Primary malignant epithelial tumors of the liver in children: a study of DNA content and oncogene expression.
Primary malignant epithelial tumors of the liver (PMETL) are rare in the pediatric age group, and very little is known about their biology as compared with adult tumors. The prognostic value of the DNA contents measured by image analysis and expression of oncogene c-erb2 and tumor suppressor gene p53 were studied in 30 cases of PMETL in children, including 24 with hepatoblastomas (HB) and 6 with hepatocellular carcinomas (HCC). p53 overexpression was detected in 12 out of 26 cases (46.0%), or in 3 of 5 HCC and 9 of 21 HB cases. A relatively high concordance of staining was observed with the two antibodies used (clone DO7, Dako and clone DO1, Santa Cruz Biotechnology). c-erb-B2 did not yield the characteristic membrane staining in any of the 27 cases in which reliable staining was obtained. However, 1 out of 4 patients with HCC and 1 of 23 with HB revealed strong granular cytoplasmic staining in several neoplastic cells. Interestingly, these were two of the three aneuploid multiploid cases. DNA histograms of 13 out of 29 cases (54.8%) were classified as DNA aneuploid (5/6 HCC and 8/23 HB): nine were hyperdiploid, one was hypodiploid (1HB), and three were multiploid (2HB and 1HCC). In the HB group, DNA aneuploidy was strongly associated with embryonal histological areas, suggesting that a disturbance in the process of cell differentiation is associated with marked genetic aberrations. Only the group of HB was submitted to univariate analysis of survival by the Kaplan-Meier method for age (< 24 months vs. > or = 24 months), sex, preoperative chemotherapy (yes vs. no), residual disease (metastasis, and/or unresectable tumor), p53 expression by immunohistochemistry (positive vs. negative), and DNA ploidy (diploid vs. aneuploid). Only residual disease at the time of diagnosis (P < 0.017) and preoperative chemotherapy (0.030) were found to be negatively correlated with biological behavior, estimated as overall survival. DNA aneuploidy tumors (P < 0.125) and male patients (P = 0.123) showed a trend toward a more aggressive clinical behavior, although the difference was not statistically significant. Combining DNA ploidy and residual disease, patients were categorized into three groups: group I, patients with no adverse prognostic factors, i.e., diploid tumors without residual disease; group II, patients with only one adverse prognostic factor, i.e., aneuploid tumor or residual disease; and group III, patients with both adverse factors, aneuploid tumors and residual disease at time of diagnosis. A log-rank test comparing the three survival curves showed a statistically significant difference between them (P < 0.003). Although the series of cases is small, the results of this study highlight the importance of including DNA ploidy in the protocols designed for HB in children by international cooperative groups.
Zerbini
M C
MC
School of Medicine, University of São Paulo, Brazil.
Sredni
S T
ST
Grier
H
H
Cristofani
L M
LM
Latorre
M R
MR
Hollister
K A
KA
Alves
V A
VA
Weinberg
D S
DS
Perez-Atayde
A R
AR
D000293:Adolescent; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004273:DNA, Neoplasm / Q000032:analysis*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018197:Hepatoblastoma / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D009857:Oncogenes / Q000235:genetics*; D011003:Ploidies; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D012189:Retrospective Studies; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
D004273:DNA, Neoplasm; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53