Departments of Pathology and Clinical Laboratories, National Cancer Center Research Institute, Tokyo, Japan.
Am J Surg Pathol. 2012 Mar;36(3):423-31. doi: 10.1097/PAS.0b013e31824230d0.
Low-grade osteosarcomas comprise a distinct subset of osteosarcomas. They may occasionally dedifferentiate into high-grade tumors, typically in the form of high-grade osteosarcoma, which are histologically indistinguishable from conventional osteosarcomas. MDM2 and CDK4 are often amplified in low-grade osteosarcomas and their dedifferentiated counterparts, and the encoded proteins are accordingly overexpressed. As MDM2/CDK4 expression was reportedly rare in conventional osteosarcoma, we hypothesized that these markers may help separate dedifferentiated osteosarcoma from the conventional type. To test this, we performed MDM2 and CDK4 immunohistochemistry on 81 primary and 26 recurrent/metastatic high-grade osteosarcomas and correlated these data with the histology of the primary resection material, with particular attention to the potential presence of any coexisting low-grade osteosarcomatous components. MDM2 and CDK4 coexpression was identified in 7 cases, and on careful histologic review 6 of them were discovered to contain foci of coexisting low-grade elements. One case was a known dedifferentiated parosteal osteosarcoma, and the remaining 5 cases were newly identified dedifferentiated osteosarcomas in which the limited low-grade components were originally unrecognized. An additional 11 cases expressed either marker alone, whereas the remaining 89 cases were negative for both markers; no resection material from these 100 cases presented with a low-grade component. MDM2/CDK4 gene amplification status, determined by quantitative polymerase chain reaction in selected cases, was largely concordant with immunoexpression. Our data suggest that MDM2 and CDK4 coexpression in high-grade osteosarcomas is sensitive and specific to those that progressed from low-grade osteosarcomas, and immunohistochemistry may help identify this dedifferentiated subgroup to facilitate accurate subclassification.
低度恶性骨肉瘤是骨肉瘤的一个独特亚型。它们偶尔会去分化为高级别肿瘤，通常表现为高级别骨肉瘤，在组织学上与传统骨肉瘤无法区分。MDM2 和 CDK4 常扩增于低度恶性骨肉瘤及其去分化的对应物中，相应的编码蛋白过表达。由于 MDM2/CDK4 表达在传统骨肉瘤中报道罕见，我们假设这些标志物可能有助于将去分化的骨肉瘤与传统类型区分开来。为了验证这一点，我们对 81 例原发性和 26 例复发性/转移性高级别骨肉瘤进行了 MDM2 和 CDK4 免疫组化检测，并将这些数据与原发性切除标本的组织学相关联，特别注意潜在存在的任何共存的低度恶性骨肉瘤成分。在 7 例中发现了 MDM2 和 CDK4 的共表达，通过仔细的组织学回顾，其中 6 例发现含有共存的低度成分的焦点。1 例为已知的去分化骨旁骨肉瘤，其余 5 例为新发现的去分化骨肉瘤，其中有限的低度成分最初未被识别。另外 11 例单独表达了其中一个标志物，而其余 89 例两个标志物均为阴性；这些 100 例的切除标本均未出现低度成分。通过定量聚合酶链反应在选定病例中确定的 MDM2/CDK4 基因扩增状态，与免疫表达大体一致。我们的数据表明，在高级别骨肉瘤中 MDM2 和 CDK4 的共表达对源自低度恶性骨肉瘤的肿瘤具有敏感性和特异性，免疫组化可能有助于识别这种去分化亚组，以促进准确的分类。
