Breast carcinomas with osteoclast-like giant cells: a comprehensive clinico-pathological and molecular portrait and evidence of RANK-L expression

• Published in: Modern pathology Vol. 35; no. 11; pp. 1624 - 1635
• Main Authors: Cyrta, Joanna, Benoist, Camille, Masliah-Planchon, Julien, Vieira, Andre F., Pierron, Gaëlle, Fuhrmann, Laetitia, Richardot, Camille, Caly, Martial, Leclere, Renaud, Mariani, Odette, Da Maia, Elisabeth, Larousserie, Frédérique, Féron, Jean Guillaume, Carton, Matthieu, Renault, Victor, Bidard, François-Clément, Vincent-Salomon, Anne
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.11.2022; Nature Publishing Group US; Elsevier Limited; Nature Publishing Group: Open Access Hybrid Model Option B
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/51; 14/63; 38/91; 45/23; 631/208/68; 631/67/1347; 631/67/1857; 692/698/690/797; 692/699/67/1347; AKT protein; Breast; Breast cancer; Breast carcinoma; Breast Neoplasms - pathology; Cancer; Carcinoma - pathology; CD163 antigen; CD34 antigen; ErbB-2 protein; Female; Gelatinase B; Gene expression; Giant cells; Giant Cells - pathology; Humans; Immunohistochemistry; Iron; Laboratory Medicine; Life Sciences; Macrophage Colony-Stimulating Factor; Matrix Metalloproteinase 9; Medicine; Medicine & Public Health; Metastases; Osteoclasts; Osteoclasts - pathology; Osteoprotegerin; Pathology; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; RANK Ligand - genetics; Therapeutic targets; TOR protein; TOR Serine-Threonine Kinases; TRANCE protein; Transcriptomics; Tumors
• DOI: 10.1038/s41379-022-01112-9
• ISSN: 0893-3952

Breast carcinomas (BC) with osteoclast-like giant cells (OGC) are rare. Despite their distinct stromal features, their molecular characteristics remain unknown. Here, we report comprehensive clinico-pathological and molecular findings for 27 patients diagnosed with BC-OGC at Institut Curie between 2000 and 2021. Seventeen (63%) cases were invasive carcinomas of no special type (IC NST) with OGC (OGC-IC NST), four (15%) were mixed or multifocal cases with and without OGC (OGC-Mixed), and six (22%) were metaplastic carcinomas with OGC (OGC-MC). All OGC-IC NST and OGC-Mixed cases were ER+ HER2− tumors (most being luminal A based on transcriptomic subtyping, when available), while all OGC-MC were triple-negative. The median age at diagnosis was 46, 45 and 62 years for OGC-IC NST, OGC-Mixed and OGC-MC, respectively. Three patients developed distant metastases (one OGC-IC NST, two OGC-Mixed), one of whom died of metastatic disease (OGC-Mixed), and one other patient died of locally advanced disease (OGC-MC). Histopathological evaluation comparing 13 OGC-IC NST and 19 control IC NST without OGC confirmed that OGC-IC NST showed significantly higher density of vessels (by CD34 immunohistochemistry (IHC)), iron deposits (Perls stain), and CD68 and CD163-positive cell infiltrates. Genomic findings for nine OGC-IC NST and four OGC-MC were consistent with the underlying histologic subtype, including activating alterations of the PI3K/AKT/mTOR pathway in 7/13 cases. Using RNA-seq data, differential gene expression analysis between OGC-IC NST (n = 7) and control IC NST without OGC (n = 7) revealed significant overexpression of TNFSF11 (RANK-L), TNFRSF11A (RANK), CSF1 (M-CSF), CSF1R, and genes encoding osteoclastic enzymes (MMP9, ACP5, CTSK, CTSB) in OGC-IC NST, while OPG (osteoprotegerin) was underexpressed. We also confirmed for the first time RANK-L expression in BC with OGC by IHC (seen in 15 out of 16 cases, and only in 2 of 16 controls without OGC). These findings could offer a rationale for further investigating RANK-L as a therapeutic target in BC with OGC.