Hepatoblastoma and its serum markers

Author: miriam poggioli
Date: 01/04/2013


Martina De Giorgis & Miriam Poggioli


Hepatoblastoma is the most frequent malignant primary liver tumor in infancy and early childhood, even so it is relatively rare, since it comprises only 1 % of all childhood malignant tumors.



The cause of development is not exactly clear, but it is a fact that besides genetic and environmental factors, there is a higher incidence in boys and in prematurely born, low weight children. In general, hepatoblastoma appears under the age of 3 years, but the mean age regarding diagnosis is 1 year.
The prognosis of hepatoblastoma in older children and young adults is worse than in infancy and early childhood (1-3 years of age).
Hepatoblastomas originate from immature liver precursor cells, however, increasing evidence suggests that the tumor is derived from pluripotent stem cells of the liver. In contrast to hepatocellular carcinoma, which often develops on the ground of cirrhosis, hepatoblastoma develops in cirrhosis-free liver.


The currently used diagnostic serum marker for hepatoblastoma is AFP; however, 5–10% of hepatoblastomas are AFP-negative. Furthermore, AFP levels are not always
reliable in young infants with hepatoblastoma due to the physiologically elevated levels of AFP in this age group.
Additionally, histological examination of liver needle biopsies can be difficult in differentiating between fetal hepatoblastoma and benign liver tumors like hemangioendothelioma, often necessitating open biopsy. Thus, there is a need for additional biochemical markers to differentiate hepatoblastoma from benign liver lesions specifically in young infants and in AFP-negative hepatoblastomas.
We report the finding of a novel reliable marker protein, namely DLK1.


Delta-like 1 homolog (DLK1) belongs to the EGF-like family of proteins, and is believed to signal through the developmentally conserved Notch signaling pathway.
DLK1 is a transmembrane protein which extracellular domain can be cleaved off and secreted in serum, previously identified as Fetal Antigen1 (FA1), found to be highly elevated in serum during the 2nd and 3rd trimester of pregnancy.
The precise role of DLK1 in mammalian development is unclear, but the strong decline of its expression during development and its almost complete absence after birth, including in the liver, suggests that its presence identifies a fetal phenotype. In agreement, DLK1 has been used as a marker for liver stem cells. Previous reports showed DLK1 upregulation in hepatoblastomas, both at the mRNA and protein level [18–20] in up to 100% of hepatoblastomas.

Similar to serum AFP control levels (Fig. B, black squares), DLK1 serum levels (Fig. A; black dots) decline with increasing age. DLK1 serum levels decline from 10 ng/ml in the first 3 months till 6 months of age, to reach adult levels afterwards.
Furthermore AFP in hepatoblastoma patients (Fig. B, red squares) and DLK1 levels (Fig. A, red dots) are significantly elevated.
DLK1 seems to be a superior marker compared to AFP to diagnose hepatoblastoma in the young infant age group because DLK1 levels in hepatoblastoma results above the control range more frequently than AFP levels (Fig. C and D).
"DLK1, a Serum Marker for Hepatoblastoma in Young Infants,2012" :http://onlinelibrary.wiley.com/doi/10.1002/pbc.24024/pdf


The DLK protein is exclusively located on the epithelial components of the tumours, while the mesenchymal part of the mixed hepatoblastomas staines negative.
The cellular distribution and the extent and intensity of the DLK staining does not show significant correlation with the histological subtype, infact the tumour are also positive for AFP and the distribution of AFP and DLK occasionally overlapped. Therefore is belived that the application of both antibodies may increase the diagnostic sensitivity .
In addition AFP can be present in HCCs, but the great majority of the HCCs are negative for DLK; consequently DLK can be applied for the histological distinction between HCC and hepatoblastoma.
DLK is also preserved in the metastases.
"Delta-like protein (DLK) is a novel immunohistochemical marker for human hepatoblastomas, 2008" : http://www.ncbi.nlm.nih.gov/pubmed/18236070


DLK is a membrane protein of hepatoblasts and hepatocytes during embryonic and fetal development and a highly sensitive and specific immunophenotypic marker of this childhood liver tumour.

2013-06-30T18:27:37 - martina de giorgis
2013-04-29T16:12:06 - miriam poggioli
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