The t(14;18) Translocation in Hodgkin's Disease
Authors: M. Stetler-Stevenson
Journal: JNCI Journal of the National Cancer Institute (1992)

In this issue of the Journal, Poppema et al. (7) contribute significantly to our understanding of the role of the t(14;18) translocation involving the bcl-2 gene (also known as BCL2) in Hodgkin's disease. This is an issue that has been shrouded in controversy since we first detected the t(14;18) translocation in tissues of 32% of unselected Hodgkin's disease patients (2). Although Hodgkin's disease is a well-defined clinical entity, its pathogenesis and cellular origin have remained an enigma. The malignant Reed-Sternberg cells and their variants constitute only 1% or less of the total cell population in Hodgkin's disease, with the remainder consisting primarily of benign inflammatory (reactive) cells. Immunohistological analysis with cell lineage-associated markers has suggested a variety of cells as the cell of origin for Reed-Sternberg cells (3): These cells include monocytes, macrophages, interdigitating reticulum cells, and B or T lymphocytes. Minor clones containing either immunoglobulin (4,5) or T-cell-receptor (6,7) gene rearrangements and indicating a Bor T-cell origin for this disease have been identified in tissues with high percentages of ReedSternberg cells or in samples enriched with malignant cells by cell separation techniques. Using the polymerase chain reaction (PCR) technique, we were able to demonstrate, in Hodgkin's disease tissues, the presence of cells containing the t(14;18) translocation, a genetic event previously limited to B-cell lymphomas and highly associated with follicular lymphoma (2). This translocation in follicular lymphoma causes the deregulation of the putative oncogene bcl-2 on chromosome 18 and overproduction of its product, the bcl-2 protein, resulting in blockage of programmed cell death (8). These findings, therefore, suggested a B-cell origin for some Hodgkin's disease cases and indicated possible mechanisms involved in the pathogenesis of this disease. Several other laboratories subsequently reported a failure to detect the t(14;18) translocation in Hodgkin's disease with PCR (9-11). In two of those reports (9,10), the discrepancy in findings may be explained by use of different primers, analysis of a smaller proportion of reaction products, or reduced PCR sensitivity for the t(14;18) sequences. However, Louie et al. (77) achieved comparable PCR sensitivity, used the same primers, and analyzed similar proportions of PCR products, but they still failed to detect the t(14;18) translocation in Hodgkin's disease. Masih et al. (72) and Reid et al. (75) reported PCR detection of the t(14;18) translocation in Hodgkin's disease in fresh (29%) and paraffin-embedded (5% parrafin) tissues, respectively. LeBrun et al. (14) reported finding the t(14;18) translocation by PCR in only four of 38 cases and, upon further investigation, discovered that all four patients had a prior or concurrent diagnosis of follicular lymphoma; case patients with previous or concurrent diagnosis of follicular lymphoma had been excluded from other studies. In 1992, Gupta et al. (75) not only detected t(14;18) translocations in 20% of Hodgkin's disease tissues, but also sequenced all PCR products, demonstrating that the observed translocations were not due to contamination from positive controls and that they were similar in nature to the breakpoints observed in follicular lymphoma. We believe the discrepancies in detection of the t(14;18) translocation in Hodgkin's disease tissues may be due to problems in PCR sensitivity, although differing patient populations cannot be excluded as an explanation. The controversy surrounding these discrepancies in findings intensified with the report of Limpens et al. (76), who found t(14;18) translocations in 54% of lymph nodes and tonsils with follicular hyperplasia in patients with no history of lymphoma. The sequences of the PCR products revealed differing breakpoints, again indicating a lack of contamination, and were similar to those observed in follicular lymphoma and by Gupta et al. (75) in Hodgkin's disease. The findings of Limpens et al. (76) were confirmed in hyperplastic lymphoid tissues from American and Japanese patients (77), indicating the presence of the t(14;18) translocation in benign tissues. These PCR studies on Hodgkin's disease were performed with DNA extracted from tissues containing both the malignant cells and the predominant reactive cell population. Thus, the actual identity of the cells containing the translocated sequences is uncertain. In view of the finding of t(14;18) sequences in tissues containing only reactive cells as well as in tissues containing malignant cells, it is possible that the translocations observed were present in the background reactive lymphocytes instead of the ReedSternberg cells. To address the issue of which cells contained the translocation, we analyzed tumor tissue from selected Hodgkin's disease cases, using a monoclonal antibody reactive with bcl-2 protein as an immunohistochemical stain (8). Because the t(14;18) translocation results in overproduction of the bcl-2 protein, cells containing the translocation should be positive for the bcl-2 antibody. The bcl-2 protein was detected by the antibody in the Reed-