Prognostic relevance of the loss of stromal CD34 positive fibroblasts in invasive lobular carcinoma of the breast

Paul Jank,Roland Moll,Peter J Barth,Ute-Susann Albert,Schokufe Ebrahimsade,Christina C Westhoff,Christian O Jacke

doi:10.1007/s00428-020-02835-3

Abstract

CD34+ fibroblasts are constitutive stromal components of virtually all organs, including the mammary stroma, being involved in matrix synthesis, antigen presentation, and tumor-associated stromal remodeling. The most common subtype of invasive breast carcinoma, invasive carcinoma of no special type (IBC-NST), is known for its stromal loss of CD34+ fibroblasts while acquiring alpha smooth muscle actin-positive (α-SMA+) myofibroblasts, i.e., cancer-associated fibroblasts (CAF), whereas invasive lobular carcinoma (ILC) displays partial preservation of CD34+ fibroblasts. The aim of this study was to evaluate the prognostic relevance of stromal CD34+ fibroblasts and α-SMA+ myofibroblasts in an extended collection of ILC. A total of 133 cases of ILC, primarily resected between 1996 and 2004 at University Hospital Marburg, were examined semiquantitatively for stromal content of CD34+ fibroblasts and α-SMA+ myofibroblasts. Partial preservation of CD34+ fibroblasts in the tumor stroma of ILC was confirmed. Absence of CD34+ fibroblasts in the tumor stroma significantly correlated with the presence of α-SMA+ myofibroblasts (p = 0.010), positive lymph node status (p = 0.004), and pN stage (p = 0.006). Stromal loss of CD34+ fibroblasts was significantly associated with lower overall and disease-free survival rates (p = 0.012 and 0.013, respectively). Multivariate analysis adjusted for pT and pN stage revealed stromal loss of CD34+ fibroblasts as independent prognostic parameter (p = 0.05). To our knowledge, this is the first report defining prognostically relevant stromal subtypes of ILC with long-term follow-up. Future research targeting the potential diagnostic and therapeutic implications of CD34+ fibroblasts and CAF in breast cancer, especially ILC, is a promising field of interest.

Highlights

Breast cancer is the most frequent malignant tumor in women, leading both in incidence and mortality rate [1]
Stromal loss of CD34+ fibroblasts was significantly associated with lower overall overall survival (OS) rates (5-year overall survival CD34−, 73%; CD34+, 90%; p = 0.012), (Fig. 3a) and lower disease-free survival (DFS) rates (5-year disease-free survival CD34−, 75%; CD34+, 91%; p = 0.013) (Fig. 3b)
This larger study population with long-term follow-up emphasizes that the absence of CD34+ fibroblasts in the tumor stroma of a subset of Invasive lobular carcinoma (ILC) is associated with the presence of αSMA+ myofibroblasts and indicates a phenotypic switch to cancer-associated fibroblasts (CAFs) for this subgroup

Summary

Introduction

Breast cancer is the most frequent malignant tumor in women, leading both in incidence and mortality rate [1]. CD34 is a 110 kDa highly glycosylated transmembrane protein belonging to the family of sialomucins, a group of cell surface proteins including podocalyxin, thrombomucin, and endoglycan [5]. It was originally demonstrated on hematopoietic stem cells [6], but is expressed on vascular endothelial cells and fibroblasts in diverse organs [6, 7]. The known functions of this protein include cellular adhesion, e.g., homing of T lymphocytes in lymph nodes via L-selectin [5, 6], trafficking of hematopoietic cells, enhancing proliferation and blocking differentiation [5]

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