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Alshemmari S, Hamadah A, Ousia S, Hamed RAT, Zaky H. Management of Diffuse Large B-Cell Lymphoma as Post-Transplant Lymphoproliferative Disorder in a Kidney Transplant Recipient: A Case Report. Hematol Rep 2025; 17:22. [PMID: 40407632 PMCID: PMC12101285 DOI: 10.3390/hematolrep17030022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 03/01/2025] [Accepted: 03/03/2025] [Indexed: 05/26/2025] Open
Abstract
Background and Clinical Significance: Post-transplant lymphoproliferative disorder (PTLD) is a severe complication of solid organ transplantation, often associated with prolonged immunosuppression. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype. Managing PTLD requires a balance between reducing immunosuppression and preventing graft rejection. Case Presentation: A 41-year-old female kidney transplant recipient developed PTLD eight years post-transplant, presenting with a right submandibular mass. Biopsy confirmed CD20-positive DLBCL. Initial treatment involved reducing immunosuppression and rituximab monotherapy, which failed to prevent disease progression. The patient underwent six cycles of R-CHOP chemotherapy, achieving complete metabolic remission. Relapse occurred twice, with disease progression in the cervical nodes and tonsils. Salvage therapies, including polatuzumab vedotin and rituximab, achieved remission. During a subsequent relapse, loncastuximab tesirine induced metabolic resolution. Compromised renal function limited treatment options and a second renal transplant was delayed, reducing the risk of PTLD recurrence. Conclusions: This case underscores the challenges of managing PTLD in transplant recipients, especially in relapsed/refractory cases. Single-agent rituximab was insufficient, but combination chemotherapy and novel agents like loncastuximab tesirine were effective. Balancing oncologic control and graft preservation remains critical. This case highlights the need for individualized approaches and novel therapies in managing PTLD while addressing the complexities of immunosuppression and organ preservation.
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Affiliation(s)
- Salem Alshemmari
- Oncology/Hematology Department, Kuwait Cancer Control Center, Kuwait City 70653, Kuwait; (A.H.); (S.O.); (R.A.T.H.); (H.Z.)
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Volaric AK, Fedoriw Y. Epstein-Barr virus-associated B-cell lymphoproliferative disorders and lymphomas: Diagnostic overlaps and defining features. Hum Pathol 2025; 156:105697. [PMID: 39571693 PMCID: PMC11890961 DOI: 10.1016/j.humpath.2024.105697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/14/2024] [Accepted: 11/18/2024] [Indexed: 11/24/2024]
Abstract
This review explores four Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders (LPD) and lymphomas with significant diagnostic overlap: EBV(+) mucocutaneous ulcer (EBVMCU), EBV(+) polymorphic LPD, EBV(+) classic Hodgkin lymphoma (CHL), and EBV(+) diffuse large B-cell lymphoma (DLBCL). Each entity is compared for both overlapping and defining features of clinical presentation, morphology, immunohistochemical profile and EBV expression pattern and latency. Our aims for this review are to provide useful guidance to the practicing pathologist in the diagnosis of these EBV-associated entities.
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MESH Headings
- Humans
- Epstein-Barr Virus Infections/virology
- Epstein-Barr Virus Infections/complications
- Epstein-Barr Virus Infections/pathology
- Epstein-Barr Virus Infections/diagnosis
- Lymphoproliferative Disorders/virology
- Lymphoproliferative Disorders/pathology
- Lymphoproliferative Disorders/diagnosis
- Herpesvirus 4, Human/isolation & purification
- Hodgkin Disease/virology
- Hodgkin Disease/pathology
- Hodgkin Disease/diagnosis
- Lymphoma, Large B-Cell, Diffuse/virology
- Lymphoma, Large B-Cell, Diffuse/pathology
- Lymphoma, Large B-Cell, Diffuse/diagnosis
- B-Lymphocytes/virology
- B-Lymphocytes/pathology
- Lymphoma, B-Cell/virology
- Lymphoma, B-Cell/pathology
- Diagnosis, Differential
- Immunohistochemistry
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Affiliation(s)
- Ashley K Volaric
- Department of Pathology and Laboratory Medicine, University of Vermont Larner College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA
| | - Yuri Fedoriw
- Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Lineberger Comprehensive Cancer Center, 160 Medical Drive, Brinkhouse-Bullitt Building, CB#7525, Chapel Hill, NC, 27599, USA.
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3
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Potluri VS, Zhang S, Schaubel DE, Shaikhouni S, Blumberg EA, Nasta SD, Bloom RD, Cruz-Peralta M, Mehta RB, Lavu NR, Getachew B, Tandukar S, Reese PP, Puttarajappa CM. The Association of Epstein-Barr Virus Donor and Recipient Serostatus With Outcomes After Kidney Transplantation : A Retrospective Cohort Study. Ann Intern Med 2025; 178:157-166. [PMID: 39869913 DOI: 10.7326/annals-24-00165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2025] Open
Abstract
BACKGROUND Prior studies indicate that 1% to 4% of Epstein-Barr virus (EBV)-seronegative recipients of EBV-seropositive donor (EBV D+/R-) kidneys develop posttransplant lymphoproliferative disorder (PTLD). However, these estimates are based on limited data that lack granularity. OBJECTIVE To determine the associations between pretransplant EBV D+/R- and recipient EBV-seropositive status (R+) and the outcomes of PTLD and graft and patient survival among adult kidney transplant recipients. DESIGN Retrospective cohort study. SETTING Two large U.S. transplant centers. PARTICIPANTS Epstein-Barr virus D+/R- and EBV R+ recipients matched 1:3 on donor, recipient, and transplant characteristics between 1 January 2010 and 30 June 2022. MEASUREMENTS Exposure was pretransplant donor and recipient EBV serostatus. The primary outcome was biopsy-proven PTLD. Secondary outcomes were all-cause graft loss (death, retransplant, or graft failure) and death. Follow-up was truncated to 3 years after transplant. RESULTS The final cohort comprised 104 EBV D+/R- recipients matched to 312 EBV R+ recipients. The mean age was 42 years (SD, 17.1), 59% were living donor transplants, and 95% received thymoglobulin induction. Among EBV D+/R- recipients, 50 (48.1%) developed EBV DNAemia, with a median time of 198 days (IQR, 110 to 282 days) after transplantation. Posttransplant lymphoproliferative disorder occurred in 23 (22.1%) EBV D+/R- recipients at a median of 202 days (IQR, 118 to 317 days) after transplantation. Epstein-Barr virus D+/R- recipients had higher all-cause graft failure (hazard ratio, 2.21 [95% CI, 1.06 to 4.63]); mortality was higher but not statistically significant (hazard ratio, 2.19 [CI, 0.94 to 5.13]). LIMITATION Two-center study. CONCLUSION Compared with previous studies, this study showed that EBV D+/R- kidney recipients face a 5- to 10-fold higher cumulative incidence of PTLD. Strategies to mitigate the PTLD risk are urgently needed. PRIMARY FUNDING SOURCE National Institutes of Health.
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Affiliation(s)
- Vishnu S Potluri
- Renal-Electrolyte and Hypertension Division, Hospital of the University of Pennsylvania, and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania (V.S.P.)
| | - Siqi Zhang
- Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania (S.Z., D.E.S.)
| | - Douglas E Schaubel
- Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania (S.Z., D.E.S.)
| | - Salma Shaikhouni
- Renal-Electrolyte and Hypertension Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania (S.S., R.D.B., S.T.)
| | - Emily A Blumberg
- Division of Infectious Disease, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania (E.A.B.)
| | - Sunita D Nasta
- Division of Hematology and Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania (S.D.N.)
| | - Roy D Bloom
- Renal-Electrolyte and Hypertension Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania (S.S., R.D.B., S.T.)
| | - Massiel Cruz-Peralta
- Renal-Electrolyte Division, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (M.C.-P., R.B.M., C.M.P.)
| | - Rajil B Mehta
- Renal-Electrolyte Division, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (M.C.-P., R.B.M., C.M.P.)
| | | | | | - Srijan Tandukar
- Renal-Electrolyte and Hypertension Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania (S.S., R.D.B., S.T.)
| | - Peter P Reese
- Vanderbilt Center for Transplant Science, Vanderbilt University Medical Center, Nashville, Tennessee (P.P.R.)
| | - Chethan M Puttarajappa
- Renal-Electrolyte Division, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (M.C.-P., R.B.M., C.M.P.)
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Dharnidharka VR, Wylie KM, Wylie TN, Ruzinova MB, Goss CW, Storch GA, Mehta-Shah N, Byers D, Walther L, Jaza L, Gu H, Agarwal M, Green M, Moore E, Swerdlow SH, Silveira F, Marks LJ, Gratzinger D, Bagg A, Law SC, Gandhi M. The Post-transplant Lymphoproliferative Disorders-Metagenomic Shotgun Microbial Sequencing (PTLD-MSMS) Study Methods and Protocol. Transplant Direct 2024; 10:e1723. [PMID: 39473523 PMCID: PMC11521023 DOI: 10.1097/txd.0000000000001723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 07/16/2024] [Indexed: 11/02/2024] Open
Abstract
Post-transplant lymphoproliferative disorders (PTLDs) remain a feared complication of transplantation, with significant morbidity and mortality. The oncogenic Epstein-Barr virus (EBV) is a key pathogenic driver in 50%-80% of cases. Numerous prognostic indices, comprising multiple clinical, epidemiological and tumor characteristics, including EBV tumor positivity, do not consistently associate with worse patient survival, suggesting a potential role for EBV genome variants in determining outcome. However, the precision medicine tools for determining if a viral genome variant is pathogenic are very limited compared with human genome variants. Further, targeted studies have not implicated a specific viral etiological agent in EBV-negative PTLD. Using novel cutting-edge technologies, we are extracting viral nucleic acids from formalin-fixed, paraffin-embedded archived, or frozen PTLD tissues or plasma, to test for all vertebrate viruses simultaneously in an unbiased fashion, using metagenomic shotgun sequencing (MSS). We are collecting such samples from multiple transplant centers to address the following specific aims and close the following knowledge gaps: (1) Validate our novel observation that PTLD tissue positivity by MSS for anellovirus (and confirmed by PCR) serves as a biomarker for higher transplant recipient mortality after the diagnosis of PTLD; (2) determine the role of other oncogenic viruses in EBV-negative PTLD by unbiased MSS of multiple viral groupings, confirmed by other techniques; and (3) develop the necessary computational, algorithmic and software analytic tools required to determine association of EBV genome variants with worse presentations or outcomes in PTLD. Study completion will contribute to better patient care and may provide avenues for novel therapies.
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Affiliation(s)
| | | | - Todd N. Wylie
- Washington University School of Medicine, St. Louis, MO
| | | | | | | | | | - Derek Byers
- Washington University School of Medicine, St. Louis, MO
| | | | - Lujain Jaza
- Washington University School of Medicine, St. Louis, MO
| | - Hongjie Gu
- Washington University School of Medicine, St. Louis, MO
| | - Mansi Agarwal
- Washington University School of Medicine, St. Louis, MO
| | - Michael Green
- UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA
| | - Erika Moore
- University of Pittsburgh School of Medicine, Pittsburgh
| | | | | | | | | | - Adam Bagg
- University of Pennsylvania, Philadelphia, PA
| | - Soi Cheng Law
- Mater Research, University of Queensland, Woolloongabba
| | - Maher Gandhi
- Mater Research, University of Queensland, Woolloongabba
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Furlano PL, Böhmig GA, Puchhammer-Stöckl E, Vietzen H. Mechanistic Understanding of EBV+Lymphoproliferative Disease Development After Transplantation. Transplantation 2024; 108:1867-1881. [PMID: 39166902 DOI: 10.1097/tp.0000000000004919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
Posttransplant lymphoproliferative disorders (PTLDs) are among the most common malignant complications after transplantation, leading to a drastic reduction in patient survival rates. The majority of PTLDs are tightly linked to Epstein-Barr virus (EBV+PTLDs) and are the result of an uncontrolled proliferation of EBV-infected cells. However, although EBV infections are a common finding in transplant recipients, most patients with high EBV loads will never develop EBV+PTLD. Natural killer cells and EBV-specific CD8+ T lymphocytes are critical for controlling EBV-infected cells, and the impairment of these cytotoxic immune responses facilitates the unfettered proliferation of EBV-infected cells. Recent years have seen a considerable increase in available literature aiming to describe novel risk factors associated with the development of EBV+PTLD, which may critically relate to the strength of EBV-specific natural killer cell and EBV-CD8+ T lymphocyte responses. The accumulation of risk factors and the increased risk of developing EBV+PTLD go hand in hand. On the one hand, most of these risk factors, such as the level of immunosuppression or the EBV donor and recipient serologic mismatch, and distinct genetic risk factors are host related and affect cytotoxic EBV-specific immune responses. On the other hand, there is growing evidence that distinct EBV variants may have an increased malignant potential and are thus more likely to induce EBV+PTLD. Here, we aim to review, from a mechanistic point of view, the risk factors for EBV+PTLD in the host and the infecting EBV variants that may explain why only a minority of transplant recipients develop EBV+PTLD.
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Affiliation(s)
| | - Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | | | - Hannes Vietzen
- Center for Virology, Medical University of Vienna, Vienna, Austria
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6
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El-amir Z, Jamil A, Solanki D, Mansuri U, Mathew M, Singh J, Aslam S, Akram H, Mandal S, Kichloo A. Admissions for posttransplant lymphoproliferative disorder: a 9-year longitudinal analysis of the National (Nationwide) Inpatient Sample. Proc AMIA Symp 2024; 37:804-812. [PMID: 39165820 PMCID: PMC11332645 DOI: 10.1080/08998280.2024.2375688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 05/14/2024] [Accepted: 06/24/2024] [Indexed: 08/22/2024] Open
Abstract
Background Posttransplant lymphoproliferative disorder (PTLD), a term that encompasses a wide array of malignancies that occur after transplant, can be one of the most devastating transplant complications. While there have been major advancements in care, especially after the landmark PTLD-1 trial in 2012, there is a paucity of information on hospitalizations for PTLD and the changes in hospitalizations over time. Methods This retrospective cohort study used the National Inpatient Sample to identify hospitalizations for PTLD that occurred between 2009 and 2018. We extracted data for hospitalizations with a primary or secondary diagnosis of PTLD and examined a range of variables, including age, gender, race, hospital type, hospital location, and disposition status. We also collected data on hospital region, median household income, insurance status, and bed size. Results There was a statistically significant increase in the number of hospitalizations from 2009 to 2019 and an increasing rate of hospitalizations over the study period. Hypertension, electrolyte imbalances, renal failure, and anemia were among the most common comorbidities. We found an increased mortality rate, but this was not statistically significant. Conclusion Our study provides insight into the changes in hospitalizations for PTLD over nearly a decade, showing an increase in hospitalizations and reports of comorbidities.
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Affiliation(s)
- Zain El-amir
- Department of Internal Medicine, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Abdur Jamil
- Division of Internal Medicine, Samaritan Medical Center, Watertown, New York, USA
| | | | - Uvesh Mansuri
- Department of Medicine, Medstar Harbor Hospital, Baltimore, Maryland, USA
| | | | - Jagmeet Singh
- Division of Nephrology, Guthrie Robert Packer Hospital, Sayre, Pennsylvania, USA
| | - Shehroz Aslam
- Division of Internal Medicine, Samaritan Medical Center, Watertown, New York, USA
| | - Hamza Akram
- Division of Internal Medicine, Samaritan Medical Center, Watertown, New York, USA
| | - Shobha Mandal
- Hospitalist Department, Guthrie Robert Packer Hospital, Sayre, Pennsylvania, USA
| | - Asim Kichloo
- Division of Internal Medicine, Samaritan Medical Center, Watertown, New York, USA
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7
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Liu D, Youssef MM, Grace JA, Sinclair M. Relative carcinogenicity of tacrolimus vs mycophenolate after solid organ transplantation and its implications for liver transplant care. World J Hepatol 2024; 16:650-660. [PMID: 38689747 PMCID: PMC11056899 DOI: 10.4254/wjh.v16.i4.650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 01/30/2024] [Accepted: 03/19/2024] [Indexed: 04/24/2024] Open
Abstract
BACKGROUND De novo malignancy is a leading cause of late morbidity and mortality in liver transplant recipients. Cumulative immunosuppression has been shown to contribute to post-transplant malignancy (PTM) risk. There is emerging evidence on the differential carcinogenic risk profile of individual immunosuppressive drugs, independent of the net effect of immunosuppression. Calcineurin inhibitors such as tacrolimus may promote tumourigenesis, whereas mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil, may limit tumour progression. Liver transplantation (LT) is relatively unique among solid organ transplantation in that immunosuppression monotherapy with either tacrolimus or MPA is often achievable, which makes careful consideration of the risk-benefit profile of these immunosuppression agents particularly relevant for this cohort. However, there is limited clinical data on this subject in both LT and other solid organ transplant recipients. AIM To investigate the relative carcinogenicity of tacrolimus and MPA in solid organ transplantation. METHODS A literature search was conducted using MEDLINE and Embase databases using the key terms "solid organ transplantation", "tacrolimus", "mycophenolic acid", and "carcinogenicity", in order to identify relevant articles published in English between 1st January 2002 to 11th August 2022. Related terms, synonyms and explosion of MeSH terms, Boolean operators and truncations were also utilised in the search. Reference lists of retrieved articles were also reviewed to identify any additional articles. Excluding duplicates, abstracts from 1230 records were screened by a single reviewer, whereby 31 records were reviewed in detail. Full-text articles were assessed for eligibility based on pre-specified inclusion and exclusion criteria. RESULTS A total of 6 studies were included in this review. All studies were large population registries or cohort studies, which varied in transplant era, type of organ transplanted and immunosuppression protocol used. Overall, there was no clear difference demonstrated between tacrolimus and MPA in de novo PTM risk following solid organ transplantation. Furthermore, no study provided a direct comparison of carcinogenic risk between tacrolimus and MPA monotherapy in solid organ transplantation recipients. CONCLUSION The contrasting carcinogenic risk profiles of tacrolimus and MPA demonstrated in previous experimental studies, and its application in solid organ transplantation, is yet to be confirmed in clinical studies. Thus, the optimal choice of immunosuppression drug to use as maintenance monotherapy in LT recipients is not supported by a strong evidence base and remains unclear.
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Affiliation(s)
- Dorothy Liu
- Department of Gastroenterology, Austin Health, Melbourne 3084, Victoria, Australia
- Victorian Liver Transplant Unit, Austin Health, Melbourne 3084, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne 3084, Victoria, Australia.
| | - Mark M Youssef
- Department of Medicine, University of Melbourne, Melbourne 3084, Victoria, Australia
| | - Josephine A Grace
- Department of Gastroenterology, Austin Health, Melbourne 3084, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne 3084, Victoria, Australia
| | - Marie Sinclair
- Department of Gastroenterology, Austin Health, Melbourne 3084, Victoria, Australia
- Victorian Liver Transplant Unit, Austin Health, Melbourne 3084, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne 3084, Victoria, Australia
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Ergisi M, Ooi B, Salim O, Papalois V. Post-transplant lymphoproliferative disorders following kidney transplantation: A literature review with updates on risk factors, prognostic indices, screening strategies, treatment and analysis of donor type. Transplant Rev (Orlando) 2024; 38:100837. [PMID: 38430887 DOI: 10.1016/j.trre.2024.100837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 01/31/2024] [Accepted: 02/19/2024] [Indexed: 03/05/2024]
Abstract
Post-transplant lymphoproliferative disorders (PTLD) is a devastating complication of kidney transplantation with an insidious presentation and potential to disseminate aggressively. This review delineates the risk factors, prognostic indexes, screening, current management algorithm and promising treatment strategies for PTLD. Kidneys from both extended criteria donors (ECD) and living donors (LD) are being increasingly used to expand the donor pool. This review also delineates whether PTLD outcomes vary based on these donor sources. While Epstein-Barr virus (EBV) is a well-known risk factor for PTLD development, the use of T-cell depleting induction agents has been increasingly implicated in aggressive, monomorphic forms of PTLD. Research regarding maintenance therapy is sparse. The international prognostic index seems to be the most validate prognostic tool. Screening for PTLD is controversial, as annual PET-CT is most sensitive but costly, while targeted monitoring of EBV-seronegative patients was more economically feasible, is recommended by the American Society of Transplantation, but is limited to a subset of the population. Other screening strategies such as using Immunoglobulin/T-cell receptor require further validation. A risk-stratified approach is taken in the treatment of PTLD. The first step is the reduction of immunosuppressants, after which rituximab and chemotherapy may be introduced if unsuccessful. Some novel treatments have also shown potential benefit in studies: brentuximab vedotin, chimeric antigen receptor T-cell therapy and EBV-specific cytotoxic T lymphocytes. Analysis of LD v DD recipients show no significant difference in incidence and mortality of PTLD but did reveal a shortened time to development of PTLD from transplant. Analysis of SCD vs ECD recipients show a higher incidence of PTLD in the ECD group, which might be attributed to longer time on dialysis for these patients, age, and the pro-inflammatory nature of these organs. However, incidence of PTLD overall is still extremely low. Efforts should be focused on optimising recipients instead. Minimising the use of T-cell depleting therapy while encouraging research on the effect of new immunosuppressants on PTLD, screening for EBV status are essential, while enabling shared decision-making during counselling when choosing kidney donor types and individualised risk tailoring are strongly advocated.
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Affiliation(s)
- Mehmet Ergisi
- Norfolk and Norwich University Hospital, Norfolk and Norwich University Hospitals NHS Foundation Trust, Department of Medicine, Norwich, United Kingdom.
| | - Bryan Ooi
- Department of Medicine, Imperial College London, London, United Kingdom.
| | - Omar Salim
- Isle of Wight NHS Trust, Parkhurst Road, Newport, United Kingdom
| | - Vassilios Papalois
- Hammersmith Hospital, Imperial College Healthcare NHS Trust, Department of Transplant and General Surgery, London, United Kingdom.
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Rampersad C, Wiebe C, Balshaw R, Bullard J, Cortes Villalobos AP, Trachtenberg A, Shaw J, Karpinski M, Goldberg A, Birk P, Pinsk M, Rush DN, Nickerson PW, Ho J. Epidemiology of Epstein-Barr Virus Chronic High Viral Load in Kidney Transplant Recipients. Transplant Direct 2024; 10:e1579. [PMID: 39877647 PMCID: PMC11774561 DOI: 10.1097/txd.0000000000001579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/15/2023] [Accepted: 11/09/2023] [Indexed: 01/31/2025] Open
Abstract
Background Epstein-Barr virus (EBV) chronic high viral load (CHVL) may be defined by >16 000 copies/mL whole blood or >200 copies/105 peripheral blood mononuclear cells in >50% samples exceeding 6 mo. EBV CHVL has only been characterized in a few small pediatric studies, with heterogeneous results and unclear clinical significance. Methods This single-center observational study evaluated adult and pediatric kidney transplant recipients transplanted between 2010 and 2021 on tacrolimus/mycophenolate-based/prednisone immunosuppression. The primary outcome was EBV CHVL prevalence. Secondary outcomes included recipient characteristics, DNAemia kinetics, and posttransplant lymphoproliferative disorder (PTLD) in recipients with EBV CHVL versus low-grade DNAemia or no DNAemia. Results Five hundred forty-one recipients had a mean follow-up of 4.6 y. Fourteen recipients (2.6%) developed EBV CHVL, 70 (12.9%) had low-grade EBV DNAemia, and 457 (84.5%) had no EBV DNAemia. EBV CHVL was more common in recipients who were Caucasian (P = 0.04), younger (P = 0.04), received induction immunosuppression (P = 0.02), and had high-risk donor-recipient EBV serologic mismatch (P < 0.0001). CHVL patients had a higher first viral load (P = 0.03), longer time to maximum viral load (P = 0.02), and did not achieve sustained DNAemia clearance versus low-grade DNAemia. Three EBV-positive PTLD cases occurred in recipients with a history of EBV DNAemia. PTLD was present in 7.1% (1/14) CHVL versus 2.9% (2/70) low-grade DNAemia patients (P = 0.002). EBV DNAemia developed in 32 EBV seronegative recipients (32/59; 54%); clearance was achieved in 70% (14/20) with low-grade DNAemia but no CHVL (0/12; P = 0.0001). Conclusions CHVL was uncommon and appeared to occur after primary EBV infection. Future studies should explore other potentially modifiable risk factors for PTLD, including optimal management of EBV DNAemia.
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Affiliation(s)
- Christie Rampersad
- Transplant Nephrology and Ajmera Transplant Center, University Health Network, University of Toronto, Toronto, ON, Canada
- Institute of Health Policy, Management and Evaluation (IHPME), Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
| | - Chris Wiebe
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
- Transplant Manitoba Adult Kidney Program, Transplant Manitoba, Shared Health Manitoba, Winnipeg, MB, Canada
| | - Robert Balshaw
- George and Fay Yee Centre for Healthcare Innovation, University of Manitoba, Winnipeg, MB, Canada
| | - Jared Bullard
- Cadham Provincial Laboratory, Shared Health Manitoba, Winnipeg, MB, Canada
- Department of Pediatrics, University of Manitoba, Winnipeg, MB, Canada
| | - Armelle Perez Cortes Villalobos
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
- Transplant Manitoba Adult Kidney Program, Transplant Manitoba, Shared Health Manitoba, Winnipeg, MB, Canada
| | - Aaron Trachtenberg
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
- Transplant Manitoba Adult Kidney Program, Transplant Manitoba, Shared Health Manitoba, Winnipeg, MB, Canada
| | - James Shaw
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
- Transplant Manitoba Adult Kidney Program, Transplant Manitoba, Shared Health Manitoba, Winnipeg, MB, Canada
| | - Martin Karpinski
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
- Transplant Manitoba Adult Kidney Program, Transplant Manitoba, Shared Health Manitoba, Winnipeg, MB, Canada
| | - Aviva Goldberg
- Department of Pediatrics, University of Manitoba, Winnipeg, MB, Canada
| | - Patricia Birk
- Department of Pediatrics, University of Manitoba, Winnipeg, MB, Canada
| | - Maury Pinsk
- Department of Pediatrics, University of Manitoba, Winnipeg, MB, Canada
| | - David N. Rush
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
- Transplant Manitoba Adult Kidney Program, Transplant Manitoba, Shared Health Manitoba, Winnipeg, MB, Canada
| | - Peter W. Nickerson
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
- Transplant Manitoba Adult Kidney Program, Transplant Manitoba, Shared Health Manitoba, Winnipeg, MB, Canada
- Department of Immunology, Winnipeg, MB, Canada
| | - Julie Ho
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
- Transplant Manitoba Adult Kidney Program, Transplant Manitoba, Shared Health Manitoba, Winnipeg, MB, Canada
- Department of Immunology, Winnipeg, MB, Canada
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Volaric AK, Saleem A, Younes SF, Zhao S, Natkunam Y. Epstein-Barr virus latency patterns in polymorphic lymphoproliferative disorders and lymphomas in immunodeficiency settings: Diagnostic implications. Ann Diagn Pathol 2024; 70:152286. [PMID: 38447253 DOI: 10.1016/j.anndiagpath.2024.152286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 02/23/2024] [Accepted: 02/25/2024] [Indexed: 03/08/2024]
Abstract
Epstein-Barr virus (EBV) is responsible for many B cell lymphoproliferative disorders (LPD) spanning subclinical infection to immunodeficiency-related neoplasms. EBV establishes a latent infection in the host B cell as defined histologically by the expression of EBV latent membrane proteins and nuclear antigens. Herein, we characterize the latency patterns of immunodeficiency-related neoplasms including post-transplant lymphoproliferative disorders (PTLD) and therapy-related LPD (formerly iatrogenic) with latent membrane protein-1 (LMP-1) and EBV nuclear antigen-2 (EBNA-2) immunohistochemistry. The latency pattern was correlated with immunodeficiency and dysregulation (IDD) status and time from transplant procedure. 38 cases of EBV+ PTLD in comparison to 27 cases of classic Hodgkin lymphoma (CHL) and diffuse large B cell lymphoma (DLBCL) arising in either the therapy-related immunodeficiency setting (n = 12) or without an identified immunodeficiency (n = 15) were evaluated for EBV-encoded small RNAs by in situ hybridization (EBER-ISH) and for LMP-1 and EBNA-2 by immunohistochemistry. A full spectrum of EBV latency patterns was observed across PTLD in contrast to CHL and DLBCL arising in the therapy-related immunodeficiency setting. Polymorphic-PTLD (12 of 16 cases, 75 %) and DLBCL-PTLD (9 of 11 cases, 82 %) showed the greatest proportion of cases with latency III pattern. Whereas, EBV+ CHL in an immunocompetent patient showed exclusively latency II pattern (13 of 13 cases, 100 %). The majority of EBV+ PTLD occurred by three years of transplant procedure date and were enriched for latency III pattern (21 of 22 cases, 95 %). Immunohistochemical identification of EBV latency by LMP-1 and EBNA-2 can help classify PTLD in comparison to other EBV+ B cell LPD and lymphomas arising in therapy-related immunodeficiency and non-immunodeficiency settings.
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Affiliation(s)
- Ashley K Volaric
- Department of Pathology and Laboratory Medicine, University of Vermont Larner College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405, USA; Department of Pathology, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA 94305, USA.
| | - Atif Saleem
- Department of Pathology, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA 94305, USA
| | - Sheren F Younes
- Department of Pathology, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA 94305, USA
| | - Shuchun Zhao
- Department of Pathology, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA 94305, USA
| | - Yasodha Natkunam
- Department of Pathology, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA 94305, USA
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11
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Preiksaitis J, Allen U, Bollard CM, Dharnidharka VR, Dulek DE, Green M, Martinez OM, Metes DM, Michaels MG, Smets F, Chinnock RE, Comoli P, Danziger-Isakov L, Dipchand AI, Esquivel CO, Ferry JA, Gross TG, Hayashi RJ, Höcker B, L'Huillier AG, Marks SD, Mazariegos GV, Squires J, Swerdlow SH, Trappe RU, Visner G, Webber SA, Wilkinson JD, Maecker-Kolhoff B. The IPTA Nashville Consensus Conference on Post-Transplant lymphoproliferative disorders after solid organ transplantation in children: III - Consensus guidelines for Epstein-Barr virus load and other biomarker monitoring. Pediatr Transplant 2024; 28:e14471. [PMID: 37294621 DOI: 10.1111/petr.14471] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/10/2022] [Accepted: 01/02/2023] [Indexed: 06/11/2023]
Abstract
The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders after solid organ transplantation in children. In this report from the Viral Load and Biomarker Monitoring Working Group, we reviewed the existing literature regarding the role of Epstein-Barr viral load and other biomarkers in peripheral blood for predicting the development of PTLD, for PTLD diagnosis, and for monitoring of response to treatment. Key recommendations from the group highlighted the strong recommendation for use of the term EBV DNAemia instead of "viremia" to describe EBV DNA levels in peripheral blood as well as concerns with comparison of EBV DNAemia measurement results performed at different institutions even when tests are calibrated using the WHO international standard. The working group concluded that either whole blood or plasma could be used as matrices for EBV DNA measurement; optimal specimen type may be clinical context dependent. Whole blood testing has some advantages for surveillance to inform pre-emptive interventions while plasma testing may be preferred in the setting of clinical symptoms and treatment monitoring. However, EBV DNAemia testing alone was not recommended for PTLD diagnosis. Quantitative EBV DNAemia surveillance to identify patients at risk for PTLD and to inform pre-emptive interventions in patients who are EBV seronegative pre-transplant was recommended. In contrast, with the exception of intestinal transplant recipients or those with recent primary EBV infection prior to SOT, surveillance was not recommended in pediatric SOT recipients EBV seropositive pre-transplant. Implications of viral load kinetic parameters including peak load and viral set point on pre-emptive PTLD prevention monitoring algorithms were discussed. Use of additional markers, including measurements of EBV specific cell mediated immunity was discussed but not recommended though the importance of obtaining additional data from prospective multicenter studies was highlighted as a key research priority.
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Affiliation(s)
- Jutta Preiksaitis
- Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Upton Allen
- Division of Infectious Diseases and the Transplant and Regenerative Medicine Center, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Catherine M Bollard
- Center for Cancer and Immunology Research, Children's National Hospital, The George Washington University, Washington, District of Columbia, USA
| | - Vikas R Dharnidharka
- Department of Pediatrics, Division of Pediatric Nephrology, Hypertension & Pheresis, Washington University School of Medicine & St. Louis Children's Hospital, St. Louis, Missouri, USA
| | - Daniel E Dulek
- Division of Pediatric Infectious Diseases, Monroe Carell Jr. Children's Hospital at Vanderbilt and Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Michael Green
- Division of Pediatric Infectious Diseases, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Olivia M Martinez
- Department of Surgery and Program in Immunology, Stanford University School of Medicine, Stanford, California, USA
| | - Diana M Metes
- Departments of Surgery and Immunology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Marian G Michaels
- Division of Pediatric Infectious Diseases, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Françoise Smets
- Pediatric Gastroenterology and Hepatology, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | | | - Patrizia Comoli
- Cell Factory & Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico, Pavia, Italy
| | - Lara Danziger-Isakov
- Division of Infectious Disease, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA
| | - Anne I Dipchand
- Labatt Family Heart Centre, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | | | - Judith A Ferry
- Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Thomas G Gross
- Center for Cancer and Blood Diseases, Children's Hospital Colorado, Aurora, Colorado, USA
| | - Robert J Hayashi
- Division of Pediatric Hematology/Oncology, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Britta Höcker
- University Children's Hospital, Pediatrics I, Heidelberg, Germany
| | - Arnaud G L'Huillier
- Faculty of Medicine, Pediatric Infectious Diseases Unit and Laboratory of Virology, Geneva University Hospitals, Geneva, Switzerland
| | - Stephen D Marks
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
- NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, Great Ormond Street Institute of Child Health, London, UK
| | - George Vincent Mazariegos
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - James Squires
- Division of Gastroenterology, Hepatology and Nutrition, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Steven H Swerdlow
- Division of Hematopathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Ralf U Trappe
- Department of Hematology and Oncology, DIAKO Ev. Diakonie-Krankenhaus Bremen, Bremen, Germany
- Department of Internal Medicine II: Hematology and Oncology, University Medical Centre Schleswig-Holstein, Kiel, Germany
| | - Gary Visner
- Division of Pulmonary Medicine, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Steven A Webber
- Department of Pediatrics, Vanderbilt School of Medicine, Nashville, Tennessee, USA
| | - James D Wilkinson
- Department of Pediatrics, Vanderbilt School of Medicine, Nashville, Tennessee, USA
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12
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Lim W, Moon S, Lee NR, Shin HG, Yu SY, Lee JE, Kim I, Ko KP, Park SK. Group I pharmaceuticals of IARC and associated cancer risks: systematic review and meta-analysis. Sci Rep 2024; 14:413. [PMID: 38172159 PMCID: PMC10764325 DOI: 10.1038/s41598-023-50602-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 12/21/2023] [Indexed: 01/05/2024] Open
Abstract
We aimed to summarize the cancer risk among patients with indication of group I pharmaceuticals as stated in monographs presented by the International Agency for Research on Cancer working groups. Following the PRISMA guidelines, a comprehensive literature search was conducted using the PubMed database. Pharmaceuticals with few studies on cancer risk were identified in systematic reviews; those with two or more studies were subjected to meta-analysis. For the meta-analysis, a random-effects model was used to calculate the summary relative risks (SRRs) and 95% confidence intervals (95% CIs). Heterogeneity across studies was presented using the Higgins I square value from Cochran's Q test. Among the 12 group I pharmaceuticals selected, three involved a single study [etoposide, thiotepa, and mustargen + oncovin + procarbazine + prednisone (MOPP)], seven had two or more studies [busulfan, cyclosporine, azathioprine, cyclophosphamide, methoxsalen + ultraviolet (UV) radiation therapy, melphalan, and chlorambucil], and two did not have any studies [etoposide + bleomycin + cisplatin and treosulfan]. Cyclosporine and azathioprine reported increased skin cancer risk (SRR = 1.32, 95% CI 1.07-1.62; SRR = 1.56, 95% CI 1.25-1.93) compared to non-use. Cyclophosphamide increased bladder and hematologic cancer risk (SRR = 2.87, 95% CI 1.32-6.23; SRR = 2.43, 95% CI 1.65-3.58). Busulfan increased hematologic cancer risk (SRR = 6.71, 95% CI 2.49-18.08); melphalan was associated with hematologic cancer (SRR = 4.43, 95% CI 1.30-15.15). In the systematic review, methoxsalen + UV and MOPP were associated with an increased risk of skin and lung cancer, respectively. Our results can enhance persistent surveillance of group I pharmaceutical use, establish novel clinical strategies for patients with indications, and provide evidence for re-categorizing current group I pharmaceuticals into other groups.
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Affiliation(s)
- Woojin Lim
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
- Cancer Research Institute, Seoul National University, Seoul, 03080, Republic of Korea
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, 03080, Republic of Korea
| | - Sungji Moon
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
- Cancer Research Institute, Seoul National University, Seoul, 03080, Republic of Korea
- Interdisciplinary Program in Cancer Biology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Na Rae Lee
- National Evidence-based Healthcare Collaborating Agency (NECA), Seoul, 04933, Republic of Korea
| | - Ho Gyun Shin
- National Evidence-based Healthcare Collaborating Agency (NECA), Seoul, 04933, Republic of Korea
| | - Su-Yeon Yu
- National Evidence-based Healthcare Collaborating Agency (NECA), Seoul, 04933, Republic of Korea
| | - Jung Eun Lee
- Department of Food and Nutrition, Seoul National University College of Human Ecology, Seoul, 08826, Republic of Korea
| | - Inah Kim
- Department of Occupational and Environmental Medicine, Hanyang University College of Medicine, Seoul, 04763, Republic of Korea
| | - Kwang-Pil Ko
- Clinical Preventive Medicine Center, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea
| | - Sue K Park
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
- Cancer Research Institute, Seoul National University, Seoul, 03080, Republic of Korea.
- Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
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13
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Order KE, Rodig NM. Pediatric Kidney Transplantation: Cancer and Cancer Risk. Semin Nephrol 2024; 44:151501. [PMID: 38580568 PMCID: PMC11734768 DOI: 10.1016/j.semnephrol.2024.151501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2024]
Abstract
Children with end-stage kidney disease (ESKD) face a lifetime of complex medical care, alternating between maintenance chronic dialysis and kidney transplantation. Kidney transplantation has emerged as the optimal treatment of ESKD for children and provides important quality of life and survival advantages. Although transplantation is the preferred therapy, lifetime exposure to immunosuppression among children with ESKD is associated with increased morbidity, including an increased risk of cancer. Following pediatric kidney transplantation, cancer events occurring during childhood or young adulthood can be divided into two broad categories: post-transplant lymphoproliferative disorders and non-lymphoproliferative solid tumors. This review provides an overview of cancer incidence, types, outcomes, and preventive strategies in this population.
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Affiliation(s)
- Kaitlyn E Order
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Boston, MA
| | - Nancy M Rodig
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Boston, MA.
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14
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Hahn SM, Lee M, Hyun J, Lim S, Kang JM, Ahn JG, Joo DJ, Jung I, Ihn K. Incidence and Features of Lymphoid Proliferation and Lymphomas after Solid Organ or Hematopoietic Stem Cell Transplantation in a National Database Cohort. Cancer Res Treat 2024; 56:305-313. [PMID: 37475137 PMCID: PMC10789964 DOI: 10.4143/crt.2023.647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 07/17/2023] [Indexed: 07/22/2023] Open
Abstract
PURPOSE Post-transplantation lymphoproliferative disorders (PTLDs) after hematopoietic stem transplantation (HCT) or solid organ transplantation (SOT) result in poorer outcomes, including death. There are limited large cohort data on the incidence and natural course of PTLD in Asians. MATERIALS AND METHODS We investigated PTLD using Korean national health insurance claims data of 47,518 patients who underwent HCT or SOT in 2008-2020. Patient demographics, time and type of PTLD diagnosis, type of PTLD treatment, and death data were collected. We used Fine and Gray subdistribution hazard models to calculate the cumulative incidence and risk factors for PTLD. RESULTS During median follow-up of 5.32 years, PTLD occurred in 294 of 36,945 SOT patients (0.79%) and 235 of 10,573 HCT patients (2.22%). Cumulative incidence of PTLD were 0.49% at 1 year, 1.02% at 5 years, and 1.50% at 10 years post-transplantation. Age < 20 years (subdistribution hazard ratio [SHR] of 1.67 in age 10-19, SHR 1.51 in age 0-9), HCT (SHR 3.02), heart transplantation (SHR 2.27), and liver transplantation (SHR 1.47) were significant risk factors for PTLD. The presence of PTLD was associated with an increased risk of death (hazard ratio of 2.84). Overall, 5-year survival of PTLD patients was 68.9% (95% confidence interval, 64.9 to 73.2). CONCLUSION We observed a steady increase in PTLD over 10 years after HCT or SOT in this large cohort study. Pediatric age group, HCT, liver transplantation, and heart transplantation were suggested to be risk factors for PTLD, and PTLD was associated with a higher risk of death.
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Affiliation(s)
- Seung Min Hahn
- Department of Pediatric Hematology-Oncology, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Myeongjee Lee
- Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea
| | - JongHoon Hyun
- Division of Infectious Diseases, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Korea
| | - Sungmin Lim
- Department of Pediatrics, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Korea
| | - Ji-Man Kang
- Department of Pediatrics, Severance Children’s Hospital, Yonsei University College of Medicine, Seoul, Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea
| | - Jong Gyun Ahn
- Department of Pediatrics, Severance Children’s Hospital, Yonsei University College of Medicine, Seoul, Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea
| | - Dong Jin Joo
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Inkyung Jung
- Division of Biostatistics, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea
| | - Kyong Ihn
- Division of Pediatric Surgery, Severance Children’s Hospital, Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
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15
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Yadav R, El Kossi M, Belal D, Sharma A, Halawa A. Post-transplant malignancy: Focusing on virus-associated etiologies, pathogenesis, evidence-based management algorithms, present status of adoptive immunotherapy and future directions. World J Meta-Anal 2023; 11:317-339. [DOI: 10.13105/wjma.v11.i7.317] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 08/23/2023] [Accepted: 10/08/2023] [Indexed: 12/14/2023] Open
Abstract
Modern immunosuppression has led to a decrease in rejection rates and improved survival rates after solid organ transplantation. Increasing the potency of immunosuppression promotes post-transplant viral infections and associated cancers by impairing immune response against viruses and cancer immunoediting. This review reflects the magnitude, etiology and immunological characteristics of various virus-related post-transplant malignancies, emphasizing the need for future research. A multidisciplinary and strategic approach may serve best but overall literature evidence targeting it is sparse. However, the authors attempted to provide a more detailed update of the literature consensus for the prevention, diagnosis, management and surveillance of post-transplant viral infections and associated malignancies, with a focus on the current role of adoptive immunotherapy and the way forward. In order to achieve long-term patient and graft survival as well as superior post-transplant outcomes, collaborative research on holistic care of organ recipients is imperative.
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Affiliation(s)
- Rahul Yadav
- Department of Urology, Kidney Transplant and Robotic Uro-oncology, Tender Palm Super Speciality Hospital, Lucknow 226010, Uttar Pradesh, India
- Department of Urology and Kidney Transplant, Charak Hospital and Research Centre, Lucknow 226003, Uttar Pradesh, India
| | - Mohsen El Kossi
- Department of Nephrology, Doncaster Royal Infirmary, Doncaster DN2 5LT, United Kingdom
| | - Dawlat Belal
- Department of Nephrology and Medicine, Kasr El-Ainy School of Medicine, Cairo University, Cairo 11562, Egypt
| | - Ajay Sharma
- Department of Transplant Surgery, Royal Liverpool University Hospitals, Liverpool L7 8XP, United Kingdom
| | - Ahmed Halawa
- Department of Transplantation, Sheffield Teaching Hospitals, Sheffield S57AU, United Kingdom
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16
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Atamna A, Yahav D, Hirzel C. Prevention of Oncogenic Gammaherpesvirinae (EBV and HHV8) Associated Disease in Solid Organ Transplant Recipients. Transpl Int 2023; 36:11856. [PMID: 38046068 PMCID: PMC10689273 DOI: 10.3389/ti.2023.11856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 11/07/2023] [Indexed: 12/05/2023]
Abstract
Long-term risk for malignancy is higher among solid organ transplant (SOT) recipients compared to the general population. Four non-hepatitis viruses have been recognized as oncogenic in SOT recipients-EBV, cause of EBV-associated lymphoproliferative diseases; human herpes virus 8 (HHV8), cause of Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease; human papilloma virus, cause of squamous cell skin cancers, and Merkel cell polyomavirus, cause of Merkel cell carcinoma. Two of these viruses (EBV and HHV8) belong to the human herpes virus family. In this review, we will discuss key aspects regarding the clinical presentation, diagnosis, treatment, and prevention of diseases in SOT recipients associated with the two herpesviruses.
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Affiliation(s)
- Alaa Atamna
- Infectious Diseases Unit, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel
- Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Dafna Yahav
- Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Infectious Diseases Unit, Sheba Medical Center, Ramat-Gan, Israel
| | - Cédric Hirzel
- Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland
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17
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Zaffiri L, Chambers ET. Screening and Management of PTLD. Transplantation 2023; 107:2316-2328. [PMID: 36949032 DOI: 10.1097/tp.0000000000004577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
Posttransplant lymphoproliferative disorder (PTLD) represents a heterogeneous group of lymphoproliferative diseases occurring in the setting of immunosuppression following hematopoietic stem cells transplant and solid organ transplantation. Despite its overall low incidence, PTLD is a serious complication following transplantation, with a mortality rate as high as 50% in transplant recipients. Therefore, it is important to establish for each transplant recipient a personalized risk evaluation for the development of PTLD based on the determination of Epstein-Barr virus serostatus and viral load following the initiation of immunosuppression. Due to the dynamic progression of PTLD, reflected in the diverse pathological features, different therapeutic approaches have been used to treat this disorder. Moreover, new therapeutic strategies based on the administration of virus-specific cytotoxic T cells have been developed. In this review, we summarize the available data on screening and treatment to suggest a strategy to identify transplant recipients at a higher risk for PTLD development and to review the current therapeutic options for PTLD.
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Affiliation(s)
- Lorenzo Zaffiri
- Division of Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
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18
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Viswam V, Puducherry Ravichandran S, George P, Karuvat Narayanan SL. Submandibular gland abscess in a kidney transplant recipient: a diagnostic and therapeutic enigma. BMJ Case Rep 2023; 16:e254154. [PMID: 37907312 PMCID: PMC10619107 DOI: 10.1136/bcr-2022-254154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2023] Open
Abstract
A renal allograft transplant recipient presented to our emergency department with pus discharging right-sided cheek swelling. She had the same presentation 1 year after kidney transplant surgery. The abscess was incised and drained, and a sample was sent for culture and sensitivity. The culture initially grew Aspergillus fumigatus for which she was started on itraconazole. While the patient was on antifungal therapy, immunohistochemistry revealed diffuse large B-cell lymphoma to be the primary disease, and rituximab chemotherapy was initiated. The patient is being followed up and is currently in remission.We are reporting this rare case to raise awareness so that clinicians consider the possibility of post-transplant lymphoproliferative disorder when they see a similar presentation.
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Affiliation(s)
| | | | - Paul George
- Plastic, Reconstructive & Aesthetic surgery, Aster Medcity, Kochi, Kerala, India
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19
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Santos AH, Mehta R, Ibrahim H, Leghrouz MA, Alquadan K, Belal A, Lee JJ, Wen X. Role of standard HLA mismatch in modifying associations between non-pharmacologic risk factors and solid organ malignancy after kidney transplantation. Transpl Immunol 2023; 80:101885. [PMID: 37414265 DOI: 10.1016/j.trim.2023.101885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 06/18/2023] [Accepted: 07/01/2023] [Indexed: 07/08/2023]
Abstract
BACKGROUND Human leukocyte antigen mismatch(es) (HLA-mm) between donors and recipients has not been extensively studied either as a risk factor for solid organ malignancy (SOM) or as a modifier of associations between nonpharmacologic risk factors and SOM in kidney transplant recipients (KTRs). METHODS In a secondary analysis from a previous study, 166,256 adult KTRs in 2000-2018 who survived the first 12 months post-transplant free of graft loss or malignancy were classified into 0, 1-3, and 4-6 standard HLA-mm cohorts. Multivariable cause-specific Cox regressions analyzed the risks of SOM and all-cause mortality (ac-mortality) in 5 years following the first KT year. Comparisons of associations between SOM and risk factors in HLA mismatch cohorts were made by estimating the ratios of adjusted hazard ratios. RESULTS Compared with 0 HLA-mm, 1-3 HLA-mm was not associated, and 4-6 HLA-mm was equivocally associated with increased risk of SOM [hazard ratio, (HR) = 1.05, 95%, confidence interval (CI) = 0.94-1.17 and HR = 1.11, 95% CI = 1.00-1.34, respectively]. Both 1-3 HLA-mm and 4-6 HLA-mm were associated with increased risk of ac-mortality compared with 0 HLA mm [hazard ratio (HR) = 1.12, 95%, Confidence Interval (CI) = 1.08-1.18) and (HR = 1.16, 95% CI = 1.09-1.22), respectively]. KTR's history of pre-transplant cancer, age 50-64, and >/=65 years were associated with increased risks of SOM and ac-mortality in all HLA mismatch cohorts. Pre-transplant dialysis >2 years, diabetes as the primary renal disease, and expanded or standard criteria deceased donor transplantation were risk factors for SOM in the 0 and 1-3 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. KTRs male sex or history of previous kidney transplant was a risk factor for SOM in the 1-3 and 4-6 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. CONCLUSION Direct association between SOM and the degree of HLA mismatching is equivocal and limited to the 4-6 HLA-mm stratum; however, the degree of HLA mismatching has significant modifying effects on the associations between specific nonpharmacologic risk factors and SOM in KTRs.
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Affiliation(s)
- Alfonso H Santos
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
| | - Rohan Mehta
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Hisham Ibrahim
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Muhannad A Leghrouz
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Kawther Alquadan
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Amer Belal
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Jessica J Lee
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States of America
| | - Xuerong Wen
- Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, RI, USA
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Franco A, Hernandez D, Zarraga S, Fructuoso AS, Crespo M, Mazuecos A, Corte CD, Benot AR, Ruiz JC, Beneyto I. Lymphoproliferative disorders after renal transplantation along 2 decades: a large longitudinal study of 21.546 recipients. Nefrologia 2023; 43:427-434. [PMID: 37813738 DOI: 10.1016/j.nefroe.2023.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 02/17/2022] [Accepted: 02/20/2022] [Indexed: 10/11/2023] Open
Abstract
INTRODUCTION Post transplant lymphoproliferative disorders (PTLD) are heterogeneous lymphoid proliferations in recipients of solid organs which seem to be related to Epstein Barr Virus (EBV). The use of antilymphocyte antibodies, EBV seronegativity in the recipient,acute rejection and CMV infection have been identified as classical risk factors. MATERIAL Y METHODS We have studied in a retrospective observational study, the incidence of PTLD in a period of 22 years, its relationship with EBV, presence of classical risk factors and outcome in 21546 simple adult renal transplant recipients from cadaveric and living donors, transplanted in 21 hospitals from 1990 to 2009. RESULTS A total of 275 recipients developed PTLD (1,2%),195 males (70,9%), 80 females (29,1%) aged 59.2 (p25 44.7 p75 68)years. Two hundred forty-five (89.0%) were 1st transplant recipients and 269 (97,8%) from cadaveric donors. EBV in the tissue was reported in 94 out of the 155 studied recipients (60.6%) and 86.0% of the proliferations were due to B lymphocytes. PTLD median appearance after transplant were 42.months (p25, 75, 12, 77, 5). One hundred eighty-eight recipients out of 275 patients (68.3%) had any classical risk factor and the use of antilymphocyte antibodies was the most frequent. During the follow-up, 172 patients died (62,5%) and 103 (37,5%) had a complete remission. The main cause of death was PTLD progression (n = 91, 52,9%), followed by sepsis (n = 24, 13,9%). The follow-up period post-transplant of the recipients was between 3 and 22 years. The incidence was 0,14% during the first year post-trasplant and 0.98% the cumulative incidence at 10 years. Patient survival after diagnosis was 51%, 44% and 39% after 1, 2 and 5 years, respectively. Finally, overall graft survival was 48%, 39% and 33% at the same periods. CONCLUSION PTLD has a low incidence in renal transplant recipients. Most of the proliferations are due to B lymphocytes and seem to have a close relationship with EBV. PTLD can develop in the absence of classical risk factors. The prognosis is poor, mainly due to PTLD progression, but the survivors can even maintain their grafts.
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Affiliation(s)
- Antonio Franco
- Servicio de Nefrología, Hospital General de Alicante, Alicante, Spain.
| | | | - Sofia Zarraga
- Servicio de Nefrologia, Hospital de Cruces, Baracaldo, Vizcaya, Spain
| | | | - Marta Crespo
- Servicio de Nefrologia, Hospital del Mar, Barcelona, Spain
| | | | | | | | - Juan Carlos Ruiz
- Servicio de Nefrologia, Hospital Marque de Valdecilla, Santander, Cantabria, Spain
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Vergote VKJ, Deroose CM, Fieuws S, Laleman W, Sprangers B, Uyttebroeck A, Van Cleemput J, Verhoef G, Vos R, Tousseyn T, Dierickx D. Characteristics and Outcome of Post-Transplant Lymphoproliferative Disorders After Solid Organ Transplantation: A Single Center Experience of 196 Patients Over 30 Years. Transpl Int 2022; 35:10707. [PMID: 36589262 PMCID: PMC9794588 DOI: 10.3389/ti.2022.10707] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 11/29/2022] [Indexed: 12/15/2022]
Abstract
Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening complication after transplantation. In this retrospective, monocentric study we aimed to collect real life data regarding PTLD and determine the role of Epstein Barr Virus (EBV) status and year of diagnosis on prognosis. We identified 196 biopsy-proven PTLD after solid organ transplantation (SOT) diagnosed at the University Hospitals Leuven (Belgium) from 1989 to 2019. EBV status was positive in 61% of PTLD. The median overall survival (OS) was 5.7 years (95% CI: 2.99-11.1). Although EBV positivity was not significantly correlated with OS in multivariate analyses (HR: 1.44 (95% CI: 0.93-2.24); p = 0.10), subgroup analysis showed a significantly better median OS for EBV negative post-transplant diffuse large B-cell lymphoma (DLBCL) compared to EBV positive post-transplant DLBCL (8.8 versus 2.5 years respectively; p = 0.0365). There was a significant relation between year of PTLD diagnosis and OS: the more recent the PTLD diagnosis, the lower the risk for death (adjusted HR: 0.962 (95% CI: 0.931-0.933); p = 0.017). In conclusion, the prognosis of PTLD after SOT has improved in the past decades. Our analysis shows a significant relation between EBV status and OS in post-transplant DLBCL.
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Affiliation(s)
- Vibeke K. J. Vergote
- Department of Hematology, University Hospitals Leuven, Leuven, Belgium,*Correspondence: Vibeke K. J. Vergote, , orcid.org/0000-0003-1100-5600
| | | | - Steffen Fieuws
- Interuniversity Institute for Biostatistics and Statistical Bioinformatics, KU Leuven—University of Leuven, Leuven, Belgium
| | - Wim Laleman
- Department of Liver and Biliopancreatic Disorders, University Hospitals Leuven, Leuven, Belgium
| | - Ben Sprangers
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium,Department of Nephrology, University Hospitals Leuven, Leuven, Belgium
| | - Anne Uyttebroeck
- Department of Pediatric Hemato-Oncology, Department of Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | | | - Gregor Verhoef
- Department of Hematology, University Hospitals Leuven, Leuven, Belgium
| | - Robin Vos
- Department of Respiratory Medicine, University Hospitals Leuven, Leuven, Belgium,BREATHE, KU Leuven, Leuven, Belgium
| | - Thomas Tousseyn
- Department of Pathology, University Hospitals Leuven, Leuven, Belgium
| | - Daan Dierickx
- Department of Hematology, University Hospitals Leuven, Leuven, Belgium
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22
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Ylinen E, Merras-Salmio L, Jahnukainen T. Gastrointestinal symptoms and endoscopy findings after pediatric solid organ transplantation: A case series. Pediatr Transplant 2022; 26:e14374. [PMID: 35950902 DOI: 10.1111/petr.14374] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 06/22/2022] [Accepted: 07/25/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Gastrointestinal symptoms are common among solid organ transplant (SOT) recipients. Information about colonoscopy findings after pediatric SOT is limited. This retrospective study reports endoscopy findings in a nationwide pediatric transplant recipient cohort. METHODS All pediatric recipients (kidney, liver, or heart) transplanted between 2010 and 2020 at our institution (n = 193) who had undergone ileocolonoscopy and upper gastrointestinal endoscopy after SOT were enrolled. Sixteen patients were identified. A meticulous search on clinical data including transplantation, gastrointestinal symptoms, endoscopy findings, and follow-up data was performed. RESULTS Endoscopy was performed at a median of 2.6 years (0.4-13.3) after the first transplantation (median age at SOT 1.2 years). Gastrointestinal symptoms leading to endoscopy did not differ between the different transplant groups. The leading endoscopy indications were prolonged diarrhea and anemia. PTLD was found in 8 (50%) patients. Five were histologically early PTLD lesions and three were monomorphic large B-cell PTLDs (two EBV-positive and one EBV-negative), one having previously been diagnosed with autoimmune enteropathy. One patient had EBV enteritis. De novo inflammatory bowel disease was found in one patient, eosinophilic gastroenteritis in another, and in one patient with several episodes of watery diarrhea, the histological finding was mild non-specific colitis. In four patients, the endoscopy finding remained unclear and the symptoms were suspected to be caused by infectious agents or mycophenolate. CONCLUSIONS PTDL with various stages is a common finding after pediatric SOT in patients with gastrointestinal symptoms. Endoscopy should be considered in transplant recipients with prolonged diarrhea, anemia, and/or abdominal pain.
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Affiliation(s)
- Elisa Ylinen
- Department of Pediatric Nephrology and Transplantation, New Children's Hospital, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - Laura Merras-Salmio
- Department of Gastroenterology, New Children's Hospital, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - Timo Jahnukainen
- Department of Pediatric Nephrology and Transplantation, New Children's Hospital, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
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23
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Incidence of Lymphoproliferative Disorders After Renal Transplantation is Down, but the Poor Prognosis Remains. Multicenter 32-Year Cohort Study. Transplant Proc 2022; 54:2462-2466. [DOI: 10.1016/j.transproceed.2022.10.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/01/2022] [Indexed: 11/15/2022]
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24
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Grenda R. Non-Hodgkin lymphoma after pediatric kidney transplantation. Pediatr Nephrol 2022; 37:1759-1773. [PMID: 34633534 PMCID: PMC9239945 DOI: 10.1007/s00467-021-05205-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/27/2021] [Accepted: 06/24/2021] [Indexed: 11/18/2022]
Abstract
Non-Hodgkin lymphoma (NHL) that develops after kidney transplantation belongs to post-transplant lymphoproliferative disorders (PTLD) occurring with an incidence of 2-3%. Most pediatric cases are related to primary infection with Epstein-Barr virus (EBV), able to transform and immortalize B cells and widely proliferate due to the lack of relevant control of cytotoxic T cells in patients receiving post-transplant immunosuppression. NHL may develop as a systemic disease or as a localized lesion. The clinical pattern is variable, from non-symptomatic to fulminating disease. Young age of transplant recipient, seronegative EBV status at transplantation, and EBV mismatch between donor and recipient (D+/R-) are regarded as risk factors. Immunosuppression impacts the development of both early and late NHLs. Specific surveillance protocols, including monitoring of EBV viral load, are used in patients at risk; however, detailed histopathology diagnosis and evaluation of malignancy staging is crucial for therapeutic decisions. Minimizing of immunosuppression is a primary management, followed by the use of rituximab in B-cell NHLs. Specific chemotherapeutic protocols, adjusted to lymphoma classification and staging, are used in advanced NHLs. Radiotherapy and/or surgical removal of malignant lesions is limited to the most severe cases. Outcome is variable, depending on risk factors and timing of diagnosis, however is positive in pediatric patients in terms of graft function and patient survival. Kidney re-transplantation is possible in survivors who lost the primary graft due to chronic rejection, however may be performed after at least 2-3 years of waiting time, careful verification of malignancy-free status, and gaining immunity against EBV.
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Affiliation(s)
- Ryszard Grenda
- Department of Nephrology, Kidney Transplantation & Hypertension, Children's Memorial Health Institute, Warsaw, Poland.
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25
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van den Bogaart L, Lang BM, Rossi S, Neofytos D, Walti LN, Khanna N, Mueller NJ, Boggian K, Garzoni C, Mombelli M, Manuel O. Central Nervous System Infections in Solid Organ Transplant Recipients: Results from the Swiss Transplant Cohort Study. J Infect 2022; 85:1-7. [PMID: 35605804 DOI: 10.1016/j.jinf.2022.05.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 01/25/2022] [Accepted: 05/17/2022] [Indexed: 11/15/2022]
Abstract
OBJECTIVES To describe the epidemiology and clinical presentation of central nervous system (CNS) infections in solid organ transplant (SOT) recipients in the current era of transplantation. METHODS Patients from the Swiss Transplant Cohort Study (STCS) transplanted between 2008 and 2018 were included with a median follow-up of 3.8 years. Epidemiological, microbiological, and clinical data were extracted from the STCS database and patients' medical records. We calculated incidence rates and 90-day survival of transplant recipients with CNS infection. RESULTS Among 4762 patients, 42 episodes of CNS infection in 41 (0.8%) SOT recipients were identified, with an overall incidence rate of 2.06 per 1000 patient-years. Incidence of CNS infections was similar across all types of transplantations. Time to CNS infection onset ranged from 0.6 to 97 months after transplant. There were 22/42 (52.4%) cases of viral infections, 11/42 (26.2%) of fungal infections, 5/42 (11.9%) of bacterial infections and 4/42 (9.5%) of probable viral/bacterial etiology. Clinical presentation was meningitis/encephalitis in 25 cases (59.5%) and brain-space occupying lesions in 17 cases (40.5%). Twenty-three cases (60.5%) were considered opportunistic infections. Diagnosis were achieved mainly by brain biopsy/necropsy (15/42, 36%) or by cerebrospinal fluid analysis (20/42, 48%). Up to 40% of cases (17/42) had concurrent extra-neurological disease localizations. Overall, 90-day mortality rate was 29.0% (73.0% for fungal, 14.0% for viral and 11.0% for bacterial and probable infections, p<0.0001). CONCLUSIONS CNS infections were rare in the STCS, with viral meningoencephalitis being the most common disease. Fungal infections were associated with a high mortality.
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Affiliation(s)
- Lorena van den Bogaart
- Service of Infectious Diseases and Transplantation Center, Lausanne University Hospital, Lausanne, Switzerland.
| | - Brian M Lang
- Transplantationsimmunologie and Nephrologie Data Center of Swiss Transplant Cohort Study, Basel University Hospital, Basel, Switzerland
| | - Simona Rossi
- Transplantationsimmunologie and Nephrologie Data Center of Swiss Transplant Cohort Study, Basel University Hospital, Basel, Switzerland
| | - Dionysios Neofytos
- Transplant Infectious Diseases Unit, Geneva University Hospital, Geneva, Switzerland
| | - Laura N Walti
- Department of Infectious Diseases, Inselspital Bern University Hospital, Bern, Switzerland
| | - Nina Khanna
- Division of Infectious Diseases and Hospital Epidemiology, Basel University Hospital, Basel, Switzerland
| | - Nicolas J Mueller
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Katia Boggian
- Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St Gallen, St Gallen, Switzerland
| | - Christian Garzoni
- Clinic of Internal Medicine and Infectious Diseases, Clinica Luganese Moncucco, Lugano, Switzerland
| | - Matteo Mombelli
- Service of Infectious Diseases and Transplantation Center, Lausanne University Hospital, Lausanne, Switzerland
| | - Oriol Manuel
- Service of Infectious Diseases and Transplantation Center, Lausanne University Hospital, Lausanne, Switzerland
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Santarsieri A, Rudge JF, Amin I, Gelson W, Parmar J, Pettit S, Sharkey L, Uttenthal BJ, Follows GA. Incidence and outcomes of post-transplant lymphoproliferative disease after 5365 solid-organ transplants over a 20-year period at two UK transplant centres. Br J Haematol 2022; 197:310-319. [PMID: 35235680 DOI: 10.1111/bjh.18065] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 01/14/2022] [Accepted: 01/14/2022] [Indexed: 11/29/2022]
Abstract
Post-transplant lymphoproliferative disease (PTLD) is a life-threatening complication of solid-organ transplantation (SOT). We present the incidence and outcomes of PTLD in a cohort of 5365 SOT recipients over a 20-year period at two UK transplant centres. With a median follow-up of 7.7 years, 142 of 5365 patients have developed PTLD. Cumulative incidence was 18% at five years after multivisceral transplant and 1%-3% at five years following the other SOT types. Twenty-year cumulative incidence was 2%-3% following liver and heart transplantation and 10% following kidney transplantation. Median overall survival (OS) following SOT was 16 years, which is significantly reduced compared with the age-adjusted UK population. There is relatively high early mortality following diagnosis of PTLD and only patients surviving two years regained a longer-term survival approaching the non-PTLD SOT cohort. Of 90 patients with monomorphic PTLD, diffuse large B-cell lymphoma, 66 were treated with first-line rituximab monotherapy and 24 received first-line rituximab plus chemotherapy. Up-front rituximab monotherapy does not appear to compromise OS, but the number of patients dying from non-lymphoma causes before and after treatment remains high with both treatment approaches. Multivariate analysis of all 90 monomorphic PTLD patients identified an International Prognostic Index (IPI) of 3+ as the strongest pretreatment variable associating with inferior one-year OS.
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Affiliation(s)
- Anna Santarsieri
- Department of Haematology, Addenbrooke's Hospital, Cambridge, UK
- Anglia Ruskin University, Cambridge, UK
| | - John F Rudge
- Bullard Laboratories, University of Cambridge, Cambridge, UK
| | - Irum Amin
- Department of General Surgery, Addenbrooke's Hospital, Cambridge, UK
| | - Will Gelson
- Department of Hepatology, Addenbrooke's Hospital, Cambridge, UK
| | - Jasvir Parmar
- Cardio-Thoracic Transplant Unit, Royal Papworth Hospital, Cambridge, UK
| | - Stephen Pettit
- Cardio-Thoracic Transplant Unit, Royal Papworth Hospital, Cambridge, UK
| | - Lisa Sharkey
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge, UK
| | | | - George A Follows
- Department of Haematology, Addenbrooke's Hospital, Cambridge, UK
- Anglia Ruskin University, Cambridge, UK
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27
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Rodrigues AC, Fernandes S, Bustorff M, Nunes AT, Ferreira I, Tavares I, Rocha A, Carneiro A, Sampaio SN. Spleen-Restricted Posttransplant Lymphoproliferative Disorder in the First Year After Kidney Transplant - A Case Report. Transplant Proc 2022; 54:1624-1626. [PMID: 35487782 DOI: 10.1016/j.transproceed.2022.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 03/07/2022] [Indexed: 11/30/2022]
Abstract
Posttransplant lymphoproliferative disorders (PTLDs) are a feared complication after transplant. They are mostly of B cell origin and are frequently Epstein-Barr virus (EBV)-positive, particularly in early onset PTLD. Later on, non-B and EBV-negative PTLD are increasingly reported. EBV seronegative receptors (particularly when paired with an EBV seropositive donor) together with the net degree of immunosuppression-a concept often difficult to quantify-are the most consistently described risk factors for the development of PTLD. Conversely, its association with a particular immunosuppressive agent or other virus, namely cytomegalovirus (CMV) infection or disease, has been inconsistently reported. We present a challenging case where an EBV negative monomorphic peripheric T-cell lymphoma was diagnosed in the first year after kidney transplant in a patient with a recent history of CMV disease from a resistant strain.
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Affiliation(s)
| | - Sara Fernandes
- Nephrology Department, Hospital Beatriz Ângelo, Loures, Portugal
| | - Manuela Bustorff
- Nephrology Department, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Ana Teresa Nunes
- Nephrology Department, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Inês Ferreira
- Nephrology Department, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Isabel Tavares
- Nephrology Department, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Ana Rocha
- Nephrology Department, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Ana Carneiro
- Hematology Department, Centro Hospitalar Universitário de São João, Porto, Portugal
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28
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Enfermedad linfoproliferativa difusa postrasplante renal: estudio longitudinal de 21.546 receptores durante 2 décadas en España. Nefrologia 2022. [DOI: 10.1016/j.nefro.2022.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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Asleh R, Alnsasra H, Habermann TM, Briasoulis A, Kushwaha SS. Post-transplant Lymphoproliferative Disorder Following Cardiac Transplantation. Front Cardiovasc Med 2022; 9:787975. [PMID: 35282339 PMCID: PMC8904724 DOI: 10.3389/fcvm.2022.787975] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 02/01/2022] [Indexed: 11/24/2022] Open
Abstract
Post-transplant lymphoproliferative disorder (PTLD) is a spectrum of lymphoid conditions frequently associated with the Epstein Barr Virus (EBV) and the use of potent immunosuppressive drugs after solid organ transplantation. PTLD remains a major cause of long-term morbidity and mortality following heart transplantation (HT). Epstein-Barr virus (EBV) is a key pathogenic driver in many PTLD cases. In the majority of PTLD cases, the proliferating immune cell is the B-cell, and the impaired T-cell immune surveillance against infected B cells in immunosuppressed transplant patients plays a key role in the pathogenesis of EBV-positive PTLD. Preventive screening strategies have been attempted for PTLD including limiting patient exposure to aggressive immunosuppressive regimens by tailoring or minimizing immunosuppression while preserving graft function, anti-viral prophylaxis, routine EBV monitoring, and avoidance of EBV seromismatch. Our group has also demonstrated that conversion from calcineurin inhibitor to the mammalian target of rapamycin (mTOR) inhibitor, sirolimus, as a primary immunosuppression was associated with a decreased risk of PTLD following HT. The main therapeutic measures consist of immunosuppression reduction, treatment with rituximab and use of immunochemotherapy regimens. The purpose of this article is to review the potential mechanisms underlying PTLD pathogenesis, discuss recent advances, and review potential therapeutic targets to decrease the burden of PTLD after HT.
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Affiliation(s)
- Rabea Asleh
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States
- Heart Institute, Hadassah University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Hilmi Alnsasra
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States
- Soroka University Medical Center, Ben Gurion University of the Negev, Beer Sheva, Israel
| | - Thomas M. Habermann
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, United States
| | - Alexandros Briasoulis
- Division of Cardiovascular Disease, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
| | - Sudhir S. Kushwaha
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States
- *Correspondence: Sudhir S. Kushwaha
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30
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Abstract
Cancer remains a significant cause of morbidity and mortality in kidney transplant recipients, due to long-term immunosuppression. Salient issues to consider in decreasing the burden of malignancy among kidney transplant recipients include pretransplant recipient evaluation, post-transplant screening and monitoring, and optimal treatment strategies for the kidney transplant recipients with cancer. In this review, we address cancer incidence and outcomes, approaches to cancer screening and monitoring pretransplant and post-transplant, as well as treatment strategies, immunosuppressive management, and multidisciplinary approaches in the kidney transplant recipients with cancer.
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31
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Kato T, Yoshida T, Taniguchi A, Kawamura M, Nakazawa S, Namba-Hamano T, Yamanaka K, Abe T, Kishikawa H, Nonomura N, Imamura R. Incidence and mortality of post-transplant lymphoproliferative disorders after kidney transplantation: A real-world retrospective analysis in Japan. Int J Urol 2021; 29:206-211. [PMID: 34897833 DOI: 10.1111/iju.14750] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 11/08/2021] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Post-transplant lymphoproliferative disorder is a potentially life-threatening complication that has a greater risk of occurrence in the setting of immunosuppression and oncogenic viral infections after transplant surgery. Few studies have reported the cumulative incidence, histological subtypes and clinical outcomes of this disorder in kidney transplant recipients. METHODS We retrospectively investigated 34 post-transplant lymphoproliferative disorder patients diagnosed out of the 1210 kidney transplant recipients who had undergone the surgery at the two largest centers in Japan between January 1983 and December 2017. RESULTS A total of 32 patients (94.1%) developed late-onset post-transplant lymphoproliferative disorder (diagnosed 1 year after transplantation). The cumulative incidence rates were 0.76% and 1.59% at 5 and 10 years post-transplantation, respectively. The central nervous system was the most common site (35.3%, 12/34). Overall survival was similar between patients with and without central nervous system lesions (P = 0.676). Of all of the cases, 23.5% (8/34) were detected through cancer screening. Importantly, patients with screening-detected post-transplant lymphoproliferative disorder had better overall survival than those with the disorder who had been symptom detected (P = 0.0215). Overall survival was significantly reduced in patients who developed the disorder compared with those who did not (P = 0.0001). CONCLUSIONS Post-transplant lymphoproliferative disorder was more likely to occur in the late post-transplantation period, which showed that long-term medical examination for transplant recipients is required. Based on our findings, we propose vigilant, long-term, cancer screening in kidney transplant recipients.
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Affiliation(s)
- Taigo Kato
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takahiro Yoshida
- Department of Urology, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Japan
| | - Ayumu Taniguchi
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Masataka Kawamura
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Shigeaki Nakazawa
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tomoko Namba-Hamano
- Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kazuaki Yamanaka
- Department of Urology, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Japan
| | - Toyofumi Abe
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hidefumi Kishikawa
- Department of Urology, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Japan
| | - Norio Nonomura
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryoichi Imamura
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan
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32
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Krendl FJ, Messner F, Bösmüller C, Scheidl S, Cardini B, Resch T, Weissenbacher A, Oberhuber R, Maglione M, Schneeberger S, Öfner D, Margreiter C. Post-Transplant Malignancies following Pancreas Transplantation: Incidence and Implications on Long-Term Outcome from a Single-Center Perspective. J Clin Med 2021; 10:jcm10214810. [PMID: 34768331 PMCID: PMC8584646 DOI: 10.3390/jcm10214810] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/12/2021] [Accepted: 10/18/2021] [Indexed: 11/30/2022] Open
Abstract
Chronic immunosuppression is associated with an increased risk of malignancy. The main objective of this study is to evaluate the incidence and effect of post-transplant malignancies (PTMs) following pancreas transplantation. The 348 first pancreas transplants performed between 1985 and 2015 were retrospectively analyzed in this study. Incidences of PTMs, as well as patient and graft survival, were evaluated. Out of 348 patients, 71 (20.4%) developed a PTM. Median time to diagnosis was 130 months. Thirty-six patients (50.7%) developed skin cancers (four patients with melanoma, 32 with NMSCs). Solid organ malignancy occurred in 25 (35.2%), hematologic malignancy in ten patients (14.1%). Affected patients were transplanted earlier [2000 (IQR 1993−2004) vs. 2003 (IQR 1999−2008); p < 0.001]. No differences in induction therapy were seen, both groups demonstrated comparable patient and graft survival. Pancreas transplant recipients with solid organ and hematologic malignancies had a three- and six-fold increased hazard of death compared to those with skin cancers [aHR 3.04 (IQR 1.17–7.91); p = 0.023; aHR 6.07 (IQR 1.87–19.71); p = 0.003]. PTMs affect every fifth patient following pancreas transplantation. Skin cancers are the most common malignancies accounting for 50% of all PTMs. These results underscore the importance of close dermatologic follow-up.
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Legeard I, Chevrollier MA, Bader G. Diagnosis of a plasmoblastic lymphoma of the mandible after renal transplantation: a case report. JOURNAL OF ORAL MEDICINE AND ORAL SURGERY 2021. [DOI: 10.1051/mbcb/2021036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Introduction: Post-transplant lymphoproliferations (PTL) are a severe complication of solid organ transplants. Their locations can be extra-nodal. Observation: The diagnosis and management of a non-Hodgkin's plasmablastic lymphoma of mandibular localization affecting a 66-year-old kidney transplanted patient are reported here. Comment: The main risk factors for non-Hodgkin lymphoma are immunosuppression and infection with Epstein-Barr virus. Clinical and radiographic examinations, which are not specific, must be supplemented by a histological examination. Treatment which is not consensual will most often consist of a reduction in immunosuppression coupled with chemotherapy. Conclusion: Despite a constant evolution in the incidence and clinical picture of post-transplant lymphomas, the role of the dentist remains essential in the early detection of lesions.
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Ashrafi F, Shahidi S, Mehrzad V, Mortazavi M, Hosseini SF. Survival of Post-Transplant Lymphoproliferative Disorder after Kidney Transplantation in Patients under Rapamycin Treatment. Int J Hematol Oncol Stem Cell Res 2021; 15:239-248. [PMID: 35291663 PMCID: PMC8888361 DOI: 10.18502/ijhoscr.v15i4.7479] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 12/12/2020] [Indexed: 11/24/2022] Open
Abstract
Background: One of the important causes of mortality and morbidity in kidney transplanted patients is Post Transplant Lymphoproliferative Disease (PTLD), which is due to immunosuppression therapy and viral activity. It seems that Rapamycin, with dual antineoplastic and immunosuppressive effects, may have a pivotal role in the treatment of PTLD patients and preserving transplanted kidneys. Methods and Materials: Twenty patients with PTLD were enrolled. Immunosuppressive therapy was reduced or ceased, and Rapamycin was initiated at the time of PTLD diagnosis. We evaluated the effects of switching immunosuppressive drugs to Rapamycin on graft status, the response of tumor, and 6, 12 months, and 5-year survival in patients. Results: PTLD remission was achieved in 14 patients, while six patients died; no relapse was detected in recovered patients. The median of PTLD free time was 25 months, and the mean overall survival in patients with PTLD treated by Rapamycin was 84.8 (95% CI=61.3-108.23).The five-year survival rate was 67%, 12 months survival was 73.8%, and six months' survival was 80%. The response rate to Rapamycin and immunosuppression reduction alone was 46.6%. Four out of 13 Diffuse Large B-Cell Lymphoma patients achieved a complete response just only after the reduction of immunosuppressive drugs and the consumption of Rapamycin. Conclusion: The present study demonstrated the effectiveness of conversion from immunosuppressive medication, particularly of Calcineurin inhibitors to Rapamycin in PTLD patients. However, more research is needed to confirm the Rapamycin effect on patients with PTLD.
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Affiliation(s)
- Farzaneh Ashrafi
- Hematology Oncology Division, Department of Internal Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shahrzad Shahidi
- Nephrology Division, Department of Internal Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Valiollah Mehrzad
- Department of Clinical Oncology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Sayyideh Forough Hosseini
- Department of Oncology, Hematology, Cancer Prevention Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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Füreder A, Kropshofer G, Benesch M, Dworzak M, Greil S, Huber W, Hubmann H, Lawitschka A, Mann G, Michel‐Behnke I, Müller‐Sacherer T, Pichler H, Simonitsch‐Klupp I, Schwinger W, Szepfalusi Z, Crazzolara R, Attarbaschi A, Austrian Society of Pediatric Hematology and Oncology. Characteristics, management, and outcome of pediatric patients with post-transplant lymphoproliferative disease-A 20 years' experience from Austria. Cancer Rep (Hoboken) 2021; 4:e1375. [PMID: 33755341 PMCID: PMC8551996 DOI: 10.1002/cnr2.1375] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/02/2021] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Management of pediatric post-transplantation lymphoproliferative disorder (PTLD) after hematopoietic stem cell (HSCT) and solid organ transplantation (SOT) is challenging. AIM This study of 34 PTLD patients up to 19-years old diagnosed in Austria from 2000 to 2018 aimed at assessing initial characteristics, therapy, response, and outcome as well as prognostic markers of this rare pediatric disease. METHODS AND RESULTS A retrospective data analysis was performed. Types of allografts were kidney (n = 12), liver (n = 7), heart (n = 5), hematopoietic stem cells (n = 4), lungs (n = 2), multi-visceral (n = 2), small intestine (n = 1), and vessels (n = 1). Eighteen/34 were classified as monomorphic PTLD, with DLBCL accounting for 15 cases. Polymorphic disease occurred in nine, and non-destructive lesions in six cases. One patient had a non-classifiable PTLD. Thirteen/34 patients are surviving event-free in first remission (non-destructive, n = 4/6; polymorphic, n = 4/9; monomorphic, n = 6/18). Fourteen/34 patients lacked complete response to first-line therapy, of whom seven died. Four/34 patients relapsed, of whom two died. In 3/34 patients, death occurred as a first event. The 5-year overall and event-free survival rates were 64% ± 9% and 35% ± 9% for the whole cohort. Among all parameters analyzed, only malignant disease as the indication for transplantation had a significantly poor influence on survival. CONCLUSIONS This study shows PTLD still to be a major cause of mortality following SOT or HSCT in children. A continued understanding of the molecular biology of the disease shall allow to decrease treatment intensity for lower risk patients and to identify patients who may benefit from newer therapy approaches to improve outcome and decrease morbidity.
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Affiliation(s)
- Anna Füreder
- Department of Pediatric Hematology and OncologySt. Anna Children's HospitalViennaAustria
- Department of Pediatrics and Adolescent MedicineMedical University of ViennaViennaAustria
| | - Gabriele Kropshofer
- Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent MedicineMedical University of InnsbruckInnsbruckAustria
| | - Martin Benesch
- Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent MedicineMedical University of GrazGrazAustria
| | - Michael Dworzak
- Department of Pediatric Hematology and OncologySt. Anna Children's HospitalViennaAustria
- Department of Pediatrics and Adolescent MedicineMedical University of ViennaViennaAustria
| | - Sabine Greil
- Division of Pediatric Cardiology, Department of Pediatrics and Adolescent Medicine, Pediatric Heart CenterMedical University of ViennaViennaAustria
| | - Wolf‐Dietrich Huber
- Department of Pediatrics and Adolescent MedicineMedical University of ViennaViennaAustria
| | - Holger Hubmann
- Division of General Pediatrics, Department of Pediatrics and Adolescent MedicineMedical University of GrazGrazAustria
| | - Anita Lawitschka
- Department of Pediatric Hematology and OncologySt. Anna Children's HospitalViennaAustria
- Department of Pediatrics and Adolescent MedicineMedical University of ViennaViennaAustria
| | - Georg Mann
- Department of Pediatric Hematology and OncologySt. Anna Children's HospitalViennaAustria
| | - Ina Michel‐Behnke
- Division of Pediatric Cardiology, Department of Pediatrics and Adolescent Medicine, Pediatric Heart CenterMedical University of ViennaViennaAustria
| | - Thomas Müller‐Sacherer
- Department of Pediatrics and Adolescent MedicineMedical University of ViennaViennaAustria
| | - Herbert Pichler
- Department of Pediatric Hematology and OncologySt. Anna Children's HospitalViennaAustria
- Department of Pediatrics and Adolescent MedicineMedical University of ViennaViennaAustria
| | | | - Wolfgang Schwinger
- Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent MedicineMedical University of GrazGrazAustria
| | - Zsolt Szepfalusi
- Division of Pediatric Pulmonology, Allergy and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center PediatricsMedical University of ViennaViennaAustria
| | - Roman Crazzolara
- Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent MedicineMedical University of InnsbruckInnsbruckAustria
| | - Andishe Attarbaschi
- Department of Pediatric Hematology and OncologySt. Anna Children's HospitalViennaAustria
- Department of Pediatrics and Adolescent MedicineMedical University of ViennaViennaAustria
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King RL, Khurana A, Mwangi R, Fama A, Ristow KM, Maurer MJ, Macon WR, Ansell SM, Bennani NN, Kudva YC, Walker RC, Watt KD, Schwab TR, Kushwaha SS, Cerhan JR, Habermann TM. Clinicopathologic Characteristics, Treatment, and Outcomes of Post-transplant Lymphoproliferative Disorders: A Single-institution Experience Using 2017 WHO Diagnostic Criteria. Hemasphere 2021; 5:e640. [PMID: 34514344 PMCID: PMC8423401 DOI: 10.1097/hs9.0000000000000640] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 08/09/2021] [Indexed: 12/31/2022] Open
Abstract
The World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (WHO 2017) included updated criteria for diagnosis and classification of post-transplant lymphoproliferative disorders (PTLDs). This study evaluated the clinicopathologic spectrum using WHO 2017 criteria and adult PTLD patients' outcomes over 30 years between 1987 and 2017 at Mayo Clinic (Rochester, MN). Patients were retrospectively reviewed for clinical features, outcomes, and diagnostic pathology material and classified based on WHO 2017 criteria. A total of 227 patients were diagnosed with PTLD, with a median time from transplant to PTLD of 45 months. PTLD occurred >1 year after transplant in 149 (66%) patients. Monomorphic PTLD was the most common subtype (173, 76%), with diffuse large B cell lymphoma as the commonest morphology (n = 137). Epstein-Barr virus was positive in 61% of total cases and 90% of PTLD that developed within 1 year from transplant. The median event-free survival (EFS) and overall survival for the entire cohort were 21 months (95% confidence interval [CI]: 9-35) and 82 months (95% CI: 39-115), respectively. The EFS or overall survival was not impacted by Epstein-Barr virus status but differed based on WHO subtypes and year of diagnosis. Management changed over time with increased use of rituximab or chemotherapy + immunosuppression reduction as initial therapy. When compared to the matched general population and de novo diffuse large B cell lymphoma, patients not achieving EFS 24 status (no progression/treatment or death within 24 mo of diagnosis) had a worse standardized mortality ratio 16.75 (95% CI: 13.91-20) versus SMR 1.72 (95% CI: 1.26-2.28) in those who achieved EFS24. Cause of death was mostly attributed to non-lymphoma-related causes in those achieving EFS 24.
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Affiliation(s)
- Rebecca L. King
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Arushi Khurana
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | - Raphael Mwangi
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Angelo Fama
- Hematology, Azienda Unità Sanitaria Locale di Reggio Emilia - IRCCS, Italy
| | - Kay M. Ristow
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | - Matthew J. Maurer
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - William R. Macon
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - N. Nora Bennani
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | - Yogish C. Kudva
- Department of Endocrinology, Diabetes and Metabolism, Mayo Clinic, Rochester, Minnesota, USA
| | - Randall C. Walker
- Department of Infectious Disease, Mayo Clinic, Rochester, Minnesota, USA
| | - Kymberly D. Watt
- Division of Gastroenterology/Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Thomas R. Schwab
- Department of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Sudhir S. Kushwaha
- 9Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | - James R. Cerhan
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
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Augusto JF, Gatault P, Sayegh J, Garnier AS, Duveau A, Merieau E, Bailly E, Subra JF, Büchler M. Successful Treatment of Acute Kidney Allograft Rejection using Extracorporeal Photopheresis in the Context of Post-Transplant Lymphoproliferative Diseases: 3 Successive Cases. Transpl Int 2021; 34:2415-2417. [PMID: 34358369 DOI: 10.1111/tri.14006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Kidney allograft loss occurs within 2 years in one third of patients with post-transplant lymphoproliferative disease (PTLD). Acute rejection (AR) risk is increased as a result of strong immunosuppression minimization following PTLD (1-3). Here, we report extracorporeal photopheresis (ECP) use in three successive kidney transplant recipients for treatment of concomitant acute cellular and humoral rejection occurring after immunosuppression minimization following PTLD diagnosis.
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Affiliation(s)
- Jean-François Augusto
- Service de Néphrologie-Dialyse-Transplantation, Université d'Angers, CHU Angers, Angers, France.,CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France
| | - Philippe Gatault
- Service de Néphrologie et Immunologie Clinique, CHRU de Tours, Tours, France
| | - Johnny Sayegh
- Service de Néphrologie-Dialyse-Transplantation, Université d'Angers, CHU Angers, Angers, France
| | - Anne-Sophie Garnier
- Service de Néphrologie-Dialyse-Transplantation, Université d'Angers, CHU Angers, Angers, France
| | - Agnès Duveau
- Service de Néphrologie-Dialyse-Transplantation, Université d'Angers, CHU Angers, Angers, France
| | - Elodie Merieau
- Service de Néphrologie et Immunologie Clinique, CHRU de Tours, Tours, France
| | - Elodie Bailly
- Service de Néphrologie et Immunologie Clinique, CHRU de Tours, Tours, France
| | - Jean-François Subra
- Service de Néphrologie-Dialyse-Transplantation, Université d'Angers, CHU Angers, Angers, France.,CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France
| | - Matthias Büchler
- Service de Néphrologie et Immunologie Clinique, CHRU de Tours, Tours, France
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Patil R, Prashar R, Patel A. Heterogeneous Manifestations of Posttransplant Lymphoma in Renal Transplant Recipients: A Case Series. Transplant Proc 2021; 53:1519-1527. [PMID: 34134932 DOI: 10.1016/j.transproceed.2021.04.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 04/05/2021] [Accepted: 04/19/2021] [Indexed: 01/07/2023]
Abstract
Posttransplant lymphoproliferative disorder (PTLD) occurs in 1% to 3% of adult renal transplant recipients (RTRs). PTLD has a heterogeneous presentation and is often associated with Epstein-Barr virus (EBV) and immunosuppression. We present a descriptive case series of 16 RTRs who demonstrate a variety of PTLD manifestations. Fifty-six percent received rabbit antithymocyte globulin induction, and 37.5% received basiliximab. Maintenance immunosuppression included glucocorticoids, tacrolimus, and mycophenolate mofetil. Median time from transplantation to PTLD diagnosis was 96.5 months. PTLD involved a single site in 44% of RTRs and multiple sites in 56%. PTLD was localized to the gastrointestinal tract in 9 RTRs, in lymph nodes in 9, central nervous system in 4, bone marrow in 3, skin in 3, lungs in 2, perinephric space in 2, mediastinum in 1, and native kidney in 1. PTLD was EBV positive in 8 RTRs, monomorphic/monoclonal in 14, and of B-cell lineage in 13. Three RTRs had T-cell PTLD. Immunosuppressive agents, except glucocorticoids, were discontinued at diagnosis. Treatment was chemotherapy either alone (in 14 RTRs) or in combination with radiation. Complete remission was achieved in 62.5% of RTRs. Renal dysfunction developed in 62.5% of RTRs, and 4 received dialysis. The overall mortality rate was 62.5%, with median time of death 6.5 months after diagnosis. PTLD that was EBV negative and had T-cell involvement presented with aggressive disease and a higher mortality. Clinicians should be aware of the various PTLD manifestations. Early diagnosis and a multidisciplinary approach to treatment is crucial for improved patient outcomes.
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Affiliation(s)
- Rujuta Patil
- Wayne State University School of Medicine, Detroit, Michigan
| | - Rohini Prashar
- Kidney and Pancreas Transplant Program, Henry Ford Transplant Institute, Detroit, Michigan
| | - Anita Patel
- Kidney and Pancreas Transplant Program, Henry Ford Transplant Institute, Detroit, Michigan.
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39
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Kinch A, Baecklund E, Molin D, Pauksens K, Sundström C, Tufveson G, Enblad G. Prior antithymocyte globulin therapy and survival in post-transplant lymphoproliferative disorders. Acta Oncol 2021; 60:771-778. [PMID: 33793378 DOI: 10.1080/0284186x.2021.1904520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Background: Treatment with antithymocyte globulin (ATG) is a well-recognized risk factor for the development of post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation, but it is unknown how its use affects overall survival after PTLD.Methods: A total of 114 patients with PTLD and available data on immunosuppressive regimen were included from a nation-wide case series of solid organ transplant recipients in Sweden. Prior use of ATG was correlated to clinical features, PTLD subtype, and survival.Results: A total of 47 (41%) patients had received ATG prior to the diagnosis of PTLD. The ATG-treated patients were more likely to be recipients of hearts or lungs, and less likely of kidneys (p < 0.01). They had experienced more acute rejections (p = 0.02). The PTLDs arose earlier, median 2.0 vs. 6.6 years post-transplant (p = 0.002) and were more often situated in the allograft (32% vs. 7%, p < 0.001) in patients with prior ATG vs. no ATG treatment. The PTLDs in the ATG group were more often Epstein-Barr virus-positive (80% vs. 40%, p < 0.001). There were more polymorphic PTLDs (17% vs. 1.5%, p = 0.004) and less T-cell PTLDs (4% vs. 19%, p = 0.02) in the ATG group than in the no ATG group. Diffuse large B-cell lymphoma was equally common in patients with and without prior ATG therapy, but the non-germinal center subtype was more frequent in the ATG group (p = 0.001). In an adjusted Cox proportional hazards regression model, prior ATG treatment and better performance status were associated with superior overall survival, whereas older age, T-cell subtype of PTLD, presence of B symptoms, and elevated lactate dehydrogenase were associated with inferior overall survival. Patients receiving ATG solely as rejection therapy had superior overall survival compared with those receiving ATG as induction therapy or both (p = 0.03).Conclusions: ATG therapy, especially rejection therapy, prior to PTLD development is an independent prognostic factor for superior overall survival after PTLD diagnosis.
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Affiliation(s)
- Amelie Kinch
- Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden
| | - Eva Baecklund
- Department of Medical Sciences, Section of Rheumatology, Uppsala University, Uppsala, Sweden
| | - Daniel Molin
- Experimental and Clinical Oncology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Karlis Pauksens
- Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden
| | - Christer Sundström
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Gunnar Tufveson
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Gunilla Enblad
- Experimental and Clinical Oncology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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40
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Association of HLA mismatch and MTOR inhibitor regimens with malignancy and mortality after kidney transplantation. Transpl Immunol 2021; 66:101391. [PMID: 33838299 DOI: 10.1016/j.trim.2021.101391] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/28/2021] [Accepted: 04/04/2021] [Indexed: 01/20/2023]
Abstract
Background The association of mammalian target of rapamycin inhibitors (MTORI) with malignancies and mortality in kidney transplant recipients (KTR) with different degrees of human leukocyte antigen mismatch (HLA-mm) at transplant has not been previously studied. Methods Our observational cohort study included 166, 256 adult KTRs in 2000-2018. Immunosuppression in the first post-transplant year were MTORIs in 13,056 (7.85%) and non-MTORIs in 153,200 (92.15%). We used Cox multivariable regression models to determine the cause-specific hazard ratio (HRcs) of non-melanoma skin cancer (NMSC),solid organ malignancies (SOM)] and all-cause death (deathac); and the HR of the composite outcomes of NMSC or deathac and SOM or deathac associated with MTORI versus non-MTORI regimens in the overall study sample and the 0, 1-3, and 4-6 HLA-A, B and DR mm subgroups. Results NMSC risk was lower with MTORI than non-MTORI in all HLA-mm subgroups [(0 mm, HRcs = 0.67; 95% CI = 0.46-0.97, 1-3 mm, HRcs = 0.73; 95% CI = 0.61-0.87, 4-6 mm, HRcs = 0.69; 95% CI = 0.62-0.76)]. SOM risks were similar between regimens in the 0 HLA mm subgroup (HRcs = 1.10 (95% CI = 0.78-1.57) and lower with MTORI than non-MTORI in the 1-3, and 4-6 HLA-mm subgroups, [(HR = 0.84; (95% CI = 0.71-0.99), and (HR = 0.86; 95% CI = 0.78-0.94); respectively]. Risks of deathac and composite outcomes (NMSC or deathac and SOM or deathac) were higher with MTORI than non-MTORI in almost all HLA-mm subgroups. Conclusion MTORIs are associated with protection from NMSC and SOM in almost all HLA-mm subgroups ca; however, their association with increased all-cause mortality in adult kidney transplant recipients needs further investigation.
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Plummer RM, Linden MA, Beckman AK. Update on B-cell lymphoproliferative disorders of the gastrointestinal tract. Semin Diagn Pathol 2021; 38:14-20. [PMID: 33863577 DOI: 10.1053/j.semdp.2021.03.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/25/2021] [Accepted: 03/22/2021] [Indexed: 12/14/2022]
Abstract
The gastrointestinal (GI) tract is home to a significant portion of the immune system, which interacts daily with the antigenic milieu of its contents. Therefore, the presence of white blood cells within the walls of the GI tract upon histologic examination is a familiar sight on GI biopsies-both in health and disease. The GI tract is the most common site of extranodal lymphomas, most of which are B-cell neoplasms. Here, we review common and uncommon B-cell neoplasms of the GI tract - extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), mantle cell lymphoma, duodenal-type follicular lymphoma, diffuse large B-cell lymphoma, plasmablastic lymphoma, EBV-positive mucocutaneous ulcer, and post-transplant lymphoproliferative disorders - with special focus on literature published during the past five years. Along with the other articles in this edition of Seminars in Diagnostic Pathology, it is the authors' hope that this review proves to be a useful resource in the workup of the array of hematopoietic processes that can involve the GI tract.
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Affiliation(s)
- Regina M Plummer
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, USA
| | - Michael A Linden
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, 420 Delaware St. SE, Minneapolis, MN 55455, USA
| | - Amy K Beckman
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, 420 Delaware St. SE, Minneapolis, MN 55455, USA.
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42
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Zaffiri L, Frankel C, Bush EJ, Neely ML, Pavlisko EN, Mokrova IL, Luftig MA, Palmer SM. Evidence of Epstein-Barr virus heterogeneous gene expression in adult lung transplant recipients with posttransplant lymphoproliferative disorder. J Med Virol 2021; 93:5040-5047. [PMID: 33704812 PMCID: PMC9208898 DOI: 10.1002/jmv.26936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/15/2021] [Accepted: 03/09/2021] [Indexed: 11/10/2022]
Abstract
Epstein-Barr virus (EBV)-driven posttransplant lymphoproliferative disorder (PTLD) is a serious complication following lung transplant. The extent to which the presence of EBV in PTLD tissue is associated with survival is uncertain. Moreover, whether the heterogeneity in expression of EBV latency programs is related to the timing of PTLD onset remains unexplored. We retrospectively performed a comprehensive histological evaluation of EBV markers at the tissue level in 34 adult lung transplant recipients with early- and late-onset PTLD. Early-onset PTLD, occurring within the first 12 months posttransplant, had higher odds to express EBV markers. The presence of EBV in PTLD was not associated with a difference in survival relative to EBV-negative tumors. However, we found evidence of heterogeneous expression of EBV latency programs, including type III, IIb, IIa, and 0/I. Our study suggests that the heterogeneous expression of EBV latency programs may represent a mechanism for immune evasion in patients with PLTD after lung transplants. The recognition of multiple EBV latency programs can be used in personalized medicine in patients who are nonresponsive to traditional types of chemotherapy and can be potentially evaluated in other types of solid organ transplants.
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Affiliation(s)
- Lorenzo Zaffiri
- Department of Medicine, Duke University, Durham, North Carolina, USA
| | - Courtney Frankel
- Department of Medicine, Duke University, Durham, North Carolina, USA
| | - Erika J Bush
- Department of Medicine, Duke University, Durham, North Carolina, USA
| | - Megan L Neely
- Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, USA
| | | | - Irina L Mokrova
- Department of Medicine, Duke University, Durham, North Carolina, USA
| | - Micah A Luftig
- Department of Molecular Genetics and Microbiology, Duke Center for Virology, Duke University, Durham, North Carolina, USA
| | - Scott M Palmer
- Department of Medicine, Duke University, Durham, North Carolina, USA
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43
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Sprangers B, Riella LV, Dierickx D. Posttransplant Lymphoproliferative Disorder Following Kidney Transplantation: A Review. Am J Kidney Dis 2021; 78:272-281. [PMID: 33774079 DOI: 10.1053/j.ajkd.2021.01.015] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 01/02/2021] [Indexed: 12/13/2022]
Abstract
Posttransplant lymphoproliferative disorder (PTLD) is one of the most feared complications following kidney transplantation. Over a 10-year period, the risk of PTLD in kidney transplant recipients (KTRs) is 12-fold higher than in a matched nontransplanted population. Given the number of kidney transplants performed, KTRs who experience PTLD outnumber other organ transplant recipients who experience PTLD. Epstein-Barr virus infection is one of the most important risk factors for PTLD, even though 40% of PTLD cases in contemporary series are not Epstein-Barr virus-associated. The overall level of immunosuppression seems to be the most important driver of the increased occurrence of PTLD in solid organ transplant recipients. Reduction in immunosuppression is commonly accepted to prevent and treat PTLD. Although the cornerstone of PTLD treatment had been chemotherapy (typically cyclophosphamide-doxorubicin-vincristinr-prednisone), the availability of rituximab has changed the treatment landscape in the past 2 decades. The outcome of PTLD in KTRs has clearly improved as a result of the introduction of more uniform treatment protocols, improved supportive care, and increased awareness and use of positron emission tomography combined with computed tomography in staging and response monitoring. In this review, we will focus on the most recent data on epidemiology, presentation, risk factors, and management of PTLD in KTRs.
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Affiliation(s)
- Ben Sprangers
- Department of Microbiology, Immunology and Transplantation, Laboratory of Molecular Immunology (Rega Institute for Medical Research), KU Leuven; Division of Nephrology, University Hospitals Leuven, Leuven, Belgium
| | - Leonardo V Riella
- Division of Nephrology and Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Daan Dierickx
- Laboratory of Experimental Hematology, Department of Oncology, KU Leuven; Department of Hematology, University Hospitals Leuven, Leuven, Belgium.
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44
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Montes de Jesus F, Dierickx D, Vergote V, Noordzij W, Dierckx RAJO, Deroose CM, Glaudemans AWJM, Gheysens O, Kwee TC. Prognostic superiority of International Prognostic Index over [ 18F]FDG PET/CT volumetric parameters in post-transplant lymphoproliferative disorder. EJNMMI Res 2021; 11:29. [PMID: 33738643 PMCID: PMC7973341 DOI: 10.1186/s13550-021-00769-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 03/03/2021] [Indexed: 11/19/2022] Open
Abstract
Background Post-transplant lymphoproliferative disorders (PTLDs) are a spectrum of hematological malignancies occurring after solid organ and hematopoietic stem cell transplantation. [18F]FDG PET/CT is routinely performed at PTLD diagnosis, allowing for both staging of the disease and quantification of volumetric parameters, such as whole-body metabolic tumor volume (MTV) and total lesion glycolysis (TLG). In this retrospective study, we aimed to determine the prognostic value of MTV and TLG in PTLD patients, together with other variables of interest, such as the International Prognostic Index (IPI), organ transplant type, EBV tumor status, time after transplant, albumin levels and PTLD morphology. Results A total of 88 patients were included. The 1-, 3-, 5- year overall survival rates were 67%, 58% and 43% respectively. Multivariable analysis indicated that a high IPI (HR: 1.56, 95% CI: 1.13–2.16) and an EBV-negative tumor (HR: 2.71, 95% CI: 1.38–5.32) were associated with poor overall survival. Patients with a kidney transplant had a longer overall survival than any other organ recipients (HR: 0.38 95% CI: 0.16–0.89). IPI was found to be the best predicting parameter of overall survival in our cohort. Whole-body MTV, TLG, time after transplant, hypoalbuminemia and PTLD morphology were not associated with overall survival. Conclusion [18F]FDG PET/CT whole-body volumetric quantitative parameters were not predictive of overall survival in PTLD. In our cohort, high IPI and an EBV-negative tumor were found to predictors of worse overall survival while kidney transplant patients had a longer overall survival compared to other organ transplant recipients
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Affiliation(s)
- F Montes de Jesus
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.
| | - D Dierickx
- Department of Hematology, University Hospitals Leuven, Leuven, Belgium
| | - V Vergote
- Department of Hematology, University Hospitals Leuven, Leuven, Belgium
| | - W Noordzij
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
| | - R A J O Dierckx
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
| | - C M Deroose
- Department of Nuclear Medicine, University Hospitals Leuven, Leuven, Belgium
| | - A W J M Glaudemans
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
| | - O Gheysens
- Department of Nuclear Medicine, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - T C Kwee
- Department of Radiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Lau E, Moyers JT, Wang BC, Jeong ISD, Lee J, Liu L, Kim M, Villicana R, Kim B, Mitchell J, Kamal MO, Chen CS, Liu Y, Wang J, Chinnock R, Cao H. Analysis of Post-Transplant Lymphoproliferative Disorder (PTLD) Outcomes with Epstein-Barr Virus (EBV) Assessments-A Single Tertiary Referral Center Experience and Review of Literature. Cancers (Basel) 2021; 13:899. [PMID: 33669937 PMCID: PMC7924879 DOI: 10.3390/cancers13040899] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 02/09/2021] [Accepted: 02/14/2021] [Indexed: 12/23/2022] Open
Abstract
Post-transplant lymphoproliferative disorders (PTLDs) are lymphoid or plasmacytic proliferations ranging from polyclonal reactive proliferations to overt lymphomas that develop as consequence of immunosuppression in recipients of solid organ transplantation (SOT) or allogeneic bone marrow/hematopoietic stem cell transplantation. Immunosuppression and Epstein-Barr virus (EBV) infection are known risk factors for PTLD. Patients with documented histopathologic diagnosis of primary PTLD at our institution between January 2000 and October 2019 were studied. Sixty-six patients with PTLD following SOT were followed for a median of 9.0 years. The overall median time from transplant to PTLD diagnosis was 5.5 years, with infant transplants showing the longest time to diagnosis at 12.0 years, compared to pediatric and adolescent transplants at 4.0 years and adult transplants at 4.5 years. The median overall survival (OS) was 19.0 years. In the monomorphic diffuse large B-cell (M-DLBCL-PTLD) subtype, median OS was 10.7 years, while median OS for polymorphic subtype was not yet reached. There was no significant difference in OS in patients with M-DLBCL-PTLD stratified by quantitative EBV viral load over and under 100,000 copies/mL at time of diagnosis, although there was a trend towards worse prognosis in those with higher copies.
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Affiliation(s)
- Eric Lau
- Department of Medicine, Division of Hematology and Oncology, Loma Linda University Adventist Health Center, Loma Linda University, Loma Linda, CA 92354, USA; (J.T.M.); (M.O.K.); (C.-S.C.); (H.C.)
| | - Justin Tyler Moyers
- Department of Medicine, Division of Hematology and Oncology, Loma Linda University Adventist Health Center, Loma Linda University, Loma Linda, CA 92354, USA; (J.T.M.); (M.O.K.); (C.-S.C.); (H.C.)
| | - Billy Chen Wang
- Department of Pediatrics, Division of Critical Care Medicine, Loma Linda University Children’s Hospital, Loma Linda, CA 92354, USA;
| | - Il Seok Daniel Jeong
- School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (I.S.D.J.); (J.L.)
| | - Joanne Lee
- School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (I.S.D.J.); (J.L.)
| | - Lawrence Liu
- Department of Medicine, Washington University, St. Louis, MO 63110, USA;
| | - Matthew Kim
- Department of Nephrology, University of California, Irvine, CA 92868, USA;
| | - Rafael Villicana
- Department of Medicine, Division of Nephrology, Loma Linda University Adventist Health Center, Loma Linda University, Loma Linda, CA 92354, USA;
| | - Bobae Kim
- Department of Medicine, Loma Linda University Adventist Health Center, Loma Linda, CA 92354, USA; (B.K.); (J.M.)
| | - Jasmine Mitchell
- Department of Medicine, Loma Linda University Adventist Health Center, Loma Linda, CA 92354, USA; (B.K.); (J.M.)
| | - Muhammed Omair Kamal
- Department of Medicine, Division of Hematology and Oncology, Loma Linda University Adventist Health Center, Loma Linda University, Loma Linda, CA 92354, USA; (J.T.M.); (M.O.K.); (C.-S.C.); (H.C.)
| | - Chien-Shing Chen
- Department of Medicine, Division of Hematology and Oncology, Loma Linda University Adventist Health Center, Loma Linda University, Loma Linda, CA 92354, USA; (J.T.M.); (M.O.K.); (C.-S.C.); (H.C.)
| | - Yan Liu
- Department of Pathology, Loma Linda University Adventist Health Center, Loma Linda University, Loma Linda, CA 92354, USA; (Y.L.); (J.W.)
| | - Jun Wang
- Department of Pathology, Loma Linda University Adventist Health Center, Loma Linda University, Loma Linda, CA 92354, USA; (Y.L.); (J.W.)
| | - Richard Chinnock
- Department of Pediatrics, Loma Linda University Adventist Health Center, Loma Linda University, Loma Linda, CA 92354, USA;
| | - Huynh Cao
- Department of Medicine, Division of Hematology and Oncology, Loma Linda University Adventist Health Center, Loma Linda University, Loma Linda, CA 92354, USA; (J.T.M.); (M.O.K.); (C.-S.C.); (H.C.)
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Robinson CH, Coughlin CC, Chanchlani R, Dharnidharka VR. Post-transplant malignancies in pediatric organ transplant recipients. Pediatr Transplant 2021; 25:e13884. [PMID: 33111463 DOI: 10.1111/petr.13884] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 09/13/2020] [Accepted: 09/24/2020] [Indexed: 12/11/2022]
Abstract
The majority of cancer diagnoses in pediatric solid organ transplant recipients (SOTRs) are post-transplantation lymphoproliferative disorders (PTLD) or skin cancers. However, pediatric SOTRs are also at significantly elevated risk for multiple other solid and hematological cancers. The risks of specific cancers vary by transplanted organ, underlying disease, and immunosuppression factors. More than one-quarter of pediatric SOTRs develop cancer within 30 years of transplantation and their risk of solid cancer is 14 times greater than the general population. Pediatric SOTRs are at significantly higher risk of cancer-associated death. Improving patient survival among pediatric SOTRs puts them at risk of adult epithelial cancers associated with environmental carcinogenic exposures. Vaccination against oncogenic viruses and avoidance of excessive immunosuppression may reduce the risk of solid cancers following transplantation. Patient and family education regarding photoprotection is an essential component of skin cancer prevention. There is significant variability in cancer screening recommendations for SOTRs and general population approaches are typically not validated for transplant populations. An individualized approach to cancer screening should be developed based on estimated cancer risk, patient life expectancy, and screening test performance.
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Affiliation(s)
- Cal H Robinson
- Department of Pediatrics, McMaster University, Hamilton, ON, Canada
| | - Carrie C Coughlin
- Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Rahul Chanchlani
- Division of Pediatric Nephrology, Department of Pediatrics, McMaster University, Hamilton, ON, Canada.,Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada.,ICES McMaster, Hamilton, ON, Canada
| | - Vikas R Dharnidharka
- Division of Pediatric Nephrology, Hypertension and Pheresis, Washington University School of Medicine, Saint Louis, MO, USA
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47
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Wang Z, Xu Y, Zhao J, Fu YX. Epstein-Barr virus-associated monomorphic post-transplant lymphoproliferative disorder after pediatric kidney transplantation: A case report. World J Clin Cases 2021; 9:469-475. [PMID: 33521117 PMCID: PMC7812878 DOI: 10.12998/wjcc.v9.i2.469] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/18/2020] [Accepted: 11/29/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Post-transplant lymphoproliferative disease (PTLD) is the most common malignant tumor that occurs after kidney transplantation in children, and is associated with Epstein-Barr virus (EBV).
CASE SUMMARY We report a case of PTLD that occurred in a 17-year-old female patient at 5 mo post-transplant. The first symptom was abdominal pain accompanied by fever, nausea, and vomiting. EBV-associated monomorphic PTLD with multiple abdominal nodules was diagnosed by pathology, clinical manifestations, imaging results, and the presence of EB-DNA. After successful treatment with rituximab, the abdominal nodules in the spleen and liver disappeared.
CONCLUSION Early pathological biopsy to confirm the diagnosis is critical to treatment and prognosis. Reducing immunosuppression and rituximab therapy are effective methods for treating PTLD, but need to be initiated as early as possible.
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Affiliation(s)
- Zhen Wang
- Department of Kidney Transplantation, Tianjin First Central Hospital, Tianjin 300192, China
| | - Yang Xu
- Department of Kidney Transplantation, Tianjin First Central Hospital, Tianjin 300192, China
| | - Jie Zhao
- Department of Kidney Transplantation, Tianjin First Central Hospital, Tianjin 300192, China
| | - Ying-Xin Fu
- Department of Kidney Transplantation, Tianjin First Central Hospital, Tianjin 300192, China
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Overkamp M, Granai M, Bonzheim I, Steinhilber J, Schittenhelm J, Bethge W, Quintanilla-Martinez L, Fend F, Federmann B. Comparative analysis of post-transplant lymphoproliferative disorders after solid organ and hematopoietic stem cell transplantation reveals differences in the tumor microenvironment. Virchows Arch 2020; 478:1135-1148. [PMID: 33324999 PMCID: PMC8203555 DOI: 10.1007/s00428-020-02985-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 10/19/2020] [Accepted: 12/01/2020] [Indexed: 02/02/2023]
Abstract
Post-transplant lymphoproliferative disorders (PTLD) occur after solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HCT) and are frequently associated with Epstein-Barr virus (EBV). Because of the complex immune setup in PTLD patients, the tumor microenvironment (TME) is of particular interest to understand PTLD pathogenesis and elucidate predictive factors and possible treatment options. We present a comparative study of clinicopathological features of 48 PTLD after HCT (n = 26) or SOT (n = 22), including non-destructive (n = 6), polymorphic (n = 23), and monomorphic (n = 18) PTLD and classic Hodgkin lymphoma (n = 1). EBV was positive in 35 cases (73%). A detailed examination of the TME with image analysis-based quantification in 22 cases revealed an inflammatory TME despite underlying immunosuppression and significant differences in its density and composition depending on type of transplant, PTLD subtypes, and EBV status. Tumor-associated macrophages (TAMs) expressing CD163 (p = 0.0022) and Mannose (p = 0.0016) were enriched in PTLD after HCT. Double stains also showed differences in macrophage polarization, with more frequent M1 polarization after HCT (p = 0.0321). Higher counts for TAMs (CD163 (p = 0.0008) and cMaf (p = 0.0035)) as well as in the T cell compartment (Granzyme B (p = 0.0028), CD8 (p = 0.01), and for PD-L1 (p = 0.0305)) were observed depending on EBV status. In conclusion, despite the presence of immunosuppression, PTLD predominantly contains an inflammatory TME characterized by mostly M1-polarized macrophages and cytotoxic T cells. Status post HCT, EBV positivity, and polymorphic subtype are associated with an actively inflamed TME, indicating a specific response of the immune system. Further studies need to elucidate prognostic significance and potential therapeutic implications of the TME in PTLD.
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Affiliation(s)
- Mathis Overkamp
- Institute of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tuebingen, Liebermeisterstraße 8, 72076, Tuebingen, Germany
| | - Massimo Granai
- Institute of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tuebingen, Liebermeisterstraße 8, 72076, Tuebingen, Germany
- Section of Pathology, Department of Medical Biotechnology, University of Siena, Siena, Italy
| | - Irina Bonzheim
- Institute of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tuebingen, Liebermeisterstraße 8, 72076, Tuebingen, Germany
| | - Julia Steinhilber
- Institute of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tuebingen, Liebermeisterstraße 8, 72076, Tuebingen, Germany
| | - Jens Schittenhelm
- Institute of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tuebingen, Liebermeisterstraße 8, 72076, Tuebingen, Germany
| | - Wolfgang Bethge
- Department of Internal Medicine Hematology and Oncology, Comprehensive Cancer Center and University Hospital Tuebingen, Tuebingen, Germany
| | - Leticia Quintanilla-Martinez
- Institute of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tuebingen, Liebermeisterstraße 8, 72076, Tuebingen, Germany
| | - Falko Fend
- Institute of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tuebingen, Liebermeisterstraße 8, 72076, Tuebingen, Germany
| | - Birgit Federmann
- Institute of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tuebingen, Liebermeisterstraße 8, 72076, Tuebingen, Germany.
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Kirtane T, Uberoi GS, Uberoi AS, Loghavi S, Medeiros LJ, Bhutani MS. Posttransplant Lymphoproliferative Disorder Involving the Gastrointestinal Tract. JOURNAL OF DIGESTIVE ENDOSCOPY 2020. [DOI: 10.1055/s-0040-1713710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
AbstractPosttransplant lymphoproliferative disorder (PTLD) is a rare and life-threatening complication of both solid organ transplantation and hematopoietic stem cell transplantation. In most cases, PTLD develops in Epstein–Barr virus (EBV)-seropositive individuals in the setting of chronic immunosuppression and decreased T-cell surveillance. Clinical manifestations of PTLD may be nonspecific, resembling primary EBV infection (fever, night sweats, malaise, and cervical lymphadenopathy), or it can involve the central nervous system, bone marrow, kidneys, liver, lungs, and gastrointestinal tract. Gastrointestinal symptoms in the posttransplant setting may indicate underlying PTLD, and it is important for physicians to be able to recognize its appearance on endoscopy.
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Affiliation(s)
- Tejas Kirtane
- Department of Gastroenterology Hepatology and Nutrition, University of Texas Health Science Center, Texas, United States
| | - Guneesh S. Uberoi
- Department of Gastroenterology Hepatology and Nutrition, University of Texas Health Science Center, Texas, United States
| | - Angad S. Uberoi
- Department of Gastroenterology Hepatology and Nutrition, University of Texas Health Science Center, Texas, United States
| | - Sanam Loghavi
- Department of Hematopathology, University of Texas MD Anderson Cancer Center, Texas, United States
| | - L. Jeffrey Medeiros
- Department of Hematopathology, University of Texas MD Anderson Cancer Center, Texas, United States
| | - Manoop S. Bhutani
- Department of Gastroenterology Hepatology and Nutrition, University of Texas Health Science Center, Texas, United States
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Epstein-Barr Virus-negative Marginal Zone Lymphoma as an Uncommon Form of Monomorphic Posttransplant Lymphoproliferative Disorder. Am J Surg Pathol 2020; 44:1340-1352. [PMID: 32554995 DOI: 10.1097/pas.0000000000001514] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Monomorphic posttransplant lymphoproliferative disorders have been defined as lymphoid or plasmacytic proliferations that fulfill criteria for one of the B-cell or T/NK-cell neoplasms recognized in immunocompetent hosts in the current WHO Classification. Low-grade B-cell neoplasms have historically been excluded from this category, although rare reports of marginal zone lymphoma (MZL) have been described. We report 9 cases of posttransplant Epstein-Barr virus-negative MZL, all arising in solid organ transplant recipients (4 renal, 3 liver, 1 cardiac, and 1 liver, pancreas, and small bowel). Seven were extranodal MZL of mucosa-associated lymphoid tissue type, all of which had gastrointestinal involvement (4 colon, 1 duodenum, 1 stomach, and 1 oropharynx/base of tongue). Notably, the preferential involvement of intestine distinguishes posttransplant extranodal MZL from sporadic cases. Immunoglobulin light-chain restriction was seen in all cases, with polymerase chain reaction showing a monoclonal pattern in 7 of 8 cases with successful amplification of polymerase chain reaction products. A clonally unrelated recurrence was seen in one case. Next-generation sequencing identified recurrent mutations previously reported in MZL in 3/5 cases. MZL was diagnosed at least 1 year after solid organ transplant (median time to presentation, 84 mo; range, 13 to 108 mo). The median age was 44 (range, 9 to 73 y); the male: female ratio was 5:4. The mean follow-up was 33.4 months, with an indolent clinical course observed. A subset responded to reduction in immunosuppression and anti-CD20 therapy alone. These data support the designation of Epstein-Barr virus-negative MZL as an uncommon form of monomorphic posttransplant lymphoproliferative disorders.
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