Contributed by Jennifer Yoest, MD and Sarangarajan Ranganathan, MDFINAL DIAGNOSIS
WELL-DIFFERENTIATED FETAL HEPATOBLASTOMA
DISCUSSION
Liver tumors in children are rare, however, two thirds of pediatric liver masses are malignant and close to 70% of these malignancies are of hepatocellular origin. The two main differential diagnoses for this category of malignancies are hepatocellular carcinoma (HCC) and hepatoblastoma (HB). Of these, hepatoblastoma is the most common pediatric liver malignancy and accounts for 1% of pediatric malignancies overall. Hepatoblastoma typically presents before the first 3 to 4 years of life and can be associated with congenital syndromes or heritable tumor or cancer syndromes. There is a strong predilection for low birth weight infants, the etiology of which is unclear. Specific syndromes associated with HB include Beckwith-Wiedemann syndrome and Familial Adenomatosis Polyposis syndrome (FAP). Pediatric hepatocellular carcinomas, on the other hand, tend to present later in childhood and be secondary to other underlying pathologies which cause cirrhosis, especially metabolic liver diseases.
Clinically, hepatoblastoma usually presents as an abdominal mass and an elevated serum AFP level. Grossly, they are well-circumscribed, solid tumors with heterogeneous areas of hemorrhage and necrosis, especially after treatment.
There are several histologic patterns seen in hepatoblastomas which resemble various stages of hepatocyte development, which are then grouped into larger histologic subtypes. The most commonly seen subtype is the epithelial subtype, which includes fetal, crowded fetal, embryonal, macrotrabecular and small cell undifferentiated (also called anaplastic) patterns. Other subtypes include mesenchymal and a catch-all category of other components. Overall, hepatoblastoma histology is quite variable. However, epithelial patterns, either purely or mixed with other subtypes, account for more than 95% of hepatoblastomas.
Pure well-differentiated fetal pattern: 100% of neoplastic hepatocytes display a recapitulation of fetal liver parenchyma with smaller hepatocyte size and nuclear to cytoplasmic ratio, abundant eosinophilic, amphophilic or clear cytoplasm and small central nuclei with no nucleoli. The lesional cells are arranged in 2-cell-thick cords with rare (<2/10hpf) mitoses. Low power views of this pattern have a characteristic "light and dark" appearance due to cytoplasmic tinctorial qualities. This diagnosis can only be suggested on biopsy, but can be made definitively on resection if the specimen is well sampled and the entire tumor is composed of this single histologic pattern.
Crowded fetal pattern (also called "mitotically active" fetal HB): architecturally resembles the fetal pattern, but with a larger nuclear to cytoplasmic ratio, more eosinophilic cytoplasm and more numerous mitoses (less than 2/10hpf). This pattern is usually intermixed between areas of fetal pattern and embryonal pattern, and frequently bridges and merges the two. Extramedullary hematopoiesis can be seen.
Embryonal pattern: emulates the embryonal stage of liver development and features high nuclear to cytoplasmic ratio with indistinct cell borders and a large nucleus with prominent nucleolus. The nuclei may be angulated and are larger than in fetal patterns. Crowding of cells and frequent mitoses are also features of this pattern. Extramedullary hematopoiesis is a more prominent feature than in the crowded fetal pattern, but is not a reliable measure for distinguishing the patterns from each other.
Small cell (anaplastic or undifferentiated) pattern: resembles the most primitive stage of liver development and consists of round blue cells with large nuclear to cytoplasmic ratio, nuclei that vary from pale and vesicular to hyperchromatic, and indistinct cell borders. Rhabdoid features including eccentric nucleoli and eosinophilic cytoplasmic globules can be seen. Mitoses can be numerous, but can also be rare. This pattern is usually seen as a small component intermixed with other epithelial subtypes but rarely can be the predominant component (>70%) in which case they may be associated with loss of INI1 staining seen in the group of malignant rhabdoid tumors.
Mixed mesenchymal-epithelial subtypes of hepatoblastoma are tumors which can include osteoid, rhabdomyomatous, or primitive spindled cell components. Patterns containing ductular components (cholangioblastic) melanin pigment and retinal epithelium or immature neuroepithelium (teratoid), and even squamous or mucinous epithelium can also be seen.
Immunohistochemical staining patterns can be an important part of the diagnosis, especially with the variation in histologic appearance and when differentiating hepatoblastoma from adenoma and hepatocellular carcinoma. Since a majority of hepatoblastomas have defects in the WNT signaling pathway, beta-catenin staining is useful, showing a nuclear staining pattern in most cases with or without significant cytoplasmic staining. This can be seen in all histologic subtypes, though the well-differentiated fetal pattern can have less nuclear staining compared to other epithelial subtypes. However, a small subset of pediatric hepatocellular carcinomas is also positive for beta-catenin, as are the beta-catenin mutated adenomas. Glypican 3 is positive in a cytoplasmic pattern in the pure fetal, crowded fetal, and embryonal patterns, with a fine granular staining often seen in the fetal histologic type (as in this case). Glypican 3 staining will distinguish hepatoblastomas and hepatocellular carcinomas from benign processes such as adenoma and focal nodular hyperplasia. Glutamine synthetase is also positive in the pure fetal and crowded fetal histologic patterns and is variably positive in the embryonal pattern. Together, positivity for beta-catenin, glypican 3 and glutamine synthetase would strongly favor a diagnosis of hepatoblastoma and be further supported by the proper clinical context.
Complete resection is the mainstay of treatment, with neoadjuvant or adjuvant chemotherapy to shrink inoperable tumors to resectable sizes. If complete resection is not possible, orthotopic liver transplantation may be considered as an alternative. Tumors with a well-differentiated histology, such as in this case, generally have a better prognosis. However, the tumor stage is the most important prognostic indicator, with Stage IV portending the worst prognosis. While the COG staging system is used primarily in the US, there is a trend to shift all staging to the European SIOPEL group staging system known as the PRETEXT system. Children's Oncology Group Staging System for Hepatoblastoma (pretreatment):
REFERENCES
Contributed by Jennifer Yoest, MD and Sarangarajan Ranganathan, MD
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