Post transplant lymphoproliferative disorder: Difference between revisions

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* 90 to 95 percent of patients with post transplant lymphoproliferative disorder shows positive [[Serology|serologic]] of infection especially with [[Epstein Barr virus|Epstein-Barr virus]] ([[Epstein Barr virus|EBV]]) infection.<ref name="pmid7598473">{{cite journal |vauthors=Hanto DW |title=Classification of Epstein-Barr virus-associated posttransplant lymphoproliferative diseases: implications for understanding their pathogenesis and developing rational treatment strategies |journal=Annu. Rev. Med. |volume=46 |issue= |pages=381–94 |date=1995 |pmid=7598473 |doi=10.1146/annurev.med.46.1.381 |url=}}</ref>
* 90 to 95 percent of patients with post transplant lymphoproliferative disorder shows positive [[Serology|serologic]] of infection especially with [[Epstein Barr virus|Epstein-Barr virus]] ([[Epstein Barr virus|EBV]]) infection.<ref name="pmid7598473">{{cite journal |vauthors=Hanto DW |title=Classification of Epstein-Barr virus-associated posttransplant lymphoproliferative diseases: implications for understanding their pathogenesis and developing rational treatment strategies |journal=Annu. Rev. Med. |volume=46 |issue= |pages=381–94 |date=1995 |pmid=7598473 |doi=10.1146/annurev.med.46.1.381 |url=}}</ref>
* Membrane proteins associated with [[Epstein Barr virus|EBV]] plays a major role in contribute to [[B cell]] growth and survival.<ref name="pmid7859281">{{cite journal |vauthors=Mosialos G, Birkenbach M, Yalamanchili R, VanArsdale T, Ware C, Kieff E |title=The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family |journal=Cell |volume=80 |issue=3 |pages=389–99 |date=February 1995 |pmid=7859281 |doi= |url=}}</ref><ref name="pmid9037073">{{cite journal |vauthors=Izumi KM, Kaye KM, Kieff ED |title=The Epstein-Barr virus LMP1 amino acid sequence that engages tumor necrosis factor receptor associated factors is critical for primary B lymphocyte growth transformation |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue=4 |pages=1447–52 |date=February 1997 |pmid=9037073 |pmc=19811 |doi= |url=}}</ref><ref name="pmid9580648">{{cite journal |vauthors=Liebowitz D |title=Epstein-Barr virus and a cellular signaling pathway in lymphomas from immunosuppressed patients |journal=N. Engl. J. Med. |volume=338 |issue=20 |pages=1413–21 |date=May 1998 |pmid=9580648 |doi=10.1056/NEJM199805143382003 |url=}}</ref><ref name="pmid11905817">{{cite journal |vauthors=Thorley-Lawson DA |title=Epstein-Barr virus: exploiting the immune system |journal=Nat. Rev. Immunol. |volume=1 |issue=1 |pages=75–82 |date=October 2001 |pmid=11905817 |doi=10.1038/35095584 |url=}}</ref><ref name="pmid10196351">{{cite journal |vauthors=Kaiser C, Laux G, Eick D, Jochner N, Bornkamm GW, Kempkes B |title=The proto-oncogene c-myc is a direct target gene of Epstein-Barr virus nuclear antigen 2 |journal=J. Virol. |volume=73 |issue=5 |pages=4481–4 |date=May 1999 |pmid=10196351 |pmc=104340 |doi= |url=}}</ref><ref name="pmid1331789">{{cite journal |vauthors=Randhawa PS, Jaffe R, Demetris AJ, Nalesnik M, Starzl TE, Chen YY, Weiss LM |title=Expression of Epstein-Barr virus-encoded small RNA (by the EBER-1 gene) in liver specimens from transplant recipients with post-transplantation lymphoproliferative disease |journal=N. Engl. J. Med. |volume=327 |issue=24 |pages=1710–4 |date=December 1992 |pmid=1331789 |pmc=2956494 |doi=10.1056/NEJM199212103272403 |url=}}</ref>
* Membrane proteins associated with [[Epstein Barr virus|EBV]] plays a major role in contribute to [[B cell]] growth and survival.<ref name="pmid7859281">{{cite journal |vauthors=Mosialos G, Birkenbach M, Yalamanchili R, VanArsdale T, Ware C, Kieff E |title=The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family |journal=Cell |volume=80 |issue=3 |pages=389–99 |date=February 1995 |pmid=7859281 |doi= |url=}}</ref><ref name="pmid9037073">{{cite journal |vauthors=Izumi KM, Kaye KM, Kieff ED |title=The Epstein-Barr virus LMP1 amino acid sequence that engages tumor necrosis factor receptor associated factors is critical for primary B lymphocyte growth transformation |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue=4 |pages=1447–52 |date=February 1997 |pmid=9037073 |pmc=19811 |doi= |url=}}</ref><ref name="pmid9580648">{{cite journal |vauthors=Liebowitz D |title=Epstein-Barr virus and a cellular signaling pathway in lymphomas from immunosuppressed patients |journal=N. Engl. J. Med. |volume=338 |issue=20 |pages=1413–21 |date=May 1998 |pmid=9580648 |doi=10.1056/NEJM199805143382003 |url=}}</ref><ref name="pmid11905817">{{cite journal |vauthors=Thorley-Lawson DA |title=Epstein-Barr virus: exploiting the immune system |journal=Nat. Rev. Immunol. |volume=1 |issue=1 |pages=75–82 |date=October 2001 |pmid=11905817 |doi=10.1038/35095584 |url=}}</ref><ref name="pmid10196351">{{cite journal |vauthors=Kaiser C, Laux G, Eick D, Jochner N, Bornkamm GW, Kempkes B |title=The proto-oncogene c-myc is a direct target gene of Epstein-Barr virus nuclear antigen 2 |journal=J. Virol. |volume=73 |issue=5 |pages=4481–4 |date=May 1999 |pmid=10196351 |pmc=104340 |doi= |url=}}</ref><ref name="pmid1331789">{{cite journal |vauthors=Randhawa PS, Jaffe R, Demetris AJ, Nalesnik M, Starzl TE, Chen YY, Weiss LM |title=Expression of Epstein-Barr virus-encoded small RNA (by the EBER-1 gene) in liver specimens from transplant recipients with post-transplantation lymphoproliferative disease |journal=N. Engl. J. Med. |volume=327 |issue=24 |pages=1710–4 |date=December 1992 |pmid=1331789 |pmc=2956494 |doi=10.1056/NEJM199212103272403 |url=}}</ref>
** LMP-1-Latent membrane protein 1
** LMP-1-Latent membrane protein 1  
** LMP-2A-Latent membrane protein 2
** LMP-2A-Latent membrane protein 2
** [[Epstein Barr virus|EBNA-2]](Epstein-Barr nuclear antigen 2) and  
** [[Epstein Barr virus|EBNA-2]](Epstein-Barr nuclear antigen 2) and  
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**Large [[Lymphoid cell|lymphoid cells]] with a diameter (2x a resting [[lymphocyte]])
**Large [[Lymphoid cell|lymphoid cells]] with a diameter (2x a resting [[lymphocyte]])
==Causes==
==Causes==
*The most common causes of post transplant lymphoproliferative disorder are:<ref name="pmid17049061">{{cite journal |vauthors=Caillard S, Lelong C, Pessione F, Moulin B |title=Post-transplant lymphoproliferative disorders occurring after renal transplantation in adults: report of 230 cases from the French Registry |journal=Am. J. Transplant. |volume=6 |issue=11 |pages=2735–42 |date=November 2006 |pmid=17049061 |doi=10.1111/j.1600-6143.2006.01540.x |url=}}</ref>  
*The most common causes of post transplant lymphoproliferative disorder are:<ref name="pmid17049061">{{cite journal |vauthors=Caillard S, Lelong C, Pessione F, Moulin B |title=Post-transplant lymphoproliferative disorders occurring after renal transplantation in adults: report of 230 cases from the French Registry |journal=Am. J. Transplant. |volume=6 |issue=11 |pages=2735–42 |date=November 2006 |pmid=17049061 |doi=10.1111/j.1600-6143.2006.01540.x |url=}}</ref><ref name="pmid16436959">{{cite journal |vauthors=Smith JM, Rudser K, Gillen D, Kestenbaum B, Seliger S, Weiss N, McDonald RA, Davis CL, Stehmen-Breen C |title=Risk of lymphoma after renal transplantation varies with time: an analysis of the United States Renal Data System |journal=Transplantation |volume=81 |issue=2 |pages=175–80 |date=January 2006 |pmid=16436959 |doi=10.1097/01.tp.0000188687.18972.a8 |url=}}</ref><ref name="pmid16314791">{{cite journal |vauthors=Caillard S, Dharnidharka V, Agodoa L, Bohen E, Abbott K |title=Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression |journal=Transplantation |volume=80 |issue=9 |pages=1233–43 |date=November 2005 |pmid=16314791 |doi= |url=}}</ref><ref name="pmid16177631">{{cite journal |vauthors=Bakker NA, van Imhoff GW, Verschuuren EA, van Son WJ, van der Heide JJ, Lems SP, Veeger NJ, Kluin PM, Kluin-Nelemans HC, Hepkema BG |title=HLA antigens and post renal transplant lymphoproliferative disease: HLA-B matching is critical |journal=Transplantation |volume=80 |issue=5 |pages=595–9 |date=September 2005 |pmid=16177631 |doi= |url=}}</ref>  
**Epstein-Barr virus.<ref name="pmid15979320">{{cite journal |vauthors=Taylor AL, Marcus R, Bradley JA |title=Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation |journal=Crit. Rev. Oncol. Hematol. |volume=56 |issue=1 |pages=155–67 |year=2005 |pmid=15979320 |doi=10.1016/j.critrevonc.2005.03.015 |url=}}</ref>
**[[Epstein-Barr virus]]<ref name="pmid15979320">{{cite journal |vauthors=Taylor AL, Marcus R, Bradley JA |title=Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation |journal=Crit. Rev. Oncol. Hematol. |volume=56 |issue=1 |pages=155–67 |year=2005 |pmid=15979320 |doi=10.1016/j.critrevonc.2005.03.015 |url=}}</ref>
**Immunosuppression
**[[Immunosuppression]]
**Recipient age and  
**Recipient [[age]]: under 25 years
**Ethnicity
**[[Ethnicity and health|Ethnicity]]
**History of pretransplant [[malignancy]]
**Fewer [[HLA]] matches
**Treatment with ATG


==Differentiating Post Transplant Lymphoproliferative Disorder from Other Diseases==
==Differentiating Post Transplant Lymphoproliferative Disorder from Other Diseases==

Revision as of 20:46, 18 October 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

Synonyms and keywords: PTLD;

Overview

Post-transplant lymphoproliferative disorder (also known as PTLD) is defined as a lymphoid (immune cells) and/or plasmacytic proliferations (rapid increase) due to therapeutic immunosuppression after organ transplantation especially in the patients who are undergoing solid organ or allogeneic (donor) hematopoietic stem cell transplantation. Patients with post-transplant lymphoproliferative disorder may develop serious complications of transplantation with infectious mononucleosis-like lesions due to Epstein-Barr virus (EBV) or polyclonal polymorphic B-cell hyperplasia. In some cases, B-cells may undergo mutations which will render them malignant, giving rise to a lymphoma. The malignant cell clone can become the dominant proliferating cell type, leading to a group of B cell lymphomas occurring in immunosuppressed patients following organ transplant. Post transplant lymphoproliferative disorder arises from germinal center or post-germinal center B cells (B-PTLD), which are normally involved the production of antibodies and durable memory B cells. Post transplant lymphoproliferative disorder was first discovered by Denis Parsons Burkitt, an Irish physician, in 1965. According to World Health Organization (WHO) classification system, post transplant lymphoproliferative disorder may be classified into 4 subtypes: early hyperplastic lesions, polymorphic lesions, monomorphic lesions, and classic Hodgkin-type lymphomas. Post transplant lymphoproliferative disorder is very rare, and the prevalence of post transplant lymphoproliferative disorder remains unknown. Post transplant lymphoproliferative disorder is more commonly observed among young patients. The medical treatment for post transplant lymphoproliferative disorder, includes: immunosuppression, antiviral therapy, interferon alpha therapy, CD20 antibody therapy, and chemotherapy.

Historical Perspective

  • Post transplant lymphoproliferative disorder was first discovered by Denis Parsons Burkitt, an Irish physician, in 1965.

Classification

  • Post transplant lymphoproliferative disorder may be classified according to 2008 World Health Organization (WHO) classification system, into 3 subtypes:[1]
Category Subtype
Early hyperplastic lesions
Polymorphic lesions
Monomorphic lesions B-cell lymphomas

T-cell lymphomas

Other types

Pathophysiology

  • It is understood that post transplant lymphoproliferative disorder is the result of B cell proliferation induced by Epstein-Barr virus (EBV) infection.[2][3][4]
  • 90 to 95 percent of patients with post transplant lymphoproliferative disorder shows positive serologic of infection especially with Epstein-Barr virus (EBV) infection.[5]
  • Membrane proteins associated with EBV plays a major role in contribute to B cell growth and survival.[6][7][8][9][10][11]
    • LMP-1-Latent membrane protein 1
    • LMP-2A-Latent membrane protein 2
    • EBNA-2(Epstein-Barr nuclear antigen 2) and
    • EBNA-LP(Epstein-Barr nuclear antigen 2 ladder protein)
  • The overexpression of bcl-2 has been associated with the development of post transplant lymphoproliferative disorder.
  • On gross pathology, characteristic findings of post transplant lymphoproliferative disorder, include:
    • Resemblance to large cell lymphomas
    • No remarkable findings

Causes

Differentiating Post Transplant Lymphoproliferative Disorder from Other Diseases

  • Post transplant lymphoproliferative disorder must be differentiated from other diseases that cause fatigue, weight-loss, and fever, such as:

Epidemiology and Demographics

  • Post transplant lymphoproliferative disorder is very rare.
  • The prevalence of post transplant lymphoproliferative disorder remains unknown.

Age

  • Post transplant lymphoproliferative disorder is more commonly observed among young patients.

Gender

  • Females are slightly more affected with post transplant lymphoproliferative disorder than men.

Race

  • There is no racial predilection for post transplant lymphoproliferative disorder.

Risk Factors

  • The most common risk factors in the development of post transplant lymphoproliferative disorder is B cell neoplasm associated with Epstein-Barr infection.

Natural History, Complications and Prognosis

  • The majority of patients with post transplant lymphoproliferative disorder are symptomatic at the time of diagnosis.
  • Early clinical features include fatigue, fever, and weight-loss.
  • If left untreated, patients with post transplant lymphoproliferative disorder may progress to develop organ failure.
  • The most common complication of post transplant lymphoproliferative disorder is fatal infection.
  • Prognosis is generally poor, and the 5-year survival rate of patients with post transplant lymphoproliferative disorder is approximately 37- 61%.

Diagnosis

Symptoms

  • Post transplant lymphoproliferative disorder is usually asymptomatic.[16]
  • Symptoms of post transplant lymphoproliferative disorder may include the following:

Physical Examination

  • Patients with post transplant lymphoproliferative disorder usually appear pale and malnourished.[16]
  • Physical examination may be remarkable for:
  • Swelling in the lymph nodes in the neck or underarms
  • Fever
  • Night sweats
  • Unexplained weight loss

Laboratory Findings

  • There are no specific laboratory findings associated with post transplant lymphoproliferative disorder.[16]

Imaging Findings

  • There are no imaging findings associated with post transplant lymphoproliferative disorder.

Treatment

Medical Therapy

  • The medical treatment for post transplant lymphoproliferative disorder, includes: [17]
  • Immunosuppression
  • Antiviral therapy
  • Interferon alpha therapy
  • CD20 antibody therapy
  • Chemotherapy
  • Post-transplant lymphoproliferative disorder may regress spontaneously on reduction or cessation of immunosuppressant medication anti-viral therapy.

Surgery

  • Surgery is not recommended for patients with post transplant lymphoproliferative disorder.[16]

Prevention

  • There are no primary preventive measures available for post transplant lymphoproliferative disorder.

References

  1. LaCasce, A. S. (2006). "Post-Transplant Lymphoproliferative Disorders". The Oncologist. 11 (6): 674–680. doi:10.1634/theoncologist.11-6-674. ISSN 1083-7159.
  2. Kotton CN, Fishman JA (June 2005). "Viral infection in the renal transplant recipient". J. Am. Soc. Nephrol. 16 (6): 1758–74. doi:10.1681/ASN.2004121113. PMID 15829710.
  3. Patton DF, Wilkowski CW, Hanson CA, Shapiro R, Gajl-Peczalska KJ, Filipovich AH, McClain KL (June 1990). "Epstein-Barr virus--determined clonality in posttransplant lymphoproliferative disease". Transplantation. 49 (6): 1080–4. PMID 2163133.
  4. Taylor AL, Marcus R, Bradley JA (October 2005). "Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation". Crit. Rev. Oncol. Hematol. 56 (1): 155–67. doi:10.1016/j.critrevonc.2005.03.015. PMID 15979320.
  5. Hanto DW (1995). "Classification of Epstein-Barr virus-associated posttransplant lymphoproliferative diseases: implications for understanding their pathogenesis and developing rational treatment strategies". Annu. Rev. Med. 46: 381–94. doi:10.1146/annurev.med.46.1.381. PMID 7598473.
  6. Mosialos G, Birkenbach M, Yalamanchili R, VanArsdale T, Ware C, Kieff E (February 1995). "The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family". Cell. 80 (3): 389–99. PMID 7859281.
  7. Izumi KM, Kaye KM, Kieff ED (February 1997). "The Epstein-Barr virus LMP1 amino acid sequence that engages tumor necrosis factor receptor associated factors is critical for primary B lymphocyte growth transformation". Proc. Natl. Acad. Sci. U.S.A. 94 (4): 1447–52. PMC 19811. PMID 9037073.
  8. Liebowitz D (May 1998). "Epstein-Barr virus and a cellular signaling pathway in lymphomas from immunosuppressed patients". N. Engl. J. Med. 338 (20): 1413–21. doi:10.1056/NEJM199805143382003. PMID 9580648.
  9. Thorley-Lawson DA (October 2001). "Epstein-Barr virus: exploiting the immune system". Nat. Rev. Immunol. 1 (1): 75–82. doi:10.1038/35095584. PMID 11905817.
  10. Kaiser C, Laux G, Eick D, Jochner N, Bornkamm GW, Kempkes B (May 1999). "The proto-oncogene c-myc is a direct target gene of Epstein-Barr virus nuclear antigen 2". J. Virol. 73 (5): 4481–4. PMC 104340. PMID 10196351.
  11. Randhawa PS, Jaffe R, Demetris AJ, Nalesnik M, Starzl TE, Chen YY, Weiss LM (December 1992). "Expression of Epstein-Barr virus-encoded small RNA (by the EBER-1 gene) in liver specimens from transplant recipients with post-transplantation lymphoproliferative disease". N. Engl. J. Med. 327 (24): 1710–4. doi:10.1056/NEJM199212103272403. PMC 2956494. PMID 1331789.
  12. Caillard S, Lelong C, Pessione F, Moulin B (November 2006). "Post-transplant lymphoproliferative disorders occurring after renal transplantation in adults: report of 230 cases from the French Registry". Am. J. Transplant. 6 (11): 2735–42. doi:10.1111/j.1600-6143.2006.01540.x. PMID 17049061.
  13. Smith JM, Rudser K, Gillen D, Kestenbaum B, Seliger S, Weiss N, McDonald RA, Davis CL, Stehmen-Breen C (January 2006). "Risk of lymphoma after renal transplantation varies with time: an analysis of the United States Renal Data System". Transplantation. 81 (2): 175–80. doi:10.1097/01.tp.0000188687.18972.a8. PMID 16436959.
  14. Caillard S, Dharnidharka V, Agodoa L, Bohen E, Abbott K (November 2005). "Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression". Transplantation. 80 (9): 1233–43. PMID 16314791.
  15. Bakker NA, van Imhoff GW, Verschuuren EA, van Son WJ, van der Heide JJ, Lems SP, Veeger NJ, Kluin PM, Kluin-Nelemans HC, Hepkema BG (September 2005). "HLA antigens and post renal transplant lymphoproliferative disease: HLA-B matching is critical". Transplantation. 80 (5): 595–9. PMID 16177631.
  16. 16.0 16.1 16.2 16.3 16.4 Taylor AL, Marcus R, Bradley JA (2005). "Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation". Crit. Rev. Oncol. Hematol. 56 (1): 155–67. doi:10.1016/j.critrevonc.2005.03.015. PMID 15979320.
  17. BioMed Central. EBV-associated post-transplantation B-cell lymphoproliferative disorder following allogenic stem cell transplantation for acute lymphoblastic leukaemia: tumor regression after reduction of immunosuppression - a case report. https://diagnosticpathology.biomedcentral.com/articles/10.1186/1746-1596-5-21 Accessed on May 23, 2016