convey the complexity of the case and provide a differential.

The cholangioblastic pattern is also seen in a small subset of hepatoblastomas, in which small ductular structures are present within the tumor, either mixed within or surrounding areas showing a hepatocellular component. The ductular component is positive for keratins but negative for hepatocellular markers. The ductular component can be very difficult to distinguish from a benign bile ductular reaction on H&E stains. In these cases, aberrant beta-catenin nuclear expression indicates that the cholangiolar structures are neoplastic. Cholangiolar-type epithelium and structures can also be seen posttreatment, but in this setting there can be striking cytological atypia (Fig. 14.12).

While an epithelial component is a required diagnostic feature of hepatoblastoma, a mesenchymal/stromal component is present in 20–40 % of cases and may include osteoid material (Fig. 14.13), skeletal muscle, cartilage, or a nondescript spindle cell (“blastemal”) component (Fig. 14.14); tumors containing such elements are termed “mixed” hepatoblastomas. Heterologous elements, including endoderm (squamous epithelium, glandular/mucinous epithelium, etc.) and neuroectoderm derivates (neural cells, glial elements, melanin-containing cells, etc.) are present in a minority of cases (approximately 10 %) and characterize a “teratoid” component. These basic patterns serve as the “backbone” for the currently recommended subclassification of hepatoblastomas (see also Table 14.1) [16].