Objectives: Owing to the rare incidence of posttransplant lymphoproliferative disorder of the heart, there is a paucity of data concerning it. In this study, we pooled data from posttransplant lymphoproliferative disorder patients from the existing literature. We sought to analyze and compare characteristics, predictors, and prognoses of patients with posttransplant lymphoproliferative disorder of the heart.

Materials and Methods: A comprehensive search was made to gather data by PubMed and Google for reports of lymphoproliferative disorders occurring in transplant patients occurring within the heart, the heart allograft, and surrounding tissues. Pooled data were reanalyzed.

Results: Overall, 206 patients were entered into the analysis. Transplant recipients with cardiac posttransplant lymphoproliferative disorders were significantly more likely to represent multivisceral and disseminated posttransplant lympho­proliferative disorder (P = .01 and P < .001). Posttransplant lymphoproliferative disorder in patients with heart involvement were more likely to involve the genitalia (P = .035), the adrenals (P = .035), the liver (P = .007), and the kidneys (P < .001). Patients with cardiac posttransplant lympho­proliferative disorder had significantly shorter time from transplant to development of posttransplant lymphoproliferative disorder (P = .029). A log-rank test showed a significant inferior patient survival for transplant recipients with cardiac complications (P = .031). Patients with a cardiac allograft posttransplant lymphoproliferative disorder were significantly older at the time of transplant (55.3 ± 8.4 vs 38.5 ± 21.8 y; P = .002).

Conclusions: Because cardiac posttransplant lymphoproliferative disorder is associated with multiorgan and disseminated posttransplant lymphoproliferative disorder, all transplant recipients who represent posttransplant lympho­proliferative disorder in the heart should be evaluated for other organs involvement most especially in the kidneys, liver, and adrenals. Further prospective studies with a larger patient population are needed to confirm our results.

Key words : Heart, Cardiac, PTLD

Introduction

The science of organ transplantation has witnessed substantial success in the past 2 decades, owing to significant advances in techniques and development of powerful immunosuppressives for preventing episodes of rejection. These advantages offer us the opportunity to experience success transplanting the most difficult organs including the heart, which had disappointing results before recent progress. Nevertheless, these new achievements were not trouble-free; from widespread use of potent immunosuppressants to prohibit risk of rejection emerged new complications,^1-3 out of which we focus on development of posttransplant lympho­proliferative disorders (PTLD) in this study.

Development of lymphoproliferative disorder after organ transplant, first reported by Penn and associates1 in 1969, remains a critical diagnostic and therapeutic problem characterized by lymphoid proliferation of B- or T-cell origin in different organs. Worldwide reports indicate a high incidence of PTLD among recipients of all types of organs and outcomes. Investigators have suggested that the incidence, time interval, prognosis, and presentation of PTLD vary depending on the organ transplanted, the age of patients, viral infections, and intensity of immunosuppression.^4-12 The reported incidence of PTLD in heart transplant recipients varies from 2% to 10%, with higher rates in pediatric settings.^13-17

A limited number of previous studies have focused on development of PTLD in specific organs. In 3 previous studies of international data, we reviewed data from patients who developed PTLD within their renal, liver, and lung allograft^{7, 18} [unpublished data], and in 2 other reports, we studied central nervous system and oropharyngeal localization of PTLD.^{19, 20} Allograft PTLD complicated about 37%, 48%, and 32% of the studied renal, liver, and lung transplant populations, while oropharyngeal and central nervous system localization was present in 19% and 24% of the studied populations; although, owing to inclusion criteria used in those studies, we were unable to represent a precise incidence rate for the PTLD localizations in these populations. The number of reported cases of heart PTLD in transplant patients is limited, and only a small number of cases with histologic-proven PTLD have been reported in these patients, and exactly owing to the same reason: A scarcity of data exists in various aspects of heart localization of PTLD. In this study, pooling data of PTLD patients from existing literature, we sought to analyze and compare characteristics, predictors, and prognosis of heart localized PTLDs.

Methods and Materials

Approach to the study
We conducted a comprehensive search for the available data by PubMed and Google for reports of lymphoproliferative disorders occurring in transplant patients in heart and heart allograft and surrounding tissues. Key words used for this purpose were “lymphoproliferative disorder + transplantation + heart localization,” “lympho­proliferative disorders + transplantation + heart,” “PTLD + heart allograft,” “PTLD + heart localization,” “lymphoproliferative disorder + transplantation + cardiac localization,” “lympho­proliferative disorders + cardiac transplantation + graft,” “cardiac transplantation + allograft PTLD,” and “PTLD + cardiac localization.” In cases where we could not achieve the full text of the articles, e-mails were sent to corresponding authors requesting the article. Then, we only included studies where data from each patient was presented separately to minimize selection bias, we only included studies reporting their series of patients from single or multicenter populations; studies with any specific selection criteria were excluded from the analysis. Lymphoproliferative disorders occurring after transplant within heart were considered our case group and other heart transplant patients developing PTLD at other sites were used as controls. Heart localization of PTLD was defined when authors stated the heart, heart allograft, or pericardium/pericardial tissues were the site of disease. A standard questionnaire was developed to collect data from different published studies. Finally, data from 11 previously published studies from various countries^21-31 were included in the analysis. The time between transplant and onset of PTLD was defined as the time between the graft and the first signs of PTLD or diagnosis, based on the studies’ approaches.

Study population
Overall, 206 transplant recipients who developed PTLD through their treatment course were included in the analysis. Fifteen of the study population were patients with cardiac PTLD (7.3%) while the remaining 191 patients (92.7%) represented PTLD at other sites. Patients’ status regarding Epstein-Barr virus infection was documented in 112 patients (54.4%), of whom 84 (75%) were reported positive.

Because data used for this study was from different studies that followed different approaches, we were unable to gather all the data needed from the included patients. Disseminated lymphoma was diagnosed when it was declared by the authors, or when at least 3 different organs (different lymph node areas were excluded from the analyses owing to a lack of knowledge on how to categorize the data) were involved by PTLD, reported in 55 patients (39.6%; 67 missing data). Multiorgan involvement, defined as involvement of more than a unique organ as well as more than 1 lymphatic region, was available in 106 patients (61.3%; 33 missing data).

At lymphoma diagnosis, all patients were receiving and had received immunosuppressive regimens consisting of varying combinations of azathioprine, prednisone, cyclosporine, myco­phenolate mofetil, antithymocyte/lymphocyte globulin (ATG/ALG), and OKT3. A rather uniform approach was used to manage all PTLD patients in the included reports. When diagnosed with PTLD, the first step was to decrease or discontinue immunosuppressive therapy; different regimens of chemotherapy with or without surgical interventions also were used for some patients.

Response to treatment
Response to treatment was defined as any favorable change in the cancer measures, as well as the patients’ clinical condition; data of PTLD response to treatment was reported by authors for only 71 patients (34.5%), of whom 30 patients (42.3%) responded to antimalignancy treatment. However, we developed new criteria for defining remission rates for the study population; while a remission episode was defined when patients were alive after the 24th month of PTLD diagnosis (since, all reported cases having this criterion had at least 1 confirmed remission episode), and no remission was defined when a patient died within the first month after PTLD diagnosis (because among reported cases, there were no patients dying in the first posttransplant month reported to have any remission episodes). According to this criteria, 98 patients (47.6%) represented data on remission, of whom 51 (48.1%) had at least 1 response to treatment, irrespective of their future disease manner. Overall mortality was 96 patients (46.6% of the study population and 64.9% of the reported cases; 58 patients missing data); death owing to PTLD was defined when (1) the authors state it, or (2) when a patient dies within 6 months after the diagnosis, or (3) when patients died owing to PTLD treatment complications. Overall, 58 patients died (47.9% of the reported data; 60.4% of the whole mortality rate) owing to the disease based on the above-mentioned criteria.

Statistical Analyses
Statistical analyses were performed with SPSS software for Windows (Statistical Product and Service Solutions, version 13.0, SSPS Inc, Chicago, IL, USA). Statistical differences between patients’ subgroups were performed by using the chi-square and the Fisher exact tests for proportions and the t test for continuous data. Survival analysis was done with life tables, Kaplan-Meier methods, and a log-rank test. All statistical tests were performed at the .05 significance level. When analyzing heart graft PTLD, owing to the limited number of patients, we introduced P value of 0.1 as the “relevance level.”

Results

Overall, 206 patients with lymphoproliferative disorders after renal, liver, pancreas, lung, bone marrow, and heart transplant were entered into analysis. There were 110 males (67.5%) and 53 female patients (32.5%) (43 missing data). Mean age at diagnosis of PTLD was 33.6 ± 21.4 years. The mean interval between transplant and diagnosis of PTLD was 41.0 ± 43.8 months, whereas follow-up after diagnosis of PTLD was 18.2 ± 25.1 months.

Characteristics of patients regarding their malignancy site are summarized in Table 1. The chi-square test showed that transplant recipients with cardiac PTLD were significantly more likely to represent multivisceral and disseminated PTLD (according to the defined criteria described in the methods section; P = .01 and P < .001). Transplant recipients with cardiac PTLD were comparable to their counterparts with other PTLD localization in their sex (P = .34), lymphoma cell types (P = 1.0), Epstein-Barr virus infection rate (P = 1.0), PTLD presentation time (P = .59), and remission rates, both when it was reported by authors and when it was calculated based on the defined criteria (P = .429 and P = .164).

Table 2 summarizes different organ involvements by PTLD when they concomitantly do or do not complicate the heart. Posttransplant lymphoproliferative disorder in patients with heart involvement was more likely to involve the genitalia (P = .035), adrenals (P = .035), liver (P = .007), and kidneys (P < .001). Patients with cardiac PTLD had comparable age at the time of transplant with other PTLD patients (P = .786; median age 48.5 vs 36.0 y); but had significantly shorter time from transplant to PTLD development (P = .029; median 13.0 vs 22.0 mo). Histopathologic evaluations also were comparable in heart PTLD versus other PTLD patients in their morphology (P = .314) and clonality (P = .701).

At last follow-up, 96 patients were dead (64.9%) (58 missing data). When death, irrespective of the reason, was used as the outcome, a log-rank test showed a significant inferior patient survival for transplant recipients with cardiac complication (P = .031; Figure 1); moreover, when only death owing to PTLD was used as the outcome (based on the defined criteria in the Methods section), again, patients with cardiac PTLD had worse survival than other recipients (P = .019; Figure 2). We then separately analyzed the potential effect of other interfering factors on the survival of patients to evaluate any independent effect of the heart localization by conducting a multivariable analysis; however, the Kaplan-Meier analysis did not show any significant effect for adrenal, renal, liver, and genitalia PTLD localization on survival of the included patients (P > .2 for all). One and 5-year survival rates for cardiac PTLD patients were 20%; compared with 55% and 35% for the control group.

Cardiac graft posttransplant lymphoproliferative disorder
We reanalyzed the data for finding predictors, characteristics, and prognosis of heart transplant recipients when PTLD complicates their cardiac graft versus other organs. Overall, 67 heart transplant recipients were entered into analysis. Patients with cardiac graft PTLD were significantly more likely to complicate liver (3 [50%] vs 8 [13.1%]; P = .05); patients with cardiac allograft PTLD were significantly older at the time of transplant (55.3 ± 8.4 vs 38.5 ± 21.8 y; P = .002), and had relevantly shorter time from transplant to PTLD (33.3 ± 30.4 vs 56.8 ± 45.6 mo; P = .1). Survival of patients with cardiac allograft PTLD was relevantly lower that other PTLD localizations in other heart transplant patients (P = .10; Figure 3).

Discussion

Transplant patients have a 50- to 100-fold increased risk for developing lymphomas with an overall incidence of 1% to 5% in solid organ transplant recipients, and evidence suggests that the type and degree of immunosuppression as well as the type of allograft have major roles in this risk enhancement.^{3, 32} Posttransplant lymphoproliferative disorders are one of the most prevalent malignancies complicating recipients of various organs reducing graft and patient survival in this patient population. The first report of PTLD was published in 1969 and since then, several studies from all over the world have introduced numerous factors as major players in the incidence and outcome of PTLD in all types of transplants from which PTLD localization in heart and heart allograft. The PTLD.Int. survey is an attempt at reviewing and gathering international data from PTLD patients to conduct analyses on the largest possible patient population to discover new perspectives on the disease. In this study, we analyzed one of the largest series of PTLD patients to discover various characteristics of PTLD presenting within the heart and cardiac allograft and their histopathologic features, disease behavior, and prognostic factors.

In this study, we found that cardiac localization of the PTLD represents a worse outcome compared with other PTLD localizations in different organ recipients. In our previous studies, we showed that PTLD localizing in oropharynges and small intestine represent better patient outcomes in transplant recipients, while central nervous system localization represented no survival disparity with other localizations.^{19, 20, 33}

In our previous reports from the above-mentioned survey, gathering and analyzing data of several reports existing in the literature, we found that PTLD presenting within renal and lung allograft represent a more-benign course with better survival rate than other disease localizations¹¹ [unpublished data]; however, liver transplant recipients with allograft involvement had no different outcome compared with other PTLD localizations.¹⁸ However, in this study, in contrast with our previous reports, we found that cardiac allograft localization of the PTLD is associated with an inferior outcome compared with other PTLD localizations in heart transplant recipients.

Allograft PTLD in most types of organ transplants is a rare condition, and this inevitably limits our knowledge of various aspects of PTLD localizing within the allograft, including data on the natural course, potential precursors, and preventive methods that might substantially improve our approaches including diagnostic and therapeutic strategies. For example, in our previous studies about allograft localization of the PTLD in kidney, liver, and lung transplants, we showed that PTLD presenting in the graft is significantly more likely to develop within the first year after transplant. Interestingly, we found the same finding for cardiac transplant recipients, although a level of significance was not achieved. Combining the things, we suggest that all transplant patients presenting with graft dysfunction in the early stage after transplant, besides appraisal for a possible rejection episode, they should receive full evaluations for a potential graft PTLD.

A previous article by Nuckols and associates³⁴ reviewed characteristics of 25 cases of liver graft PTLD reported by 21 case reports and their own series. In that review article, uncontrolled analysis showed that most cases were males with a male:female ratio of over 3:1; however, the current study did not show any sex diversity between the 2 groups. This finding agrees with our previous study on lung and liver PTLD, but in contrast to our analysis of renal graft PTLD, which in the latter study, was similar to the study by Nuckols and associates,³⁴ we found a male preponderance for the allograft PTLD patients compared with other disease locations. Moreover, in 2 articles of liver graft PTLD by Nuckols and associates³⁴ and our previous report,18 liver graft PTLD was significantly less frequent in pediatric patients with no cases in the study by Nuckols and associates³⁴; however, in the current article, like our article on lung and renal graft PTLD7 [unpublished data], we found no difference in the age of our PTLD patients regarding heart localization (nonessential graft). Nevertheless, when we reanalyzed data, including only heart transplant recipients, patients in the cardiac allograft PTLD were significantly older at the time of transplant.

Potential criticisms may arise over our study. First, our study population was gathered from different reports with inconsistent approaches. We also believe that this is the unique major limitation for this study leading to substantial missing data for some of study variables and thus, decreasing the power of our analyses. This limitation was most prominent for special data that are not typically included in reports on PTLD patients. Another limitation owing to the inconsistencies available between included studies was that results of different studies were not presented in the same way. For example, reporting of any response to treatment was presented dissimilarly in different studies; while in 1 study, partial and complete remission was used to translate the results, in another only “response to treatment” was used, and in some no specific terminology was used. Therefore, we ought to invent new methods to cumulate the existing data for analyses.

We conclude that because cardiac PTLD is associated with multiorgan and disseminated PTLD, all transplant recipients who represent PTLD in heart should be evaluated for other organs involvement most especially in the kidneys, liver, and adrenals. Cardiac transplant recipients, besides risk assessment for a rejection episode, should receive early evaluation for a potential graft PTLD when they represent early symptoms of graft function impairment. Further prospective studies with large patient population are needed to confirm our results.

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