Diverse Immunophenotypic Abnormalities in Adult Patients with Hemophagocytic Lymphohistiocytosis

Adult hemophagocytic lymphohistiocytosis (aHLH) is a rare, aggressive, often lethal disease presenting with cytopenias and infections. By contrast, pediatric HLH is a relatively homogeneous, familial condition, with 75% response rate. The hypercytokinemia that drives hemophagocytosis in aHLH may result from one or more overactive/overgrown lymphocyte subpopulations that may or may not be clonal. Very few detailed observations characterizing such populations exist. We present immunophenotypic abnormalities in 12 patients with aHLH diagnosed following the 2004 Histiocyte Society Criteria.

Clinical and laboratory records of all patients clinically and/or pathologically diagnosed to have aHLH at Vancouver General Hospital were reviewed. Those fulfilling the 2004 Histiocyte Society Criteria for HLH, and had flow cytometry performed were further analyzed. The following markers were used: CD2, 3, 4, 5, 7, 8, 10, 16, 19, 20, 22, 23, 38, 45, 56, 57, 79b, FMC7, kappa and lambda.

Of the 29 patients with hemophagocytosis, 12 had confirmed aHLH and immunophenotyping data available (table-1). There were 4 males and 8 females; the median age was 57 years (21–76 years). Fever and splenomegaly were seen in 10 and 5 patients, bicytopenia and pancytopenia in 6 patients each while hyperferritinemia (>500ug/L), hypofibrinogenemia (<1.5g/L), fasting hypertriglyceridemia (>3mmol/L) and hemophagocytosis were seen in 12, 7, 8 and 12 patients respectively. In terms of triggering or predisposing factors, 5 patients had evidence of EBV infection, 1 had both EBV and CMV infections, and 1 had CMV infection. The remaining five patients had sarcoidosis, adult onset Still's disease, acute respiratory failure with sepsis and pulmonary emboli, and rheumatoid arthritis with Felty's syndrome and sepsis. One patient received treatment for Still's disease (no. 12), 4 patients (no. 1, 7, 9 and 11) were palliated and 6 patients (no. 2–6, 8) were treated with etoposide-based therapy as per the HLH 2004 protocol. One patient was lost to follow up (no.10). The patient treated for Still's disease (no.12) and two of 6 patients (no. 2, 3) on the HLH 2004 protocol achieved complete remission. All four patients who were palliated (nos. 1, 7, 9, 11) died. Immunophenotyping was done on bone marrow (n= 11) or blood (n= 1) specimens. The median lymphocyte percentage was 15 (range 3–70). All 12 patients showed abnormal lymphocyte populations (table-1). Six patients showed T-cell abnormalities including increased numbers of either Th2 (T-helper type II) or double negative T-cells or of CD8+ T-cells. Four patients had increased numbers of CD56+ cells (in contrast to reduced or absent NK activity reported in the literature), and two patients had polyclonal increase in B-cells. There was no correlation of underlying/precipitating factors, diagnostic clinical or laboratory parameters, type of treatment received or treatment response, with the type of Immunophenotypic abnormalities.

Diverse immunophenotypic abnormalities were seen in patients with aHLH; the type of aberrant phenotype had no relationship to either clinical or laboratory findings, underlying/predisposing factors or to the response to treatment. This finding confirms the varied pathogenetic mechanisms leading to hemophagocytosis, and prompts further investigations into their role in aHLH.

No relevant conflicts of interest to declare.