Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD 21231, USA.
Hum Pathol. 2013 Nov;44(11):2494-500. doi: 10.1016/j.humpath.2013.06.009. Epub 2013 Jul 31.
Breast phyllodes tumors are fibroepithelial neoplasms with variable risk of aggressive local recurrence and distant metastasis, and the molecular pathogenesis is unclear. Here, we systematically study p16 and Rb expression in 34 phyllodes tumors in relation to proliferation. Tissue microarrays were constructed from 10 benign, 10 borderline, and 14 malignant phyllodes (5 cores/tumor) and from 10 fibroadenomas (2 cores/tumor). Tissue microarrays were labeled by immunohistochemistry for p16, Rb, and Ki-67 and by in situ hybridization for high-risk human papillomavirus. Cytoplasmic and nuclear p16 were scored by percentage labeling (0%-100%, diffuse >95%) and intensity. Nuclear Rb was scored by percentage labeling (0%-100%, diffuse >75%) and intensity. p16 and Rb labeling were repeated on whole sections of cases with Rb loss on the tissue microarray. Twenty-nine percent (4/14) malignant phyllodes showed diffuse strong p16 labeling with Rb loss in malignant cells (diffuse p16+/Rb-), whereas 21% (3/14) malignant phyllodes showed the reverse pattern of p16 loss with diffuse strong Rb (p16-/diffuse Rb+). Results were consistent between tissue microarrays and whole sections. No borderline phyllodes, benign phyllodes, or fibroadenoma showed diffuse p16+/Rb- or p16-/diffuse Rb+ phenotypes. No cases contained high-risk human papillomavirus. Average Ki-67 proliferation indices were 15% in malignant phyllodes, 1.7% in borderline phyllodes, 0.5% in benign phyllodes, and 0% in fibroadenoma. Ki-67 was highest in malignant phyllodes with diffuse p16+/Rb- labeling. In summary, 50% malignant phyllodes display evidence of Rb/p16 pathway alterations, likely reflecting p16 or Rb inactivation. These and other mechanisms may contribute to the increased proliferation in malignant phyllodes relative to other fibroepithelial neoplasms.
乳腺叶状肿瘤是一种具有不同侵袭性局部复发和远处转移风险的纤维上皮性肿瘤，其分子发病机制尚不清楚。在这里，我们系统地研究了 34 例叶状肿瘤中 p16 和 Rb 的表达与增殖的关系。构建了 10 例良性、10 例交界性和 14 例恶性叶状肿瘤（每例肿瘤 5 个核心）和 10 例纤维腺瘤（每例肿瘤 2 个核心）的组织微阵列。通过免疫组织化学对 p16、Rb 和 Ki-67 进行标记，并通过原位杂交对高危型人乳头瘤病毒进行标记。通过百分比标记（0%-100%，弥漫性>95%）和强度对细胞质和核 p16 进行评分。通过百分比标记（0%-100%，弥漫性>75%）和强度对核 Rb 进行评分。在组织微阵列上 Rb 丢失的情况下，对 Rb 丢失病例的整个切片进行 p16 和 Rb 标记的重复。29%（4/14）的恶性叶状肿瘤显示恶性细胞中弥漫性强 p16 标记和 Rb 丢失（弥漫性 p16+/Rb-），而 21%（3/14）的恶性叶状肿瘤显示 p16 丢失与弥漫性强 Rb 的相反模式（p16-/弥漫性 Rb+）。组织微阵列和全切片之间的结果一致。没有交界性叶状肿瘤、良性叶状肿瘤或纤维腺瘤显示弥漫性 p16+/Rb-或 p16-/弥漫性 Rb+表型。没有病例含有高危型人乳头瘤病毒。恶性叶状肿瘤的平均 Ki-67 增殖指数为 15%，交界性叶状肿瘤为 1.7%，良性叶状肿瘤为 0.5%，纤维腺瘤为 0%。弥漫性 p16+/Rb-标记的恶性叶状肿瘤 Ki-67 最高。总之，50%的恶性叶状肿瘤显示 Rb/p16 途径改变的证据，这可能反映了 p16 或 Rb 的失活。这些和其他机制可能导致恶性叶状肿瘤相对于其他纤维上皮性肿瘤增殖增加。
