Open Access Research article

Peritumoral vascular invasion and NHERF1 expression define an immunophenotype of grade 2 invasive breast cancer associated with poor prognosis

Andrea Malfettone1, Concetta Saponaro1, Angelo Paradiso2, Giovanni Simone3 and Annita Mangia1*

Author Affiliations

1 Functional Biomorphology Laboratory, National Cancer Centre, Viale Orazio Flacco, 65-70124 Bari, Italy

2 Scientific Direction, National Cancer Centre, Viale Orazio Flacco, 65-70124 Bari, Italy

3 Pathology Department, National Cancer Centre, Viale Orazio Flacco, 65-70124 Bari, Italy

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BMC Cancer 2012, 12:106  doi:10.1186/1471-2407-12-106

Published: 22 March 2012



Traditional determinants proven to be of prognostic importance in breast cancer include the TNM staging, histological grade, proliferative activity, hormone receptor status and HER2 overexpression. One of the limitations of the histological grading scheme is that a high percentage of breast cancers are still classified as grade 2, a category with ambiguous clinical significance. The aim of this study was to best characterize tumors scored as grade 2.


We investigated traditional prognostic factors and a panel of tumor markers not used in routine diagnosis, such as NHERF1, VEGFR1, HIF-1α and TWIST1, in 187 primary invasive breast cancers by immunohistochemistry, stratifying patients into good and poor prognostic groups by the Nottingham Prognostic Index.


Grade 2 subgroup analysis showed that the PVI (p = 0.023) and the loss of membranous NHERF1 (p = 0.028) were adverse prognostic factors. Relevantly, 72% of grade 2 tumors were associated to PVI+/membranous NHERF1- expression phenotype, characterizing an adverse prognosis (p = 0.000). Multivariate logistic regression analysis in the whole series revealed poor prognosis correlated with PVI and MIB1 (p = 0.000 and p = 0.001, respectively). Furthermore, in the whole series of breast cancers we found cytoplasmic NHERF1 expression positively correlated to VEGFR1 (r = 0.382, p = 0.000), and in VEGFR1-overexpressing tumors the oncogenic receptor co-localized with NHERF1 at cytoplasmic level.


The PVI+/membranous NHERF1- expression phenotype identifies a category of grade 2 tumors with the worst prognosis, including patient subgroup with a family history of breast cancer. These observations support the idea of the PVI+/membranous NHERF1- expression immunophenotype as a useful marker, which could improve the accuracy of predicting clinical outcome in grade 2 tumors.

NHERF1; Peritumoral Vascular Invasion; Histological grade; Breast cancer; VEGFR1; Nottingham Prognostic Index