A Subset of Malignant Phyllodes Tumors Harbors Rb/p16 Pathway Alterations
Ashley Cimino-Mathews, Jessica L Hicks, Rajni Sharma, Russell Vang, Peter B Illei, Angelo De Marzo, Pedram Argani. Johns Hopkins Hospital, Baltimore, MD
Background: Breast phyllodes tumors are rare fibroepithelial neoplasms with variable risk of aggressive local recurrence and distant metastasis. The molecular pathogenesis of phyllodes tumors is unclear. One study showed loss of chromosomes 13p14 (Retinoblastoma (Rb) locus) and 9p21 (p16 locus) in malignant/borderline phyllodes; however, another showed increased Rb and p16 labeling by immunohistochemistry (IHC) in malignant phyllodes. Rb plays a role in cell cycle regulation, and loss of Rb in human cancers typically results in compensatory upregulation of p16, and vice versa. Here, we systematically study p16 and Rb expression in a series of benign (BP), low grade (LGP) and malignant phyllodes (MP) tumors in relation to proliferation.
Design: Tissue microarrays (TMAs) were constructed from paraffin tissue blocks of 34 phyllodes tumors including 10 BP, 10 LGP and 14 MP tumors (5 spots per tumor), and from 10 FA (2 spots per tumor). TMAs were labeled by IHC for p16, Rb and Ki67. Cytoplasmic p16 labeling was scored by percentage labeling (0-100%, diffuse defined as >95%) and labeling intensity [weak (W), moderate (M) or strong (S)]. Nuclear Rb labeling was scored by percentage labeling (0-100%, diffuse defined as >75%) and labeling intensity [W, M, S]. p16 and Rb labeling were repeated on whole slide sections of donor blocks from cases with absence of Rb labeling on the TMA.
Results: 29% (4/14) MP showed diffuse strong p16 expression with Rb loss in cytologically malignant cells (diffuse p16+/Rb-), while 21% (3/14) MP showed the reverse pattern of p16 loss with diffuse strong Rb expression (p16-/diffuse Rb+). In cases with Rb loss in the malignant stromal cells, there were abundant admixed vessels and nonatypical stromal cells (likely representing entrapped native stroma) which exhibited intact Rb labeling. Results were consistent between TMA and whole sections. No LGP, BP or FA showed the diffuse p16+/Rb- or p16-/diffuse Rb+ phenotypes. Average Ki67 proliferation indices were as follows: 15% (range <1-50%) in MP, 1.7% (range <1-10%) in LGP, 0.5% (range <5%) in BP, and 0% (range <1%) in FA. Ki67 index did not correlate with patterns of p16/Rb labeling.
Conclusions: Approximately 50% MP tumors display evidence of Rb/p16 pathway alterations. A subset of MP cases demonstrates loss of p16 with diffuse Rb labeling, likely reflecting p16 inactivation. Another subset of MP demonstrates diffuse p16 expression with loss of Rb labeling in the pleomorphic cells, suggesting Rb inactivation. These and other mechanisms likely contribute to the increased proliferation in MP relative to other fibroepithelial neoplasms.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 42, Monday Morning