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Hemophagocytic lymphohistiocytosis in marrows
DLBCL and based on morphology likely represented ingested tumor cells. Additionally, distinguishing between nucleated erythrocytes, lymphocytes, and hematopoietic progenitor cells within the cytoplasm of a histiocyte is challenging and subject to interpretive variability. As such, we created an additional CART excluding lymphocytes. This CART is identical to the first two levels of the previ- ous model, with patients having a 92% chance of having an HLH diagnosis with a presence of at least one hemo- phagocyte with an ingested granulocyte and two or more hemophagocytes with ingested nRBCs (Figure 4B). While the CV AUC was identical to that of the first, overall accu- racy was slightly higher in the CART without lympho- cytes (88% CV accuracy vs. 86%).
Qualitative evaluation
The initial description of virus-associated hemophago- cytic syndrome described histiocytes that were “filled” with ingested hematopoietic elements.11 We frequently observe the phenomenon of multiple nucleated cells with- in individual histiocytes in patients with established HLH and hypothesized that this finding may be indicative of a pathological hemophagocytic state. To evaluate the signif- icance of the degree of hemophagocytosis within individ- ual hemophagocytes, we analyzed the presence of multi- ple nucleated cells within histiocytes (Figure 1). Our analy- sis ultimately demonstrated that at least one hemophago- cyte-containing multiple nucleated cells was identified in 37 patients with HLH compared to only 4 patients in the non-HLH group (AUC: 0.91, 0.845-0.947), indicating that this binary qualitative feature performs similarly to the quantitative metrics described above for distinguishing patients with HLH from non-HLH patients (Table 3).
Discussion
Given the rarity of the diagnosis and non-specific clini- cal presentation, HLH is a challenging diagnosis for clini- cians and pathologists. Once considered in the differential, expedient workup including evaluation of each of the HLH-2004 criteria is commonly pursued, as early thera- peutic intervention improves outcomes in these often crit- ically ill patients. Unfortunately, there is no defined threshold to satisfy the diagnostic criterion of hemo- phagocytosis in the bone marrow and evidence-based guidelines for reporting findings have not been estab- lished.
Towards this goal, we designed this retrospective study to determine whether quantitative features of hemo- phagocytosis at the time of initial bone marrow assess- ment are predictive of the ultimate diagnosis of HLH in patients presenting with clinical features concerning for the diagnosis. Given that HLH classically presents with multilineage cytopenia that is thought to result from con- sumption of hematopoietic cells by activated macrophages,12 we suspected that patients with HLH would be more likely to display hemophagocytosis of nucleated erythrocytes, granulocytes and lymphocytes compared to patients without HLH. In addition to evalu- ating for possible quantitative differences in hemophago- cytosis, we simultaneously assessed for the presence of multiple nucleated cells within a single hemophagocyte as a candidate binary morphological feature that may differ- entiate patients with pathological hemophagocytosis.
Overall, we found that patients with HLH displayed sig- nificantly higher numbers of HPCs by each of the lineages examined (Table 3). We also identified quantitative thresh-
Table 2. Underlying medical conditions of patients in hemophagocytic lymphohistiocytosis (HLH) and non-HLH groups.
HLH
Diagnosis (N. of patients)
Diffuse large B-cell lymphoma (9)
Peripheral T-cell lymphoma (6)
NK/T-cell lymphoma/leukemia (2)
EBV+ lymphoproliferative disorder (2)
Classical Hodgkin Lymphoma (EBV+) (1)
Langerhans cell histiocytosis (1)
Primary effusion lymphoma (HIV+ and HHV-8+) (1) Juvenile xanthogranuloma (1)
B-cell acute lymphoblastic leukemia (1)
Rheumatoid arthritis (3)
Systemic lupus erythematosus (2)
Sarcoidosis (2)
Dermatomyositis (1)
Atypical Kawasaki disease (1)
Ulcerative colitis (1)
Idiopathic (5)
Post ventricular assist device (3)
Griscelli syndrome (homozygous Rab27a mutation) (1)
Homozygous perforin mutation (1)
N: number; NK: natural killer cell; EBV: Epstein-Barr virus; NOS: not otherwise specified.
Non-HLH Diagnosis (N. of patients)
Classical Hodgkin lymphoma (EBV+) (2)
Diffuse Large B-cell lymphoma (1) Peripheral T-cell lymphoma (2)
T-Cell Acute lymphoblastic leukemia (1) FIP1L1-PDGFRa myeloid leukemia (1) Blastic plasmacytoid dendritic cell neoplasm (1) Autoimmune hemolytic anemia (2) Systemic lupus erythematosus (5)
Adult onset still's disease (3) Autoimmune hepatitis (1)
Severe acquired neutropenia (1) Aplastic anemia (1)
Autoimmune disorder NOS Dermatomyositis (1)
Autoimmune lymphoproliferative Syndrome (1) Mixed connective tissue disease (1) Infection (6)
White cell aplasia (1)
Other (15)
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