Identification of risk groups in hepatoblastoma--another step in optimising therapy.

As in the geriatric population, early childhood is the period of life with a high risk of suering from malignant disease. However, in contrast to adults, in infants and young children so-called embryonal tumours predominantly occur, which display fundamental dierences in their biology compared with adulthood cancers. These tumours, which are derived from undierentiated embryonal tissue compartments, are characterised by extremely rapid growth and an often high sensitivity to cytotoxic drugs and also sometimes radiation. One of the rarer neoplasms of this group is hepatoblastoma, an embryonal liver tumour [1]. It occurs with an incidence of 0.7±1 case per million children under 15 years of age in Western countries [2], and still is the most common liver tumour during childhood in Europe and North America. Hepatoblastoma particularily aects children between 6 months and 3 years of age. Because of missing clinical symptoms during early growth, these patients often present with locally extended tumours. Distant metastases, however, usually occur very late in advanced disease stages. Approximately 30% of patients have highly elevated serum levels of alpha-fetoprotein (aFP), which is a sensitive diagnostic marker and can be used to monitor therapy. Histologically, all hepatoblastomas are composed of epithelial tissue, but one-third of them contain additional mesenchymal tissue components with immature ®brous areas, spindle cells and cartilage-like osteoid and are then called mixed tumours. The epithelial components mostly display a high `fetal` or a poor `embryonal` dierentiation. Rarely, other features such as macrotrabecular arrrangement, small undierentiated cell areas, teratoid characteristics or a hepatocellular carcinoma-like histology are found [1]. The pathogenesis of hepatoblastoma is still unclear. Histological and immunohistochemical ®ndings indicate that the tumour cells may be derived from early progenitor cells or stem cells of the liver and during tumorigenesis undergo variable dierentiation [3,4]. One constant feature of hepatoblastomas is their ability to sustain extramedullary intratumoral erythroand thrombopoiesis, thus imitating the prenatal liver [5]. As with other embryonal tumours, hepatoblastoma is associated with familial tumour syndromes, the most important of which are the Beckwith±Wiedemann syndrome and familial polyposis coli (FAP). Cytogenetic analysis has revealed the most typical chromosomal changes to be deletions on chromosome arms 1p and 11p, rearrangements on chromosome arm 2q and multisomy of chromosome 20 [6]. Recently, a variety of dierent chromosomal changes have been identi®ed by application of the comparative genomic hybridisation (CGH) technique [6]. At this time, the most important molecular genetical abnormalities in hepatoblastoma seem to be loss of heterozygosity (LOH) at chromosome 11p15.5 [7], 1p and 1q [8], as well as activating mutations of the -catenin gene in more than 50% of the tumours [9]. Since this is the central eector of the wingless/WNT developmental pathway, the latter seems to have an important role in the molecular pathogenesis of hepatoblastoma. Thirty years ago, only children whose hepatoblastoma could be completely resected had a chance of survival [10]. In the early 1970s, evidence began to accumulate that hepatoblastomas usually respond to chemotherapy [11]. Thereafter, a dramatic improvement in response to therapy could be achieved by combining surgery with multi-agent chemotherapy in several multicentric cooperative trials [12]. Cisplatin and doxorubicin proved to be the most eective drugs and are now used in all study protocols. Treatment strategies still vary, with primary surgery generally being performed in the USA [13]. This contrasts with European groups, which increasingly use preoperative chemotherapy, as in the trial of the International Society of Paediatric Oncology (SIOPEL), which is described in