Hemophagocytic lymphohistiocytosis complicating a T-cell rich B-cell lymphoma

Hemophagocytic lymphohistiocytosis (HLH) is a rare and often fatal inflammatory disease. It is either primary or secondary to inflammatory diseases, infections or malignancies. In the latter case, T phenotype non-Hodgkin lymphoma (NHL) is the most common cause [1]. The association with B lymphomas is rare [2]. In this situation, lymphoma chemotherapy treatment should be initiated promptly to control HLH. T-cell rich B-cell lymphoma is a rare entity representing 1 to 3 % of diffuse large B-cell NHL [3].

We describe in this paper the case of a patient with a hemophagocytic lymphohistiocytosis revealing a T cells rich B-cell NHL.

A 52-year-old male patient without any significant medical history was admitted to our department for febrile bicytopenia. He reported an anemic syndrome as he had been complaining of fatigue and exertional dyspnea for 8 months before his admission. Fever and significant weight loss were also reported over the last month before his admission.

Physical examination revealed fever (39.8 °), pallor, splenomegaly (4 cm below left costal margin), right axillary and bilateral inguinal lymphadenopathies (the most voluminous measured 3 cm of diameter).

Laboratory tests found haemoglobin level at 70 g/L (range 130–165 G/L) with a mean corpuscular volume of 80 fl (range 80–96 fl), leukocytes at 2.9 G/L (range 4–10 G/L) (neutrophils 1.5 G/L and lymphocytes 0.9 G/L). Platelets were 39 G/L (range 150–400 G/L). Reticulocyte count was 43 G/L (50–120 G/L). Biochemical tests showed an increased LDH rate at 508 IU/L (upper limit: 192 UI/L) and serum ferritin at 4456 ng/mL (range 23–336 ng/mL). Triglycerides were 225 mg/dL (range 101–150 mg/dL). Fibrinogen was also raised at 6,72 g/L (range 1,5–4 g/L). Infectious tests, including EBV PCR screening, were negative.

Hemophagocytic lymphohistiocytosis was strongly suspected according to Henter criteria [4] and a bone marrow aspiration was performed showing a rich marrow with hemophagocytosis (Fig. 1) without lymphomatous infiltration. Thus, the diagnosis of hemophagocytic lymphohistiocytosis was confirmed.

The patient received a pulse of steroids (methylprednisolone 25 mg/kg/day for 3 days followed by prednisolone 2 mg/kg/day) as well as red blood cells and platelets supportive transfusion.

A biopsy of axillary lymphadenopathy showed a lymph node parenchyma which overall architecture is erased by diffuse immunoblastic large cells proliferation. These scattered large neoplastic cells are present on a background rich in histiocytes and small lymphocytes (Fig. 2). Immunohistochemistry studies showed expression of CD20 in the large neoplastic cells (Fig. 3) and CD3 in the small T cells (Fig. 4). CD30, CD15 and EBV stains were negative.

Computed tomography (CT) scan of the chest, abdomen and pelvis showed enlarged lymph nodes on both sides of diaphragm and a 20 cm large spleen with multiple hypodensities, likely to be related to infarcts (Fig. 5). A bone marrow biopsy was also performed and showed no infiltration.

Therefore, this case was diagnosed as T-cell rich B-cell Hodgkin lymphoma stage III B (Ann Arbor staging) complicated by a HLH.

The patient was treated with chemotherapy combining rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). He received eight 21-day cycles associated to 4 injections of prophylactic intrathecal chemotherapy (methotrexate, cytarabine, methylprednisolone). The interim and the end of treatment revaluations showed complete remission with normalization of initially abnormal biological parameters.

After 10 months of follow-up, the patient presented with axillar lymph nodes without general symptoms. The biopsy of the lymph nodes showed the same aspect as at the diagnosis. The patient is now undergoing salvage therapy by Rituximab, dexamethasone, ifosfamide, carboplatin and etoposide (R-DICE) regimen. It will be followed by intensification and autologous stem cell transplantation.

HLH is the result of a secondary immune response to stimuli which regulation is no longer controlled by the natural killer lymphocytes (NK-L) [5]. In familiar cases, the major mutations affect granule-mediated cytotoxicity pathways. The cytotoxicity defect of the NK lymphocytes is the main pathophysiological signature of HLH [6]. This promotes proliferation and continuous activation of antigen presenting cells with a hyper-secretion of cytokines and chemokines, causing a “cytokine storm” [7]. Indeed, activated T lymphocytes (TL) secrete interferon gamma in large amounts inducing expansion and activation of CD8 T cells, histiocytes and macrophages. These cells infiltrate various organs, including the hematopoïetic organs [1]. The “cytokine storm” is responsible for clinical features and laboratory findings of multi-organ failure as seen in the HLH. Interleukin (IL) 1, IL-6 and tumor necrosis factor alpha are responsible for fever. Hypertriglyceridemia is secondary to the inhibition of lipoprotein lipase and stimulation of the synthesis of triglycerides by INFγ et TNFa [8]. These cytokines also inhibit normal hematopoiesis inducing cytopenias. Hyperferritinaemia and hypofibrinogenemia are secondary to the continuous activation of macrophages [5].

Hemophagocytic lymphohistiocytosis is a diagnostic and therapeutic emergency. The main underlying causes of this syndrome in adults are either infectious or T lymphomatous proliferations. The association with T cells rich B lymphoma is rarely described. A prompt antilymphomatous chemotherapy should be initiated to control the life-threatening HLH.