Anaplastic large cell lymphoma presenting as hemophagocytic syndrome in an adolescent

To the Editor: Krenova et al. [1] reported the unusual case of a patient with anaplastic large cell lymphoma presenting as hemophagocytic lymphohistiocytosis (HLH). As this is a rare condition posing considerable diagnostic difficulties we would like to report a similar patient treated at our institution. A 15.7-year-old male presented with a 4-week history of painful right-sided cervical swelling, hepatosplenomegaly and fever not responding to intravenous antibiotics. Laboratory findings included the following: leukocyte count, 5.0 10/L; hemoglobin, 10.1 g/ dL; platelets, 167 10/L; LDH, 1218 U/L (NR:120–240); CRP, 25 mg/L (NR:<8); triglycerides, 218 mg/dL (NR:<150); fibrinogen, 210 mg/dL (NR:180–400); ferritin, 9270 mg/L (NR:24–336); s-IL2 receptor,>50,000 pg/ml (NR:680–2130 pg/ml); TNF-alpha, 84.0 pg/ml (NR:<15.0). CT scans showed a cervical mass of 18 5 5 cm diameter. Bone scan, cranial MRI, and CSF were without pathological findings. Cervical lymph-node biopsy performed by the referring hospital had been interpreted as lymphadenitis with activated T-immunoblasts, without signs of malignancy and some erythrophagocytosis. Bone marrow aspiration/biopsy demonstrated normocellular hematopoiesis and striking hemophagocytosis without evidence of lymphoma. Parvovirus was detected by PCR in bone marrow. The patient fulfilled the criteria of fever, splenomegaly, and hemophagocytosis in bone marrow/lymph nodes according to the HLH-94 diagnostic guidelines [2] as well as hyperferritinemia and very high soluble IL-2-receptor according to the revised diagnostic guidelines [3]. Infection-associated hemophagocytic syndrome (IAHS) was diagnosed and treatment with dexamethasone and etoposide administered according to the HLH-94 protocol [2] for 1week leading to rapid clinical improvement.Meanwhile, review of lymph-node biopsy sections revealed an infiltration by large blasts characterized by CD 45þ, CD43þ, CD30þ, partially EMAþ, CD2þ, CD8þ with cytoplasmic granules positive for granzyme B and TIA-1; the blasts were negative for ALK1 leading to the definitive diagnosis of anaplastic large cell lymphoma of T-cell phenotype,ALKnegative. Treatmentwas instituted according to the ALCL 99 International Protocol (high-risk group; MTX 3 g/m, VBLþ) consisting of six cycles of chemotherapy followed by weekly vinblastine until 1 year of total therapy duration. Four years after the end of therapy, the patient is in continuous complete remission. HLH is an aberrant immune response to a variety of stimuli to an unbalanced immune system leading to a hyperinflammatory phenotype classically characterized by fever, hepatosplenomegaly, cytopenias, central nervous system symptoms, coagulopathy, and lipid changes on the basis of an inherited (primaryHLH) or acquired defect (secondary HLH) of immune effector cells [4]. Secondary HLHmay be associated with malignancies (malignancy-associated hemophagocytic syndrome, MAHS) and may develop before or during treatment with or without a known infectious trigger. HLH secondary to malignant lymphoma may manifest with a fulminant clinical course masking the underlying malignancy and leading to the misdiagnosis of IAHS [4] as in our patient. In nonfamilial cases, even if an infectious trigger is plausible or proven, the possibility of a masked malignant disease should be considered and ruled out by means of biopsies of involved sites and bone marrow with extensive work-up by immunohistochemistry and molecular genetic methods.