Weaver Joshua, Downs-Kelly Erinn, Goldblum John R, Turner Sondra, Kulkarni Sucheta, Tubbs Raymond R, Rubin Brian P, Skacel Marek
Pathology and Laboratory Medicine Institute, Cleveland Clinic and the Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA.
Mod Pathol. 2008 Aug;21(8):943-9. doi: 10.1038/modpathol.2008.84. Epub 2008 May 23.
Well-differentiated liposarcoma/atypical lipomatous tumor and dedifferentiated liposarcoma can be difficult to distinguish from benign lipomatous neoplasms and other high-grade sarcomas, respectively. Cytogenetics in these tumors has identified ring and giant chromosomes composed of 12q13-15 amplicons including the MDM2 gene. Identifying MDM2 amplification by fluorescence in situ hybridization may prove an adjunctive tool in the diagnosis of lipomatous neoplasms. Dual color fluorescence in situ hybridization employing a laboratory-developed BAC label probe cocktail specific for MDM2 (12q15) and a probe for the centromeric region of chromosome 12 (Abbott Molecular, DesPlaines, IL) was performed on formalin-fixed and paraffin-embedded tissue including whole sections from atypical lipomatous tumors (n=13), dedifferentiated liposarcomas (n=14), benign lipomatous tumors (n=30), and pleomorphic sarcoma, not otherwise specified (n=10), and a tissue microarray containing a variety of high-grade sarcomas (n=63). An MDM2/chromosome 12 ratio >or=2.0 was considered amplified, <2.0 nonamplified, and cases displaying >2 signals of both probes and an MDM2 ratio <2.0 polysomic for chromosome 12. Of the well-differentiated and dedifferentiated liposarcomas, 100% showed amplification of MDM2. Chromosome 12 polysomy was noted in 89% of spindle cell/pleomorphic lipomas, while all angiolipomas and lipomas were nonamplified and eusomic. MDM2 amplification was observed in 40% of pleomorphic sarcomas and a small subset of high-grade sarcomas (3/63). MDM2/chromosome 12 fluorescence in situ hybridization is a sensitive and specific tool (both 100%) in evaluating low-grade lipomatous neoplasms. The specificity decreases in high-grade sarcomas, as MDM2 amplification was observed in a small portion of pleomorphic sarcomas and high-grade sarcomas other than dedifferentiated liposarcomas. Importantly, none of the benign lipomatous lesions were MDM2 amplified and even cells in areas of well-differentiated liposarcomas with minimal cytologic atypia were amplified, making the probe a valuable tool in the diagnosis of even limited biopsy samples of well-differentiated lipomatous neoplasms.
高分化脂肪肉瘤/非典型脂肪瘤性肿瘤与去分化脂肪肉瘤分别难以与良性脂肪瘤性肿瘤和其他高级别肉瘤相区分。这些肿瘤的细胞遗传学研究已鉴定出由12q13 - 15扩增子组成的环状和巨大染色体，其中包括MDM2基因。通过荧光原位杂交鉴定MDM2扩增可能是诊断脂肪瘤性肿瘤的一种辅助工具。采用实验室开发的针对MDM2（12q15）的BAC标记探针混合物和针对12号染色体着丝粒区域的探针（雅培分子公司，伊利诺伊州德斯普兰斯）进行双色荧光原位杂交，检测对象包括福尔马林固定石蜡包埋组织，其中有非典型脂肪瘤性肿瘤的全切片（n = 13）、去分化脂肪肉瘤（n = 14）、良性脂肪瘤性肿瘤（n = 30）、未另行指定的多形性肉瘤（n = 10）以及包含多种高级别肉瘤的组织芯片（n = 63）。MDM2/12号染色体比率≥2.0被视为扩增，＜2.0为未扩增，同时显示两种探针信号均＞2且MDM2比率＜2.0的病例为12号染色体多体性。在高分化和去分化脂肪肉瘤中，100%显示MDM2扩增。在89%的梭形细胞/多形性脂肪瘤中发现12号染色体多体性，而所有血管脂肪瘤和脂肪瘤均未扩增且染色体数目正常。在40%的多形性肉瘤和一小部分高级别肉瘤（3/63）中观察到MDM2扩增。MDM2/12号染色体荧光原位杂交在评估低级别脂肪瘤性肿瘤方面是一种敏感且特异的工具（敏感性和特异性均为100%）。在高级别肉瘤中特异性降低，因为在除去分化脂肪肉瘤外的一小部分多形性肉瘤和高级别肉瘤中观察到了MDM2扩增。重要的是，没有良性脂肪瘤性病变出现MDM2扩增，甚至在细胞异型性极小的高分化脂肪肉瘤区域的细胞也出现扩增，这使得该探针成为诊断即使是有限活检样本的高分化脂肪瘤性肿瘤的有价值工具。
