Teratoid Hepatoblastoma With Abundant Neuroendocrine and Squamous Differentiation With Extensive Parenchymal Metastasis

A 1½-year-old girl presented to another institution with decreased oral intake, lethargy, and increased abdominal girth. On physical examination she was found to have an abdominal mass. A computed tomography scan of her abdomen demonstrated numerous nodules replacing most of the left lobe of her liver in addition to many nodules throughout the right lobe of her liver and both lungs. Serum alpha fetoprotein level was 105 000 ng/mL (reference range, <8.0 ng/mL). She underwent open liver biopsy and was treated according to Children's Oncology Group protocol for stage IV hepatoblastoma. She had significant reduction in the liver tumor burden; lung biopsies showed no viable tumor. She underwent liver transplantation at our institution and is alive with no evidence of disease 1 year later.

Review of the pretreatment liver biopsy revealed an epithelial neoplasm with prominent desmoplastic stroma. Tumor cells were arranged in irregular angulated nests and nodules with central comedo-type necrosis. Epithelial tumor cells varied from basaloid at the periphery of the nodules to larger cells centrally with squamous differentiation and keratin pearl formation. The nuclei were hyperchromatic and nucleoli were inconspicuous. Variable amounts of eosinophilic to clear cytoplasm were seen with distinct cytoplasmic borders. Mitotic figures were easily seen. Tumor cells stained focally with immunohistochemical stains directed against epithelial membrane antigen, keratin 5, 6, and 19, and P63. An immunohistochemical stain for α-fetoprotein was equivocal and stains for both hepatocyte antigen and glypican 3 were negative. A stain for β-catenin showed nuclear and cytoplasmic staining.

The explanted liver weighed 550 g. The capsular surface was extensively nodular. The cut section showed many well-circumscribed whitish tumor nodules in both lobes; the largest, in the posterior portion of the left lobe, measured 2.5 cm and showed necrosis and hemorrhage (Figure 1). The right lobe nodules clustered in the anterior portion without obvious treatment effect.

Extensive sampling of the whitish nodules from both lobes revealed tumor with exuberant desmoplasia and squamous differentiation similar to the biopsy without hepatocytic or any other line of differentiation (Figure 2). The larger necrotic nodule from the left lobe showed rare foci resembling fetal and embryonal hepatoblastoma mixed with bone, undifferentiated glandular elements with stratified squamous epithelium, neuroepithelial tissue with rosette formation, cords and nests of small cells with bland nuclei reminiscent of neuroendocrine differentiation, spindle cell mesenchyme, and aggregates of melanin-containing cells consistent with mixed hepatoblastoma with teratoid features (Figures 3 and 4). No small cell anaplastic component was noted. Numerous tumor vascular thrombi were present in many portal areas even away from grossly recognizable tumor nodules. Stains for α-fetoprotein, hepatocyte antigen, and glypican 3 (Figure 5) were positive in the residual fetal and embryonal epithelial hepatocytic areas in the left lobe nodule, but were completely negative in the basaloid squamous and glandular areas. Immunohistochemical stains using a pancytokeratin cocktail (AE1/3) and an antibody directed against cytokeratin 19 were strongly positive in the glandular and squamous areas and focally positive in the more differentiated fetal and embryonal hepatoblastoma areas. A stain for high-molecular-weight cytokeratins (cytokeratins 5 and 6) was focally positive in the basaloid elements. Chromogranin A was strongly positive in several cords and nests adjacent to the classic fetal/embryonal hepatoblastoma, in some glandular structures, and focally in the basaloid squamous areas, indicating neuroendocrine differentiation (Figure 6). CD56 highlighted some of the undifferentiated glandular structures. P63 stained some of the peripheral basaloid cells, and β-catenin showed cytoplasmic and focal nuclear staining in the basaloid, squamous, and glandular structures. Stains for desmin and myogenin were negative. Portal lymph nodes were negative for metastasis.

Our patient's liver biopsy raised an unusual differential diagnosis that included an unusual variant of hepatoblastoma and metastatic poorly differentiated epithelial neoplasm (because of the lack of obvious hepatocytic differentiation). Metastasis from other sites was ruled out by imaging, and a combination of clinical, laboratory, and histologic features was most consistent with hepatoblastoma. The diagnosis of mixed hepatoblastoma with teratoid features was confirmed at hepatectomy.

The largest nodule in our patient's left hepatic lobe was likely the primary tumor, and revealed classic fetal and embryonal hepatocytic differentiation mixed with primitive spindle cell areas and osteoid in addition to teratoid features that included neuroepithelial, neuroendocrine, and cholangioblastic differentiation as well as basaloid/squamoid islands and melanin-containing areas. This hepatoblastoma exhibited several unusual features, including extensive intrahepatic vascular and parenchymal metastasis noted before and after therapy. The bulk of the tumor showed prominent basaloid/squamoid differentiation and desmoplastic response. Only the basaloid/squamoid elements were present in the innumerable sampled metastatic nodules in both lobes of liver and appeared viable, suggesting that this was a more aggressive part of this neoplasm. This component also did not have significant morphologic treatment effect following standard chemotherapy protocol for hepatoblastoma, suggesting it was resistant to chemotherapy.

Primary malignant liver tumors are rare, accounting for about 1% of all childhood malignancies, and the most common types are hepatoblastomas, hepatocellular carcinomas, and sarcomas.¹  Ninety percent of hepatoblastomas occur in the first 5 years of life, and 5% of the cases are congenital. There is a noticeable trend in the last couple of decades of increased incidence of hepatoblastomas in infants who were born prematurely or with very low birth weight.¹  There are several syndromes associated with hepatoblastoma, including familial adenomatous polyposis, Beckwith-Wiedemann syndrome, and trisomy 18.¹  Clinically, 80% of patients present with a single mass and 20% present with multiple nodules.

Hepatoblastomas have been histologically classified into 2 broad categories, epithelial and mixed type.¹  The latter contains epithelial and mesenchymal elements. The majority of hepatoblastomas are epithelial, with variable amounts of embryonal and fetal cell morphology similar to the developing liver. The mixed type may also show a combination of bone, cartilage, fibrous tissue, and skeletal muscle differentiation. Rare mixed tumors classified as hepatoblastomas with teratoid features show variable amounts of other heterologous elements such as stratified squamous, mucinous, and ductular cholangioblastic epithelium, immature neuroepithelium, neuroendocrine differentiation, and melanin pigment.^2–4  This category of hepatoblastomas was first recognized by Manivel et al¹ in 1986. Some reports describe mixed hepatoblastoma and teratoma as combined tumors that probably represent teratoid hepatoblastomas.^5,6  This divergent differentiation is thought to be related to the pluripotential stem cell precursors, which have the ability to differentiate into all of these different components.^4,7 

Neoadjuvant chemotherapy for hepatoblastoma usually results in considerable reduction of tumor. Typical changes include tumor necrosis, a fibrohistiocytic response, peliosis-like areas, cytoarchitectural differentiation mimicking nonneoplastic hepatocytes and bile ducts, and hepatocellular carcinoma–like changes.⁷  Only the large nodule in our case showed some of these changes, mainly necrosis, fibrohistiocytic response, and cytoarchitectural differentiation. The metastatic nodules did not show these secondary changes. A previous study⁷  suggested that larger posttreatment tumor size and vascular invasion were associated with metastatic disease, but it is not clear if different histologic subtypes have different potential for recurrence or metastasis. Our case suggests that the basaloid/squamous differentiation may be associated with increased potential for hematogenous spread and possibly resistance to standard chemotherapy.

Teratoid hepatoblastomas may mimic other pediatric tumors, especially teratomas, and their recognition can be challenging in small biopsy samples. This case emphasizes the importance of recognizing this rare and unusual variant of hepatoblastoma and the need for additional staining to better categorize these types of tumors.⁷