Cellular Classification

Hepatoblastoma
Hepatocellular Carcinoma
Undifferentiated Embryonal Sarcoma of the Liver
Infantile Choriocarcinoma of the Liver

Hepatoblastoma arises from precursors of hepatocytes and can have several morphologies, including the following:

• Small cells that reflect neither epithelial nor stromal differentiation.
• Embryonal epithelial cells resembling the liver epithelium at 6 to 8 weeks of gestation.
• Well-differentiated fetal hepatocytes morphologically indistinguishable from normal fetal liver cells.

Most often the tumor consists of a mixture of epithelial hepatocyte precursors. About 20% of tumors have stromal derivatives such as osteoid, chondroid, and rhabdoid elements. Occasionally neuronal, melanocytic, squamous, and enteroendocrine elements are found. Two histologic subtypes have clinical relevance: pure fetal histology throughout the tumor and foci of small cell undifferentiated cells.

Analysis of patients with initially resected hepatoblastoma tumors (prior to receiving chemotherapy) has suggested that those patients with pure fetal histology (PFH) tumors have a better prognosis than those having an admixture of more primitive and rapidly dividing embryonal components or other undifferentiated tissues. In a study of patients with hepatoblastoma and (PFH) tumors, there was a 100% survival rate for patients who received four doses of single-agent doxorubicin.[1] This suggested that patients with PFH tumors might not need chemotherapy after complete resection of a stage I tumor.[2,3] In the Children's Oncology Group (COG) study COG-P9645, patients with stage I PFH hepatoblastoma with two or fewer mitoses per 10 high power fields were not treated with chemotherapy.

Small cell undifferentiated hepatoblastoma is an uncommon hepatoblastoma variant that represents a few percentage of all hepatoblastomas. It tends to occur at a younger age (6–10 months) compared to other cases of hepatoblastoma[4,5] and is associated with low alpha-fetoprotein at presentation.[4,6]

Histologically, small cell undifferentiated hepatoblastoma is typified by a diffuse population of small cells with scant cytoplasm resembling neuroblasts.[7] The chromosomal abnormalities reported for small cell undifferentiated hepatoblastoma are distinctive from those occurring in other hepatoblastoma subtypes and are more similar to those observed in malignant rhabdoid tumors. These abnormalities include translocations involving a breakpoint on chromosome 22q11 and homozygous deletion at the chromosome 22q12 region that harbors the SMARCB1/INI1 gene.[4,8] Lack of detection of INI1 by immunohistochemistry is another characteristic shared by small cell undifferentiated hepatoblastoma and malignant rhabdoid tumors.[4] A third characteristic shared between small cell undifferentiated hepatoblastoma and malignant rhabdoid tumors is the poor prognosis associated with each.[4,5,9] Patients with small cell undifferentiated hepatoblastoma whose tumors are unresectable have an especially poor prognosis.[4] Patients with Stage I tumors appear to have increased risk of treatment failure when small cell elements are present.[10] For this reason, completely resected tumors composed of pure fetal histology or of mixed fetal and embryonal cells must have a thorough histologic examination as small foci of undifferentiated small cell histology indicates a need for aggressive chemotherapy.[10] Aggressive treatment for this histology is under investigation in the current COG study COG-AHEP0731. Hepatoblastoma which would otherwise be considered very low or low-risk is upgraded to intermediate-risk if any small cell undifferentiated elements are found (See Stage Information section for more information.)

The cells of the adult-type hepatocellular carcinoma are epithelial while hepatoblastoma has a less differentiated embryonal appearance. Hepatocellular carcinoma also differs from hepatoblastoma in that it often arises in a previously abnormal, cirrhotic liver. Both histologic types more commonly arise in the right lobe of the liver.

A distinctive histologic variant of hepatocellular carcinoma, termed fibrolamellar carcinoma, has been described in the livers of older children and young adults. Fibrolamellar carcinoma has been associated with an improved prognosis and is not associated with cirrhosis.[11-13] The improved outcome in older series may be related to a higher proportion of tumors being less invasive and more resectable in the absence of cirrhosis, as the outcome in recent prospective studies, when compared stage for stage, is not different from other hepatocellular carcinomas.[14,15] Fibrolamellar hepatocellular carcinoma has also been reported in infants.[16]

Undifferentiated embryonal sarcoma of the liver is a distinct clinical and pathologic entity and accounts for 2% to 15% of pediatric hepatic malignancies.[17] Distinctive features are intracellular hyaline globules and marked anaplasia on a mesenchymal background.[18]

These tumors are usually very friable and hemorrhagic and may present with bleeding into the tumor. Cytotrophoblasts and syncytiotrophoblasts are both present. The former are closely packed nests of medium-sized cells with clear cytoplasm, distinct cell margins, and vesicular nuclei. The latter are very large multinucleated syncytia formed from the cytotrophoblasts.[19]

References

1. Ortega JA, Douglass EC, Feusner JH, et al.: Randomized comparison of cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: A report from the Children's Cancer Group and the Pediatric Oncology Group. J Clin Oncol 18 (14): 2665-75, 2000.  [PUBMED Abstract]
   
   
2. Weinberg AG, Finegold MJ: Primary hepatic tumors of childhood. Hum Pathol 14 (6): 512-37, 1983.  [PUBMED Abstract]
   
   
3. Haas JE, Muczynski KA, Krailo M, et al.: Histopathology and prognosis in childhood hepatoblastoma and hepatocarcinoma. Cancer 64 (5): 1082-95, 1989.  [PUBMED Abstract]
   
   
4. 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 52 (3): 328-34, 2009.  [PUBMED Abstract]
   
   
5. Meyers RL, Rowland JR, Krailo M, et al.: Predictive power of pretreatment prognostic factors in children with hepatoblastoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 53 (6): 1016-22, 2009.  [PUBMED Abstract]
   
   
6. De Ioris M, Brugieres L, Zimmermann A, et al.: Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: the SIOPEL group experience. Eur J Cancer 44 (4): 545-50, 2008.  [PUBMED Abstract]
   
   
7. Rowland JM: Hepatoblastoma: assessment of criteria for histologic classification. Med Pediatr Oncol 39 (5): 478-83, 2002.  [PUBMED Abstract]
   
   
8. Gunawan B, Schäfer KL, Sattler B, et al.: Undifferentiated small cell hepatoblastoma with a chromosomal translocation t(22;22)(q11;q13). Histopathology 40 (5): 485-7, 2002.  [PUBMED Abstract]
   
   
9. Conran RM, Hitchcock CL, Waclawiw MA, et al.: Hepatoblastoma: the prognostic significance of histologic type. Pediatr Pathol 12 (2): 167-83, 1992 Mar-Apr.  [PUBMED Abstract]
   
   
10. Haas JE, Feusner JH, Finegold MJ: Small cell undifferentiated histology in hepatoblastoma may be unfavorable. Cancer 92 (12): 3130-4, 2001.  [PUBMED Abstract]
    
    
11. Lack EE, Neave C, Vawter GF: Hepatocellular carcinoma. Review of 32 cases in childhood and adolescence. Cancer 52 (8): 1510-5, 1983.  [PUBMED Abstract]
    
    
12. Craig JR, Peters RL, Edmondson HA, et al.: Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinico-pathologic features. Cancer 46 (2): 372-9, 1980.  [PUBMED Abstract]
    
    
13. Farhi DC, Shikes RH, Murari PJ, et al.: Hepatocellular carcinoma in young people. Cancer 52 (8): 1516-25, 1983.  [PUBMED Abstract]
    
    
14. Czauderna P, Mackinlay G, Perilongo G, et al.: Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 20 (12): 2798-804, 2002.  [PUBMED Abstract]
    
    
15. Katzenstein HM, Krailo MD, Malogolowkin MH, et al.: Fibrolamellar hepatocellular carcinoma in children and adolescents. Cancer 97 (8): 2006-12, 2003.  [PUBMED Abstract]
    
    
16. Cruz O, Laguna A, Vancells M, et al.: Fibrolamellar hepatocellular carcinoma in an infant and literature review. J Pediatr Hematol Oncol 30 (12): 968-71, 2008.  [PUBMED Abstract]
    
    
17. Nicol K, Savell V, Moore J, et al.: Distinguishing undifferentiated embryonal sarcoma of the liver from biliary tract rhabdomyosarcoma: a Children's Oncology Group study. Pediatr Dev Pathol 10 (2): 89-97, 2007 Mar-Apr.  [PUBMED Abstract]
    
    
18. Stocker JT: Hepatic tumors in children. Clin Liver Dis 5 (1): 259-81, viii-ix, 2001.  [PUBMED Abstract]
    
    
19. Cushing B, Perlman EJ, Marina NM, et al.: Germ cell tumors. In: Pizzo P, Poplack D: Principles and Practice of Pediatric Oncology. 5th ed. Philadelphia, Pa: Lippincott Williams and Wilkins, 2005, pp 1116-38.