title: Mixed micropapillary-ductal carcinomas of the breast: a genomic and immunohistochemical analysis of morphologically distinct components.
abstract: Micropapillary carcinomas (MPCs) can present as a rare histological special type of breast cancer; however, this histological type is more frequently found admixed with invasive ductal carcinomas of no special type (IDC-NSTs). We have previously demonstrated that pure MPCs constitute a distinct entity at the morphological and genetic levels. Here, we sought to determine whether mixed MPCs have genomic aberrations similar to those found in pure MPCs, and to investigate whether the distinct morphological components of MPCs harbour different genetic aberrations. Using high-resolution microarray comparative genomic hybridization (aCGH), we profiled a series of 10 MPCs of mixed histology and 20 IDC-NSTs matched for grade and oestrogen receptor (ER) status. In addition, we generated tissue microarrays containing a series of 24 pure and 40 mixed MPCs and performed immunohistochemical analysis with ER, progesterone receptor (PR), Ki-67, HER2, cytokeratin (CK) 5/6, CK14, CK17, EGFR, topoisomerase-IIalpha, cyclin D1, caveolin-1 and E-cadherin antibodies. In situ hybridization was employed to evaluate the prevalence of HER2, TOP2A, EGFR, CCND1, MYC and FGFR1 gene amplification. Our results demonstrate that mixed MPCs harbour similar patterns of genomic aberrations and phenotype (82.5% luminal and 17.5% HER2) compared to pure MPCs. A comparison between the distinct morphological components of mixed MPCs in a pairwise fashion revealed that both components harbour strikingly similar genomic profiles. When compared to grade- and ER-matched IDC-NSTs, mixed MPCs significantly more frequently harboured amplification of multiple regions on 8q (adjusted Fisher's p value < 0.05). Furthermore, mixed MPCs displayed higher proliferative rates than grade- and ER-matched IDC-NSTs. Our results suggest that micropapillary differentiation in breast cancer may identify a subgroup of more aggressive ER-positive breast carcinomas, even in those featuring a mixed histology, and that mixed MPCs are more closely related to pure MPCs than to IDC-NSTs.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Caterina
authors.initials: C
authors.lastname: Marchiò
authors.forename: Marjan
authors.initials: M
authors.lastname: Iravani
authors.forename: Rachael
authors.initials: R
authors.lastname: Natrajan
authors.forename: Maryou B K
authors.initials: MB
authors.lastname: Lambros
authors.forename: Felipe C
authors.initials: FC
authors.lastname: Geyer
authors.forename: Kay
authors.initials: K
authors.lastname: Savage
authors.forename: Suzanne
authors.initials: S
authors.lastname: Parry
authors.forename: Narinder
authors.initials: N
authors.lastname: Tamber
authors.forename: Kerry
authors.initials: K
authors.lastname: Fenwick
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.forename: Fernando C
authors.initials: FC
authors.lastname: Schmitt
authors.forename: Gianni
authors.initials: G
authors.lastname: Bussolati
authors.forename: Ian
authors.initials: I
authors.lastname: Ellis
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Anna
authors.initials: A
authors.lastname: Sapino
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D009363:Neoplasm Proteins / Q000378:metabolism; D018193:Neoplasms, Complex and Mixed / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins