Relationship of Terminal Duct Lobular Unit Involution of the Breast with Area and Volume Mammographic Densities

Abstract

Elevated mammographic density (MD) is an established breast cancer risk factor. Reduced involution of terminal duct lobular units (TDLU), the histologic source of most breast cancers, has been associated with higher MD and breast cancer risk. We investigated relationships of TDLU involution with area and volumetric MD, measured throughout the breast and surrounding biopsy targets (perilesional). Three measures inversely related to TDLU involution (TDLU count/mm(2), median TDLU span, median acini count/TDLU) assessed in benign diagnostic biopsies from 348 women, ages 40-65, were related to MD area (quantified with thresholding software) and volume (assessed with a density phantom) by analysis of covariance, stratified by menopausal status and adjusted for confounders. Among premenopausal women, TDLU count was directly associated with percent perilesional MD (P trend = 0.03), but not with absolute dense area/volume. Greater TDLU span was associated with elevated percent dense area/volume (P trend<0.05) and absolute perilesional MD (P = 0.003). Acini count was directly associated with absolute perilesional MD (P = 0.02). Greater TDLU involution (all metrics) was associated with increased nondense area/volume (P trend ≤ 0.04). Among postmenopausal women, TDLU measures were not significantly associated with MD. Among premenopausal women, reduced TDLU involution was associated with higher area and volumetric MD, particularly in perilesional parenchyma. Data indicating that TDLU involution and MD are correlated markers of breast cancer risk suggest that associations of MD with breast cancer may partly reflect amounts of at-risk epithelium. If confirmed, these results could suggest a prevention paradigm based on enhancing TDLU involution and monitoring efficacy by assessing MD reduction.

Conflict of interest statement

Conflict of Interest Disclosure

S.D. Herschorn is a stockholder in Hologic.

©2015 American Association for Cancer Research.

Figures

Figure 1. Representative full-field digital mammograms from two premenopausal study participants

The digital mammogram is acquired with the density phantom in the corner of the image to allow for automated computation of volumetric mammographic density. To compute peri-lesional mammographic density, the radiologist recorded the biopsy location and radius of the biopsy target (noted in green) on a craniocaudal view of the pre-biopsy digital mammogram. Percent peri-lesional fibroglandular volume was estimated at a volume twice the size of but excluding the biopsy target, centered at the biopsy site. H&E images from each participant’s breast biopsy are also shown. In this example, Panel A represents a breast biopsy specimen with marked TDLU involution and with comparable mammographic density estimates of percent fibroglandular volume (43.9%) and percent peri-lesional fibroglandular volume (43.8%). In contrast, Panel B depicts a breast biopsy specimen with limited TDLU involution, as reflected in the increased number of TDLUs (TDLU spans are annotated and measured in microns using a digital ruler) and number of acini within the TDLUs; the mammogram in panel B has lower percent fibroglandular volume (36.3%) as compared with percent peri-lesional fibroglandular volume (60.2%).

Figure 2. Average TDLU count by age

A lowess function was used to estimate the average of TDLU counts as a function of age.