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

Malfettone A, Saponaro C, Paradiso A, Simone G, Mangia A - BMC Cancer (2012)

Bottom Line: Grade 2 subgroup analysis showed that the PVI (p = 0.023) and the loss of membranous NHERF1 (p = 0.028) were adverse prognostic factors.Multivariate logistic regression analysis in the whole series revealed poor prognosis correlated with PVI and MIB1 (p = 0.000 and p = 0.001, respectively).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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Functional Biomorphology Laboratory, National Cancer Centre, Bari, Italy.

ABSTRACT

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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Peritumoral vascular invasion and NHERF1 expression in grade 2 invasive breast carcinoma. (A) Representative images of peritumoral vascular invasion by H&E and NHERF1 protein expression by immunoistochemistry: (I) a tumor with the absence of peritumoral vascular invasion and (II) with the overexpression of membranous NHERF1, in addition to cytoplasmic localization (arrow). (III) A case showing peritumoral vascular invasion (arrowhead) and (IV) negative expression of membranous NHERF1. Original magnification × 100, inset × 200. (B) Assessment of the peritumoral vascular invasion in a breast tumor section stained with CD31 and NHERF1 antibodies and detected with Alexa Fluor 568 (red) and Alexa Fluor 488 (green) secondary antibodies, respectively. Immunofluorescence analysyis shows a tumor cell cluster within the endothelial-lined vascular space (arrowheads), with strong cytoplasmic NHERF1 expression similarly to the invasive cellular component at right zone of the image. Scale bar = 10 μm.
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Figure 3: Peritumoral vascular invasion and NHERF1 expression in grade 2 invasive breast carcinoma. (A) Representative images of peritumoral vascular invasion by H&E and NHERF1 protein expression by immunoistochemistry: (I) a tumor with the absence of peritumoral vascular invasion and (II) with the overexpression of membranous NHERF1, in addition to cytoplasmic localization (arrow). (III) A case showing peritumoral vascular invasion (arrowhead) and (IV) negative expression of membranous NHERF1. Original magnification × 100, inset × 200. (B) Assessment of the peritumoral vascular invasion in a breast tumor section stained with CD31 and NHERF1 antibodies and detected with Alexa Fluor 568 (red) and Alexa Fluor 488 (green) secondary antibodies, respectively. Immunofluorescence analysyis shows a tumor cell cluster within the endothelial-lined vascular space (arrowheads), with strong cytoplasmic NHERF1 expression similarly to the invasive cellular component at right zone of the image. Scale bar = 10 μm.

Mentions: When we applied the NPI to 187 breast patients, 49 (26%) were in the good prognostic group, 88 (47%) in the moderate prognostic group and 50 (27%) in the poor prognostic group (Table 1). We examined if tumors with grade 2 and poor prognosis were associated with some distinct clinicopathological parameters or with some tumor markers not currently used in routine diagnosis. Subgroup analysis revealed that the PVI (p = 0.023) and negative membranous NHERF1 expression (p = 0.028) were adverse prognostic factors for grade 2 tumors (Figure 2A, 3). When we analyzed the distribution of the PVI/membranous NHERF1 immunophenotypes in the three distinct histological groups, we showed that 72% of grade 2 and 92% of grade 3 tumors were significantly associated to the PVI+/membranous NHERF1-expression phenotype, both characterized by a poor prognosis (p = 0.000) (Figure 2B). Then, we explored the prognostic relevance of the PVI/membranous NHERF1 immunophenotypes in the whole cohort and, notably, 100% of tumors with poor prognosis significantly displayed the PVI+/membranous NHERF1- expression phenotype, compared with 27% of tumors with good prognosis (p = 0.000) (Figure 2C). Moreover, the PVI+/membranous NHERF1-phenotype in the subgroup of grade 2 familial tumors showed a higher significant proportion than proportion within subgroup of grade 2 sporadic tumors (90% vs. 50%; p = 0.030) (Figure 2D).


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

Malfettone A, Saponaro C, Paradiso A, Simone G, Mangia A - BMC Cancer (2012)

Peritumoral vascular invasion and NHERF1 expression in grade 2 invasive breast carcinoma. (A) Representative images of peritumoral vascular invasion by H&E and NHERF1 protein expression by immunoistochemistry: (I) a tumor with the absence of peritumoral vascular invasion and (II) with the overexpression of membranous NHERF1, in addition to cytoplasmic localization (arrow). (III) A case showing peritumoral vascular invasion (arrowhead) and (IV) negative expression of membranous NHERF1. Original magnification × 100, inset × 200. (B) Assessment of the peritumoral vascular invasion in a breast tumor section stained with CD31 and NHERF1 antibodies and detected with Alexa Fluor 568 (red) and Alexa Fluor 488 (green) secondary antibodies, respectively. Immunofluorescence analysyis shows a tumor cell cluster within the endothelial-lined vascular space (arrowheads), with strong cytoplasmic NHERF1 expression similarly to the invasive cellular component at right zone of the image. Scale bar = 10 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3362775&req=5

Figure 3: Peritumoral vascular invasion and NHERF1 expression in grade 2 invasive breast carcinoma. (A) Representative images of peritumoral vascular invasion by H&E and NHERF1 protein expression by immunoistochemistry: (I) a tumor with the absence of peritumoral vascular invasion and (II) with the overexpression of membranous NHERF1, in addition to cytoplasmic localization (arrow). (III) A case showing peritumoral vascular invasion (arrowhead) and (IV) negative expression of membranous NHERF1. Original magnification × 100, inset × 200. (B) Assessment of the peritumoral vascular invasion in a breast tumor section stained with CD31 and NHERF1 antibodies and detected with Alexa Fluor 568 (red) and Alexa Fluor 488 (green) secondary antibodies, respectively. Immunofluorescence analysyis shows a tumor cell cluster within the endothelial-lined vascular space (arrowheads), with strong cytoplasmic NHERF1 expression similarly to the invasive cellular component at right zone of the image. Scale bar = 10 μm.
Mentions: When we applied the NPI to 187 breast patients, 49 (26%) were in the good prognostic group, 88 (47%) in the moderate prognostic group and 50 (27%) in the poor prognostic group (Table 1). We examined if tumors with grade 2 and poor prognosis were associated with some distinct clinicopathological parameters or with some tumor markers not currently used in routine diagnosis. Subgroup analysis revealed that the PVI (p = 0.023) and negative membranous NHERF1 expression (p = 0.028) were adverse prognostic factors for grade 2 tumors (Figure 2A, 3). When we analyzed the distribution of the PVI/membranous NHERF1 immunophenotypes in the three distinct histological groups, we showed that 72% of grade 2 and 92% of grade 3 tumors were significantly associated to the PVI+/membranous NHERF1-expression phenotype, both characterized by a poor prognosis (p = 0.000) (Figure 2B). Then, we explored the prognostic relevance of the PVI/membranous NHERF1 immunophenotypes in the whole cohort and, notably, 100% of tumors with poor prognosis significantly displayed the PVI+/membranous NHERF1- expression phenotype, compared with 27% of tumors with good prognosis (p = 0.000) (Figure 2C). Moreover, the PVI+/membranous NHERF1-phenotype in the subgroup of grade 2 familial tumors showed a higher significant proportion than proportion within subgroup of grade 2 sporadic tumors (90% vs. 50%; p = 0.030) (Figure 2D).

Bottom Line: Grade 2 subgroup analysis showed that the PVI (p = 0.023) and the loss of membranous NHERF1 (p = 0.028) were adverse prognostic factors.Multivariate logistic regression analysis in the whole series revealed poor prognosis correlated with PVI and MIB1 (p = 0.000 and p = 0.001, respectively).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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Functional Biomorphology Laboratory, National Cancer Centre, Bari, Italy.

ABSTRACT

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Show MeSH
Related in: MedlinePlus