Large Natural Killer Cell Lymphoma Arising From an Indolent Natural Killer Cell Large Granular Lymphocyte Proliferation

Archives of Pathology & Laboratory Medicine, Nov 2006 by Roullet, Michele R, Cornfield, Dennis B

* Natural killer cell large granular lymphocyte proliferation is a relatively rare disorder that typically runs a chronic, indolent course. We present a patient with a 31/2-year history of natural killer cell large granular lymphocyte proliferation terminating in large cell lymphoma with natural killer cell features. The diagnosis of natural killer cell large granular lymphocyte proliferation was based on flow cytometric demonstration of an expanded population of CD3-CD16 /CD56 lymphocytes in the peripheral blood. The patient experienced various rheumatologic symptoms, but was hematologically stable for 31/2 years. He then developed fevers, night sweats, weight loss, and a left lower lobe lung mass. Resection of the mass showed a large cell lymphoma with immunohistochemical positivity for CD2, CD7, CD56, and T-cell intracellular antigen-1, compatible with natural killer cell origin. In situ hybridization for Epstein-Barr virus and polymerase chain reaction analysis for T-cell receptor gene rearrangement were negative. To our knowledge, this is the second documented report of chronic natural killer cell large granular lymphocyte proliferation terminating in an aggressive large natural killer cell lymphoma.

(Arch Pathol Lab Med. 2006;130:1712-1714)

Large granular lymphocyte (LGL) proliferations are broadly divided into T cell and natural killer cell (NKLGL) types, with T cell LGL comprising approximately 85% of cases and NK-LGL 15% of cases.1 Among the NKLGL, Epstein-Barr virus (EBV)-driven aggressive leukemia/ lymphoma predominates in the Far East, and a more chronic, indolent disease that is unrelated to EBV predominates in the United States and Europe. Because of the overall rarity of indolent NK-LGL, details regarding clinical outcomes in this subset of patients are relatively sparse. To our knowledge, only 1 case of indolent NK-LGL terminating in an aggressive large NK cell lymphoma has been described.2 A second such case is detailed in the present report.

REPORT OF A CASE

A 63-year-old man was first noted to have mild peripheral blood lymphocytosis in February 2001. Physical examination showed no organomegaly or lymphadenopathy. Flow cytometric analysis performed in May 2001 showed that 88% of lymphocytes had a CD3-CD16 /CD56 phenotype, consistent with NK-LGL. He was followed for the next 31/2 years without specific treatment for the NK-LGL. His complete blood count values typically showed hemoglobin and platelet levels in the normal range, and white blood counts of 10 000 to 19 000/µL with 60% to 80% lymphocytes, many of which were enlarged and contained prominent cytoplasmic granules (Figure 1). He was troubled by intermittent episodes of arthralgia and myalgia, which required antiinflammatory treatment, but a clear-cut rheumatologic diagnosis could not be established.

Between late 2004 and early 2005, the patient experienced a 20-lb weight loss, drenching night sweats, and fevers to 102°F. He was hospitalized in January 2005 with a left lower lobe pneumonitis, which responded incompletely to antibiotics. Serial computerized tomographic scans demonstrated a left lower lobe mass, which gradually increased in size. In April 2005 he underwent a left lower lobe lobectomy. The mass showed a lymphoma consisting of medium-and large-sized mononuclear cells, compatible with NK cell origin by extensive immunohistochemical evaluation (see "Results"). The patient continued with intermittent fevers after recovery from surgery. Combination chemotherapy was planned, but he required additional hospitalizations for dehydration and for right basilic vein thrombosis. His final hospitalization in May 2005 was marked by right arm cellulitis with eventual sepsis, renal failure, atrial fibrillation, cerebral hemorrhage, and respiratory insufficiency. A computerized tomographic scan showed no organomegaly or lymphadenopathy. He expired in late June 2005. Autopsy showed sparse inflammatory infiltrates with only occasional large, atypical-appearing lymphoid cells in numerous organs, especially the pancreas. The right lung contained a focal fungal infiltrate, morphologically consistent with Aspergillus.

MATERIALS AND METHODS

Morphologic Evaluation

Resected lung tissue was fixed in 10% buffered formalin, embedded in paraffin, and processed for routine histologic examination and for immunohistochemical and molecular evaluation.

Immunophenotypic Characterization

Immunohistochemical evaluation was performed on a Bio-Genex I-6000 (San Ramon, Calif) or a DakoCytomation Plus (Carpinteria, Calif) autostainer with antibodies and dilutions as follows: CD2 (1:40; Novocastra, Norwell, Mass), CD3 (1:200; LabVision/NeoMarkers, Fremont, Calif), CD4 (1:40; Novocastra), CD5 (1:40; BioGenex), CD7 (1:50; Novocastra), CD8 (1:80; DakoCytomation), CD20 (1:75; BioGenex), CD30 (1:30; Dako-Cytomation), CD56 (1:200; Biocare Medical, Walnut Creek, Calif), CD79a (1:20; DakoCytomation), anaplastic lymphoma kinase-1 (1:10; DakoCytomation), T-cell intracellular antigen-1 (1:400; Immunotech, Miami, Fla), and paired box gene-5 (1:25; Biocare).