Abstract
BackgroundTraditional 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.MethodsWe 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.ResultsGrade 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.ConclusionsThe 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.
Highlights
Traditional determinants proven to be of prognostic importance in breast cancer include the TNM staging, histological grade, proliferative activity, hormone receptor status and human epidermal growth factor receptor 2 (HER2) overexpression
All breast cancers showed Na+⁄H+ exchanger regulatory factor 1 (NHERF1) protein localized in the cytoplasm of tumor cells and 31% of overexpressing cytoplasmic NHERF1 tumors exhibited a significant association with tumor grade 3 (p = 0.035), negative progesterone receptor (PR) status (p = 0.008), high MIB1 (p = 0.033), positive HER2 status (p = 0.036) and with moderate Nottingham Prognostic Index (NPI) (p = 0.029)
Pearson’s rank test showed that cytoplasmic NHERF1 expression was positively correlated to VEGF receptor 1 (VEGFR1) (r = 0.382, p = 0.000) (Figure 1A). The analysis of their relative localization by immunohistofluorescence studies indicated that the receptor VEGFR1 colocalized with NHERF1 when both proteins were overexpressed within cytoplasmic and/or membranous compartments in invasive clusters disseminated into the stroma (Figure 1B)
Summary
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 degree of histological differentiation in operable breast carcinomas has long represented one of the best established prognostic factors which have been validated in multiple independent studies [2,3,4]. The Elston and Ellis modification of the Scarff-Bloom-Richardson grading system separates breast cancer patients into distinct prognosis groups: grade 1, 2 or 3, with a low, intermediate or high risk of recurrence, respectively [5]. Internationally accepted among pathologists, one of the limitations of the histological grading scheme is that a high percentage (30% to 60%) of breast cancer is still classified as grade 2, a category with ambiguous clinical significance [6]. Histological grading has been combined with tumor size and lymph node stage to form the Nottingham Prognostic Index (NPI), which allows stratification of patients into three different prognostic groups [3] and satisfying these criteria
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