Korcheva Veselina B, Levine Judith, Beadling Carol, Warrick Andrea, Countryman Gayle, Olson Neal R, Heinrich Michael C, Corless Christopher L, Troxell Megan L
Department of Pathology, L471, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
Appl Immunohistochem Mol Morphol. 2011 Mar;19(2):119-25. doi: 10.1097/PAI.0b013e3181f5349a.
Phyllodes tumors of the breast are diagnostically and managerially enigmatic, as their malignant potential is difficult to predict based on the standard morphologic criteria. Thus, there is a need for additional markers of biologic potential. Although a number of ancillary tests have been reported, consensus in the literature is lacking. We studied 38 cellular fibroadenomas and phyllodes tumors of various grade (World Health Organization benign, borderline, and malignant) with a panel of immunohistochemical stains (p53, CD117, phospho-Histone3, mdm2, cdk4) and screened 26 of the tumors for mutations across 30 cancer-related genes using PCR and mass-spectrometry based methods. p53 and phospho-Histone3 (mitotic marker) showed increased staining in higher grade phyllodes tumors. CD117, mdm2, and cdk4 showed no difference in expression across different grades of phyllodes tumors. Mutational analysis revealed an S8R substitution in FBX4 (an E3 ubiquitin ligase) in 3 cases: 1 benign and 2 borderline. The S8R substitution seems to be more common in phyllodes tumors (11.5%) as compared with other cancers. FBX4 S8R cases had high cyclin D1 expression, but this finding was not specific. Our data support earlier studies showing that p53 has potential use in pathologic assessment of phyllodes tumors, and we newly characterized phospho-Histone3 for this application. Further studies are needed to characterize the molecular pathogenesis of the phyllodes tumors, as we were unable to identify activating mutations despite screening for a large panel of activating hotspot mutations. The significance of the FBX4 substitution deserves further investigation.
乳腺叶状肿瘤在诊断和管理方面具有迷惑性，因为基于标准形态学标准很难预测其恶性潜能。因此，需要其他生物学潜能标志物。尽管已经报道了许多辅助检查，但文献中仍缺乏共识。我们用一组免疫组化染色剂（p53、CD117、磷酸化组蛋白H3、mdm2、细胞周期蛋白依赖性激酶4）研究了38例不同分级（世界卫生组织良性、交界性和恶性）的细胞性纤维腺瘤和叶状肿瘤，并使用基于聚合酶链反应和质谱的方法对其中26例肿瘤进行了30个癌症相关基因的突变筛查。p53和磷酸化组蛋白H3（有丝分裂标志物）在高级别叶状肿瘤中染色增加。CD117、mdm2和细胞周期蛋白依赖性激酶4在不同分级的叶状肿瘤中表达无差异。突变分析在3例病例中发现FBX4（一种E3泛素连接酶）存在S8R替代：1例良性和2例交界性。与其他癌症相比，S8R替代似乎在叶状肿瘤中更常见（11.5%）。FBX4 S8R病例中细胞周期蛋白D1表达较高，但这一发现并不特异。我们的数据支持早期研究，表明p53在叶状肿瘤的病理评估中有潜在用途，并且我们首次将磷酸化组蛋白H3用于此用途。由于尽管对一大组激活热点突变进行了筛查但仍未能鉴定出激活突变，因此需要进一步研究以阐明叶状肿瘤的分子发病机制。FBX4替代的意义值得进一步研究。
