Γδ-t Large Granular Lymphocyte Leukemia Associated Hemaphagocytic Syndrome Complicated with Multiple Organ Dysfunction

Hemophagocytic syndrome (HPS) usually presents as a complication of T/NK cell lymphoma. However, γδ-T large granular lymphocyte leukemia (LGL) associated HPS was rarely reported. Herein, we reported a case of γδ-T LGL associated HPS. A previously healthy 21-year-old Chinese man was admitted with high fever, severe pancytopenia and liver dysfunction. He developed disseminated intravascular coaggulation (DIC), shock, gastrointestinal bleeding, acute renal failure as well as central nervous system involvement. Bone marrow aspiration showed infiltration of large granular lymphocytes and hemophagocytic histiocytes. Immunophenotyping analysis by four-color flow cytometry showed the leukemic cells with large side scatter TCRβ and γ chain gene rearrangement confirmed TCRγδ T cell clone. Thus, a diagnosis of γδ-T LGL associated HPS was established. The patient worsened rapidly and died of multiple organ failure.


Introduction
Hemophagocytic syndrome (HPS) is a rare disorder characterized by the clinical features of fever, pancytopenia, hepatosplenomegaly, and liver dysfunctiona.Which is a clinicopathological entity characterized by increased proliferation and activation of benign macrophages with hemophagocytosis throughout the reticuloendothelial system.HPS can be developed as a rare but potentially fatal complication of several disorders including malignancies, infections, and autoimmune disorders.γδ-T large granular lymphocyte leukemia is particularly rare.Tanaka et al. reported a case of γδ-T large granular lymphocyte leukemia preceded by pure read cell aplasia and complicated with hemophagocytic syndrome causesd by Epstein-Barr Virus infection [1].Herein, we reported an unusual case of HPS with rapid evolution of multiple organ failure preceded by γδ-T large granular lymphocyte leukemia, and its prevalence, pathogenesis, diagnosis and treatment were discussed.

Discussion
In this case report, we described a rare case of γδ T cell leukemia proceeding with aggressive HPS.The clinical manifestations of this case are largely attributed to the accompanied HPS.The quick worsening of his clinical condition indicates the aggressiveness of the disease.This is probably due to the activation of the malignant clonal γδ T cells, which can produce high levels of pro-inflammatory cytokines causing dysfunction or even failure of multiple organs as described in this case.γδ T cell leukemia is mostly described in case reports.There have been no available data on its prevalence in certain populations.Its diagnosis is dependent on marrow cell morphology, flow cytometric analysis as well as PCR detection of TCR γ and δ chain gene rearrangement.γδ T cell leukemia is treated by chemotherapy using CHOP protocol.The prognosis depends on the progression and response to chemotherapy of the disease [1] [2].Hemophagocytic syndrome (HPS) is a rare but life-threatening disease caused by inappropriate activation of T-lymphocytes and histocytes, hypercytokinemia and hemophagocytosis.The most common symptoms are fever, hepatosplenomegaly, pancytopenia, coagulopathy, hyperferritinemia and lipid abnormalities (elevated triglyceride) [3].HPS is classified into two forms: primary, inherited (Familial Hamophagocytic Lymphohistocytosis, FHL) and secondary (associated with infection [4] [5], malignancy [6], autoimmune disease [7] [8].HLH Secondary to malignancy occurs most commonly in T or NK-cell lymphoid neoplasms.B-cell malignancies are less common complicated with HLH [9].Although the diagnostic guidelines have been available [10], because of its rarity, it is often unrecognized in the clinic.The overall prognosis of HPS is poor, but varies depending on the underlying disease and aggressiveness [11].Early diagnosis and appropriate treatment is crucial for the management of this disease.However, many patients die because of the aggressive nature of the disease.The case presented in this report died of multiple organ failure because of rapid progressing and uncontrollable HPS. HPS usually presents as a complication of malignant tumors such as lymphoma.It is common that large granular NK cell leukemia leads to HPS because leukemic NK cells secrete high levels of pro-inflammatory cytokines subsequently activating macrophages which in turn phagocytose blood cells causing HPS.NK cell granular leukemic cells express CD57 but are negative for CD3 and TCR.γδ-T large granular lymphocyte leukemia resembles NK granular lymphocyte leukemia morphologically, but the leukemic cells express T cell markers and γδ TCRs.These T cells can produce large amount of cytokines after activation [12].γδ-T large granular lymphocytes leukemia is usually diagnosed by flow cytometry showing clonal γδ T cells, or through polymerase chain reaction (PCR) for γ chain gene rearrangement.This patient is a γδ T granular lymphocyte leukemia diagnosed by PCR for γ chain gene rearrangement.The case was positive for CD8 but negative for CD4.γδ T granular lymphocyte leukemia usually shows aggressive nature clinically with unclear mechanism.The prognosis of γδ T granular lymphocyte leukemia complicated with HPS is extremely poor.It has been documented that serum fibrinogen level is an independent adverse prognostic factor.Early diagnosis is, therefore mandatory, the intensive care should be commenced early, and new treatments including bone marrow transplantation should be considered [12].
Because of the hyperactivation state of the global immune system, treatment should be surrounding immune suppression.Treatment options include chemotherapy usually using CHOP protocol, plasma exchange, immunosuppressants such as cyclosporine, as well as hematopoietic stem cell transplantation.Because of the elevated levels of pro-inflammatory cytokines such as TNF-α and IFN-γ, which may largely contribute to the progression of the disease, plasma exchange should be considered early to remove those detrimental factors.Overall, γδ T granular lymphocyte leukemia is a rare condition especially complicated with HPS.The prognosis is poor, which may be improved by early diagnosis and intensive effective management.

Figure 1 .
Figure 1.Bone marrow smear showing LGL and macrophage with hemophagocytosis (Wright Stain, ×1000).The left two images display LGL cells with large granular particles in the cytoplasm.The right images exhibit activated macrophages with phagocytosis of blood cells.

Figure 2 .
Figure 2. Immunophenotype of bone marrow cells examined using 4-color flow cytometry.Bone marrow cells were stained with a panel of fluorescent antibodies against a variety of T cell markers indicated in the above flow plots, and analyzed using FCS express software using different combinations.The population pointed by the arrow in each plot is the LGL cell population.

Table 1 .
Laboratory findings at different time points.