The phosphatidylserine receptors, T cell immunoglobulin mucin proteins 3 and 4, are markers of histiocytic sarcoma and other histiocytic and dendritic cell neoplasms

Abstract

The T cell immunoglobulin mucin (TIM) proteins are a family of cell surface phosphatidyserine receptors that are important for the recognition and phagocytosis of apoptotic cells. Because TIM-4 is expressed by macrophages and dendritic cells in human tissue, we examined its expression in a range of histiocytic and dendritic cell neoplasms and found moderate to strong immunohistochemical staining in cases of juvenile xanthogranuloma and histiocytic sarcoma, and lower level staining in interdigitating dendritic cell sarcoma, Langerhans cell histiocytosis, acute monocytic leukemia (leukemia cutis), and blastic plasmacytoid dendritic cell neoplasm (hematodermic tumor). TIM-3 was first described on activated T(H)1 cells but was recently shown to also be a phosphatidylserine receptor and mediate phagocytosis. We found TIM-3 was expressed by peritoneal macrophages, monocytes and splenic dendritic cells. We found that it, like TIM-4, is expressed in a range of histiocytic and dendritic cell neoplasms, typically with strong immunohistochemical staining. Cases of diffuse large B cell lymphoma, anaplastic large cell lymphoma, metastatic malignant melanoma, and metastatic poorly differentiated carcinoma generally exhibited negative to minimal heterogenous staining for TIM-4 and TIM-3. We conclude that histiocytic and dendritic cell neoplasms consistently express TIM-3 and TIM-4 and that these molecules are new markers of neoplasms derived from histiocytic and dendritic cells.

Figure 1

Human tonsil (A–C) stained with specific antibodies recognizing TIM-4 (A and C) and CD68 (B and C) shows positive staining for TIM-4 in tingible body macrophages in germinal centers (A) as well as in interfollicular dendritic cells (not shown). Tingible body macrophages show positive staining with CD68 (B) and coexpression of TIM-4 and CD68 in double staining experiments (C). Peritoneal tissue (D–F) stained with specific antibodies recognizing TIM-3 (D and F) and CD68 (E and F) shows positive staining for TIM-3 in peritoneal macrophages (D). Peritoneal macrophages show positive staining with CD68 (E) and coexpression of TIM-3 and CD68 in double staining experiments (F). Magnification × 400.

Figure 2

Juvenile xanthogranuloma (A, hematoxylin and eosin staining) shows strong cytoplasmic positive staining for TIM-4 (B) and TIM-3 (C), with accentuated membrane staining noted for TIM-3. Interdigitating dendritic cell sarcoma (D, hematoxylin and eosin staining) demonstrates weak to moderate cytoplasmic staining for TIM-4 (E) and strong cytoplasmic and membrane staining for TIM-3 (F). Magnification: A–C, × 200; D–F, × 400.

Figure 3

Two cases of histiocytic sarcoma (A and D, hematoxylin and eosin staining) showing strong cytoplasmic staining for TIM-4 (B and E). Other cases exhibited weak to strong staining for TIM-4. All cases of histiocytic sarcoma tested exhibited strong cytoplasmic staining for TIM-3 (C) or strong cytoplasmic and membrane staining for TIM-3 (F). Magnification × 400.

Figure 4

A case of Langerhans cell histiocytosis involving lymph node (A, hematoxylin and eosin staining), shows weak cytoplasmic staining for TIM-4 (B), strong staining for Langerin (C) and strong membrane and cytoplasmic staining for TIM-3 (D). Magnification × 400.

Figure 5

A case of acute monocytic leukemia involving skin (leukemia cutis) (A, hematoxylin and eosin staining) showing moderate cytoplasmic staining for TIM-4 (B) and strong cytoplasmic staining for TIM-3 (C). A case of blastic plasmacytoid dendritic cell neoplasm involving skin (D, hematoxylin and eosin staining) showing moderate cytoplasmic staining for TIM-4 (E) and moderate cytoplasmic staining for TIM-3 (F). Magnification × 400.