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Hemophagocytic lymphohistiocytosis in marrows
Table 3. Quantities of hemophagocytic cells by lineage of ingested hematopoietic cells and optimal cutoff values derived from Youden’s index.
Lineage
RBC
nRBC Granulocyte Lymphocyte HPC sum
mHPC
Mean (range)*
Threshold AUC (95% CI)
4 0.83 (0.74-0.93)
2 0.92 (0.87-0.98) 1 0.92 (0.86-0.99) 1 0.80 (0.72-0.88) 6 0.92 (0.85-0.98)
NA 0.91 (0.85-0.95)
HLH
Non-HLH
3.1 (0-18)
0.8 (0-6)
0.5 (0-5)
0
4.3 (0-19)
4
7.7 (1-21)
5.2 (1-15) 4.3 (0-21) 1.3 (0-11) 18.4 (4-44) 37
RBC: red blood cells; nRBC: nucleated RBCs; HPC sum: total hematopoietic progenitor cell count from all four lineages; mHPC: multiple nucleated cells within a single HPC. *Per 1000 cells.
ulation that reflects those seen in routine diagnostic prac- tice.
A recent study by Ho et al. examined the specificity of hemophagocytosis for HLH by quantifying the absolute amount of hemophagocytosis identified in bone marrow aspirates of patients whose diagnostic pathology report described hemophagocytosis.10 They demonstrated that the presence of hemophagocytosis, even when present in a high amount, lacks specificity for HLH. Our institutional experience is consistent with their conclusion that signifi- cant hemophagocytosis is not predictive of the diagnosis of HLH in the absence of clinical features of concern for the disease; however, the presence of substantial hemophago- cytosis is a relatively rare finding. Incidental hemophagocy- tosis was reported in 86 of 8097 (1.1%) in-house bone mar- row biopsy reports at Stanford University Hospital from 2013-2017. The majority of reports indicate “rare” hemo- phagocytosis (61%) while the remainder describe “scat- tered”, “occasional”, or “brisk” hemophagocytosis. A subset (n=12) of these latter cases was reviewed. All 12 cases demonstrated erythrophagocytosis. Half of the cases show ingested granulocytes and 3 cases demonstrated multiple nucleated cells within individual HPCs. None of these patients were ultimately diagnosed with HLH.
One major limitation of this study is its retrospective nature. Our population is limited to patients in whom the clinical diagnosis was thoroughly evaluated and a defini- tive determination was made concerning the diagnosis of
HLH. We excluded patients in whom the ultimate diagno- sis was ambiguous. Additionally, although our cohort includes all of the patients at our institution that met cri- teria for evaluation, including children, only a single patient in our cohort had a homozygous mutation diag- nostic of primary HLH, limiting the applicability of our findings to patients with genetic forms of the disease. Finally, we note that while CD107a testing has been described as a more sensitive test for primary HLH,13 this recently developed assay was not utilized in this retro- spective cohort.
Ultimately, the diagnosis of HLH rests on the thorough assessment of patients in the appropriate clinical context. Similarly, microscopic examination of bone marrow aspi- rate smears in patients suspected of having HLH requires careful evaluation for the presence of hemophagocytosis. Our results demonstrate that quantitative thresholds of the lineage of ingested cells, either alone or in combina- tion, accurately predict the eventual diagnosis of HLH. We additionally demonstrate that identification of a single hemophagocyte containing multiple nucleated hematopoietic cells within its cytoplasm performs similar- ly to our quantitative approach. With external validation and further prospective study, we hope that these data will help to provide a method for pathologists and clini- cians to systematically evaluate and accurately classify patients with HLH and contribute to establishment of consensus guidelines of diagnosis and reporting.
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