In this issue of Blood, Perry and colleagues describe a form of plasmacytic posttransplant lymphoproliferative disorder (PTLD) that occurs in pediatric organ recipients, is not associated with Epstein-Barr virus (EBV), and is responsive to minimal therapy.1 Might this represent a separate pathway for PTLD development?
Aberrant posttransplant lymphoproliferations are categorized under the umbrella term of PTLD. A range of such disorders and their frequent association with EBV was first recognized in 19812 and dependence in many cases on a crippled immune system was shown a few years later by effecting tumor regression with reduced immunosuppression (RIS).3 The PTLD spectrum has since expanded to include lymphomas of non-B-cell origin, as well as tumors that do not contain EBV. The World Health Organization has defined PTLD categories, among which plasma cell hyperplasia, plasmacytoma-like, and plasma cell myeloma are recognized.4
Perry et al present 5 pediatric transplant recipients who developed oligoclonal/clonal PTLD without evidence of EBV. Four had “atypical plasma cell hyperplasia,” a term not recognized in the WHO classification. In these cases, features intermediate between hyperplastic and malignant plasma cell growths were seen, often with evidence of marrow involvement. The final patient had extramedullary plasmacytoma. Four patients were treated; none responded to RIS, but all went into remission following high-dose steroids (with thalidomide in 1 case).
This series raises the interesting question of whether there exists a distinctive subset of posttransplant neoplasias that range from EBV-negative oligoclonal to clonal “atypical plasma cell hyperplasias” to posttransplant plasmacytomas and myelomas. If so, what is their relationship to plasma cell neoplasms in the nonimmunosuppressed host? What is the driving force(s) behind these growths? What is the best way to categorize these tumors? What is the best therapy?
Posttransplant plasmacytomas and myelomas typically arise years after transplant. This series differs in that all lesions arose relatively soon after transplant. The fact that most of these clonal lesions appear to retain some histologic vestiges of a reactive condition suggests but does not prove that this may represent an early form of more fully developed plasma cell malignancies.
No evidence of EBV, HHV-6, HHV-8, or CMV was found in any case. Trisomy 3 was found in 1 case and an extra X chromosome in a second tumor. Two patients had lesions with normal karyotypes although the patient with the most extensive bone marrow involvement showed del 13q14 and del 13q34. Trisomy 3, del 13q14, and del 13q34 are among the many cytogenetic changes described in multiple myeloma (MM). This hints that these lesions might have more features in common with typical plasma cell dyscrasias than with EBV-associated B-cell lymphoproliferations. Duplication of the X chromosome is not described in plasma cell tumors and suggests that additional neoplastic pathways may be operative in the posttransplant state.
Contemporary sequencing studies show that MM may be genetically stable, may evolve as linearly related clones, or may evolve with the additional feature of clonal branch points in which particular clones evolve early and lie dormant only to re-emerge as a dominant clone(s) following eradication of the prevailing population by iatrogenic or other means.5,6
The tumors studied by Perry et al may provide a unique window into the early stages of this process, perhaps showing tumoral outgrowth of cells normally rendered silent by an intact immune system, or perhaps characterized as “dysplastic” or “preneoplastic.” In terms of tumor progression it may be noteworthy that translocation of the immunoglobulin heavy chain gene, one of the more common genetic changes in fully developed MM, was not seen.
Another unique vantage point centers on host:donor origin. In 2 patients, in situ hybridization for sex chromosomes showed both donor and recipient cells. Further analysis was not performed, and conventional wisdom would suggest that only 1 subpopulation represented tumor. However, interpretation remains open. Do the presumed nonneoplastic cells represent a host immune response, play no role, or provide an environment to facilitate tumor growth? Do we also need to consider the possibility that, in the immunodeficient state, tumors can actually be derived from 2 separate founder cells? Such questions are not considered in our current clinical approach to these disorders, and certainly cannot be answered in a clinical report. But the questions can be raised, and directed study of tumors arising in this population may be the way to answer them.
Regarding host:donor tumor origins, posttransplant myeloma of donor origin can arise up to 14 years after transplant,7 which could reflect a stochastic event based on chronic donor stem cell microchimerism.8 In one murine study, overexpression of Maf oncogene in B cells had little consequence, whereas expression in the stem/progenitor cell compartment led to plasma cell neoplasia.9 Alternatively, it could reflect prolonged stress, for example, “chronic antigenic stimulation,” to this minority population. Such concepts raised by early investigators may seem stale with age and need to be reframed, but have yet to be satisfactorily answered.
This small series also suggests that therapy might be aligned more toward approaches that are of benefit in plasma cell dyscrasias, rather than the usual algorithmic approach of treating PTLD. The therapeutic response in this pediatric cohort is heartening, as it sidesteps risk of secondary tumors related to alkylating agents. However, additional experience is needed before making treatment recommendations, particularly considering clonal mutability in MM evolution. It would also be helpful if future reports of post-transplant plasmacytic tumors that do not respond satisfactorily to therapy examine translocations such as t(4;14), t(14;20), and t(14;16) that represent adverse prognostic markers in standard plasma cell tumors.10
It is easy to overinterpret clinical series in terms of underlying mechanisms, and Perry and colleagues have taken pains to avoid this indulgence. However, it is also clear that the immunodeficiency-related lymphoproliferations still have many secrets to teach us, and it is sobering to recall that the entire concept of PTLD began with a description of only 5 kidney transplant patients when neither sophisticated molecular techniques nor even monoclonal antibodies existed.2 It is time to take a fresh look at these extraordinary tumors.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■
