Large granular lymphocyte leukemia and lymphomatoid granulomatosis in the same patient: fortuitous association?

Large granular lymphocyte (LGL) leukemia and lymphomatoid granulomatosis (LG) are two rare and distinct hematological diseases, without apparent association, resulting from the clonal expansion of Tand B-cell lineages, respectively. LGL leukemia was fi rst described in 1985 by Loughran et al . as a clonal disorder with invasion of the bone marrow, spleen and liver [1]. Clinical presentation is dominated by recurrent bacterial infections related to neutropenia, anemia, splenomegaly and autoimmune diseases, particularly rheumatoid arthritis, which is associated with LGL leukemia in 11 – 36% of cases [2]. Th e elderly are mainly aff ected (median age 60 years). In 2008, the World Health Organization distinguished the two major LGL lineages: T-cell LGL and chronic lymphoproliferative disorder of natural killer (NK) cells [3]. Lymphomatoid granulomatosis is a rare Epstein – Barr virus (EBV)-induced B lymphoproliferation occurring in immunocompromised patients (human immunodefi ciency virus [HIV] infection, organ transplant, X-linked agammaglobulinemia, etc.). Th e lungs are most commonly involved, with pulmonary nodules, with less frequent involvement of the skin, central nervous system, kidney and liver [4]. We report here for the fi rst time a case of T-LGL leukemia associated with EBV grade 2 lymphomatoid granulomatosis in the nasal sinuses. A 49-year-old Caucasian woman presented 3 years ago with a chronic neutropenia secondary to LGL leukemia. Neutropenia was fi rst discovered on a routine blood test. Her past medical history was unremarkable, without arthritis or recurrent infections. Clinical examination showed splenomegaly (measured at 17 cm on ultrasound). Hemoglobin was 11.9 g/dL, neutrophils 0.61 10 9 /L, lymphocytes 1.1  10 9 /L and platelets 60 10 9 /L. A peripheral blood smear revealed large granular lymphocytes with well-condensed chromatin. Bone marrow examination was normal, with normal megakaryocytes present. A direct antiglobulin test was weakly positive (immunoglobulin G [IgG] ). Rheumatoid factor was positive (45 IU/mL, normal value  15). Antinuclear antibodies were negative. Antineutrophil anti-CD16 antibodies were IgG positive and IgM negative (by immunofl uorescence). Serum electrophoresis showed polyclonal hypergammaglobulinemia, with serum IgG levels at 22 g/L (normal 7.2 – 14.7); IgA and IgM were within normal ranges. Virological tests for HIV, hepatitis C virus (HCV), hepatitis B virus (HBV) and human T-lymphotropic virus types 1 and 2 (HTLV1/2) were all negative. Th ere was no monoclonal gammopathy on serum gel immunoelectrophoresis. Ninety-fi ve percent of circulating lymphocytes were T cells. Th ere were 0.44 10 9 /L CD4 cells and 0.56  10 9 /L CD8 cells, with a CD4/CD8 ratio of 0.79. Th ere were very few CD19 B cells (0.004  10 9 /L or 3% of total lymphocyte count). CD57 LGLs accounted for 58% of the total CD8 T cell population (0.330 10 9 /L). LGLs expressed a CD8 Teff ector phenotype (CD45RA CCR7 ). Molecular analysis showed an expansion of the V beta 16 (20%) and V beta 21.3 (27%) repertoires. DNA was extracted from total peripheral blood mononuclear cells (PBMCs), and polymerase chain reaction (PCR) amplifi cation of T-cell receptor (TCR) γ and TCR δ chain variable region genes revealed a monoclonal rearrangement with immunoglobulin heavy chain (IgH). To date, T-LGL leukemia has not progressed and treatment has not been warranted [2]. Two years after her initial diagnosis, the patient was admitted for febrile pan-sinusitis with cellulitis of the face, requiring antibiotics and surgery. Microbiology of nasal sinus samples was negative (standard culture, mycological and mycobacterial cultures). Histology showed an EBVassociated lymphoproliferation related to grade 2 lymphomatoid granulomatosis. Positron emission tomography (PET) showed a localized sinus involvement with a maximal standardized uptake value (SUV) of 4.2. EBV PCR amplifi cation in the blood was negative. EBV-specifi c IgG, but not IgM, was present in the serum. In vitro functional study in a blood sample of anti-EBV eff ector T cell responses by enzymelinked immunosorbent spot (ELISPOT) assay showed a L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y IN SE R M o n 12 /1 0/ 12