Breast Tissue Composition and Immunophenotype and Its Relationship with Mammographic Density in Women at High Risk of Breast Cancer

Abstract

Aim: To investigate the cellular and immunophenotypic basis of mammographic density in women at high risk of breast cancer.

Methods: Mammograms and targeted breast biopsies were accrued from 24 women at high risk of breast cancer. Mammographic density was classified into Wolfe categories and ranked by increasing density. The histological composition and immunophenotypic profile were quantified from digitized haematoxylin and eosin-stained and immunohistochemically-stained (ERα, ERβ, PgR, HER2, Ki-67, and CD31) slides and correlated to mammographic density.

Results: Increasing mammographic density was significantly correlated with increased fibrous stroma proportion (rs (22) = 0.5226, p = 0.0088) and significantly inversely associated with adipose tissue proportion (rs (22) = -0.5409, p = 0.0064). Contrary to previous reports, stromal expression of ERα was common (19/20 cases, 95%). There was significantly higher stromal PgR expression in mammographically-dense breasts (p=0.026).

Conclusions: The proportion of stroma and fat underlies mammographic density in women at high risk of breast cancer. Increased expression of PgR in the stroma of mammographically dense breasts and frequent and unexpected presence of stromal ERα expression raises the possibility that hormone receptor expression in breast stroma may have a role in mediating the effects of exogenous hormonal therapy on mammographic density.

Fig 1. Quantification of proportion of fibrous stroma, fat, and epithelium in breast biopsies.

a) H&E-stained section; b) marked-up image of panel a showing strongly staining pixels in red, largely corresponding to epithelium, moderately and weakly staining pixels in orange and yellow respectively, largely corresponding to fibrous stroma, and non-stained pixels in blue, largely corresponding to fat.

Fig 2. Quantification of IHC staining.

a) ERα IHC-stained section with epithelial (filled arrowhead) and stromal (arrow) ERα staining; b) marked-up image of epithelium in panel a showing positive-staining nuclei (filled arrowhead); c) marked-up image of stroma in panel a (epithelium and non-specific staining manually excluded) showing positive-staining nuclei (arrow).

Fig 3. Proportion of fibrous stroma, fat, epithelium, and vascular area by mammographic density rank.

Fig 4. Stromal and epithelial immunophenotype and mammographic density by Wolfe categories.

*indicates statistically significant difference, ns = not statistically significant.