Case of the Month

Discussion

Hepatoblastoma is malignant and is the most common primary liver tumor in children, though with an incidence of only about 0.9 per million children (1). This rarity, combined with their histologic diversity detailed below can make them a challenging tumor for pathologists.

Most are diagnosed before the age of 2, and 4% are present at birth. The most common presentation is abdominal distention in a previously healthy child. Other symptoms include failure to thrive, weight loss, and rarely vomiting, diarrhea or jaundice. Precocious puberty is another rare symptom that can occur when the tumor produces human chorionic gonadotropin (2-5). Up to one third of cases are associated with congenital abnormalities such as Beckwith-Wiedemann syndrome, Down syndrome, other chromosomal abnormalities, familial polyposis coli, hemihypertrophy, renal malformations, etc. Trisomy 2, trisomy 20, and 4q abnormalities are the most common chromosomal abnormalities (2). Alpha-fetoprotein is a serum marker for this tumor, but may be normal in the small cell undifferentiated variant described below. Serum marker assessment before 1 year of age is also difficult as this is physiologically elevated in babies (3).

Hepatoblastomas can be divided into at least seven histologic patterns (1-7):

1. The pure fetal pattern accounts for approximately 30% of cases and falls under the more general category of epithelial hepatoblastomas. It is characterized by hepatocytes with mildly increased N:C ratio and an alternating light and dark architectural pattern. Like the normal liver, the cells are arranged in cords two to three cells thick, but unlike normal liver it will lack other structures such as portal tracts.
2. The pure embryonal pattern accounts for 20% of cases and is another epithelial type. Compared to the fetal pattern, it consists of hepatocytes that have coarser chromatin, a higher N:C ratio, a less developed trabecular pattern, mitosis and necrosis.
3. The mixed epithelial and mesenchymal pattern (44% of cases) will contain epithelial cells like those in the previous two types, but will additionally contain mesenchymal components that can be spindle cells, chondroid, rhabdomyoblastic, or osteoid. Osteoid is the most common mesenchymal component.
4. The macrotrabecular pattern (3% of cases) will involve fetal or embryonal-type hepatocytes that form trabeculae at least 5 cells thick (formerly 10 or 20).
5. The small cell undifferentiated pattern (3% of cases) is the least differentiated of the epithelial types and appears similar to other small round blue cell neoplasms.
6. There are also mesenchymal tumors with teratoid features, which means they can produce a variety of mature tissue much like mature teratomas.
7. Recently, a new category called pleomorphic epithelial was added (1, 6). These are similar to fetal or embryonal patterns, but with more atypical morphology that resembles hepatocellular carcinoma.

In this rare tumor, data on the prognostic significance of the various subtypes is limited. However, studies suggest that a pure fetal pattern has a better prognosis, particularly if fully resected (5 year survival approaching 100%). Fully resected, pure fetal type tumors may not require chemotherapy, while chemotherapy is needed for other types (6).

The small cell undifferentiated pattern has a poorer prognosis than other types (5-year survival <50%, range 0-50%). It is unclear how much small cell histology needs to be present to be significant (6-8). The tumors can be heterogeneous in the distribution of histologic subtypes, and so generous sampling is even more critical than usual (1-5).

Resectability is the primary prognostic determinant in this tumor, and so the evaluation of margins by the pathologist will guide therapy and predict prognosis. Per the CAP protocol, staging uses the Children’s Oncology Group system, in which Stage I is fully resected, Stage II is microscopic residual tumor (or intraoperative tumor rupture), Stage III is grossly unresectable, and Stage IV is metastatic, most commonly to the lungs. Unfortunately, historically about 2/3 of cases are unresectable at presentation (1).

In most cases, prognosis is fair in disease confined to the liver with 80% survival at 5 years, but the survival falls to about 40% when metastatic disease is present. However, it should be noted that prognosis may continue to improve over time as treatment is refined. Treatment involves a liver transplant or arterial embolization of the tumor along with chemotherapy (1). The pathologist plays an important role in this disease in determining the course of therapy through careful documentation of histologic subtype and margins.

References

1. Ranganathan, S, et al. (Aug 2016). “Protocol for the Examination of Specimens from Pediatric Patients With Hepatoblastoma.” College of American Pathologists. www.cap.org/cancerprotocols
2. Odze, R., Goldblum, J, editors et al. (2015). Odze and Goldblum surgical pathology of the GI tract, liver, biliary tract, and pancreas. Philadelphia, PA :Saunders/Elsevier.
3. Mills, S., editor et al. (2015). Sternberg's Diagnostic Surgical Pathology, 6th edition. Philadelphia: Wolters Kluwer Health.
4. Bosman, F, editor (2010). WHO Classification of Tumours of the Digestive System. World Health Organization International Agency for Research on Cancer. Lyon: IARC Press.
5. Iacobuzio-Donahue, C. A., & Montgomery, E. (2012). Gastrointestinal and liver pathology. Philadelphia: Elsevier/Saunders.
6. Meyers RL, Tiao G, de Ville de Goyet J, Superina R, Aronson DC. “Hepatoblastoma state of the art: Pre-treatment extent of disease, surgical resection guidelines and the role of liver transplantation.” Curr Opin Pediatr 2014;26:29-36.
7. Haas JE, Feusner J, Finegold MJ. “Small cell undifferentiated histology in hepatoblastoma may be unfavorable.” Cancer 2001; 92:3130–3134.
8. Trobaugh-Lotrario AD, Tomlinson GE, Finegold MJ, et al. “Small cell undifferentiated variant of hepatoblastoma: adverse clinical and molecular features similar to rhabdoid tumors.” Pediatr Blood Cancer 2009; 52:328–334.