Transmission of a follicular lymphoma by allogeneic bone marrow transplantation – evidence to support the existence of lymphoma progenitor cells

The existence of neoplastic stem cells for haematological malignancies has been postulated (Kuppers et al, 1999), although evidence to support this concept is relatively lacking. We report a case of transmission of follicular lymphoma (FL) in the setting of allogeneic bone marrow transplantation (BMT) between a father (donor) and his son (recipient). We believe that the findings from this case study provide support to the existence of lymphoma progenitor cells. A 32-year-old man was diagnosed with acute myeloid leukaemia in 1992, for which he received allogeneic bone marrow stem cells from his father. The stem cells were collected by bone marrow harvest, and given directly with no cryopreservation or T-cell depletion, after conditioning with busulfan and cyclophosphamide. The donor and recipient had five out of six identical human leucocyte antigens. The patient's post-transplant clinical course was uncomplicated and immunosuppression was completely removed 1 year after BMT. He has remained in remission from his acute leukaemia since transplantation. In 1995, the patient's father was diagnosed with FL, stage IV; no treatment was given as he was asymptomatic. Eighteen months later, he developed bulky lymphadenopathy. He was given chlorambucil without significant response. Another lymph node biopsy revealed diffuse large B-cell lymphoma. He died of the disease in 1998 despite combination chemotherapy. In 2003, the patient developed bulky retroperitoneal lymphadenopathy. A biopsy revealed FL with large cell transformation that was Epstein–Barr virus-negative. He was treated with eight cycles of chemotherapy followed by radiation therapy administered to residual retroperitoneal lymphadenopathy. Despite an initial clinical response, his disease has slowly progressed since 2003. To examine the biological relationship of the two lymphomas, we performed human identity testing using the human identifier kit (Applied Biosystems, Foster City, CA, USA). The results showed that the recipient's lymphoma was donor cell-derived. BCL2/IGH was then amplified as described (Limpens et al, 1995). Analysis of the BCL2/IGH from both lymphomas revealed an identical fusion site (Fig 1). We analysed the monoclonal IGH species in both tumours using a method previously published (Timms et al, 2003). All five IGH subclones derived from the donor's lymphoma revealed VH3-74 with 97% homology, whereas those from the recipient's lymphoma were VH1-69 with 97–98% homology. Thus, both tumours had features of postgerminal centre cells. Analysis of the sequence of the BCL2/IGH fusion gene that was present in the recipient and donor lymphomas. Findings from our case study are analogous to those of another reported case, in which both the donor and recipient developed peripheral T-cell lymphoma after BMT at 3 and 5 years respectively (Berg et al, 2001). The finding of the identical T-cell receptor gene rearrangement supports that the two lymphomas were derived from the same progenitors. Our finding of the identical BCL2/IGH fusion in both FL leads to the same notion. The possibility that the recipient FL was derived from the rare circulating lymphoma cells from the donor is considered unlikely due to: (i) the lack of evidence of lymphoma in the donor at the time of transplantation; (ii) the long latency (i.e. 11 years) for the lymphoma to develop in the recipient; and (iii) the use of different IGH variable regions in the two tumours. One other possibility is that the recipient's lymphoma was derived from the donor's non-neoplastic, peripheral B-cells that carry the t(14;18) abnormality. This translocation is detectable in 40–50% normal individuals (Limpens et al, 1995). We consider this unlikely, as mature B-cells generally lack regenerative ability. Thus, we believe that the two lymphomas were most probably derived from the same neoplastic progenitors that were transmitted during the transplant, and the findings of this case study support the existence of lymphoma progenitor cells. The concept that B-cell lymphomas develop from lymphoma progenitor cells has been previously postulated. Molecular analysis of rare cases of bigenotypic and biphenotypic, t(14;18)-positive lymphomas showed that two distinct neoplastic B-cell clones may be derived from a single progenitor cell (Cleary et al, 1988). Another study of a composite lymphoma also revealed a common genetic abnormality that was found in three different lymphomatous components (van de Berg et al, 2002). The presence of a dormant lymphoma progenitor cell may explain why FL, a highly chemosensitive disease, remains incurable. Further studies to isolate and characterise these lymphoma progenitors will help better understand the biology of FL.

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