Abstract

Hemophagocytic lymphohistiocytosis is a rare multi-system inflammatory disorder with diagnostic criteria based on the HLH-2004 trial. Hemophagocytosis is the only histomorphologic criterion, but in isolation is neither specific nor sensitive for the diagnosis of hemophagocytic lymphohistiocytosis. While objective thresholds for clinical and laboratory criteria have been established, specific criteria for histomorphologic evidence of hemophagocytosis in hemophagocytic lymphohistiocytosis have not been rigorously evaluated or established. We sought to determine if numerical and objective criteria for morphologic hemophagocytosis could be identified, and if such criteria would aid in the diagnosis of hemophagocytic lymphohistiocytosis. We analyzed the morphologic features of hemophagocytosis in 78 patients presenting with clinical features suspicious for hemophagocytic lymphohistiocytosis: 40 patients with hemophagocytic lymphohistiocytosis and 38 patients without hemophagocytic lymphohistiocytosis. We demonstrate that non-nucleated erythrophagocytosis alone is a non-specific finding, while hemophagocytosis of granulocytes (1 per 1000 cells, area under the curve: 0.92, 95% confidence interval: 0.86, 0.99), nucleated erythrocytes (4 per 1000 cells, area under the curve: 0.92, 95% confidence interval: 0.87, 0.98), and at least one hemophagocyte containing multiple nucleated cells (area under the curve: 0.91, 95% confidence interval: 0.85, 0.95) are strongly associated with hemophagocytic lymphohistiocytosis. Joint modeling of hemophagocytes containing engulfed granulocytes, nucleated erythrocytes, and lymphocytes effectively distinguished between hemophagocytic lymphohistiocytosis and non-hemophagocytic lymphohistiocytosis (cross-validated area under curve: 0.90, 95% confidence interval: 0.83, 0.97).

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