Bone marrow macrophages containing other cells, or large pieces of other cells, represent a distinctive feature of diseases such as Hemophagocytic Lymphohistiocytosis (HLH) and Rosai-Dorfman disease. We describe a distinct variation of phagocytic histiocyte morphology, featuring histiocytes containing predominantly fragments of neutrophil nuclei. We retrospectively reviewed initial bone marrow samples for Hodgkin lymphoma, Burkitt lymphoma, Ewing sarcoma, or evaluation for nonneoplastic conditions, scoring the presence or absence of the above-described histiocytes. We find that these histiocytes, which we term “fragmentophages,” are associated with staging marrow sampling for malignancy, especially Hodgkin lymphoma (Hodgkin lymphoma: 28/34 or 82.4%, Ewing sarcoma: 11/26 or 42.3%, Burkitt lymphoma: 4/13 or 30.8%). These cells are significantly less common in marrow samples for nonneoplastic conditions (4/21 or 19.0%). Fragmentophages are significantly associated with malignancy, especially Hodgkin lymphoma, and their recognition has the potential to provide a clue to an underlying malignancy.
The histologic patterns of Hemophagocytic Lymphohistiocytosis (HLH) and Rosai-Dorfman disease are distinctive, each characterized by macrophages containing large parts of other cells. HLH is characterized by increased macrophage uptake and destruction of red blood cells, red blood cell precursors, and platelets, resulting in potentially lethal peripheral cytopenias. Rosai-Dorfman disease features the proliferation of distinctive, large histiocytic cells which accumulate usually in the sinuses of lymph nodes and contain predominantly intact lymphocytes. Both of these diseases can involve the bone marrow. Thus, the identification of bone marrow macrophages containing other cells in their cytoplasm evokes consideration of these diagnoses [
A retrospective review of initial bone marrow samples and patient chart material over a 5-year period was performed in accordance with an Institutional Review Board approved protocol. Staging marrow samples represented patients treated at our pediatric center for Hodgkin lymphoma, Ewing Sarcoma, and Burkitt lymphoma or were initial bone marrow biopsies for nonneoplastic conditions. Marrow samples which were involved by the associated malignancy were excluded. The identified marrow samples included 34 patients with Hodgkin lymphoma (age 3 to 19 years, 15 males and 19 females), 13 patients with Burkitt lymphoma (age 2 to 18 years, 10 males and 3 females), 26 patients with Ewing sarcoma (age 4 to 37 years, 19 males and 7 females), and 21 patients who underwent initial marrow sampling for a nonneoplastic condition (age 1 to 18 years, 15 males and 6 females). On review of bone marrow samples, the presence or absence of macrophages containing predominantly neutrophils or neutrophil fragments was scored.
Macrophages containing neutrophils were observed in core biopsy sections (Figures
Macrophages containing granulocyte nuclear debris. Macrophages containing granulocyte nuclear debris can be seen dispersed throughout marrow biopsies in H&E stained sections ((a) H&E 40x objective magnification, (b) H&E 100x oil objective magnification) and aspirate marrow smears ((c) Wright-Giemsa 100x oil). Immunohistochemical staining for myeloperoxidase highlights the phagocytosed cells ((d) 100x oil). H&E: Hematoxylin and Eosin.
Distinct histologic features of macrophages containing other cell types. Macrophages containing neutrophils, or “fragmentophages,” show cytoplasmic inclusion of cells with lobulated nuclei ((a) H&E 100x oil). In contrast, HLH features macrophages containing red blood cells ((b) Wright-Giemsa 100x oil) and Rosai-Dorfman with macrophages containing intact lymphocytes ((c) Wright-Giemsa 100x oil). Tingible body macrophages are distinguished by cytoplasm which contains a range of fragments, from whole lymphocytes to small debris ((d) Wright-Giemsa 100x oil).
The characteristic histiocytes we observed were seen most often in staging marrow samples for Hodgkin lymphoma (82.4%) (Figure
Distribution of bone marrow macrophages containing neutrophils by underlying diagnosis.
Since the characteristic macrophages we describe are seen to engulf neutrophils, and cytokines are known to be elevated in patients with Hodgkin lymphoma [
We report a distinct pattern of macrophage morphology which is easily distinguished from the macrophages characteristic of HLH and Rosai-Dorfman disease, as well as tingible body macrophages. These macrophages engulf predominantly neutrophils or fragments of neutrophils, and we find that these cells are significantly associated with malignancy, in particular Hodgkin lymphoma. During the 5-year period we examined, we found that these macrophages were more than 6 times as likely to occur in the setting of the malignancies we examined when compared to bone marrow biopsies for nonneoplastic conditions. Additionally, these cells were more than 19 times more likely to be seen in initial bone marrow biopsies for Hodgkin lymphoma than in initial biopsies for nonneoplastic conditions.
Further systematic characterization of this intriguing morphologic finding is required to determine if this association is restricted to the malignancies we examined in children, or if these macrophages are universally associated with malignancy. Correlation with bone marrow biopsies in adults may be important, as it is possible that the inherently more brisk physiologic reactions in children contribute to the production of these macrophages. In this series, however, we did not identify a correlation between the occurrence of these macrophages and patient age.
Awareness of this morphologic pattern will be a key to further elucidate its potential clinical significance. We therefore propose utilizing a uniform nomenclature to facilitate the further description of these distinctive macrophages containing predominantly neutrophils, such as the term “fragmentophages.” While phagocytosis in the bone marrow has been vaguely mentioned in older medical literature on bone marrow findings in Hodgkin lymphoma [
The mechanism which drives the formation of these cells is unclear. Hodgkin lymphoma is known to be associated with increased production of cytokines [
This paper was presented in abstract at the annual meeting of Society for Pediatric Pathology on March 1, 2014, in San Diego, CA, USA.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors thank Maria Nunez for her help in preparing this paper.