Bone marrow histomorphological criteria can accurately diagnose hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare multi-system inflammatory disorder with diagnostic criteria based on the HLH2004 trial. Hemophagocytosis is the only histomorphological criterion, but in isolation is neither specific nor sensitive for the diagnosis of HLH. While objective thresholds for clinical and laboratory criteria have been established, specific criteria for histomorphological evidence of hemophagocytosis in HLH have not been rigorously evaluated or established. We sought to determine if numerical and objective criteria for morphological hemophagocytosis could be identified, and if such criteria would aid in the diagnosis of HLH. We analyzed the morphological features of hemophagocytosis in 78 patients presenting with clinical features suspicious for HLH: 40 patients with and 38 patients without HLH. We demonstrate that non-nucleated erythrophagocytosis alone is a non-specific finding, while hemophagocytosis of granulocytes [1 per 1000 cells, area under the curve (AUC): 0.92, 95% Confidence Interval (CI): 0.86, 0.99], nucleated erythrocytes (4 per 1000 cells, AUC: 0.92, 95% CI: 0.87, 0.98), and at least one hemophagocyte containing multiple nucleated cells (AUC: 0.91, 95% CI: 0.85, 0.95) are strongly associated with HLH. Joint modeling of hemophagocytes containing engulfed granulocytes, nucleated erythrocytes, and lymphocytes effectively distinguished between HLH and non-HLH (cross-validated AUC: 0.90, 95% CI: 0.83, 0.97).