Clonal CD3+CD8+ Large Granular Lymphocyte (LGL)/NK-Associated (NKa) Expansions: Primary Malignancies or Secondary Reactive Phenomena?

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Abstract
This study reports the clinical, haematological and immunophenotypic features of a series of 25 patients with clonal expansions of large granular lymphocytes (LGL)/NK-associated (NKa) cells. These showed a male predominance (16:9) with a median age of 67 (range 38-91) years; four had a documented history of rheumatoid arthritis, a further 18 had diverse clinical disorders, and the remaining three were clinically well. Mild anaemia was found in approximately half the patients and a lymphocytosis (seen in approximately 70% of the cases) was usually modest (< 10.0 × 109/1). Neutropenia was the most frequently observed feature, and this was typically persistent in nature. Serum studies revealed few consistent features although positive rheumatoid factor and increased soluble CD8 levels were noted in 67% and 87% of those cases tested. Phenotypically, all cases were CD2+CD3*CD8* and expressed membrane TCRαβ chains; most (17/22) were additionally CD5+ and (19/22) CD7+. The staining intensities of CD5 and CD7 antigens were however lower than that of normal CD4+ and CD8+ blood lymphocytes. Expression of NKa antigens was variable although 16/22 cases were CD 16+CD56- and 19/22 were CD57+. Clonal CD3+CD8+ LGL/NKa expansions with a CD 16+CD56+ composite phenotype were not seen in this patient series. Analyses of ‘activation’ antigens showed a consistent lack of CD25 expression by CD3+ cells, but increased CD3/Ia co-expression was found in a high proportion (19/25) of cases. Studies of CD45R isoform expression by CD8+ LGL/NKa cell fractions revealed a consistent CD45RA+RO profile for all cases tested. It is suggested that the clinical and cellular findings in these patients raise the distinct possibility that most of these clonal LGL/NKa disorders have a chronic reactive rather than neoplastic aetiology.

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