Two cases of breast carcinoma with osteoclastic giant cells: are the osteoclastic giant cells pro-tumoural differentiation of macrophages?

Abstract

Breast carcinoma with osteoclastic giant cells (OGCs) is characterized by multinucleated OGCs, and usually displays inflammatory hypervascular stroma. OGCs may derive from tumor-associated macrophages, but their nature remains controversial. We report two cases, in which OGCs appear in common microenvironment despite different tumoural histology. A 44-year-old woman (Case 1) had OGCs accompanying invasive ductal carcinoma, and an 83-year-old woman (Case 2) with carcinosarcoma. Immunohistochemically, in both cases, tumoural and non-tumoural cells strongly expressed VEGF and MMP12, which promote macrophage migration and angiogenesis. The Chalkley count on CD-31-stained sections revealed elevated angiogenesis in both cases. The OGCs expressed bone-osteoclast markers (MMP9, TRAP, cathepsin K) and a histiocyte marker (CD68), but not an MHC class II antigen, HLA-DR. The results indicate a pathogenesis: regardless of tumoural histology, OGCs derive from macrophages, likely in response to hypervascular microenvironments with secretion of common cytokines. The OGCs have acquired bone-osteoclast-like characteristics, but lost antigen presentation abilities as an anti-cancer defense. Appearance of OGCs may not be anti-tumoural immunological reactions, but rather pro-tumoural differentiation of macrophage responding to hypervascular microenvironments induced by breast cancer.

Figure 1

Gross and microscopic findings of breast carcinoma with OGCs. OGCs in Case 1 appeared associated with invasive ductal carcinoma, grade 1, and in Case 2 with carcinosarcoma. A-H: Case 1. A: Gross appearance. B: Low power view of the tumor. C, D: High power views of the tumor. E, F: Bi-, tri-, tetranucleate cells were observed as well as OGCs in hypervascular inflammatory stroma. G: CK AE1/AE3 staining. H: ER staining. I-N: Case 2, corresponding to A-F in Case 1. O: CK AE1/AE3 staining. P: Vimentin staining.

Figure 2

Topography of CD68-positive cells and expression of VEGF and MMP12. Case 1 and Case 2 showed distinct vascular patterns, but in both cases OGCs preferentially appeared in hypervascular stroma. Marked expression of VEGF and MMP12 was evident. A: Distribution of blood vessels marked with CD31 in Case 1. B, C: CD68-positive cells in Case 1. D: Distribution of blood vessels marked with CD31 in Case 2. E, F: CD68-positive cells in Case 2. G-R: VEGF and MMP12 expression in Case 1 (G-L), and Case 2 (M-R).

Figure 3

Expression of phenotypic markers of OGCs. Phenotypes of OGCs in the breast (center panels) were compared those of osteoclastic cells in the bone (far left) and foreign body giant cells (far right). OGCs in the breast displayed both osteoclastic and histiocytic characteristics but lacked antigen presentation abilities. A-D: CD68, a phenotypic marker for histiocytes. E-H: MMP9, a broad marker for macrophage-osteoclast lineage cells. I-L: TRAP. M-P: Cathepsin K. Q-T: HLA-DR.