| Abstract|| |
Post-transplant lymphoproliferative disorders (PTLD) are one of the fatal complications of transplantation, and there is scarcity of data on the relevance of antigen expression by tumor cells in PTLD. In the current study, we aimed to investigate the potential effects of CD20 antigen expression by PTLD lesions developing in heart/lung transplant recipients. A comprehensive search was performed for reports indicating CD20 antigen tests in PTLD lesions developing in heart and/or lung transplant recipients. For data accumulation, we developed a standard questionnaire and data of patients presented in different published reports were entered into it. Finally, data from 26 previously published reports from different centers around the world were included in the analysis. CD20-positive PTLD lesions are significantly more likely to be of the B cell type (P = 0.006). PTLD in patients with a CD20-positive test represented relevantly shorter time from transplantation to PTLD, although it did not reach a significance level (P = 0.08). At the last follow-up, 53% patients were dead. Survival analysis showed no prognosis difference regarding CD20 test. When data were reanalyzed separately for heart and lung transplant recipients, lung recipients developing PTLD with a CD20-positive test were significantly more likely to represent remission episodes (P = 0.03), and also represented a significantly better outcome than CD20-negative PTLD patients (P = 0.04). CD20-positive PTLD lesions in heart/lung recipients are more likely of the B cell type and develop PTLD lesions earlier than their CD20-negative counterparts. Lung recipients developing CD20-positive PTLD lesions represented higher remission rates and better outcome. Further studies with prospective follow-up of patients are needed for confirming our findings.
|How to cite this article:|
Gholipour-Shoiili A, Gholipour-Shoiili H, Taheri S. CD20 antigen expression by lymphoma cells in lung allograft recipients is associated with higher remission rate and superior survival: A study on heart and lung transplant recipients. Saudi J Kidney Dis Transpl 2014;25:29-37
|How to cite this URL:|
Gholipour-Shoiili A, Gholipour-Shoiili H, Taheri S. CD20 antigen expression by lymphoma cells in lung allograft recipients is associated with higher remission rate and superior survival: A study on heart and lung transplant recipients. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2016 May 31];25:29-37. Available from: http://www.sjkdt.org/text.asp?2014/25/1/29/124468
| Introduction|| |
Development of post-transplant lymphoproliferative disorders (PTLD) is a well known and inauspicious complication in transplantation practice, which develops in the context of highly potent immunosuppression. The incidence of PTLD varies depending on the transplanted organ as well, and it usually occurs early after transplantation especially in patients with Epstein-Barr virus (EBV) infection.  Most PTLD lesions arise from B cell lineage, and the most common subtype is diffuse large B cell lymphoma. For the diagnosis of the disease, histopathological evaluations are needed, and such evaluations empower us to classify the pathology into three different groups with prognostic and severity grading, including early lesions, polymorphic PTLD and mono-morphic PTLD based on a categorization by the World Health Organization. 
The reported incidence of PTLD in different transplant recipients is highly different with regard to several factors, but most notable of them is the type of transplanted organ, with the lowest rate of occurrence in bone marrow graft recipients and the highest in multiviceral transplant patients. The incidence of PTLD in heart and lung transplant patients is considered high, and is up to 10%. ,
Human cells express various antigens on and within their cell membranes that can affect their resistance and weakness to several diseases, including lymphomas. Although PTLD is genotypically considered a B-cell lymphoma in over 90% of the cases, the classical B-cell marker CD20 is expressed in a minority of such cases. CD20 is a membrane-embedded phosphorylated protein ,, that appears on the B-cell surface.  CD20 resembles a Ca  + ion channel  and is involved in signal transduction for B-cell differentiation and proliferation and cell cycle progression during human B-cell activation. ,
There is a scarcity of data on the relevance of CD20 expression in the PTLD cells and its potential prognostic value. However, due to the very limited volume of its population size, only one study was found in the literature on CD20 relevance in PTLD and the inconsistencies in the study population;  findings from this study cannot be considered with confidence. In their study, pediatric recipients of different types of organ allograft were equally entered into analysis regarding their tumoral CD20 antigen test results. However, it is a very well known fact that prognosis of PTLD developing in recipients of different organs (e.g., kidney or liver versus heart or lung) are quite diverse. ,,, Therefore, we think that analysis of data gathered from a very limited number of patients who have received different types of organ transplants cannot be considered trustable. In the current study, however, conducting a very comprehensive review of the literature, we aimed to find and gather data on heart and lung allograft recipients who have developed a PTLD in their post-transplant era and had a documented a report on the CD20 antigen testing result to prepare and analyze the largest possible data on the disease and to reveal any potential specific feature, behavior or prognosis of CD20-positive PTLD lesions compared with their CD20-negative counterparts.
| Materials and Methods|| |
Approach to the study
For searching the literature for reports indicating test results for CD20 antigen in PTLD lesions developing in heart and/or lung transplant recipients, we performed a very comprehensive search using Pubmed and Google scholar. Keywords used for this purpose were "lymphoproliferative disorders + heart transplantation + CD20," "lymphoproliferative disorders + cardiac graft + CD20," "PTLD + CD20 + heart transplant," "PTLD + CD20 + cardiac graft," "lymphoproliferative disorders + lung transplantation + CD20," "lymphoproliferative disorders + pulmonary graft + CD20," "PTLD + CD20 + lung transplant" and "PTLD + CD20 + pulmonary graft". Wherever we failed to get the full text of the articles, we sent e-mails to the correspondent authors - and sometimes to other authors, when we did not receive a reply - requesting for the article. After completing the search, only studies in which data of each patient were presented separately were included. To minimize selection bias, we only included series reporting their study of patients from single- or multi-center populations, and reports with any particular selection criterion were excluded. For data accumulation, we developed a standard questionnaire and data of patients presented in different published reports were entered into it. Finally, data from 26 previously published reports from different centers around the world ,,,,,,,,,,,,,,,,,,,,,,,,,,, were included in the analysis. The time to PTLD onset was defined as the period between the grafting and the first signs of PTLD or diagnosis, based on the studies' approaches.
Overall, 81 recipients of heart and/or lung allograft were included in the analysis. Eighty-six (93.8%) patients of the study population were patients with a positive result for CD20 antigen evaluation of their PTLD lesions, while the remaining five (6.2%) patients represented CD20-negative test results.
Because of the inconsistencies in the approaches of different studies of patients enrolled in this study, we were not able to get all required data from all the included patients, and in some cases we had to introduce new standardized measures to be able to cumulate data from different studies into a unique database. Disseminated lymphoma was diagnosed when it was declared by the authors or at least three different organs (excluding different lymph node areas) were involved by PTLD, reported in nine (14.1%; 17 unreported) patients. Multi-organ involvement, defined as involvement of more than a unique organ as well as more than one lymphatic region, was seen in 16 (23.9%; 14 unreported) patients.
At lymphoma diagnosis, all patients were receiving and had received immunosuppressive regimens consisting of varying combinations of azathioprine, prednisone, cyclosporine, mycophenolate mofetil and antithymocyte/lymphocyte globulin (ATG/ALG) and OKT3. More or less, a rather uniform approach was used to manage all PTLD patients in the included reports. On diagnosis of PTLDs, the first step in almost all reports was to decrease or discontinue immunosuppressive therapy; different regimens of chemotherapy with or without surgical interventions were also used for some of the patients.
Response to treatment
Response to treatment was defined as any favorable change in the cancer measures as well as patients' clinical condition; data of PTLD response to treatment was reported by authors for 44 (54.3%) patients, of whom 31 (70.5%; 37 unreported) patients responded to anti-malignancy treatment. However, we developed new criteria for defining remission rates for the study population; while remission episode was defined when patients were alive after their 24 th month of PTLD diagnosis (because all reported cases having this criterion had at least one confirmed remission episode) and no remission was defined when a patient dies within the first month post-PTLD diagnosis (because among the reported cases there were no patients dying at the first post-transplant month and reported to have any remission episodes). According to the abovementioned criteria, 20 patients were added to the list and the remission rate reached to 44 (74.6%; 22 missing) cases. Overall mortality was 39 (54.2% of the reported cases; nine unreported) patients, of whom 23 (59%) were reportedly due to PTLD progression.
| Statistical Analysis|| |
Software used for data analyses was SPSS v.13.0. Statistical differences between patients' subgroups were performed using the χ2 and Fishers' exact tests for proportions and the Student's t test for continuous data. Survival analysis was performed with life tables and Kaplan-Meier methods and log-rank test. All statistical tests were performed at the 0.05 significance level. P-values below 0.1 were considered relevant.
| Results|| |
Data of an overall of 81 recipients of heart and/or lung allograft developing PTLD were entered into analysis. There were 57 (73.1%) male and 21 (26.9%) female patients (three unreported). Mean ± SD age at diagnosis of PTLD was 40.3 ± 19.3 years. The mean interval between transplantation and the diagnosis of PTLD was 50.6 ± 50.7 months, whereas the follow-up time after diagnosis of PTLD was 32.8 ± 40.4 months.
Characteristics of the patients regarding their malignancy site are summarized in [Table 1]. Chi square test showed that CD20-positive PTLD lesions are significantly more likely to be of the B cell type (P = 0.006). PTLD in patients with a CD20-positive test had a relevantly shorter time from transplantation to PTLD, although it did not reach a significance level (P = 0.08). CD20-positive PTLD patients were comparable with their CD20-negative counterparts regarding age, gender, immunosuppression types, histopathological pattern of PTLD lesions, remission rates, multiorgan involvement and disseminated PTLD rates. The EBV positivity rate was also comparable between the two patient groups. [Table 2] summarizes the organ involvement frequencies in the two patient groups. As is evident in [Table 2], no preponderance was found in organ complication regarding CD20 positivity.
|Table 1: Characteristics of PTLD heart/lung recipients regarding CD20-positive and -negative results.|
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At the last follow-up, 41 (52.6%) patients were dead (nine unreported). When death irrespective of the reason was used as the final outcome, the log-rank test showed comparable survival for heart/lung graft recipients regarding CD20 antigen expression (P = 0.998) [Figure 1]. The 1- and 5-year survival rates for PTLD patients with CD20-positive results were 70% and 45%, respectively, compared with 63% and 38%, respectively, for CD20 negative-PTLD patients.
|Figure 1: Survival curves of heart/lung graft recipients in relation to their CD20 test result.|
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Then, the data were reanalyzed separately for heart and lung transplant recipients. For heart recipients, no change in the above-mentioned findings was detected; however, after splitting data of the two types of organ grafts, lung recipients developing PTLD with the CD20-positive test were significantly more likely to represent remission episodes (P = 0.026), and also represented a significantly better outcome than CD20-negative PTLD patients (P = 0.041; [Figure 2].
|Figure 2: Survival curve of the lung transplant recipients regarding their CD20 antigen expression by their PTLD lesions.|
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| Discussion|| |
Although introduction of new and potent immunosuppressive agents to transplant medicine brought several optimisms for enhancing both graft and patient survival, it has resulted in an increased incidence of diseases associated with immunosuppression, including infections and malignancies. , PTLD is one of the most frequent neoplasms developing in the post-transplant period, and causes a higher morbidity and mortality burden to the recipients. Thus, the definition of various aspects of this neoplasm and their relevance in solid organ recipients seems to be of outmost priority. However, due to the very limited number of PTLD cases diagnosed in individual transplant centers, and the inconsistent approaches in them, investigations on distinctive areas of the disease and revealing hidden factors that may affect disease behavior and outcome have been performed very rarely.
Previous studies have proposed some factors having roles for their presentation and outcome in PTLD patients, from which we have focused on CD20 antigen expression by lymphomatoid lesions in heart/lung allograft recipients. CD20 protein expression, as determined by flow cytometry, could be considered as a predictor for several drug resistance or responsive cases. , However, almost all these studies have been conducted in a non-transplant context and, to the best of our knowledge, the present study represents the first data on the relevance of CD20 antigen expression in heart and lung graft recipients developing PTLD.
The only finding of our initial analyses was that CD20-positive lesions were more frequently of the B cell type and represented a shorter time to PTLD development, although in the latter case a significance level was not achieved. It is a known fact that CD20 is a marker of normal B lymphocytes. Therefore, it is expected that B cell lymphomas also, to some degree, present it on their cell membrane, as previously reported in lymphoma cells.  On the other hand, the finding that patients with CD20-positive PTLD lesions have relatively shorter time from transplant to neoplasm development has been previously reported by Orjuela et al in their study on pediatric solid organ recipients. 
The prognostic value of CD20 antigen expression in PTLD lesions has been investigated before. In a non-transplant context, Tzankov et al  have demonstrated a better outcome for patients with CD20+ Hodgkin's lymphoma. In transplantation practice, Orjuela et al  have similarly suggested a better survival for CD20-positive PTLD patients compared with their CD20-negative counterparts. On the other hand, Rassidakis et al  reported no prognostic significance for CD20 antigen expression in patients treated with equivalent regimens. Molot et al  also reported the same findings that there was no relevance for CD20 expression on clinical outcome. In an unpublished study, we found an exactly adverse finding for renal recipients, with a relatively lower outcome for patients developing CD20-positive PTLD lesions. In the current study, however, when analysis pooled data of heart and lung recipients, no significant role for CD20 positivity was detected regarding patients' outcome [Figure 1]. But, when the analyses were repeated separately for heart or lung graft recipients, lung transplant patients with CD20-positive lesions showed a better survival and higher remission rates than CD20-negative patients [Figure 2]. This finding is in accordance with the findings of Tzankov et al  and Orjuela et al. 
This study has some limitations. Firstly, the data for this study was gathered from different reports, which more or less had inconsistent approaches. In order to resolve this problem, we tried standardizing our data to be able to present the data in a unique way to insert them into one database. For example, different studies have used dissimilar methods for defining a "remission episode"; while some of them had used terms like "complete" or "partial" remission, others only talk about a remission episode, favorable changes in tumor size, general conditions and so on. In such cases, we categorized the term to two sub-categories; for this case: "remission" and "no remission." When authors had reported any positive reaction to therapy, we used the term "remission" and when disease progressed, we used the second term. Some other standardization policies have been employed that have been described in the methods section.
In conclusion, this study is most probably is the first and only data on the relevance of CD20 antigen expression by PTLD lesions arising in heart and lung transplant recipients. According to our analyses, CD20-positive PTLD lesions are significantly of the B cell type and relatively develop earlier in time post-transplantation than their CD20-negative counterparts. When analyses were separately performed for heart and lung graft recipients, lung recipients developing CD20-positive PTLD lesions represented higher remission rates and better outcome. Further studies with prospective follow-up of patients are needed for confirming our findings.
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Department of Medicine, Guilan University of Medical Sciences, Rasht
[Figure 1], [Figure 2]
[Table 1], [Table 2]