Timms JM, Bell A, Flavell JR, et al. Lancet. 2003;361:217–223
Purpose of the Study.
To determine the types of B cells from which posttransplant lymphoproliferative disease (PTLD) arises.
Tissue samples and DNA extracted from fresh tumors were obtained from 13 patients with PTLD.
Tumor suspensions were stained with monoclonal antibodies to surface B-cell (CD20 and CD38) and T-cell (CD3) markers and cell surface and cytoplasmic immunoglobulin heavy and light chains. The presence of Epstein-Barr virus (EBV) was detected with in situ hybridization assays for EBV-encoded RNA. Immunoglobulin heavy chain sequences corresponding to framework regions and complementarity-determining (antigen-binding) regions were determined with polymerase chain reaction assays. The sequences were analyzed for suggestions of antigen-selected genotypes (normal memory B cells).
Twelve tumors were of B cell origin and expressed surface or cytoplasmic immunoglobulin. One tumor was a B cell-T cell composite. All 13 malignant B cell populations were positive for EBV-encoded RNA. Of the 11 biclonal and monoclonal tumors, 4 appeared to arise from memory B cells, 5 seemed to be derived from somatically mutated non-memory B cells, and 2 had inactivated immunoglobulin heavy chain sequences, because of a stop codon and a large deletion causing an out-of-frame mutation.
PTLD can arise from atypical, post-germinal center, B cells that have failed selection into memory cells, like the monoclonal tumors of Hodgkin’s lymphoma, as well as from the antigen-selected memory cells that are usually colonized by EBV in immunocompetent individuals.
Although the ages of the patients with PTLD were not reported in this study, young children receiving posttransplant immunosuppressive therapy are at increased risk for this disease, because they are more likely to be EBV-susceptible at the time of transplantation. The suggestion of a common initiation step in the pathogenesis of PTLD and Hodgkin’s lymphoma may lead to future diagnostic and therapeutic breakthroughs.