Hemophagocytic lymphohistiocytosis complicating a T-cell rich B-cell lymphoma
© The Author(s). 2016
Received: 29 January 2016
Accepted: 7 October 2016
Published: 24 November 2016
Hemophagocytic lymphohistiocytosis in adults is often secundary to an infection or a neoplasm. In this last case, T cell lymphomas are the most frequent causes. Hemophagocytic lymphohistiocytosis secundary to a B cell lymphoma has been rarely reported.
We describe a case of a hemophagocytic lymphohistiocytosis complicating a T-cell rich B-cell lymphoma treated with conventionnal chemotherapy leading to a complete remission.
Prompt etiologic diagnosis and treatment of hemophagocytic lymphohistiocytosis leads to satisfactory outcome.
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 . The association with B lymphomas is rare . 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 .
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.
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.
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) . 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 . This promotes proliferation and continuous activation of antigen presenting cells with a hyper-secretion of cytokines and chemokines, causing a “cytokine storm” . 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 . 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 . These cytokines also inhibit normal hematopoiesis inducing cytopenias. Hyperferritinaemia and hypofibrinogenemia are secondary to the continuous activation of macrophages .
Diagnostic criteria for HLH 
≥ five of the eight criteria listed below:
Cytopenias (affecting at least two of three lineages in the peripheral blood):
• Hemoglobin < 9 g/dl
• Platelets < 100 G/mm3
• Neutrophils <1 G/mm3
Hypertriglyceridemia (fasting, 265 mg/100 ml) and/or hypofibrinogenemia (150 mg/100 ml)
Hemophagocytosis in bone marrow, spleen or lymph nodes
Ferritin ≥ 500 ng/ml
Low or absent Natural Killer cell activity
Soluble IL-2 receptor ≥ 2400 U/ml
Clinical, biological, therapeutic and evolution features of previously reported cases of TCRBCL associated HLH
Mitterrer et al. 
B symptoms, splenomegaly
Moderate pancytopenia, high LDH
Spleen: hemophagocytosis Hepatic nodules: TCRBCL
Reactivated EBV infection serological profile
MOPP-ABV then high dose methotrexate, vincristine and etoposide followed by AHSCT
Sustained CR for 2 years
Devitt et al. 
Fever, jaundice, B symptoms, splenomegaly, repiratory failure
Hyperferritinemia Pancytopenia Hyperbilirubinemia
Elevated liver enzymes
Bone marrow: Hemophagocytosis and lymphomatous infiltration
Negative (in situ hybridization)
HLH 2004, R-EPOCH
CR followed by AHSCT
Aljitawi et Boone 
Relapse of previously treated TCRBCL
Fever, jaundice, hepatosplenomegaly, ascites
High soluble IL2-R
Bone marrow: Hemphagocytosis, relapsed TCRBCL
Salvage therapy (NA)
Relapse after months and death
Jiang et al. 
High soluble IL2-R
Bone marrow and lymph node: TCRBCL
B symptoms, splenomegaly
Bone marrow: hemophagocytosis
Lymph node: TCRBCL
Negative (biopsy and peripheral blood PCR)
Relapse after 10 months
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.
We thank doctor Mohamed Amine HAMZI who participated in the translation of the manuscript from french to english.
Availability of data and material
The data can be available from the corresponding author upon reasonable request.
EMM prepared the manuscript, reviewed the literature, prepared the figures and edited the report. MZ, MK and EMM participated in patient care. MA provided the biopsy images and the pathology interpretation. NM provided the marrow smear image and the hematology laboratory findings. KD and MM corrected the manuscript. All the authors have read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Written consent was obtained from the patient for publication of the study.
Ethics approval and consent to participate
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