The most common primary malignant liver tumor of childhood, hepatoblastoma has increased in incidence over the last 30 years, but little is still known about its pathogenesis. Discoveries in molecular biology provide clues but have yet to define targeted therapies. Disease-free survival varies according to stage, but is greater than 90% in favorable risk populations, in part due to improvements in chemotherapeutic regimens, surgical resection, and earlier referral to liver transplant centers. This article aims to highlight the principles of disease that guide current treatment algorithms. Surgical treatment, especially orthotopic liver transplantation, will also be emphasized in the context of the current Children’s Oncology Group international study of pediatric liver cancer (AHEP-1531).

Hepatoblastoma (HB) is the most common primary liver malignancy of childhood, and molecular investigations are limited and effective treatment options for chemoresistant disease are lacking. There is a knowledge gap in the investigation of key driver cells of HB in tumor. Here we show single cell ribonucleic acid sequencing (scRNAseq) analysis of human tumor, background liver, and patient derived xenograft (PDX) to demonstrate gene expression patterns within tumor and to identify intratumor cell subtype heterogeneity to define differing roles in pathogenesis based on intracellular signaling in pediatric HB. We have identified a driver tumor cell cluster in HB by genetic expression which can be examined to define disease mechanism and treatments. Identification of both critical mechanistic pathways combined with unique cell populations provide the basis for discovery and investigation of novel treatment strategies in vitro and in vivo.

Background: Hepatoblastoma is the most common primary pediatric liver malignancy. Indocyanine green (ICG) has been described as an adjunct to resection in small series. Its utility remains undefined in larger cohorts.Methods: Records for 29 patients diagnosed with hepatoblastoma who received ICG prior to surgical resection from 2017 to 2020 at a single institution were retrospectively reviewed. The primary outcome was correlation between intraoperative ICG‐avidity and histologic presence of hepatoblastoma. A secondary outcome included the histologic margin designation for resected liver specimens.Results: ICG sensitivity was 91% for 120 resected thoracic specimens from 21 patients. Specificity was 57%. In 10% of operations, HB‐positive specimens were resected solely on ICG‐avidity. In an additional 40% of cases, ICG assisted in localizing a preoperatively diagnosed lesion. ICG sensitivity during thoracotomy and thoracoscopic surgery was 95 and 74%, respectively; primary and relapsed disease demonstrated sensitivity of 94 and 73%, respectively. Sensitivity was 92% for 25 resected liver specimens from nine patients with all parenchymal margins grossly negative for disease. Four multifocal lesions were identified with two resected solely by ICG‐avidity.Conclusions: ICG is a sensitive adjunct for identifying local and metastatic hepatoblastoma, including lesions not visualized on preoperative imaging, and delineating margins during liver resection. False positives limit specificity; however, there were no adverse outcomes from additional resections. We noted that thoracoscopic surgery can be completed safely in patients with less significant disease burden, and conversion to thoracotomy, if necessary, is straightforward.

Glypican-3 (GPC3) is a cell-surface glycoprotein that is frequently overexpressed in hepatocellular carcinoma (HCC). GPC3 undergoes extensive posttranslational modification (PTM) including cleavage and glycosylation. This review focuses on the structure and function of GPC3 in liver cancer, highlighting the PTM of the tertiary and quaternary structures of GPC3 as a potential oncogenic regulatory mechanism. We propose that the function of GPC3 in normal development can vary with extensive PTM and that dysregulation of these processes leads to disease. Defining the regulatory impact of these modifications can provide a deeper understanding of the role of GPC3 in oncogenesis, epithelial–mesenchymal transition, and drug development. Through review of current literature, this article provides a unique perspective on the role of GPC3 in liver cancer, focusing on potential regulatory mechanisms of PTM on GPC3 function at the molecular, cellular, and disease level.