title: A subset of malignant phyllodes tumors harbors alterations in the Rb/p16 pathway.
abstract: 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.
authors.affiliation: Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD 21231, USA. Electronic address: acimino@jhmi.edu.
authors.forename: Ashley
authors.initials: A
authors.lastname: Cimino-Mathews
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Hicks
authors.forename: Rajni
authors.initials: R
authors.lastname: Sharma
authors.forename: Russell
authors.initials: R
authors.lastname: Vang
authors.forename: Peter B
authors.initials: PB
authors.lastname: Illei
authors.forename: Angelo
authors.initials: A
authors.lastname: De Marzo
authors.forename: Leisha A
authors.initials: LA
authors.lastname: Emens
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D018225:Neoplasms, Fibroepithelial / Q000378:metabolism* / Q000473:pathology; D027383:Papillomaviridae / Q000235:genetics / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000821:virology; D003557:Phyllodes Tumor / Q000378:metabolism* / Q000473:pathology; D016160:Retinoblastoma Protein / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism; D046888:Tissue Array Analysis; D055815:Young Adult
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D016160:Retinoblastoma Protein
keywords: Breast; Fibroepithelial neoplasm; Phyllodes tumor; Rb; p16
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