Shimada H, Stram D O, Chatten J, Joshi V V, Hachitanda Y, Brodeur G M, Lukens J N, Matthay K K, Seeger R C
Department of Pathology and Laboratory Medicine, Childrens Hospital Los Angeles, CA 90027, USA.
J Natl Cancer Inst. 1995 Oct 4;87(19):1470-6. doi: 10.1093/jnci/87.19.1470.
Neuroblastomas show different histopathologic phenotypes, and the tumor cells can carry normal or multiple copies of the N-myc proto-oncogene (MYCN). Studies of the N-myc gene and histopathology of untreated primary neuroblastomas have demonstrated that both these factors are important in risk assessment.
Our purpose was to determine if there are any associations between N-myc gene copy number, histopathologic features, clinical stage, and progression-free survival (PFS) and if joint analyses of histopathology and N-myc gene copy number improve risk assessment.
The histopathologic phenotype and N-myc gene copy number were determined for 232 biopsy/surgery specimens obtained from untreated primary neuroblastoma patients. Tumors were classified as having favorable or unfavorable histology on the basis of Schwannian stroma (rich versus poor), neuroblastic differentiation (differentiating versus undifferentiated), and mitosis-karyorrhexis (fragmenting nucleus) index (MKI; high, intermediate, or low) in the context of age at diagnosis (Shimada classification). N-myc gene amplification was considered significant when the gene copy number was at least 10-fold higher than normal as determined by Southern blot analysis. Otherwise, tumors were classified as nonamplified for N-myc.
Among 19 stroma-rich tumors, 11 had grossly visible neuroblastic nodules, and two of these had N-myc amplification. Of 213 stroma-poor tumors, 51 had N-myc amplification, all of which were undifferentiated, and 45 (88% of 51) had high MKI. This histologic phenotype was present in less than 10% of tumors with nonamplified N-myc. Of 162 stroma-poor tumors that showed nonamplified N-myc, 45 (28%) were differentiating and 121 (75%) had low MKI. Neuroblastomas of clinical stages I, II, and IV-S nearly always had favorable histology and no amplification of N-myc. Stage III (regional) and particularly stage IV (metastatic) tumors, however, frequently had unfavorable histologic features with or without N-myc amplification. The estimated PFS at the end of 4 years after diagnosis was 83% for patients whose tumors had favorable histology and no N-myc amplification. The estimated PFS for the patients whose neuroblastomas had unfavorable histology, however, was 29% without and 13% with N-myc amplification, respectively. Subsets of patients with stage II, III, or IV disease were identified by both histologic evaluation and N-myc analysis. Multivariate Cox regression analysis indicated that both the histologic and N-myc-based stratifications provided prognostic information that was independent of staging.
Neuroblastomas with N-myc amplification have a characteristic histopathologic phenotype and an aggressive clinical course. In contrast, neuroblastomas without N-myc amplification exhibit a wide range of histologic features that can define prognostic subsets.
神经母细胞瘤表现出不同的组织病理学表型，且肿瘤细胞可携带正常或多个拷贝的N - myc原癌基因（MYCN）。对未经治疗的原发性神经母细胞瘤的N - myc基因及组织病理学研究表明，这两个因素在风险评估中均很重要。
我们的目的是确定N - myc基因拷贝数、组织病理学特征、临床分期与无进展生存期（PFS）之间是否存在关联，以及组织病理学与N - myc基因拷贝数的联合分析是否能改善风险评估。
对从未经治疗的原发性神经母细胞瘤患者获取的232份活检/手术标本进行组织病理学表型及N - myc基因拷贝数测定。根据诊断时年龄的施万细胞基质（丰富与贫乏）、神经母细胞分化（分化与未分化）及有丝分裂 - 核溶解（核碎裂）指数（MKI；高、中或低），将肿瘤分类为具有良好或不良组织学特征（岛田分类法）。当通过Southern印迹分析确定基因拷贝数至少比正常高10倍时，N - myc基因扩增被认为具有显著性。否则，肿瘤被分类为N - myc未扩增。
在19例富含基质的肿瘤中，11例有肉眼可见的神经母细胞结节，其中2例有N - myc扩增。在213例基质贫乏的肿瘤中，51例有N - myc扩增，所有这些均为未分化肿瘤，且45例（51例中的88%）MKI高。这种组织学表型在N - myc未扩增的肿瘤中不到10%。在162例显示N - myc未扩增的基质贫乏肿瘤中，45例（28%）正在分化，121例（75%）MKI低。临床I期、II期和IV - S期的神经母细胞瘤几乎总是具有良好的组织学特征且无N - myc扩增。然而，III期（局部）尤其是IV期（转移）肿瘤，无论有无N - myc扩增，通常具有不良的组织学特征。诊断后4年末，肿瘤具有良好组织学特征且无N - myc扩增的患者的估计无进展生存期为83%。然而，神经母细胞瘤具有不良组织学特征的患者，无N - myc扩增时估计无进展生存期为29%，有N - myc扩增时为13%。通过组织学评估和N - myc分析确定了II期（局部）、III期（局部）或IV期（转移）疾病患者的亚组。多变量Cox回归分析表明，基于组织学和基于N - myc的分层均提供了独立于分期的预后信息。
具有N - myc扩增的神经母细胞瘤具有特征性的组织病理学表型和侵袭性的临床病程。相比之下，无N - myc扩增的神经母细胞瘤表现出广泛的组织学特征，这些特征可定义预后亚组。
