Discussion
We found an 80% increased risk for PCNs in US solid organ transplant recipients compared to the general population. This moderate elevation in risk is consistent with previous studies, although our SIR of 1.80 is lower than other reported estimates (SIRs 2.7–3.8). In the present study, most of the PCNs were multiple myeloma, but the relative risk was especially elevated for plasmacytoma (SIR 7.06). The incidence of multiple myeloma was somewhat steady over time following transplantation, whereas plasmacytoma incidence increased with extended follow-up.
PCNs are considered part of the spectrum of PTLD, although they are far less common than NHL and other EBV-related lymphoproliferations. Circulating monoclonal immunoglobulins (termed "M-proteins") are frequently detected among solid organ recipients. In immunocompetent individuals, detection of an M-protein as an isolated finding (i.e. monoclonal gammopathy of undetermined significance [MGUS]) indicates the presence of an abnormal clone of plasma cells and is associated with the subsequent development of multiple myeloma. However, among transplant recipients, M-proteins are usually transient and not clearly predictive of development of PCNs or other forms of PTLD.
Our results support the importance of EBV in the etiology of some PCNs that arise in the posttransplant setting. Thirty-nine percent of PCNs were reported as EBV-positive. In prior small series of posttransplant PCN, EBV RNA or proteins have been documented in tumor cells from a variable proportion of cases. Furthermore, an increased risk for PCN was observed in recipients who were EBV seronegative at the time of transplantation. Many of these individuals would have developed primary EBV infection following transplantation, when their immune system was impaired and unable to fully control the virus. Some recipients would have been infected by EBV transmitted from the donor. However, data on donors' EBV status were too incomplete for us to analyze (not shown). Given the amount of missing data, we could not look at the concordance of EBV serostatus and the presence of EBV in PCN tumors. In contrast to cases in transplant recipients, EBV is rarely detected in PCNs that develop in immunocompetent people.
PCN incidence increased steadily with age, which is a different pattern than seen for NHL and other forms of PTLD, where incidence is very high among pediatric transplant recipients. Although the great majority of PCNs in transplant recipients therefore occur among older adults, the effect of transplantation on increasing risk relative to the general population is actually highest in young recipients (Table 2). Indeed, we calculate that the proportion of PCNs among recipients that would be attributable to their transplant (i.e. attributable risk = [SIR-1]/SIR) is 88% among recipients 0–34 years old. In contrast, among recipients 65+ years old at transplantation, this calculation yields an attributable risk of only 27%, which is not significantly different from 0%, given the lack of significant elevation for the SIR in this age group.
These findings suggest that the etiology of PCNs in transplant recipients differs somewhat across age groups. One model that could explain this pattern is that PCN cases arising in older recipients frequently develop from age-related processes that also occur in the general population, but those that arise in younger recipients are largely related to transplantation. Along these lines, it is possible that many of the PCNs that develop among young recipients are EBV-positive and caused by primary EBV infection, although we cannot be certain that EBV is always involved given substantial missing data on EBV.
Two sets of results point to different patterns for multiple myeloma and plasmacytoma. First, as noted above, plasmacytoma incidence increased with longer follow-up after transplantation, whereas multiple myeloma incidence rates were somewhat constant. Second, induction with monoclonal antibodies increased the risk of plasmacytoma, and use of mycophenolate mofetil decreased risk of plasmacytoma, but neither drug had an effect on multiple myeloma. Use of monoclonal antibody induction is also associated with an elevated risk of NHL and other forms of PTLD, and mycophenolate mofetil may have anticancer properties. Nonetheless, it remains puzzling why medications would differentially affect risk of multiple myeloma and plasmacytoma. Our results regarding immunosuppressive medications differ from those reported previously by Caillard et al. for US kidney recipients. In that study, multiple myeloma risk was higher with use of polyclonal antibody induction and lower with use of azathioprine. A limitation of the study by Caillard et al. is that their ascertainment of PCN outcomes relied upon Medicare claims, which are less accurate than diagnoses recorded in cancer registries.
In the present study, PCN risk was elevated among liver recipients who had a diagnosis of cholestatic liver disease listed as an indication for transplant. Notably, among the cases with cholestatic liver disease, 63% had PBC, suggesting that this condition may predispose to PCN. Published case reports outside the setting of transplantation have described PBC and PCN arising in the same individuals, although limited follow-up studies of PBC (700–1700 patients) have not demonstrated an increased incidence of PCN. Among heart recipients, the higher SIR in those without coronary artery disease was likely confounded by their relatively young age, and the association with coronary artery disease was no longer significant in a multivariable model.
It is possible that local immune stimulation by the donor organ and/or chronic rejection contribute to the development of PCN. Because PBC is an autoimmune disease affecting the liver and can recur after transplantation, chronic inflammation related to this condition may have contributed to the PCN case that we observed arising in the donor liver in a recipient with PBC. Nonetheless, only a few PCNs occurred in the transplanted organ. Although a case of plasmacytoma of donor cell origin arising in a donor kidney has been reported, no study has assessed how frequently PCN tumors are of donor cell origin, and we did not have data to examine this question in our study.
Some prior studies were limited to kidney recipients, and one concern has been that the elevated risk of PCN could largely reflect reverse causation, because multiple myeloma is a well-recognized cause of end-stage renal disease. Patients with multiple myeloma can receive kidney transplants, and the malignancy can recur following transplantation. However, several points argue against this interpretation in our study. First, we saw elevated PCN risk after excluding recipients with a history of PCN or amyloidosis (a condition that is sometimes caused by a PCN). Second, consistent with Collett et al., we observed elevated PCN risk in heart recipients in addition to kidney recipients. Third, while a number of cases in our study were diagnosed in the first months after transplantation, PCN risk increased with time following transplantation. This pattern would be unlikely if most PCNs were already present but undocumented prior to transplantation. Finally, PCN risk is also elevated in HIV-infected people, pointing to an etiologic role for immunosuppression.
Strengths of our study include its large size and representative inclusion of transplant recipients from the United States. We identified PCN outcomes through linkage with comprehensive cancer registries, which allowed for complete and unbiased case ascertainment. Nonetheless, a limitation was the small number of cases, which limited the precision for some estimates and precluded subgroup analyses. Data on EBV antibody status and the presence of the virus in PCN tumors were frequently missing, which prevented detailed evaluation of this important risk factor. As in all studies of cancer in transplant recipients, the presence of competing risks (e.g. death and graft failure) may have affected the observed associations with PCN, if those events did not occur independently of PCN.
Additionally, because this study was based on linked population-based registry data, it would have been very difficult to track down archived tumor specimens, so we were unable to conduct a central pathology review or perform additional diagnostic studies. In particular, some PCNs may have been misdiagnosed cases of plasmablastic lymphoma, a variant of diffuse large B-cell lymphoma. This lymphoma subtype has a morphologic resemblance to plasmacytoma, with tumor cells that stain positive for markers indicative of plasma cell differentiation (e.g. MUM1/IRF4 and CD138/syndecan-1). Conversely, some plasmacytomas in transplant recipients have been reported to have cells that resemble plasmablasts. Although there may be overlap between these two conditions, some features may favor one diagnosis over the other. For example, the detection of EBV in tumor cells may suggest a diagnosis of plasmablastic lymphoma, whereas the presence of lytic bone lesions or an M-protein would support a diagnosis of PCN. In addition, some PCNs in our study may be misdiagnosed cases of plasmacytic hyperplasia, an EBV-related polyclonal lesion that is common early after transplantation.
In conclusion, these observations demonstrate an elevated risk of PCNs among solid organ recipients. Especially among children and young adults, the substantially elevated risk of PCN likely arises from transplant-related immunosuppression and lack of immune control of EBV infection. In contrast, PCNs among older transplant recipients may more frequently be caused by age-related processes that underlie the occurrence of PCNs in the general population. We also observed intriguing associations with PBC and, for plasmacytoma, with certain immunosuppressive medications, which require replication. In addition, future studies should aim to further characterize the clinical and molecular features of transplant-associated PCNs, which may reveal important differences from cases that arise in immunocompetent older adults.