# Breast Cancer-Associated Adipose Tissue Histologic Subtypes: Microscopic Characterization and Their Impact on Prognosis and Survival, Depending on Age

## TL;DR

This study identifies four subtypes of breast cancer-associated adipose tissue that impact prognosis and survival differently depending on patient age.

## Contribution

The paper introduces a novel immunohistochemical classification of four distinct BCAAT subtypes with age-dependent prognostic implications.

## Key findings

- Four BCAAT subtypes were identified: fibroblast-rich, myofibroblast-rich, vascular-rich, and mixed-vascular/inflammatory-rich.
- BCAAT subtypes significantly influence prognosis and survival outcomes depending on patient age.
- BMI does not correlate with BCAAT subtypes but correlates with prognostic markers within each subtype.

## Abstract

Breast cancer-associated adipose tissue (BCAAT) is a well-established subject within the field. However, the data concerning its influence on prognosis and survival continues to evoke considerable debate, likely stemming from an incomplete characterization of the phenomenon. Our objective was to highlight the BCAAT subtypes microscopic heterogeneity through an immunohistochemical evaluation of cellular and vascular elements while also examining their implications for prognosis and survival outcomes. The present paper defines four subtypes of BCAAT, each exhibiting distinct overlaps across various age subgroups. Furthermore, these subtypes demonstrate a statistically significant influence on invasion and recurrence independent of body mass index (BMI) or the presence of immune-related microscopic structures such as tertiary lymphoid structures (TLSs). Future investigations will be essential to determine whether BCAAT subtypes may influence therapeutic responses and resistance.

Background/Objectives: The fundamental classification based on white, brown, pink, and beige adipose tissue morphology together with fat vacuole content released into the tumor microenvironment incompletely defines breast cancer-associated adipose tissue (BCAAT) heterogeneity and does not sufficiently explain its controversial impact on invasion, recurrence, or survival in breast cancer (BC). We aim to expand BCAAT characterization by systematically evaluating stromal cellular elements within peritumoral adipose tissue, including CD34-positive fibroblasts, smooth muscle actin (SMA)-positive myofibroblasts, inflammatory cells, and microvascular structures to define distinct BCAAT subgroups. Methods: CD34 and smooth muscle actin (SMA) double immunohistochemistry was performed on 109 BC tissue specimens from patients aged 35 to 79 years old, followed by microscopic evaluation of cellular and vascular components inside peritumor adipose tissue. Microscopic findings were then correlated to age, body mass index (BMI), lymphovascular (LVI) and perineural invasion (PnI), recurrence (R), and tertiary lymphoid structures (TLSs). Results: Four BCAAT subtypes have been identified as fibroblast-rich (FRich_BCAAT), myofibroblast-rich (MyoFRich_BCAAT), vascular-rich (VRich_BCAAT), and mixed-vascular and inflammatory-rich (VIRich_BCAAT). The FRich_BCAAT subtype predominates for the age subgroup 35 to 49 years old and is a significantly worse prognostic factor for survival (p = 0.022). For the age subgroup of 50 to 69 years old, the VIRich_BCAAT subtype significantly influences PnI (p = 0.05) but not survival (Log-rank test, z = 0.57, p = 0.57). VRich_BCAAT was significantly impactful for BC patient survival aged 70 to 75 years old (p = 0.043). BMI did not correlate with any of the BCAAT subtypes but was strongly correlated with prognostic markers for each BCAAT subtype. Conclusions: Based on immunohistochemically detected cellular and vascular components, four microscopic BCAAT subtypes were identified. Three of four BCCAT subtypes specifically affect BC patient prognosis and survival depending on age.