We are studying a series of patients with a preliminary diagnosis of large granular lymphoproliferative disorder (LGLPD) using flow cytometric immunophenotyping as well as PCR and restriction enzyme digests for clonal T-cell populations. We have found that presence of cytopenias and observation of large granular lymphocytes in the peripheral blood are not sensitive indicators of LGLPD. We have detected B-cell neoplasms and non-cytotoxic T-cell proliferations (non-clonal) and malignancies in patients with cytopenias and peripheral blood large granular lymphocytes. Flow cytometric analysis is more sensitive than PCR (reported 60-70% sensitivity) in detecting T-cell malignancies in LGLPD. Restriction enzyme digests are being performed and sensitivity of detection will be compared. We are using multiparametric approaches to improve the sensitivity of detection of monoclonal B-cell populations. By targeting abnormal patterns of antigen expression (eg CD10, CD5, CD23, FMC7) by B-cells in light chain detection, we are attempting to achieve a pure tumor gate among admixed polyclonal B-cells.