Local Cell Death and Not Hemophagocytosis Is the Morphological Hallmark of Hemophagocytic Lymphohistiocytosis: A Study of 17 Cases
Quyen Nguyen, Parul Bhargava, German Pihan. Beth Israel Deaconess Medical Center, Boston, MA
Background: Hemophagocytic lymphohistiocytosis (HLH) arises from dysregulation of immune response activation and termination. Molecular defects in the cytolytic pathway of NK and cytotoxic T-cells in HLH result in highly stimulated, but ineffective immune responses. Hypercytokinemia generated by activated cytotoxic lymphocytes leads to systemic activation of macrophages, multiorgan dysfunction, and potentially death. The accumulation of activated M2 macrophages in the bone marrow results in hemophagocytosis and cytopenias. The diagnostic criteria for HLH include 5 major and 3 minor criteria. Of the major criteria, two are clinical (fever and splenomegaly), two are laboratory findings (cytopenia and hypertriglyceridemia or hypofibrinogenemia), and one a morphological finding (hemophagocytic cells). Previous studies have reported that the presence and number of hemophagocytic cells (HPC) on bone marrow aspirates (BMA) is neither sensitive nor specific for the diagnosis of HLH. We evaluated morphologic and immunophenotypic features of adult-onset HLH to identify more specific diagnostic features.
Design: We retrieved a total of 20 BM biopsies (BMB) from 17 patients admitted to BIDMC in the past 5 years who met criteria for a diagnosis of HLH. BMs were analyzed morphometrically and by immunohistochemistry (IHC). Number of HPC, extent of marrow necrosis, type of cell death and immunophenotypic profiles of T cells and macrophages were quantified.
Results: The number of HPC at initial BMA is often low and variable (median HPC per 500 cells 1.5, range 0-11), with 2/15 (13%) evaluated BMA having no HPCs on 1st BMA, suggesting its insensitivity as a criterion for the diagnosis of HLH. However, a more uniform early finding seen on bone marrow core biopsies is the presence of foci of marrow necrosis with eosinophilic debris, with or without macrophages with an activated phenotype. By IHC, there was a predominance of CD8-positive T-cells confirming the preeminent role of cytotoxic T-cells. In addition, an increase of M2 macrophages, some with ingested cellular debris, was seen, as highlighted by CD68 and CD163 stains.
Conclusions: Focal marrow necrosis with eosinophilic debris may be a sensitive and early criterion for HLH diagnosis. An immunohistochemical panel demonstrating expanded CD8+ cytotoxic T cells, M2 macrophages (CD68+, CD163+), and possibly markers of cell death, may be useful for diagnosing and elucidating the pathogenesis of HLH.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 225, Monday Morning