The development of adult T cell leukemia/lymphoma in renal transplant recipients: report of two cases with literature review
Renal Replacement Therapy volume 9, Article number: 36 (2023)
Therefore, reports on the risk of HTLV-1-related diseases in organ transplantation have increased in recent years, and the management of HTLV in renal transplantation remains a challenge.
Patients and methods
We retrospectively analyzed four HTLV-1-positive recipients or donors among 89 renal transplantation cases from 2006 to 2021.
Among the four HTLV-1-positive recipients, two patients developed adult T cell leukemia/lymphoma (ATL) derived from recipients at approximately 3 years (1016 days and 1195 days) after renal transplantation. Case 1 developed lymphoma-type ATL (an extranodal primary cutaneous variant), including skin and pulmonary lesions. The patient achieved CR with FK tapering and CHOP therapy following cord blood stem cell transplantation. However, the patient died 101 days after ATL development because of a severe fungal infection. Case 2 developed acute-type ATL with an unusual phenotype of CD4+8+30+. The patient was treated with FK tapering and palliative therapy because of poor PS. Notably, in case 1, histopathological findings showed high numbers of PD-1-positive TIL cells in ATL, suggesting exhausted T cells and a correlation with the early onset of ATL. Furthermore, in Case 2, histopathological findings revealed CD 30 expression in ATL cells, suggesting the importance of CD 30 in ATL development. Importantly, case 2 showed typical driver mutations, including CCR4 truncation mutations of the C-terminal, TBL1XR1 mutation, and TP53 mutation in the splice site. Notably, our present study and our previous study on renal transplantation strongly indicated that two out of two and one out of 59 “recipient” positive cases developed ATL, respectively. Furthermore, our previous nationwide study 4 out of 10 “donor” positive cases developed HAM. These findings showed that ATL may be derived from HTLV-I+ recipient cells and HAM may be derived from HTLV-1+ donor cells, although the precise mechanism remains unknown.
Thus, early onset and rapid progression of ATL with poor outcomes should be considered in HTLV-1 endemic areas. Furthermore, immunological or genetic mechanisms may be related to the development of ATL after renal transplantation. We believe that the mechanism of onset of ATL after transplantation may be important when considering the immune environment of ATL itself.
Since end-stage kidney disease (ESKD) has increased in recent years, renal transplantation and hemodialysis are increasingly performed . Although the overall survival (OS) of renal transplantation is reported to be approximately 80–90%, the main problems are rejection of transplanted kidneys, severe infection, and post-transplant lymphoproliferative disorder (PTLD) [1, 2].
Abbas reviewed post-transplantation lymphoproliferative disorders: current concepts and future therapeutic approaches . Abbas reviewed two important points: the use of immunosuppressive agents, including tacrolimus (FK), and the role of Epstein–Barr virus (EBV) as the most crucial factor in PTLD . However, in addition to these two factors , we have previously demonstrated the impact of human T cell leukemia virus type 1 (HTLV-1) on the development of adult T cell leukemia/lymphoma (ATL) after liver and renal transplantation [3,4,5].
In 2006, we described the early onset and rapid progression of three cases of ATL (6, 9, and 25 months after liver transplantation) in eight HTLV-I carriers among 164 living-donor liver transplant recipients undergoing immunosuppressive treatment with tacrolimus. These clinical findings strongly suggest that immune escape mechanisms play an important role in ATL pathophysiology. Yoshida et al.  reviewed immune escape mechanisms in ATL, especially PD-L1 (CD274) alterations, deletions, and mutations in genes related to major histocompatibility complex (MHC) class I, including HLA-A, HLA-B, and β2M.
In HTLV-1-negative renal transplant recipients from HTLV-1-positive donors, Yamauchi and Yamano et al.  reported that 4 of 10 patients (high incidence) developed HTLV-1-associated myelopathy (HAM) early after renal transplantation. Thus, previous reports on the risk of HTLV-1 infection in organ transplantation have increased, suggesting the importance of HTLV-1 testing before transplantation and clinical care with attention to the development of HTLV-1-related diseases including ATL and HTLV-1-associated myelopathy (HAM) (Tables 1 [3,4,5, 8,9,10,11,12,13,14,15,16,17,18,19,20] and 2 [21,22,23,24,25,26,27,28,29,30,31,32,33]). Furthermore, Ohshima et al. [34, 35] reported the importance of the tumor microenvironment of adult T cell leukemia/lymphoma; in particular, high numbers of programmed cell death-1-positive tumor-infiltrating lymphocytes correlate with the early onset of post-transplant lymphoproliferative disorder.
In 2022, we coincidentally experienced the early onset and rapid progression of two cases of ATL in four HTLV-I carriers of renal transplant recipients undergoing immunosuppressive treatment with tacrolimus. Thus, in this study, we retrospectively describe the clinical significance of HTLV-1-positive recipients/HTLV-1-positive donors for renal transplantation, including the pathological and genetic analysis of two ATL development cases, with a review of the literature.
Patients and methods
We retrospectively analyzed the impact of HTLV-1 infection on 89 renal transplantation cases between January 2006 and December 2021. There were four HTLV-1-positive organ transplants among the 89 renal transplantation cases. Three recipients were HTLV-1 carriers, and one HTLV-1-negative recipient was transplanted from an HLTV-1-positive donor at another hospital. Previously, we reported the impact of HTLV-1 infection on 31 renal transplantation cases between January 2006 and December 2016 .
Regarding renal transplantation, 89 cases comprised 80 living donors and nine cadaveric donor renal transplants. The status of HTLV-1 infection in recipients and donors is described below. All donors for renal transplantation tested negative for HTLV-1, and we excluded an HTLV-1-positive donor based on the recommendation of the Japanese Society for Clinical Renal Society and the Ministry of Health, Labour and Welfare in 2014 and the HAM guideline 2019 . Thus, two HTLV-1 carrier donors were excluded as renal transplantation donors during the health checkup. However, renal transplantation from an HTLV-1-positive donor to HTLV-1-negative recipient was performed at another institution. The case (Case 4) was followed up at our institution because the residence of case 4 was in Miyazaki prefecture.
The immunosuppressive protocol to prevent graft rejection in patients after renal transplantation was as follows: induction therapy with basiliximab (20 mg daily at transplant and on postoperative day 4), followed by mycophenolate mofetil (MMF; 1000 mg twice daily, tapered to 500 mg twice daily at approximately 3 months post-transplant), tacrolimus (FK), and corticosteroids (250-mg bolus injection intraoperatively, 24 mg daily in the first week, tapered to 4 mg daily by 1-month post-transplant). Rituximab was administered one week before transplantation to patients who received repeat transplants and ABO-incompatible transplants. After renal transplantation, FK immunosuppressants were used to prevent rejection by kidney transplantation. MMF was tapered at approximately 3 months post-transplant and ceased at approximately 1 year post-transplant.
This retrospective study was conducted in compliance with the guidelines for good clinical practice and ethical principles of the Declaration of Helsinki. This study was approved by the appropriate ethics committee and institutional review board of Miyazaki Prefectural Miyazaki Hospital.
Histopathological analysis and immunohistochemical staining 
Evaluation of immunohistochemical staining was performed manually by experienced hematopathologists at Kurume University (H. Miyoshi. and K. Ohshima).
Antibodies used in immunohistochemistry (IHC) included anti-CD20 (L-26; Dako Cytomation, Glostrup, Denmark), anti-CD10 (56C6; Leica Microsystems, Wetzlar, Germany), anti-CD3 (F7.2.38; Dako Japan Inc., Kyoto, Japan), anti-CD30 (Ber-H2; Dako Japan Inc.), anti-FoxP3 (SP97; Abcam, Cambridge, UK), anti-PD-1 (NAT105; Abcam), and anti-PD-L1 (E1L3N; Cell Signaling Technology, Danvers, MA, USA). An Olympus BX51 microscope (Olympus, Tokyo, Japan) was used to quantify positive cells. Neoplastic cells were scored positive when ≥ 30% staining was observed. For the quantitative analysis of PD-L1 expression, cells with distinct membranous staining were scored as positive. Neoplastic and microenvironment PD-L1 + cells were evaluated separately. To assess immunohistochemically positive TILs, ≤ 10 representative high-power fields (HPFs) were randomly selected per specimen. The total number of immunohistochemically positive TILs was determined. The average number of immunohistochemically positive TILs per HPF was calculated for all patients using immunohistochemical staining. The cut-off values for the number of PD-1, CD3, CD8, CD4, FoxP3, and microenvironmental PD-L1-positive TILs were 100, 500, 150, 30, 25, and 10, respectively.
Targeted-capture sequencing was performed using the custom SureSelect library (Agilent Technologies) for 235 lymphoma-associated genes in National Cancer Center Research Institute (Y. Kogure). To detect structural variations (SVs) affecting PD-L1, the sequences of coding exons, introns, and 5ʹ- and 3ʹ-UTRs were also included in the library. Sequencing data were generated using the Illumina HiSeq platform with a standard 150-bp paired-end read protocol. Sequence alignment and mutation calling were performed using Genomon pipeline (https://github.com/Genomonproject). Candidate mutations with (i) EBCall  p < 0.0001; (ii) > 5 variant reads in tumor samples; and (iii) a variant allele frequency > 0.05 in tumor samples were adopted and further filtered by excluding (a) synonymous SNVs, (b) variants only present in unidirectional reads, and (c) variants occurring in repetitive genomic regions. These candidate mutations were further filtered, unless they were listed ≥ 10 times in the COSMIC database version 70, by removing known germline variants (i) observed in NCBI dbSNP build 131 or (ii) observed at a frequency ≥ 0.0001 in any of the following datasets: the 1000 Genomes Project (October 2014 release); National Heart, Lung, and Blood Institute Exome Sequencing Project 6500; the Human Genome Variation Database (version 2.00); and the Exome Aggregation Consortium (ExAC) r0.3.1. Finally, all detected mutations were manually checked using Integrative Genomics Viewer (IGV) version 2.8.2.
The summary of cases 1–4 (Table 3 )
Two of the four HTLV-1 carrier patients developed aggressive-type ATL after renal transplantation. Patient characteristics at the time of ATL diagnosis and treatment outcomes are summarized in Table 3. Our report provides additional information. Given the scarcity of cases, emphasis should be placed on precise patient cohort descriptions. This may add to the knowledge base. Thus, we would like to describe the patient cohort in more detail and how diagnosis and treatment were performed.
Case 1 was a 60-year-old man with ESKD of unknown etiology. Two years and nine months after renal transplantation, the patient developed a lymphoma-type ATL (an extranodal primary cutaneous variant) according to the consensus report by Tsukasaki et al.  (Fig. 1). Once aggressive-type ATL develops, conventional chemotherapy is not curative. To suppress the progression of ATL, immunosuppressive drugs were gradually withdrawn and chemotherapy was subsequently administered. Regarding FK trough concentration in PB just prior to develop ATL, the blood levels of FK were 5.5 ng/mL (FK 3.0 mg per day). The withdrawal of FK was performed from 3.0 mg per day into 2.0 mg per day. However, these treatments have unfortunately led to PD. Subsequently, the CHOP therapy was initiated. Fortunately, these treatments led to CR. To date, there has been only one report by Mori et al.  on allo-HSCT for the development of Ph1 + ALL after liver transplantation. Based on Mori's report , we performed cord blood stem cell transplantation (CBSCT) using the conditioning regimen of FLU/MEL/TBI and GVHD prophylaxis of FK and MMF. However, the patient died on day 101 after ATL development because of severe fungal infection.
Case 2 was a 75 year-old woman with ESKD due to nephrosclerosis. Three years and three months after a renal transplantation, the case developed acute-type ATL with abnormal multi-lobulated nuclei “flower-like” lymphocyte cells in PB, which expressed an unusual phenotype of CD4 + 8 + 30 + . Regarding FK trough concentration in PB just prior to develop ATL, the blood levels of FK were 5.7 ng/mL (FK 2.5 mg per day). The withdrawal of FK was performed from 2.5 mg per day into 1.5 mg per day. The patient was treated with FK tapering and palliative therapy (PSL) because of poor PS (Fig. 2). These treatments led the case result in PD. The patient died 5 days after the diagnosis of ATL.
To elucidate the pathogenesis of ATL after renal transplantation, we performed histopathological analysis by using immunohistochemical staining .
In case 1, a high numbers of PD-1-positive TIL cells (average 20.8/HPF) were noted. The microenvironmental PD-L1 expression was also positive (50/HPF). However, Fox P3, HLA class I, HLA class II, and neoplastic PD-L1 were not detected. In case 2, low numbers of PD-1-positive TIL cells (average 0.8/HPF) were observed. Fox P3, HLA class I, HLA class II, neoplastic PD-L1, and microenvironmental PD-L1 were not expressed. In addition to the use of immunosuppressive treatment, in case 1, high numbers of PD-1-positive TIL may be related to ATL development, consistent with Ohshima's report [34, 35]. In Case 2, in addition to the use of FK, CD30 expression in ATL cells may be related to ATL development (Fig. 2A).
The genetic analysis
The results of the genetic analysis of cases 1 and 2 are shown in Table 5.
In case 1, we could not detect somatic alterations because of the low tumor cell fraction in the specimen. In Case 2, we found a TP53 mutation at the splice site, a CCR4 mutation truncating its C-terminus, and a TBL1XR1 mutation, which are typical ATL driver mutations [38, 39]. Thus, in case 2, consistent with previous reports [38, 39], typical driver mutations, including CCR4 truncation mutations of the C-terminal, TBL1XR1 mutation, and TP53 mutation in the splice site, may be related to the development of ATL after renal transplantation.
The comparison between previous our conducted study and present study
Regarding the incidence of ATL development after renal transplantation, Yamano’s study of 99 HTLV-1-positive renal transplantation cohorts in Japan (2000–2014 data from the Japanese Renal Transplant Registry) (Table 7) showed that the incidence of ATL development after renal transplantation was approximately 1% (1 out of 99 HTLV-1-positive recipients). Regarding the incidence of ATL development after liver transplantation, Yoshizumi’s study of 82 HTLV-1-positive liver transplantation cohorts in Japan (a multi-center study including 13 high-volume centers in Japan) (Table 9) showed that the incidence of ATL development after liver transplantation was approximately 6% (5 out of 89 HTLV-1-positive recipients). Thus, previous nationwide studies have shown that the incidence of ATL after renal/liver transplantation is rare (1–5%). Unfortunately, all six recipient-positive-derived ATL cases showed poor outcomes.
Importantly, our present study and our previous nationwide study on renal transplantation strongly indicated that two out of two ``recipient” positive cases and one out of 59 ``recipient” positive cases developed ATL (Tables 6 and 7). Furthermore, in the present study and previous nationwide study on renal transplantation, none of the “donor” positive cases and 4 out of 10 “donor” positive cases developed HAM, respectively (Tables 6 and 7). Furthermore, our present study and previous nationwide study in renal transplantation none of one “donor” positive cases and 4 out of 10 “donor” positive cases developed HAM, respectively (Tables 6 and 7). These findings showed that ATL may be derived from HTLV-I + recipient cells and HAM may be derived from HTLV-1 + donor cells, although the precise mechanism remains unknown.
Herein, in our study, we showed the early onset and rapid progression of two cases of ATL (33 months and 39 months after renal transplantation) in four HTLV-I carriers within 89 renal transplant recipients undergoing immunosuppressive treatment with tacrolimus. Furthermore, consistent with previous reports of poor outcomes of ATL after organ transplantation, our two cases also showed poor outcomes due to ATL progression and severe infection. Notably, we first showed that immunological mechanisms or genetic mechanisms may also be related to the development of ATL after renal transplantation under immunosuppressive treatment. Furthermore, our present study and our previous nationwide study on renal transplantation may indicate that ATL is derived from HTLV-I + recipient cells and HAM is derived from HTLV-1 + donor cells, although the precise mechanism remains unknown. Thus, the origin of HTLV-1 related disease (ATL or HAM) after renal transplantation may be different.
Abbas F et al.  demonstrated the importance of immunosuppressive agents including FK and the role of EBV in the development of PTLD after organ transplantation. In addition to these factors, our present study and our previous nationwide study showed the significance of HTLV-1 infection in the development of PTLD after organ transplantation. However, it is unclear whether the immune and genetic mechanisms are related to ATL development after renal transplantation. Recently, PD-1 + TILs were shown to play a major role in the development of PTLD in patients [34, 35]. Furthermore, CD30 expression [42,43,44,45,46,47] or/and genetic mutations [38, 39, 48] may also play an important role in the development of tumorigenesis in PTLD.
Thus, we focused on the important pathogenesis of (i) the surface and genetic features of ATL cells and (ii) the immune characteristics of CTL cells in ATL development after renal transplantation.
The importance of CD30 for ATL [42,43,44,45,46] and PTLD  on the surface increasingly reported and reviewed. Ohshima et al. [42, 43] also reported that CD30 in healthy tissues plays a role in immune system surveillance and in mediating the cross-talk between B and T cells. In addition, Ohshima et al. [42,43,44,45,46] and other researchers reported that the expression CD30 in HTLV-1-positive cells plays an important role in tumorigenesis. Notably, Nakashima et al.  reported that increased CD30 expression may be strongly related to disease progression. Previous studies have also reported that 66% of all PTLD cases are CD30-positive . Thus, these findings also highlight the importance of CD 30 in PTLD development. Consistent with previous reports [42,43,44,45,46,47], case 2 showed that CD 30 expression in ATL cells may be an important characteristic of ATL development after renal transplantation. Although the precise mechanism is unclear, CD30 expression in ATL cells and PTLD may be important for elucidating the pathogenesis of ATL and PTLD. Based on the pathogenesis of CD30 expression in ATL cells, molecular-targeted therapy may be a therapeutic option, including the anti-CD30 antibody–drug conjugate brentuximab vedotin [46, 49].
Regarding the genetic features of ATL cells in ATL development, in our study of case 2, genetic analysis revealed CCR4, TBL1XR1, and TP 53 mutations (splice site). These findings are consistent with previous reports on the genetic landscape of PTLD (T-and NK-cell PTLD) by Margolskee et al.  and ATL by Kogure et al. [38, 39]. In 19 PTLD patients (17 T-PTLD and 2 NK-PTLD cases), Margolskee et al.  reported that 377 variants with an average of 20 variants per case, mutations of epigenetic modifier genes (TET2, KMT2C, KMT2D, DNMT3A, ARID1B, ARID2, and KDM6B), and/or inactivation of TP53 (mutation and/or deletion) were the most frequent alterations. Kogure et al. [38, 39] reported that ATL is characterized by a mutation in the T cell receptor/NF-κB signaling pathway (PLCG1, PRKCB, CARD11, VAV1, CTLA4-CD28, and ICOS-CD28 fusions), molecules associated with immune surveillance (HLA-A/B, CD58, and FAS), and chemokine receptors (CCR4, CCR7, and GPR183). Among the CCR4, TBL1XR1, and TP 53 mutations (splice sites) in case 2, we focused on the TBL1XR1 mutation in ATLL. Although the TBL1XR1 mutation has been reported to be a driver of ATLL [38, 39], the function of the TBL1XR1 mutation in ATL development remains unclear. However, in DLBCL, the TBL1XR1 mutation plays a crucial role in giving rise to extranodal ABC-DLBCLs derived from memory B cells because the TBL1XR1 mutation skews the humoral immune response to produce memory B cells . Furthermore, TBL1XR1 has been reported as an important partner in the translocation of TP63 . Thus, the role of TBL1XR1 mutation may differ between DLBCL and PTCL. In ATLL, considering the normal function and pathogenesis of DLBCL and PTCL, the TBL1XR1 mutation may be speculated to be closely related to an unknown or undiscovered transcription factor in the pathogenesis of ATL development.
Regarding the immune characteristics of CTL cells for ATL, firstly, Ohshima et al. [34, 35] reported the importance of the tumor microenvironment of ATL; in particular, high numbers of programmed cell death-1-positive tumor-infiltrating lymphocytes correlate with early onset of PTLD. Notably, Ohshima et al.  reported the clinicopathological significance of the expression of PD-1, which is associated with exhausted T cells. The number of PD-1 + TILs in PTLD specimens was significantly higher in patients who developed PTLD soon after transplantation . In our study, in case 1, a high numbers of PD-1-positive TIL cells (average 20.8/HPF) may be related to ATL development after renal transplantation. Thus, T cell exhaustion may be associated with PTLD development. However, case 2 was not related to the high number of PD-1 + TILs in PTLD specimens. Thus, the underlying immune mechanisms may differ in each case. Based on the pathogenesis of the PD-1 + TIL mechanism in ATL cells, molecular-targeted therapy may be a therapeutic option including PD -1 Inhibitor therapy , in the future. Thus, immunological mechanisms or genetic mechanisms may also be related to ATL development after renal transplantation under immunosuppressive treatment. These mechanisms may assist in the early onset and rapid progression of ATL after renal transplantation.
Previous reports on ATL after organ transplantation including renal transplantation are shown in Table 1 [3,4,5, 8,9,10,11,12,13,14,15,16,17,18,19,20]. Notably, the majority of ATL development cases after renal transplantation were derived from “recipient” positive cases (Tables 6 and 7). Furthermore, the majority of HAM development cases after renal transplantation were derived from “donor” positive cases (Tables 6 and 7). These findings may suggest that ATL is derived from HTLV-I + recipient cells and HAM is derived from HTLV-1 + donor cells, although the precise mechanism remains unknown. Thus, the origin of HTLV-1-related disease (ATL or HAM) after renal transplantation may be different. Similarly, in liver transplantation, our previous nationwide study strongly indicated that 3 out of 70 “recipient” positive cases developed ATL (HTLV-1-positive recipient-derived ATL) (Table 9). Furthermore, two out of six donor-positive and recipient-positive cases developed ATL derived from HTLV-1-positive recipients. However, none out of 6 “donor” positive cases developed HAM (Table 9). To date, 16 cases of ATL development after organ transplantation have been reported within 10 years of organ transplantation under immunosuppressive circumstances. Similarly, in an immune-deficient mouse model using a primary ATL specimen, we demonstrated and validated ATL development under immune-deficient conditions . Yoshizumi et al. identified and discussed that fulminant hepatic failure during a cytokine storm in a recipient before transplantation may affect the development of ATL. I believe that the onset of ATL after transplantation is important when considering the immune environment of ATL. If we can investigate the immune environment after onset, including the differences between post-transplant ATL, post-transplant HAM, and normal ATL and HAM, we will be able to understand the pathogenesis of ATL and HAM.
At present, although there is no established prevention and treatment for ATL or HAM after organ transplantation, based on the clinical guidelines for PTLD after organ transplantation and the JSH Practical Guideline for ATL, we diagnosed and treated ATL after HTLV-1-positive organ transplantation. We also showed the summarization and graphical representation of the strategy from diagnosis to treatment of ATL in renal transplant recipients according to the clinical guideline for PTLD after organ transplantation and the JSH Practical Guidelines for ATL (Fig. 4) [54,55,56]. Thus, our experience may be a crucial example to assist in ATL development after renal transplantation in clinical practice.
In conclusion, in contrast to relatively long periods in the natural course or history of ATL (= 50–60 years), the early onset and rapid progression of ATL development with poor outcomes should be kept in mind during follow-up periods in areas endemic for HTLV-1. The HTLV-1 Positive Organ Transplant Registry by Dr. Yamauchi and Dr. Yamano was conducted in a nationwide study. Further follow-up should be essential, and the accumulation of cases should be also desired to elucidate the pathogenesis of ATL after organ transplantation in the future.
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We thank the medical staff, including nurses, laboratory technicians, pharmacists, physical therapists, mental therapists, psychiatrists, and nutritionists, for their excellent care of the patients who were treated with renal transplantation, chemotherapy, and allo-HSCT in our institution.
Ethics approval and consent to participate
This retrospective study was conducted in compliance with good clinical practice and ethical principles of the Declaration of Helsinki. This study was approved by the ethics committees of Miyazaki Prefectural Miyazaki Hospital (19-2).
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We received consent from the patients and their families regarding the use of the person’s data, including the individual details and images. Furthermore, we received informed consent for publication from the patients and their families.
The authors declare that they have no competing interests.
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Kawano, N., Kyohei, Y., Miyoshi, H. et al. The development of adult T cell leukemia/lymphoma in renal transplant recipients: report of two cases with literature review. Ren Replace Ther 9, 36 (2023). https://doi.org/10.1186/s41100-023-00480-5
- HTLV-1 carrier recipient
- The early onset and rapid progression of ATL with poor outcome after renal transplantation
- PD-1-positive TIL cells
- CD30 expression in ATL cells
- Genetic mutations