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

Abstract

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.

Giant cell tumor of distal radius: En bloc resection with allograft reconstruction: A case report

“…Radiologically, GCTs typically appear as lytic lesions with well‐defined margins and cortical thinning. Definitive diagnosis relies on histopathological examination of biopsy specimens, which reveal the characteristic features mentioned earlier 3,4 …”

“…Definitive diagnosis relies on histopathological examination of biopsy specimens, which reveal the characteristic features mentioned earlier. 3,4 Treatment of bone GCTs depends on various factors, including tumor location, size, grade, and patient factors. The mainstay of treatment is surgical resection, which aims to achieve complete tumor excision while preserving maximal function and minimizing recurrence.…”

“…Understanding these histopathological features is crucial for accurate diagnosis and management decisions, which often involve a multidisciplinary approach tailored to the tumor's behavior and grade. 4 GCTs pose a challenge in terms of management, especially when located in the distal radius. En bloc resection, a surgical technique involving the removal of the tumor along with a margin of surrounding normal tissue, is often employed in cases of large, aggressive, or challenging-toreach tumors.…”

“…Immunohistochemistry, utilizing markers such as CD68, CD163, and RANKL, aids in distinguishing GCT from other bone tumors. Understanding these histopathological features is crucial for accurate diagnosis and management decisions, which often involve a multidisciplinary approach tailored to the tumor's behavior and grade 4 …”

Giant Cell Tumor of Distal Radius: En Bloc Resection with Allograft Reconstruction: A Case Report

“…Radiologically, Bone GCTs typically appears as a lytic lesion with well-defined margins and cortical thinning. Definitive diagnosis relies on histopathological examination of biopsy specimens, which reveal the characteristic features mentioned earlier (3,4).…”