Clonal T-cell Populations and Increased Risk for Cytotoxic T-cell Lymphomas in B-CLL Patients

Abstract

Chronic lymphocytic leukemia (CLL) is associated with increased risk of malignancy, but the occurrence of other lymphomas, in particular T-cell lymphomas, is rare. We identified 7 cases of peripheral T-cell malignancy associated with B-cell-derived CLL from the files of two institutions over a 20-year period. The presence of both B and T lymphoproliferative disorders was confirmed in all cases by immunophenotype and in 6 cases by gene rearrangements. Six patients developed peripheral T-cell lymphoma (PTCL), unspecified, during the course of CLL (10-168 months). In all 5 evaluable cases, the cells had a cytotoxic T-cell phenotype; the sixth case was CD56+, but TIA-1 and Granzyme B could not be studied. A seventh patient with CLL developed mycosis fungoides, and an aggressive NK cell leukemia. To investigate possible risk factors for the development of PTCL, we screened 100 unselected peripheral blood samples from newly diagnosed CLL patients by PCR for the presence of clonal T cell populations. We found evidence of clonal T-cell expansion in 8 patients and increased lymphocytes with large granular lymphocyte morphology in 7 of 8 cases. The immunophenotype was assessed by multicolor flow cytometry and in 4 cases the T-cell expansion was composed of either CD3+/CD8+ or CD3+/CD4-/CD8- cells. The cytotoxic nature of the clonal T-cell expansions in the peripheral blood correlates with the cytotoxic nature of the PTCLs, but their role in the subsequent development of T-cell lymphomas is still unclear. PTCL following CLL should be distinguished from typical Richter syndrome, which it can mimic clinically.

Development of T-cell large granular lymphocytic leukemia in the course of B-cell chronic lymphocytic leukemia with a causal relationship inferred from a flow cytometric analysis of the bone marrow aspirate

“…This is in agreement with authors who observed a development of peripheral T-cell lymphomas with cytotoxic phenotype in the patients with B-CLL [9,10].…”

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

“…Southern blot analysis and PCR-based methods are able to detect clonal rearrangements of the T-cell receptor (TCR) in formalin-fixed, paraffin-embedded biopsy specimens [105,106]. PCR-based methods are sensitive ( 1%) and should be interpreted with caution, as TCR gene rearrangements suggesting clonality may be detected in normal elderly individuals and in patients with benign dermatoses or other disease states [107][108][109][110][111]. However, detection of identical clones from two different sites is quite specific for MF [112].…”

Rearrangement of NOTCH1 or BCL3 can independently trigger progression of CLL

“…Four months later, the patient developed peripheral T-cell lymphoma, a rare recurrent event in CLL. 7 Altogether, the present case allows us to deduce the sequence of multiple genetic defects driving development and progression of CLL. An initial clone with ϩ12, likely present at a presymptomatic CLL phase, later acquired an activating mutation of NOTCH1.…”