Zerbini M C, Sredni S T, Grier H, Cristofani L M, Latorre M R, Hollister K A, Alves V A, Weinberg D S, Perez-Atayde A R
School of Medicine, University of São Paulo, Brazil.
Pediatr Dev Pathol. 1998 Jul-Aug;1(4):270-80. doi: 10.1007/s100249900039.
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.
肝脏原发性恶性上皮性肿瘤（PMETL）在儿童年龄组中较为罕见，与成人肿瘤相比，对其生物学特性了解甚少。对30例儿童PMETL进行了研究，其中包括24例肝母细胞瘤（HB）和6例肝细胞癌（HCC），研究了通过图像分析测量的DNA含量以及癌基因c-erb2和抑癌基因p53的表达的预后价值。26例中有12例（46.0%）检测到p53过表达，其中5例HCC中有3例，21例HB中有9例。使用的两种抗体（克隆DO7，Dako和克隆DO1，Santa Cruz Biotechnology）观察到染色具有较高的一致性。在获得可靠染色的27例病例中，c-erb-B2在任何病例中均未产生特征性的膜染色。然而，4例HCC患者中有1例以及23例HB患者中有1例在几个肿瘤细胞中显示出强烈的颗粒状细胞质染色。有趣的是，这是三例非整倍体多倍体病例中的两例。29例中有13例（54.8%）的DNA直方图被分类为DNA非整倍体（5/6 HCC和8/23 HB）：9例为超二倍体，1例为亚二倍体（1例HB），3例为多倍体（2例HB和1例HCC）。在HB组中，DNA非整倍体与胚胎组织学区域密切相关，表明细胞分化过程中的紊乱与明显的基因畸变有关。仅对HB组采用Kaplan-Meier方法按年龄（<24个月与≥24个月）、性别、术前化疗（是与否）、残留疾病（转移和/或不可切除肿瘤）、免疫组织化学检测的p53表达（阳性与阴性）以及DNA倍性（二倍体与非整倍体）进行生存单因素分析。仅发现诊断时的残留疾病（P<0.017）和术前化疗（0.030）与作为总生存估计的生物学行为呈负相关。DNA非整倍体肿瘤（P<0.125）和男性患者（P = 0.123）显示出更具侵袭性临床行为的趋势，尽管差异无统计学意义。结合DNA倍性和残留疾病，将患者分为三组：第一组，无不良预后因素的患者，即无残留疾病的二倍体肿瘤；第二组，仅有一种不良预后因素的患者，即非整倍体肿瘤或残留疾病；第三组，具有两种不良因素的患者，即诊断时为非整倍体肿瘤和残留疾病。比较三条生存曲线的对数秩检验显示它们之间存在统计学显著差异（P<0.003）。尽管病例系列较小，但本研究结果突出了在国际合作组为儿童HB设计的方案中纳入DNA倍性的重要性。
