Post transplant lymphoproliferative disorder: Difference between revisions

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{{Infobox_Disease |
__NOTOC__
  Name          = {{PAGENAME}} |
{{SI}}                                                                 
  Image          = |
{{CMG}}; {{AE}} {{VKG}} {{MV}}
  Caption        = |
  DiseasesDB    = 34154 |
{{SK}} PTLD;
  ICD10          = |
  ICD9          = |
==Overview==
  ICDO          = M9970/1  |
  OMIM          = |
  MedlinePlus    = |
  MeshID        = |
}}
{{Post transplant lymphoproliferative disorder}}
{{CMG}}


'''''Synonyms and Keywords:''''' PTLD
'''Post-transplant lymphoproliferative disorder''' (also known as '''PTLD''') is defined as a [[lymphoid]] (immune cells) and/or plasmacytic [[Proliferation|proliferations]] (rapid increase) due to [[Immunosuppression|therapeutic immunosuppression]] after organ [[transplantation]] especially in the patients who are undergoing solid organ or [[allogeneic]] (donor) [[hematopoietic stem cell transplantation]]. Post transplant lymphoproliferative disorder was first discovered by Denis Parsons Burkitt, an Irish physician, in 1965. According to World Health Organization ([[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's Lymphoma|Hodgkin-type lymphomas]]. Patients with post-transplant [[Lymphoproliferative disorders|lymphoproliferative disorder]] may develop serious [[complications]] of [[transplantation]] with [[infectious mononucleosis]]-like [[Lesion|lesions]] due to [[Epstein Barr virus|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]] [[lymphoma]]s occurring in [[Immunosuppression|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 cell|memory B cells]].  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|antiviral]] therapy, [[interferon alpha]] therapy, [[CD20]] [[antibody]] therapy, and [[chemotherapy]].


==[[Post transplant lymphoproliferative disorder overview|Overview]]==
==Historical Perspective==
*Post transplant lymphoproliferative disorder was first discovered by Denis Parsons Burkitt, an Irish physician, in 1965.
*Post transplant lymphoproliferative disorder was first introduced in 1984 by Starzl.<ref name="PetraraGiunco20153">{{cite journal|last1=Petrara|first1=Maria Raffaella|last2=Giunco|first2=Silvia|last3=Serraino|first3=Diego|last4=Dolcetti|first4=Riccardo|last5=De Rossi|first5=Anita|title=Post-transplant lymphoproliferative disorders: From epidemiology to pathogenesis-driven treatment|journal=Cancer Letters|volume=369|issue=1|year=2015|pages=37–44|issn=03043835|doi=10.1016/j.canlet.2015.08.007}}</ref>


==[[Post transplant lymphoproliferative disorder historical perspective|Historical Perspective]]==
==Classification==
*Post transplant lymphoproliferative disorder may be classified according to 2008 [[World Health Organization]] ([[WHO]]) classification system, into 3 subtypes:<ref name="LaCasce2006">{{cite journal|last1=LaCasce|first1=A. S.|title=Post-Transplant Lymphoproliferative Disorders|journal=The Oncologist|volume=11|issue=6|year=2006|pages=674–680|issn=1083-7159|doi=10.1634/theoncologist.11-6-674}}</ref><ref name="PetraraGiunco20154">{{cite journal|last1=Petrara|first1=Maria Raffaella|last2=Giunco|first2=Silvia|last3=Serraino|first3=Diego|last4=Dolcetti|first4=Riccardo|last5=De Rossi|first5=Anita|title=Post-transplant lymphoproliferative disorders: From epidemiology to pathogenesis-driven treatment|journal=Cancer Letters|volume=369|issue=1|year=2015|pages=37–44|issn=03043835|doi=10.1016/j.canlet.2015.08.007}}</ref>
:
{| class="wikitable"
|+
!Category
!Subtype
|-
!Early [[hyperplastic]] [[Lesion|lesions]]
|
* [[Infectious mononucleosis]]-type acute illness
* [[Polyclonal]] [[B cell proliferation]]
* No evidence of [[malignant]] transformation
* Plasmacytic [[hyperplasia]]
|-
![[Polymorphic]] [[lesions]]
|
* Evidence of [[malignant]] [[transformation]]
* Nuclear [[atypia]]
* [[Necrosis]]
* [[Lymphoid]] architecture distortion
* Found in [[immunocompetent]] patients
|-
!Monomorphic lesions
|'''[[B-cell lymphoma|B-cell lymphomas]]'''
* [[Diffuse large B-cell lymphoma]]
* Burkitt’s/[[Burkitt's lymphoma|Burkitt’s]]-like lymphoma
* [[Plasma cell myeloma]]


* Monoclonal [[lymphoid]] [[Proliferation|proliferations]]
'''[[T-cell lymphoma|T-cell lymphomas]]'''
* Peripheral [[T-cell lymphoma]]
* [[Gamma]]/delta [[T-cell lymphoma]]
* T-[[Natural killer cell|natural killer]] ([[NK-cells|NK]]) [[lymphoma]]
|-
!Other types
|
* [[Hodgkin’s disease]]
* [[Plasmacytoma]] like [[Lymphomas|lymphoma]]
|}
:
==Pathophysiology==
* It is understood that post transplant lymphoproliferative disorder is the result of [[B cell]] [[proliferation]] induced by [[Epstein Barr virus|Epstein-Barr virus]] ([[Epstein Barr virus|EBV]]) infection.<ref name="pmid15829710">{{cite journal |vauthors=Kotton CN, Fishman JA |title=Viral infection in the renal transplant recipient |journal=J. Am. Soc. Nephrol. |volume=16 |issue=6 |pages=1758–74 |date=June 2005 |pmid=15829710 |doi=10.1681/ASN.2004121113 |url=}}</ref><ref name="pmid2163133">{{cite journal |vauthors=Patton DF, Wilkowski CW, Hanson CA, Shapiro R, Gajl-Peczalska KJ, Filipovich AH, McClain KL |title=Epstein-Barr virus--determined clonality in posttransplant lymphoproliferative disease |journal=Transplantation |volume=49 |issue=6 |pages=1080–4 |date=June 1990 |pmid=2163133 |doi= |url=}}</ref><ref name="pmid159793202">{{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 |date=October 2005 |pmid=15979320 |doi=10.1016/j.critrevonc.2005.03.015 |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>
** LMP-1-Latent membrane protein 1
** LMP-2A-Latent membrane protein 2
** [[Epstein Barr virus|EBNA-2]] (Epstein-Barr nuclear antigen 2) and
** EBNA-LP (Epstein-Barr nuclear antigen 2 ladder protein)


==[[Post transplant lymphoproliferative disorder pathophysiology|Pathophysiology]]==
*


==[[Post transplant lymphoproliferative disorder causes|Causes]]==
*Post transplant lymphoproliferative disorder arises from [[germinal center]] or [[Germinal center|post-germinal center B cell]]<nowiki/>[[Germinal center|s]] (B-PTLD) , which are normally involved the production of [[antibodies]] and durable [[Memory B cell|memory B cells]].
*The [[pathogenesis]] of post transplant lymphoproliferative disorder is also characterized by the production of [[interleukin-10]].


==[[Post transplant lymphoproliferative disorder differential diagnosis|Differentiating Post transplant lymphoproliferative disorder from other Diseases]]==
*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 [[Lymphoma|lymphomas]]
**Palpable [[lymphadenopathy]] based on the level of involvement


==[[Post transplant lymphoproliferative disorder epidemiology and demographics|Epidemiology and Demographics]]==
*On microscopic [[histopathological]] analysis, characteristic findings of post transplant lymphoproliferative disorder, include:
**Resemblance to large cell [[lymphomas]]
**Large [[Lymphoid cell|lymphoid cells]] with a diameter (2x a resting [[lymphocyte]])
==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><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>
**[[Immunosuppression]]
**Recipient [[age]]: under 25 years
**[[Ethnicity and health|Ethnicity]]
**History of pretransplant [[malignancy]]
**Fewer [[HLA]] matches
**Treatment with ATG
 
==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:<ref name="pmid18466428">{{cite journal |vauthors=Rohr JC, Wagner HJ, Lauten M, Wacker HH, Jüttner E, Hanke C, Pohl M, Niemeyer CM |title=Differentiation of EBV-induced post-transplant Hodgkin lymphoma from Hodgkin-like post-transplant lymphoproliferative disease |journal=Pediatr Transplant |volume=12 |issue=4 |pages=426–31 |date=June 2008 |pmid=18466428 |doi=10.1111/j.1399-3046.2007.00816.x |url=}}</ref>
*[[Infectious mononucleosis]]
*Diffuse [[large B-cell lymphoma]]
*[[Lymphoblastic lymphoma|Lymphoblastic]] lymphoma
*Blastic [[mantle cell lymphoma]] ([[MCL]])
 
==Epidemiology and Demographics==
 
=== '''Incidence''' ===
* The [[incidence]] of post transplant lymphoproliferative disorder is approximately 20,000 in 100,000 of all cancers especially with solid organ transplantation.<ref name="pmid7779838">{{cite journal |vauthors=Walker RC, Paya CV, Marshall WF, Strickler JG, Wiesner RH, Velosa JA, Habermann TM, Daly RC, McGregor CG |title=Pretransplantation seronegative Epstein-Barr virus status is the primary risk factor for posttransplantation lymphoproliferative disorder in adult heart, lung, and other solid organ transplantations |journal=J. Heart Lung Transplant. |volume=14 |issue=2 |pages=214–21 |date=1995 |pmid=7779838 |doi= |url=}}</ref><ref name="pmid14555552">{{cite journal |vauthors=Reams BD, McAdams HP, Howell DN, Steele MP, Davis RD, Palmer SM |title=Posttransplant lymphoproliferative disorder: incidence, presentation, and response to treatment in lung transplant recipients |journal=Chest |volume=124 |issue=4 |pages=1242–9 |date=October 2003 |pmid=14555552 |doi= |url=}}</ref><ref name="pmid14520450">{{cite journal |vauthors=Adami J, Gäbel H, Lindelöf B, Ekström K, Rydh B, Glimelius B, Ekbom A, Adami HO, Granath F |title=Cancer risk following organ transplantation: a nationwide cohort study in Sweden |journal=Br. J. Cancer |volume=89 |issue=7 |pages=1221–7 |date=October 2003 |pmid=14520450 |pmc=2394311 |doi=10.1038/sj.bjc.6601219 |url=}}</ref><ref name="pmid23222821">{{cite journal |vauthors=Morton M, Coupes B, Roberts SA, Klapper PE, Byers RJ, Vallely PJ, Ryan K, Picton ML |title=Epidemiology of posttransplantation lymphoproliferative disorder in adult renal transplant recipients |journal=Transplantation |volume=95 |issue=3 |pages=470–8 |date=February 2013 |pmid=23222821 |doi=10.1097/TP.0b013e318276a237 |url=}}</ref><ref name="pmid9346628">{{cite journal |vauthors=Penn I |title=Posttransplantation de novo tumors in liver allograft recipients |journal=Liver Transpl Surg |volume=2 |issue=1 |pages=52–9 |date=January 1996 |pmid=9346628 |doi= |url=}}</ref><ref name="PetraraGiunco2015">{{cite journal|last1=Petrara|first1=Maria Raffaella|last2=Giunco|first2=Silvia|last3=Serraino|first3=Diego|last4=Dolcetti|first4=Riccardo|last5=De Rossi|first5=Anita|title=Post-transplant lymphoproliferative disorders: From epidemiology to pathogenesis-driven treatment|journal=Cancer Letters|volume=369|issue=1|year=2015|pages=37–44|issn=03043835|doi=10.1016/j.canlet.2015.08.007}}</ref>
* The [[incidence]] of post transplant lymphoproliferative disorder in [[liver]] transplants is approximately 1000 to 2000 in 100,000 patients.
* The [[incidence]] of post transplant lymphoproliferative disorder in [[renal]] transplant is approximately 1000 to 3000 in 100,000 patients.
* The [[incidence]] of post transplant lymphoproliferative disorder in [[heart]] transplant is approximately 2000 to 6000 in 100,000 patients.
* The [[incidence]] of post transplant lymphoproliferative disorder in [[lung]] transplant is approximately 2000 to 9000 in 100,000 patients.
* The [[incidence]] of post transplant lymphoproliferative disorder in  [[Intestine|intestinal]] or multi organ transplants is approximately as high as 11,000 to 33,000 in 100,000 patients.
 
=== Prevalence ===
*The [[prevalence]] of post transplant lymphoproliferative disorder remains unknown.
 
===Age===
*Post transplant lymphoproliferative disorder is more commonly observed among young patients.<ref name="PetraraGiunco20152">{{cite journal|last1=Petrara|first1=Maria Raffaella|last2=Giunco|first2=Silvia|last3=Serraino|first3=Diego|last4=Dolcetti|first4=Riccardo|last5=De Rossi|first5=Anita|title=Post-transplant lymphoproliferative disorders: From epidemiology to pathogenesis-driven treatment|journal=Cancer Letters|volume=369|issue=1|year=2015|pages=37–44|issn=03043835|doi=10.1016/j.canlet.2015.08.007}}</ref>
===Gender===
*Females are slightly more affected with post transplant lymphoproliferative disorder than men.<ref name="LaCasce20062">{{cite journal|last1=LaCasce|first1=A. S.|title=Post-Transplant Lymphoproliferative Disorders|journal=The Oncologist|volume=11|issue=6|year=2006|pages=674–680|issn=1083-7159|doi=10.1634/theoncologist.11-6-674}}</ref>
 
===Race===
*There is no [[racial]] predilection for post transplant lymphoproliferative disorder.<ref name="LaCasce20063">{{cite journal|last1=LaCasce|first1=A. S.|title=Post-Transplant Lymphoproliferative Disorders|journal=The Oncologist|volume=11|issue=6|year=2006|pages=674–680|issn=1083-7159|doi=10.1634/theoncologist.11-6-674}}</ref>


==[[Post transplant lymphoproliferative disorder natural history, complications and prognosis|Natural History, Complications and Prognosis]]==
==Risk Factors==
*The most common risk factors in the development of post transplant lymphoproliferative disorder is:<ref name="WeissmannFerry1995">{{cite journal|last1=Weissmann|first1=David J.|last2=Ferry|first2=Judith A.|last3=Harris|first3=Nancy L.|last4=Louis|first4=David N.|last5=Delmonico|first5=Francis|last6=Spiro|first6=Ira|title=Posttransplantation Lymphoproliferative Disorders in Solid Organ Recipients Are Predominantly Aggressive Tumors of Host Origin|journal=American Journal of Clinical Pathology|volume=103|issue=6|year=1995|pages=748–755|issn=0002-9173|doi=10.1093/ajcp/103.6.748}}</ref><ref name="Cohen2000">{{cite journal|last1=Cohen|first1=Jeffrey I.|title=Epstein–Barr Virus Infection|journal=New England Journal of Medicine|volume=343|issue=7|year=2000|pages=481–492|issn=0028-4793|doi=10.1056/NEJM200008173430707}}</ref><ref name="MañezBreinig1997">{{cite journal|last1=Mañez|first1=Rafael|last2=Breinig|first2=Mary C.|last3=Linden|first3=Peter|last4=Wilson|first4=John|last5=Torre‐Cisneros|first5=Julian|last6=Kusne|first6=Shimon|last7=Dummer|first7=Stephen|last8=Ho|first8=Monto|title=Posttransplant Lymphoproliferative Disease in Primary Epstein‐Barr Virus Infection after Liver Transplantation: The Role of Cytomegalovirus Disease|journal=The Journal of Infectious Diseases|volume=176|issue=6|year=1997|pages=1462–1467|issn=0022-1899|doi=10.1086/514142}}</ref><ref name="LibertinyWatson2001">{{cite journal|last1=Libertiny|first1=G.|last2=Watson|first2=C. J. E.|last3=Gray|first3=D. W. R.|last4=Welsh|first4=K. I.|last5=Morris|first5=P. J.|title=Rising incidence of post-transplant lymphoproliferative disease in kidney transplant recipients|journal=British Journal of Surgery|volume=88|issue=10|year=2001|pages=1330–1334|issn=0007-1323|doi=10.1046/j.0007-1323.2001.01924.x}}</ref><ref name="CaillardDharnidharka2005">{{cite journal|last1=Caillard|first1=Sophie|last2=Dharnidharka|first2=Vikas|last3=Agodoa|first3=Lawrence|last4=Bohen|first4=Erin|last5=Abbott|first5=Kevin|title=Posttransplant Lymphoproliferative Disorders after Renal Transplantation in the United States in Era of Modern Immunosuppression|journal=Transplantation|volume=80|issue=9|year=2005|pages=1233–1243|issn=0041-1337|doi=10.1097/01.tp.0000179639.98338.39}}</ref><ref name="MinamitaniMa2017">{{cite journal|last1=Minamitani|first1=Takeharu|last2=Ma|first2=Yijie|last3=Zhou|first3=Hufeng|last4=Kida|first4=Hiroshi|last5=Tsai|first5=Chao-Yuan|last6=Obana|first6=Masanori|last7=Okuzaki|first7=Daisuke|last8=Fujio|first8=Yasushi|last9=Kumanogoh|first9=Atsushi|last10=Zhao|first10=Bo|last11=Kikutani|first11=Hitoshi|last12=Kieff|first12=Elliott|last13=Gewurz|first13=Benjamin E.|last14=Yasui|first14=Teruhito|title=Mouse model of Epstein–Barr virus LMP1- and LMP2A-driven germinal center B-cell lymphoproliferative disease|journal=Proceedings of the National Academy of Sciences|volume=114|issue=18|year=2017|pages=4751–4756|issn=0027-8424|doi=10.1073/pnas.1701836114}}</ref>
**[[B cell]] [[neoplasm]] associated with [[Epstein-Barr virus|Epstein-Barr infection]].
**[[Cytomegalovirus]] ([[CMV]]).
**[[Cyclosporine]] use.
**[[Tacrolimus]] use.
**Induction [[therapy]].
**The degree and duration of [[immunosuppression]] plays a very important role in the risk of developing PTLD.
**[[Epstein Barr virus|EBV]] infection from grafted [[B lymphocyte]]<nowiki/>s.
**Latent [[Epstein Barr virus|EBV]] infection leads to malignancies like:
***[[HIV]]-associated [[lymphomas]].
***[[Endemic]] [[Burkitt's lymphoma|Burkitt’s]] lymphoma.
***[[Hodgkin's lymphoma|Hodgkin’s]] lymphoma.
**
**
== Natural History, Complications and Prognosis==


==Diagnosis==
=== Natural History ===
*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]].


[[Post transplant lymphoproliferative disorder history and symptoms|History and Symptoms]] | [[Post transplant lymphoproliferative disorder physical examination|Physical Examination]] | [[Post transplant lymphoproliferative disorder laboratory findings|Laboratory Findings]] | [[Post transplant lymphoproliferative disorder other imaging findings|Other Imaging Findings]] | [[Post transplant lymphoproliferative disorder other diagnostic studies|Other Diagnostic Studies]]
=== Complications ===
*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]].


==Treatment==
=== Prognosis ===
* Depending on the extent of the disease progression at the time of [[diagnosis]], the [[prognosis]] may vary in post transplant lymphoproliferative disorder patients due to [[heterogeneity]] of the disease.<ref name="LeblondDhedin2001">{{cite journal|last1=Leblond|first1=Véronique|last2=Dhedin|first2=Nathalie|last3=Bruneel|first3=Marie-France Mamzer|last4=Choquet|first4=Sylvain|last5=Hermine|first5=Olivier|last6=Porcher|first6=Raphaël|last7=Quoc|first7=Stéphanie Nguyen|last8=Davi|first8=Frédéric|last9=Charlotte|first9=Frédéric|last10=Dorent|first10=Richard|last11=Barrou|first11=Benoit|last12=Vernant|first12=Jean-Paul|last13=Raphael|first13=Martine|last14=Levy|first14=Vincent|title=Identification of Prognostic Factors in 61 Patients With Posttransplantation Lymphoproliferative Disorders|journal=Journal of Clinical Oncology|volume=19|issue=3|year=2001|pages=772–778|issn=0732-183X|doi=10.1200/JCO.2001.19.3.772}}</ref><ref name="pmid20085936">{{cite journal |vauthors=Evens AM, David KA, Helenowski I, Nelson B, Kaufman D, Kircher SM, Gimelfarb A, Hattersley E, Mauro LA, Jovanovic B, Chadburn A, Stiff P, Winter JN, Mehta J, Van Besien K, Gregory S, Gordon LI, Shammo JM, Smith SE, Smith SM |title=Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era |journal=J. Clin. Oncol. |volume=28 |issue=6 |pages=1038–46 |date=February 2010 |pmid=20085936 |pmc=2834429 |doi=10.1200/JCO.2009.25.4961 |url=}}</ref>
* [[Prognosis]] also depends on what type of PTLD the patient is presenting.


[[Post transplant lymphoproliferative disorder medical therapy|Medical Therapy]] | [[Post transplant lymphoproliferative disorder surgery|Surgery]] | [[Post transplant lymphoproliferative disorder cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Post transplant lymphoproliferative disorder future or investigational therapies|Future or Investigational Therapies]]
*[[Prognosis]] is generally poor, and the 5-year survival rate of patients with post transplant lymphoproliferative disorder is approximately 37- 61%.
*In post transplant lymphoproliferative disorder patients estimated average survival rates range from 25%–60%.


==Case Studies==
== Diagnosis ==
[[Post transplant lymphoproliferative disorder case study one|Case #1]]
=== Symptoms ===
*[[Symptom|Symptoms]] in post transplant lymphoproliferative disorder patients are highly variable.<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>
*[[Symptoms]] are depends on type of post transplant lymphoproliferative disorder patient present with, and the [[organs]] involved.
*Symptoms of post transplant lymphoproliferative disorder may include the following:<ref name="LaCasce20065">{{cite journal|last1=LaCasce|first1=A. S.|title=Post-Transplant Lymphoproliferative Disorders|journal=The Oncologist|volume=11|issue=6|year=2006|pages=674–680|issn=1083-7159|doi=10.1634/theoncologist.11-6-674}}</ref>
:*[[Fatigue|Persistent fatigue]]
:*[[Infectious mononucleosis]]–like syndrome
:*[[Hepatosplenomegaly]]
:*[[Loss of appetite]]
:*[[Nausea]]
:*[[Vomiting]]
:*[[Weight loss|Unexplained weight loss]]
:*[[Viral]] [[infection]] symptoms like [[headache]], [[muscle aches]] etc
:*[[Swelling]] of the [[Lymph node|lymph nodes]]:The most common presenting symptom


=== Physical Examination ===
*Patients with post transplant lymphoproliferative disorder usually appear pale and malnourished.<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>
*Physical examination may be remarkable for:<ref name="pmid2845789">{{cite journal |vauthors=Nalesnik MA, Jaffe R, Starzl TE, Demetris AJ, Porter K, Burnham JA, Makowka L, Ho M, Locker J |title=The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression |journal=Am. J. Pathol. |volume=133 |issue=1 |pages=173–92 |date=October 1988 |pmid=2845789 |pmc=1880655 |doi= |url=}}</ref>
**Swelling in the [[Lymph node|lymph nodes]] in the [[neck]] or underarms.
**Patients present with extranodal [[Mass|masses]], especially in areas like:<ref name="pmid9457207">{{cite journal |vauthors=Rappaport DC, Chamberlain DW, Shepherd FA, Hutcheon MA |title=Lymphoproliferative disorders after lung transplantation: imaging features |journal=Radiology |volume=206 |issue=2 |pages=519–24 |date=February 1998 |pmid=9457207 |doi=10.1148/radiology.206.2.9457207 |url=}}</ref><ref name="pmid2547308">{{cite journal |vauthors=Randhawa PS, Yousem SA, Paradis IL, Dauber JA, Griffith BP, Locker J |title=The clinical spectrum, pathology, and clonal analysis of Epstein-Barr virus-associated lymphoproliferative disorders in heart-lung transplant recipients |journal=Am. J. Clin. Pathol. |volume=92 |issue=2 |pages=177–85 |date=August 1989 |pmid=2547308 |doi= |url=}}</ref>
***[[Gastrointestinal tract]]([[small intestine]] and [[large bowel]]).
***[[lungs]].
***[[Central nervous system]].
**[[Fever]].
**[[Sleep hyperhidrosis|Night sweats]].
**Unexplained [[weight loss]].
=== Laboratory Findings ===
[[Laboratory]] findings consistent with the [[diagnosis]] of post transplant lymphoproliferative disorder include:
* According to British Committee for Standards in Haematology (BCSH) and the British Transplantation Society (BTS) [[Biopsy]] is the [[Gold standard (test)|gold standard]] test for the [[diagnosis]] preferably an [[excisional biopsy]] of post transplant lymphoproliferative disorder.<ref name="pmid20408847">{{cite journal |vauthors=Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, Marcus R, Parameshwar J, Ramsay A, Newstead C |title=Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients - BCSH and BTS Guidelines |journal=Br. J. Haematol. |volume=149 |issue=5 |pages=675–92 |date=June 2010 |pmid=20408847 |doi=10.1111/j.1365-2141.2010.08161.x |url=}}</ref><ref name="pmid20408848">{{cite journal |vauthors=Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, Marcus R, Parameshwar J, Ramsay A, Newstead C |title=Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients - BCSH and BTS Guidelines |journal=Br. J. Haematol. |volume=149 |issue=5 |pages=693–705 |date=June 2010 |pmid=20408848 |doi=10.1111/j.1365-2141.2010.08160.x |url=}}</ref><ref name="TaylorMarcus2005">{{cite journal|last1=Taylor|first1=Anna L.|last2=Marcus|first2=Robert|last3=Bradley|first3=J. Andrew|title=Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation|journal=Critical Reviews in Oncology/Hematology|volume=56|issue=1|year=2005|pages=155–167|issn=10408428|doi=10.1016/j.critrevonc.2005.03.015}}</ref>


==Causes==
* [[Viral load]] measurement:
The disease is an uncontrolled proliferation of B cell [[lymphocytes]] following infection with [[Epstein-Barr virus]]. Production of an interleukin-10, an endogenous anti-T cell [[cytokine]], has also been implicated.
 
* Marked [[elevation]] in [[EBV]] [[viral load]].<ref name="pmid11579293">{{cite journal |vauthors=Wagner HJ, Wessel M, Jabs W, Smets F, Fischer L, Offner G, Bucsky P |title=Patients at risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantification of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction |journal=Transplantation |volume=72 |issue=6 |pages=1012–9 |date=September 2001 |pmid=11579293 |doi= |url=}}</ref><ref name="pmid12737195">{{cite journal |vauthors=Merlino C, Cavallo R, Bergallo M, Giacchino F, Bollero C, Negro Ponzi A, Cavallo G |title=Epstein Barr viral load monitoring by quantitative PCR in renal transplant patients |journal=New Microbiol. |volume=26 |issue=2 |pages=141–9 |date=April 2003 |pmid=12737195 |doi= |url=}}</ref><ref name="pmid115792932">{{cite journal |vauthors=Wagner HJ, Wessel M, Jabs W, Smets F, Fischer L, Offner G, Bucsky P |title=Patients at risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantification of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction |journal=Transplantation |volume=72 |issue=6 |pages=1012–9 |date=September 2001 |pmid=11579293 |doi= |url=}}</ref>
* In post transplant lymphoproliferative disorder patients [[viral load]] can be measured by [[polymerase chain reaction]] ([[PCR]]).<ref name="pmid10994552">{{cite journal |vauthors=Wagner HJ, Jabs W, Smets F, Wessel M, Fischer L, Offner G, Kirchner H, Bucsky P |title=Real-time polymerase chain reaction (RQ-PCR) for the monitoring of Epstein-Barr virus (EBV) load in peripheral blood mononuclear cells |journal=Klin Padiatr |volume=212 |issue=4 |pages=206–10 |date=2000 |pmid=10994552 |doi=10.1055/s-2000-9678 |url=}}</ref>
 
* [[Complete blood count]] which shows viral load measurement:
** [[Anemia]].
** [[Thrombocytopenia]].
** [[Leukopenia]].
* Increased [[Lactate dehydrogenase|LDH]].
* Increased [[calcium]].
* Increased [[uric acid]].
* [[Urine]] analysis for monoclonal [[protein]].<ref name="pmid11520779">{{cite journal |vauthors=Lemoine A, Pham P, Azoulay D, Saliba F, Emile JF, Saffroy R, Broet P, Bismuth H, Samuel D, Debuire B |title=Detection of gammopathy by serum protein electrophoresis for predicting and managing therapy of lymphoproliferative disorder in 911 recipients of liver transplants |journal=Blood |volume=98 |issue=5 |pages=1332–8 |date=September 2001 |pmid=11520779 |doi= |url=}}</ref><ref name="pmid9346679">{{cite journal |vauthors=Badley AD, Portela DF, Patel R, Kyle RA, Habermann TM, Strickler JG, Ilstrup DM, Wiesner RH, de Groen P, Walker RC, Paya CV |title=Development of monoclonal gammopathy precedes the development of Epstein-Barr virus-induced posttransplant lymphoproliferative disorder |journal=Liver Transpl Surg |volume=2 |issue=5 |pages=375–82 |date=September 1996 |pmid=9346679 |doi= |url=}}</ref><ref name="pmid9484759">{{cite journal |vauthors=Pageaux GP, Bonnardet A, Picot MC, Perrigault PF, Coste V, Navarro F, Fabre JM, Domergue J, Descomps B, Blanc P, Michel H, Larrey D |title=Prevalence of monoclonal immunoglobulins after liver transplantation: relationship with posttransplant lymphoproliferative disorders |journal=Transplantation |volume=65 |issue=3 |pages=397–400 |date=February 1998 |pmid=9484759 |doi= |url=}}</ref>
 
*


In immunocompetent patients, Epstein-Barr virus causes [[infectious mononucleosis]], characterised by a proliferation of B-lymphocytes which is controlled by [[Suppressor T cells]].  
===Imaging Findings===
*[[Fluorodeoxyglucose]] ([[Fluorodeoxyglucose|FDG]])-[[positron emission tomography]] ([[PET]]) may be helpful in the [[diagnosis]] of post transplant lymphoproliferative disorder which helps in the following:<ref name="pmid17291214">{{cite journal |vauthors=Bakker NA, van Imhoff GW, Verschuuren EA, van Son WJ |title=Presentation and early detection of post-transplant lymphoproliferative disorder after solid organ transplantation |journal=Transpl. Int. |volume=20 |issue=3 |pages=207–18 |date=March 2007 |pmid=17291214 |doi=10.1111/j.1432-2277.2006.00416.x |url=}}</ref><ref name="CamachoMoreno2014">{{cite journal|last1=Camacho|first1=Juan C.|last2=Moreno|first2=Courtney Coursey|last3=Harri|first3=Peter A.|last4=Aguirre|first4=Diego A.|last5=Torres|first5=William E.|last6=Mittal|first6=Pardeep K.|title=Posttransplantation Lymphoproliferative Disease: Proposed Imaging Classification|journal=RadioGraphics|volume=34|issue=7|year=2014|pages=2025–2038|issn=0271-5333|doi=10.1148/rg.347130130}}</ref><ref name="TaylorMarcus20052">{{cite journal|last1=Taylor|first1=Anna L.|last2=Marcus|first2=Robert|last3=Bradley|first3=J. Andrew|title=Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation|journal=Critical Reviews in Oncology/Hematology|volume=56|issue=1|year=2005|pages=155–167|issn=10408428|doi=10.1016/j.critrevonc.2005.03.015}}</ref>
**[[Staging (pathology)|Staging]].
**Response evaluation of [[malignant lymphoma]].
**Early [[diagnosis]].
*[[Computed tomography]] ([[CT]]) or [[magnetic resonance imaging]] ([[Magnetic resonance imaging|MRI]]) may be helpful in the diagnosis of post transplant lymphoproliferative disorder in finding any abnormal [[Nodal (protein)|nodal]] or extranodal masses.<ref name="VrachliotisVaswani2000">{{cite journal|last1=Vrachliotis|first1=Thomas G.|last2=Vaswani|first2=Kuldeep K.|last3=Davies|first3=Elizabeth A.|last4=Elkhammas|first4=Elmahdi A.|last5=Bennett|first5=William F.|last6=Bova|first6=James G.|title=CT Findings in Posttransplantation Lymphoproliferative Disorder of Renal Transplants|journal=American Journal of Roentgenology|volume=175|issue=1|year=2000|pages=183–188|issn=0361-803X|doi=10.2214/ajr.175.1.1750183}}</ref><ref name="CamachoMoreno20142">{{cite journal|last1=Camacho|first1=Juan C.|last2=Moreno|first2=Courtney Coursey|last3=Harri|first3=Peter A.|last4=Aguirre|first4=Diego A.|last5=Torres|first5=William E.|last6=Mittal|first6=Pardeep K.|title=Posttransplantation Lymphoproliferative Disease: Proposed Imaging Classification|journal=RadioGraphics|volume=34|issue=7|year=2014|pages=2025–2038|issn=0271-5333|doi=10.1148/rg.347130130}}</ref>


However, calcineurin inhibitors ([[tacrolimus]] and [[cyclosporine]]) used as immunosuppressants in organ transplantation inhibit [[T cell]] function, and can prevent the control of the B cell proliferation.
== Treatment ==
=== Medical Therapy ===
* According to following guidelines proposed post transplant lymphoproliferative disease is treated:<ref name="pmid204088483">{{cite journal |vauthors=Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, Marcus R, Parameshwar J, Ramsay A, Newstead C |title=Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients - BCSH and BTS Guidelines |journal=Br. J. Haematol. |volume=149 |issue=5 |pages=693–705 |date=June 2010 |pmid=20408848 |doi=10.1111/j.1365-2141.2010.08160.x |url=}}</ref><ref name="pmid29021921">{{cite journal |vauthors=Bishnoi R, Bajwa R, Franke AJ, Skelton WP, Wang Y, Patel NM, Slayton WB, Zou F, Dang NH |title=Post-transplant lymphoproliferative disorder (PTLD): single institutional experience of 141 patients |journal=Exp Hematol Oncol |volume=6 |issue= |pages=26 |date=2017 |pmid=29021921 |pmc=5622441 |doi=10.1186/s40164-017-0087-0 |url=}}</ref><ref name="DierickxTousseyn2015">{{cite journal|last1=Dierickx|first1=D.|last2=Tousseyn|first2=T.|last3=Gheysens|first3=O.|title=How I treat posttransplant lymphoproliferative disorders|journal=Blood|volume=126|issue=20|year=2015|pages=2274–2283|issn=0006-4971|doi=10.1182/blood-2015-05-615872}}</ref><ref name="BlumbergDanziger-Isakov2013">{{cite journal|last1=Blumberg|first1=Emily A.|last2=Danziger-Isakov|first2=Lara|last3=Kumar|first3=Deepali|last4=Michaels|first4=Marian G.|last5=Razonable|first5=Raymund R.|title=Foreword: Guidelines 3|journal=American Journal of Transplantation|volume=13|issue=s4|year=2013|pages=1–2|issn=16006135|doi=10.1111/ajt.12129}}</ref><ref name="pmid120916382">{{cite journal |vauthors= |title=European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.6.1. Cancer risk after renal transplantation. Post-transplant lymphoproliferative disease (PTLD): prevention and treatment |journal=Nephrol. Dial. Transplant. |volume=17 Suppl 4 |issue= |pages=31–3, 35–6 |date=2002 |pmid=12091638 |doi= |url=}}</ref>
** American Society of Transplantation (AST).
** [[World Health Organization]] ([[World Health Organization|WHO]]).
** NCCN: National Comprehensive Cancer Network.
** European best practice guidelines for renal transplantation.
** British Committee for Standards in Haematology.
** British Transplantation Society.


Depletion of T cells by use of anti-T cell [[Antibody|antibodies]] in the prevention or treatment of [[transplant rejection]] further increases the risk of developing post-transplant lymphoproliferative disorder. Such antibodies include [[Anti-thymocyte_globulin|ATG]], [[Anti-lymphocyte_globulin|ALG]] and [[OKT3]].
* Pharmacologic medical therapies for post transplant lymphoproliferative disorder highly varied based on the subtype and type of [[transplant]].<ref name="pmid11422823">{{cite journal |vauthors=Allen U, Hébert D, Moore D, Dror Y, Wasfy S |title=Epstein-Barr virus-related post-transplant lymphoproliferative disease in solid organ transplant recipients, 1988-97: a Canadian multi-centre experience |journal=Pediatr Transplant |volume=5 |issue=3 |pages=198–203 |date=June 2001 |pmid=11422823 |doi= |url=}}</ref>
* In post transplant lymphoproliferative disorder patients standardized [[therapeutic]] approach cannot be applied to all patients.


Polyclonal PTLD may form tumor masses and present with symptoms due to a mass effect, e.g. symptoms of [[bowel obstruction]]. Monoclonal forms of PTLD tend to form a disseminated malignant lymphoma.
*The medical treatment for post transplant lymphoproliferative disorder, include the followings.<ref name="Biomed">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 </ref>


==Treatment==
==== Immunosuppression ====
PTLD may spontaneously regress on reduction or cessation of [[Immunosuppression|immunosuppressant]] medication, and can also be treated with addition of anti-viral therapy. In some cases it will progress to [[non-Hodgkin's lymphoma]] and may be fatal.
* Low-dose [[immunosuppressive]] agents [[protocols]] highly reduce the [[incidence]] of post transplant lymphoproliferative disorder.<ref name="pmid14734884">{{cite journal |vauthors=Ganschow R, Schulz T, Meyer T, Broering DC, Burdelski M |title=Low-dose immunosuppression reduces the incidence of post-transplant lymphoproliferative disease in pediatric liver graft recipients |journal=J. Pediatr. Gastroenterol. Nutr. |volume=38 |issue=2 |pages=198–203 |date=February 2004 |pmid=14734884 |doi= |url=}}</ref>
* The mainstay of treatment for post transplant lymphoproliferative disorder is giving lose dose or reduction of the dose of [[immunosuppressive]] agents with the following:<ref name="pmid22241590">{{cite journal |vauthors=Jagadeesh D, Woda BA, Draper J, Evens AM |title=Post transplant lymphoproliferative disorders: risk, classification, and therapeutic recommendations |journal=Curr Treat Options Oncol |volume=13 |issue=1 |pages=122–36 |date=March 2012 |pmid=22241590 |doi=10.1007/s11864-011-0177-x |url=}}</ref><ref name="pmid20963522">{{cite journal |vauthors=Evens AM, Roy R, Sterrenberg D, Moll MZ, Chadburn A, Gordon LI |title=Post-transplantation lymphoproliferative disorders: diagnosis, prognosis, and current approaches to therapy |journal=Curr Oncol Rep |volume=12 |issue=6 |pages=383–94 |date=November 2010 |pmid=20963522 |doi=10.1007/s11912-010-0132-1 |url=}}</ref><ref name="pmid25655616">{{cite journal |vauthors=Singavi AK, Harrington AM, Fenske TS |title=Post-transplant lymphoproliferative disorders |journal=Cancer Treat. Res. |volume=165 |issue= |pages=305–27 |date=2015 |pmid=25655616 |doi=10.1007/978-3-319-13150-4_13 |url=}}</ref><ref name="pmid23737188">{{cite journal |vauthors=Al-Mansour Z, Nelson BP, Evens AM |title=Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies |journal=Curr Hematol Malig Rep |volume=8 |issue=3 |pages=173–83 |date=September 2013 |pmid=23737188 |pmc=4831913 |doi=10.1007/s11899-013-0162-5 |url=}}</ref><ref name="pmid22173060">{{cite journal |vauthors=Trappe R, Oertel S, Leblond V, Mollee P, Sender M, Reinke P, Neuhaus R, Lehmkuhl H, Horst HA, Salles G, Morschhauser F, Jaccard A, Lamy T, Leithäuser M, Zimmermann H, Anagnostopoulos I, Raphael M, Riess H, Choquet S |title=Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial |journal=Lancet Oncol. |volume=13 |issue=2 |pages=196–206 |date=February 2012 |pmid=22173060 |doi=10.1016/S1470-2045(11)70300-X |url=}}</ref><ref name="pmid23771985">{{cite journal |vauthors=Styczynski J, Gil L, Tridello G, Ljungman P, Donnelly JP, van der Velden W, Omar H, Martino R, Halkes C, Faraci M, Theunissen K, Kalwak K, Hubacek P, Sica S, Nozzoli C, Fagioli F, Matthes S, Diaz MA, Migliavacca M, Balduzzi A, Tomaszewska A, Camara Rde L, van Biezen A, Hoek J, Iacobelli S, Einsele H, Cesaro S |title=Response to rituximab-based therapy and risk factor analysis in Epstein Barr Virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation |journal=Clin. Infect. Dis. |volume=57 |issue=6 |pages=794–802 |date=September 2013 |pmid=23771985 |doi=10.1093/cid/cit391 |url=}}</ref>
**[[rituximab]].
** [[Chemotherapy]].
** [[Radiation therapy]].
'''Early Lesions'''
* Pharmacologic medical therapies for early lesions in post transplant lymphoproliferative disorder include:<ref name="pmid12091638">{{cite journal |vauthors= |title=European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.6.1. Cancer risk after renal transplantation. Post-transplant lymphoproliferative disease (PTLD): prevention and treatment |journal=Nephrol. Dial. Transplant. |volume=17 Suppl 4 |issue= |pages=31–3, 35–6 |date=2002 |pmid=12091638 |doi= |url=}}</ref><ref name="pmid204088482">{{cite journal |vauthors=Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, Marcus R, Parameshwar J, Ramsay A, Newstead C |title=Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients - BCSH and BTS Guidelines |journal=Br. J. Haematol. |volume=149 |issue=5 |pages=693–705 |date=June 2010 |pmid=20408848 |doi=10.1111/j.1365-2141.2010.08160.x |url=}}</ref>
** Reduction of [[immunosuppression]].
'''Polymorphic PTLD'''
* Pharmacologic medical therapies for polymorphic post transplant lymphoproliferative disorder include:
** Reduction of [[immunosuppression]] with use of [[rituximab]].
'''Monomorphic PTLD'''
* Pharmacologic medical therapies for monomorphic post transplant lymphoproliferative disorder include:<ref name="pmid11374406">{{cite journal |vauthors=Tsai DE, Hardy CL, Tomaszewski JE, Kotloff RM, Oltoff KM, Somer BG, Schuster SJ, Porter DL, Montone KT, Stadtmauer EA |title=Reduction in immunosuppression as initial therapy for posttransplant lymphoproliferative disorder: analysis of prognostic variables and long-term follow-up of 42 adult patients |journal=Transplantation |volume=71 |issue=8 |pages=1076–88 |date=April 2001 |pmid=11374406 |doi= |url=}}</ref>
**[[Rituximab]] with with [[chemotherapy]] and reduction of [[immunosuppression]].
'''Classic Hodgkin lymphoma-like PTLD'''
* Pharmacologic medical therapies for classic hodgkin lymphoma like post transplant lymphoproliferative disorder include:
** [[Chemotherapy]] with or without [[radiation therapy]].
'''Rituximab'''
* When it comes to treatment of post transplant lymphoproliferative disorder patients [[rituximab]] play an important role which produce anti-[[CD20]] [[monoclonal antibodies]].<ref name="pmid16468968">{{cite journal |vauthors=Elstrom RL, Andreadis C, Aqui NA, Ahya VN, Bloom RD, Brozena SC, Olthoff KM, Schuster SJ, Nasta SD, Stadtmauer EA, Tsai DE |title=Treatment of PTLD with rituximab or chemotherapy |journal=Am. J. Transplant. |volume=6 |issue=3 |pages=569–76 |date=March 2006 |pmid=16468968 |doi=10.1111/j.1600-6143.2005.01211.x |url=}}</ref><ref name="pmid10568575">{{cite journal |vauthors=Cook RC, Connors JM, Gascoyne RD, Fradet G, Levy RD |title=Treatment of post-transplant lymphoproliferative disease with rituximab monoclonal antibody after lung transplantation |journal=Lancet |volume=354 |issue=9191 |pages=1698–9 |date=November 1999 |pmid=10568575 |doi=10.1016/S0140-6736(99)02058-9 |url=}}</ref><ref name="pmid11448808">{{cite journal |vauthors=Zilz ND, Olson LJ, McGregor CG |title=Treatment of post-transplant lymphoproliferative disorder with monoclonal CD20 antibody (rituximab) after heart transplantation |journal=J. Heart Lung Transplant. |volume=20 |issue=7 |pages=770–2 |date=July 2001 |pmid=11448808 |doi= |url=}}</ref><ref name="pmid16149091">{{cite journal |vauthors=Blaes AH, Peterson BA, Bartlett N, Dunn DL, Morrison VA |title=Rituximab therapy is effective for posttransplant lymphoproliferative disorders after solid organ transplantation: results of a phase II trial |journal=Cancer |volume=104 |issue=8 |pages=1661–7 |date=October 2005 |pmid=16149091 |doi=10.1002/cncr.21391 |url=}}</ref>
* [[Rituximab]] helps in treatment of following [[non-Hodgkin lymphomas]]:
** [[Diffuse large B cell lymphoma]].
** [[Follicular lymphoma]].
* [[Rituximab]] alone can achieve complete [[Remission (medicine)|remission]] in almost 20% of the patient.<ref name="pmid16254143">{{cite journal |vauthors=Choquet S, Leblond V, Herbrecht R, Socié G, Stoppa AM, Vandenberghe P, Fischer A, Morschhauser F, Salles G, Feremans W, Vilmer E, Peraldi MN, Lang P, Lebranchu Y, Oksenhendler E, Garnier JL, Lamy T, Jaccard A, Ferrant A, Offner F, Hermine O, Moreau A, Fafi-Kremer S, Morand P, Chatenoud L, Berriot-Varoqueaux N, Bergougnoux L, Milpied N |title=Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study |journal=Blood |volume=107 |issue=8 |pages=3053–7 |date=April 2006 |pmid=16254143 |doi=10.1182/blood-2005-01-0377 |url=}}</ref>
** Preferred regimen (1): [[Rituximab]] 375 mg/m2 per week for four weeks.
'''Chemoimmunotherapy'''
* Chemoimmunotherapy medical therapy is recommended among patients with post transplant lymphoproliferative disorder.<ref name="pmid7579436">{{cite journal |vauthors=Swinnen LJ, Mullen GM, Carr TJ, Costanzo MR, Fisher RI |title=Aggressive treatment for postcardiac transplant lymphoproliferation |journal=Blood |volume=86 |issue=9 |pages=3333–40 |date=November 1995 |pmid=7579436 |doi= |url=}}</ref><ref name="pmid10755561">{{cite journal |vauthors=Smets F, Vajro P, Cornu G, Reding R, Otte JB, Sokal E |title=Indications and results of chemotherapy in children with posttransplant lymphoproliferative disease after liver transplantation |journal=Transplantation |volume=69 |issue=5 |pages=982–4 |date=March 2000 |pmid=10755561 |doi= |url=}}</ref><ref name="pmid11054435">{{cite journal |vauthors=Mamzer-Bruneel MF, Lomé C, Morelon E, Levy V, Bourquelot P, Jacobs F, Gessain A, Mac Intyre E, Brousse N, Kreis H, Hermine O |title=Durable remission after aggressive chemotherapy for very late post-kidney transplant lymphoproliferation: A report of 16 cases observed in a single center |journal=J. Clin. Oncol. |volume=18 |issue=21 |pages=3622–32 |date=November 2000 |pmid=11054435 |doi=10.1200/JCO.2000.18.21.3622 |url=}}</ref><ref name="pmid19451438">{{cite journal |vauthors=Knight JS, Tsodikov A, Cibrik DM, Ross CW, Kaminski MS, Blayney DW |title=Lymphoma after solid organ transplantation: risk, response to therapy, and survival at a transplantation center |journal=J. Clin. Oncol. |volume=27 |issue=20 |pages=3354–62 |date=July 2009 |pmid=19451438 |doi=10.1200/JCO.2008.20.0857 |url=}}</ref>
* Along with chemoimmunotherapy, [[rituximab]] is also added if the patient tested positive for [[CD20]].<ref name="pmid16586109">{{cite journal |vauthors=Oertel S, Trappe RU, Zeidler K, Babel N, Reinke P, Hummel M, Jonas S, Papp-Vary M, Subklewe M, Dörken B, Riess H, Gärtner B |title=Epstein-Barr viral load in whole blood of adults with posttransplant lymphoproliferative disorder after solid organ transplantation does not correlate with clinical course |journal=Ann. Hematol. |volume=85 |issue=7 |pages=478–84 |date=July 2006 |pmid=16586109 |doi=10.1007/s00277-006-0109-1 |url=}}</ref>
* Preferred regimen: [[R-CHOP regimen|R-CHOP]]
** [[Cyclophosphamide]].
** [[Doxorubicin]].
** [[Vincristine]].
** [[Prednisone|Prednisone.]]
* When [[rituximab]] is added to the chemoimmunotherapy regimen the complete [[Remission (medicine)|remission]] rates are estimated approximately to be 65%.


==Resources==
*  
*[http://www.guideline.gov/content.aspx?id=34206&search=ptld National Guideline Clearinghouse: EBV-associated post-transplant lymphoproliferative disease in solid organ transplant]


==Related chapters==
*  
*[[Epstein Barr virus]]


==References==
=== Surgery ===
{{reflist|2}}
*[[Surgery]] is not recommended for patients with post transplant lymphoproliferative disorder.<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>


{{Organ transplantation}}
=== Prevention ===
{{Hematological malignancy histology}}
*Effective measures for the primary prevention of post transplant lymphoproliferative disorder include:
**Tapering [[Immunosuppressive therapy|immunosuppressive]] therapy.
**[[Antiviral]] [[prophylaxis]] with [[ganciclovir]].
**Pretreatment assessment: check the patient with the following:
***[[Comorbidities]].
***[[Complete blood count|Complete blood picture]].
***[[Liver function tests|LFT]]'s.
***[[Albumin]] levels.
***[[HIV]] status.
***[[Hepatitis]] tests.
***[[EBV]] serology tests.
***


<!--Categories-->
==References==
[[Category:Transplantation medicine]]
{{Reflist|2}}
[[Category: Oncology]]
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Immunology]]
[[Category:Hematology]]
[[Category:Hematology]]
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2] Maria Fernanda Villarreal, M.D. [3]

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. 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. 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 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.
  • Post transplant lymphoproliferative disorder was first introduced in 1984 by Starzl.[1]

Classification

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.[4][5][6]
  • 90 to 95 percent of patients with post transplant lymphoproliferative disorder shows positive serologic of infection especially with Epstein-Barr virus (EBV) infection.[7]
  • Membrane proteins associated with EBV plays a major role in contribute to B cell growth and survival.[8][9][10][11][12][13]
    • 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:

Causes

Differentiating Post Transplant Lymphoproliferative Disorder from Other Diseases

Epidemiology and Demographics

Incidence

  • The incidence of post transplant lymphoproliferative disorder is approximately 20,000 in 100,000 of all cancers especially with solid organ transplantation.[20][21][22][23][24][25]
  • The incidence of post transplant lymphoproliferative disorder in liver transplants is approximately 1000 to 2000 in 100,000 patients.
  • The incidence of post transplant lymphoproliferative disorder in renal transplant is approximately 1000 to 3000 in 100,000 patients.
  • The incidence of post transplant lymphoproliferative disorder in heart transplant is approximately 2000 to 6000 in 100,000 patients.
  • The incidence of post transplant lymphoproliferative disorder in lung transplant is approximately 2000 to 9000 in 100,000 patients.
  • The incidence of post transplant lymphoproliferative disorder in intestinal or multi organ transplants is approximately as high as 11,000 to 33,000 in 100,000 patients.

Prevalence

  • The prevalence of post transplant lymphoproliferative disorder remains unknown.

Age

  • Post transplant lymphoproliferative disorder is more commonly observed among young patients.[26]

Gender

  • Females are slightly more affected with post transplant lymphoproliferative disorder than men.[27]

Race

  • There is no racial predilection for post transplant lymphoproliferative disorder.[28]

Risk Factors

Natural History, Complications and Prognosis

Natural History

  • 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.

Complications

  • 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

  • Depending on the extent of the disease progression at the time of diagnosis, the prognosis may vary in post transplant lymphoproliferative disorder patients due to heterogeneity of the disease.[35][36]
  • Prognosis also depends on what type of PTLD the patient is presenting.
  • Prognosis is generally poor, and the 5-year survival rate of patients with post transplant lymphoproliferative disorder is approximately 37- 61%.
  • In post transplant lymphoproliferative disorder patients estimated average survival rates range from 25%–60%.

Diagnosis

Symptoms

  • Symptoms in post transplant lymphoproliferative disorder patients are highly variable.[18]
  • Symptoms are depends on type of post transplant lymphoproliferative disorder patient present with, and the organs involved.
  • Symptoms of post transplant lymphoproliferative disorder may include the following:[37]

Physical Examination

Laboratory Findings

Laboratory findings consistent with the diagnosis of post transplant lymphoproliferative disorder include:

Imaging Findings

Treatment

Medical Therapy

  • According to following guidelines proposed post transplant lymphoproliferative disease is treated:[56][57][58][59][60]
    • American Society of Transplantation (AST).
    • World Health Organization (WHO).
    • NCCN: National Comprehensive Cancer Network.
    • European best practice guidelines for renal transplantation.
    • British Committee for Standards in Haematology.
    • British Transplantation Society.
  • Pharmacologic medical therapies for post transplant lymphoproliferative disorder highly varied based on the subtype and type of transplant.[61]
  • In post transplant lymphoproliferative disorder patients standardized therapeutic approach cannot be applied to all patients.
  • The medical treatment for post transplant lymphoproliferative disorder, include the followings.[62]

Immunosuppression

Early Lesions

  • Pharmacologic medical therapies for early lesions in post transplant lymphoproliferative disorder include:[70][71]

Polymorphic PTLD

  • Pharmacologic medical therapies for polymorphic post transplant lymphoproliferative disorder include:

Monomorphic PTLD

Classic Hodgkin lymphoma-like PTLD

  • Pharmacologic medical therapies for classic hodgkin lymphoma like post transplant lymphoproliferative disorder include:

Rituximab

Chemoimmunotherapy

Surgery

  • Surgery is not recommended for patients with post transplant lymphoproliferative disorder.[18]

Prevention

References

  1. ↑ Petrara, Maria Raffaella; Giunco, Silvia; Serraino, Diego; Dolcetti, Riccardo; De Rossi, Anita (2015). "Post-transplant lymphoproliferative disorders: From epidemiology to pathogenesis-driven treatment". Cancer Letters. 369 (1): 37–44. doi:10.1016/j.canlet.2015.08.007. ISSN 0304-3835.
  2. ↑ LaCasce, A. S. (2006). "Post-Transplant Lymphoproliferative Disorders". The Oncologist. 11 (6): 674–680. doi:10.1634/theoncologist.11-6-674. ISSN 1083-7159.
  3. ↑ Petrara, Maria Raffaella; Giunco, Silvia; Serraino, Diego; Dolcetti, Riccardo; De Rossi, Anita (2015). "Post-transplant lymphoproliferative disorders: From epidemiology to pathogenesis-driven treatment". Cancer Letters. 369 (1): 37–44. doi:10.1016/j.canlet.2015.08.007. ISSN 0304-3835.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 18.0 18.1 18.2 18.3 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.
  19. ↑ Rohr JC, Wagner HJ, Lauten M, Wacker HH, Jüttner E, Hanke C, Pohl M, Niemeyer CM (June 2008). "Differentiation of EBV-induced post-transplant Hodgkin lymphoma from Hodgkin-like post-transplant lymphoproliferative disease". Pediatr Transplant. 12 (4): 426–31. doi:10.1111/j.1399-3046.2007.00816.x. PMID 18466428.
  20. ↑ Walker RC, Paya CV, Marshall WF, Strickler JG, Wiesner RH, Velosa JA, Habermann TM, Daly RC, McGregor CG (1995). "Pretransplantation seronegative Epstein-Barr virus status is the primary risk factor for posttransplantation lymphoproliferative disorder in adult heart, lung, and other solid organ transplantations". J. Heart Lung Transplant. 14 (2): 214–21. PMID 7779838.
  21. ↑ Reams BD, McAdams HP, Howell DN, Steele MP, Davis RD, Palmer SM (October 2003). "Posttransplant lymphoproliferative disorder: incidence, presentation, and response to treatment in lung transplant recipients". Chest. 124 (4): 1242–9. PMID 14555552.
  22. ↑ Adami J, Gäbel H, Lindelöf B, Ekström K, Rydh B, Glimelius B, Ekbom A, Adami HO, Granath F (October 2003). "Cancer risk following organ transplantation: a nationwide cohort study in Sweden". Br. J. Cancer. 89 (7): 1221–7. doi:10.1038/sj.bjc.6601219. PMC 2394311. PMID 14520450.
  23. ↑ Morton M, Coupes B, Roberts SA, Klapper PE, Byers RJ, Vallely PJ, Ryan K, Picton ML (February 2013). "Epidemiology of posttransplantation lymphoproliferative disorder in adult renal transplant recipients". Transplantation. 95 (3): 470–8. doi:10.1097/TP.0b013e318276a237. PMID 23222821.
  24. ↑ Penn I (January 1996). "Posttransplantation de novo tumors in liver allograft recipients". Liver Transpl Surg. 2 (1): 52–9. PMID 9346628.
  25. ↑ Petrara, Maria Raffaella; Giunco, Silvia; Serraino, Diego; Dolcetti, Riccardo; De Rossi, Anita (2015). "Post-transplant lymphoproliferative disorders: From epidemiology to pathogenesis-driven treatment". Cancer Letters. 369 (1): 37–44. doi:10.1016/j.canlet.2015.08.007. ISSN 0304-3835.
  26. ↑ Petrara, Maria Raffaella; Giunco, Silvia; Serraino, Diego; Dolcetti, Riccardo; De Rossi, Anita (2015). "Post-transplant lymphoproliferative disorders: From epidemiology to pathogenesis-driven treatment". Cancer Letters. 369 (1): 37–44. doi:10.1016/j.canlet.2015.08.007. ISSN 0304-3835.
  27. ↑ LaCasce, A. S. (2006). "Post-Transplant Lymphoproliferative Disorders". The Oncologist. 11 (6): 674–680. doi:10.1634/theoncologist.11-6-674. ISSN 1083-7159.
  28. ↑ LaCasce, A. S. (2006). "Post-Transplant Lymphoproliferative Disorders". The Oncologist. 11 (6): 674–680. doi:10.1634/theoncologist.11-6-674. ISSN 1083-7159.
  29. ↑ Weissmann, David J.; Ferry, Judith A.; Harris, Nancy L.; Louis, David N.; Delmonico, Francis; Spiro, Ira (1995). "Posttransplantation Lymphoproliferative Disorders in Solid Organ Recipients Are Predominantly Aggressive Tumors of Host Origin". American Journal of Clinical Pathology. 103 (6): 748–755. doi:10.1093/ajcp/103.6.748. ISSN 0002-9173.
  30. ↑ Cohen, Jeffrey I. (2000). "Epstein–Barr Virus Infection". New England Journal of Medicine. 343 (7): 481–492. doi:10.1056/NEJM200008173430707. ISSN 0028-4793.
  31. ↑ Mañez, Rafael; Breinig, Mary C.; Linden, Peter; Wilson, John; Torre‐Cisneros, Julian; Kusne, Shimon; Dummer, Stephen; Ho, Monto (1997). "Posttransplant Lymphoproliferative Disease in Primary Epstein‐Barr Virus Infection after Liver Transplantation: The Role of Cytomegalovirus Disease". The Journal of Infectious Diseases. 176 (6): 1462–1467. doi:10.1086/514142. ISSN 0022-1899.
  32. ↑ Libertiny, G.; Watson, C. J. E.; Gray, D. W. R.; Welsh, K. I.; Morris, P. J. (2001). "Rising incidence of post-transplant lymphoproliferative disease in kidney transplant recipients". British Journal of Surgery. 88 (10): 1330–1334. doi:10.1046/j.0007-1323.2001.01924.x. ISSN 0007-1323.
  33. ↑ Caillard, Sophie; Dharnidharka, Vikas; Agodoa, Lawrence; Bohen, Erin; Abbott, Kevin (2005). "Posttransplant Lymphoproliferative Disorders after Renal Transplantation in the United States in Era of Modern Immunosuppression". Transplantation. 80 (9): 1233–1243. doi:10.1097/01.tp.0000179639.98338.39. ISSN 0041-1337.
  34. ↑ Minamitani, Takeharu; Ma, Yijie; Zhou, Hufeng; Kida, Hiroshi; Tsai, Chao-Yuan; Obana, Masanori; Okuzaki, Daisuke; Fujio, Yasushi; Kumanogoh, Atsushi; Zhao, Bo; Kikutani, Hitoshi; Kieff, Elliott; Gewurz, Benjamin E.; Yasui, Teruhito (2017). "Mouse model of Epstein–Barr virus LMP1- and LMP2A-driven germinal center B-cell lymphoproliferative disease". Proceedings of the National Academy of Sciences. 114 (18): 4751–4756. doi:10.1073/pnas.1701836114. ISSN 0027-8424.
  35. ↑ Leblond, Véronique; Dhedin, Nathalie; Bruneel, Marie-France Mamzer; Choquet, Sylvain; Hermine, Olivier; Porcher, Raphaël; Quoc, Stéphanie Nguyen; Davi, Frédéric; Charlotte, Frédéric; Dorent, Richard; Barrou, Benoit; Vernant, Jean-Paul; Raphael, Martine; Levy, Vincent (2001). "Identification of Prognostic Factors in 61 Patients With Posttransplantation Lymphoproliferative Disorders". Journal of Clinical Oncology. 19 (3): 772–778. doi:10.1200/JCO.2001.19.3.772. ISSN 0732-183X.
  36. ↑ Evens AM, David KA, Helenowski I, Nelson B, Kaufman D, Kircher SM, Gimelfarb A, Hattersley E, Mauro LA, Jovanovic B, Chadburn A, Stiff P, Winter JN, Mehta J, Van Besien K, Gregory S, Gordon LI, Shammo JM, Smith SE, Smith SM (February 2010). "Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era". J. Clin. Oncol. 28 (6): 1038–46. doi:10.1200/JCO.2009.25.4961. PMC 2834429. PMID 20085936.
  37. ↑ LaCasce, A. S. (2006). "Post-Transplant Lymphoproliferative Disorders". The Oncologist. 11 (6): 674–680. doi:10.1634/theoncologist.11-6-674. ISSN 1083-7159.
  38. ↑ Nalesnik MA, Jaffe R, Starzl TE, Demetris AJ, Porter K, Burnham JA, Makowka L, Ho M, Locker J (October 1988). "The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression". Am. J. Pathol. 133 (1): 173–92. PMC 1880655. PMID 2845789.
  39. ↑ Rappaport DC, Chamberlain DW, Shepherd FA, Hutcheon MA (February 1998). "Lymphoproliferative disorders after lung transplantation: imaging features". Radiology. 206 (2): 519–24. doi:10.1148/radiology.206.2.9457207. PMID 9457207.
  40. ↑ Randhawa PS, Yousem SA, Paradis IL, Dauber JA, Griffith BP, Locker J (August 1989). "The clinical spectrum, pathology, and clonal analysis of Epstein-Barr virus-associated lymphoproliferative disorders in heart-lung transplant recipients". Am. J. Clin. Pathol. 92 (2): 177–85. PMID 2547308.
  41. ↑ Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, Marcus R, Parameshwar J, Ramsay A, Newstead C (June 2010). "Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients - BCSH and BTS Guidelines". Br. J. Haematol. 149 (5): 675–92. doi:10.1111/j.1365-2141.2010.08161.x. PMID 20408847.
  42. ↑ Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, Marcus R, Parameshwar J, Ramsay A, Newstead C (June 2010). "Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients - BCSH and BTS Guidelines". Br. J. Haematol. 149 (5): 693–705. doi:10.1111/j.1365-2141.2010.08160.x. PMID 20408848.
  43. ↑ Taylor, Anna L.; Marcus, Robert; Bradley, J. Andrew (2005). "Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation". Critical Reviews in Oncology/Hematology. 56 (1): 155–167. doi:10.1016/j.critrevonc.2005.03.015. ISSN 1040-8428.
  44. ↑ Wagner HJ, Wessel M, Jabs W, Smets F, Fischer L, Offner G, Bucsky P (September 2001). "Patients at risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantification of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction". Transplantation. 72 (6): 1012–9. PMID 11579293.
  45. ↑ Merlino C, Cavallo R, Bergallo M, Giacchino F, Bollero C, Negro Ponzi A, Cavallo G (April 2003). "Epstein Barr viral load monitoring by quantitative PCR in renal transplant patients". New Microbiol. 26 (2): 141–9. PMID 12737195.
  46. ↑ Wagner HJ, Wessel M, Jabs W, Smets F, Fischer L, Offner G, Bucsky P (September 2001). "Patients at risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantification of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction". Transplantation. 72 (6): 1012–9. PMID 11579293.
  47. ↑ Wagner HJ, Jabs W, Smets F, Wessel M, Fischer L, Offner G, Kirchner H, Bucsky P (2000). "Real-time polymerase chain reaction (RQ-PCR) for the monitoring of Epstein-Barr virus (EBV) load in peripheral blood mononuclear cells". Klin Padiatr. 212 (4): 206–10. doi:10.1055/s-2000-9678. PMID 10994552.
  48. ↑ Lemoine A, Pham P, Azoulay D, Saliba F, Emile JF, Saffroy R, Broet P, Bismuth H, Samuel D, Debuire B (September 2001). "Detection of gammopathy by serum protein electrophoresis for predicting and managing therapy of lymphoproliferative disorder in 911 recipients of liver transplants". Blood. 98 (5): 1332–8. PMID 11520779.
  49. ↑ Badley AD, Portela DF, Patel R, Kyle RA, Habermann TM, Strickler JG, Ilstrup DM, Wiesner RH, de Groen P, Walker RC, Paya CV (September 1996). "Development of monoclonal gammopathy precedes the development of Epstein-Barr virus-induced posttransplant lymphoproliferative disorder". Liver Transpl Surg. 2 (5): 375–82. PMID 9346679.
  50. ↑ Pageaux GP, Bonnardet A, Picot MC, Perrigault PF, Coste V, Navarro F, Fabre JM, Domergue J, Descomps B, Blanc P, Michel H, Larrey D (February 1998). "Prevalence of monoclonal immunoglobulins after liver transplantation: relationship with posttransplant lymphoproliferative disorders". Transplantation. 65 (3): 397–400. PMID 9484759.
  51. ↑ Bakker NA, van Imhoff GW, Verschuuren EA, van Son WJ (March 2007). "Presentation and early detection of post-transplant lymphoproliferative disorder after solid organ transplantation". Transpl. Int. 20 (3): 207–18. doi:10.1111/j.1432-2277.2006.00416.x. PMID 17291214.
  52. ↑ Camacho, Juan C.; Moreno, Courtney Coursey; Harri, Peter A.; Aguirre, Diego A.; Torres, William E.; Mittal, Pardeep K. (2014). "Posttransplantation Lymphoproliferative Disease: Proposed Imaging Classification". RadioGraphics. 34 (7): 2025–2038. doi:10.1148/rg.347130130. ISSN 0271-5333.
  53. ↑ Taylor, Anna L.; Marcus, Robert; Bradley, J. Andrew (2005). "Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation". Critical Reviews in Oncology/Hematology. 56 (1): 155–167. doi:10.1016/j.critrevonc.2005.03.015. ISSN 1040-8428.
  54. ↑ Vrachliotis, Thomas G.; Vaswani, Kuldeep K.; Davies, Elizabeth A.; Elkhammas, Elmahdi A.; Bennett, William F.; Bova, James G. (2000). "CT Findings in Posttransplantation Lymphoproliferative Disorder of Renal Transplants". American Journal of Roentgenology. 175 (1): 183–188. doi:10.2214/ajr.175.1.1750183. ISSN 0361-803X.
  55. ↑ Camacho, Juan C.; Moreno, Courtney Coursey; Harri, Peter A.; Aguirre, Diego A.; Torres, William E.; Mittal, Pardeep K. (2014). "Posttransplantation Lymphoproliferative Disease: Proposed Imaging Classification". RadioGraphics. 34 (7): 2025–2038. doi:10.1148/rg.347130130. ISSN 0271-5333.
  56. ↑ Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, Marcus R, Parameshwar J, Ramsay A, Newstead C (June 2010). "Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients - BCSH and BTS Guidelines". Br. J. Haematol. 149 (5): 693–705. doi:10.1111/j.1365-2141.2010.08160.x. PMID 20408848.
  57. ↑ Bishnoi R, Bajwa R, Franke AJ, Skelton WP, Wang Y, Patel NM, Slayton WB, Zou F, Dang NH (2017). "Post-transplant lymphoproliferative disorder (PTLD): single institutional experience of 141 patients". Exp Hematol Oncol. 6: 26. doi:10.1186/s40164-017-0087-0. PMC 5622441. PMID 29021921.
  58. ↑ Dierickx, D.; Tousseyn, T.; Gheysens, O. (2015). "How I treat posttransplant lymphoproliferative disorders". Blood. 126 (20): 2274–2283. doi:10.1182/blood-2015-05-615872. ISSN 0006-4971.
  59. ↑ Blumberg, Emily A.; Danziger-Isakov, Lara; Kumar, Deepali; Michaels, Marian G.; Razonable, Raymund R. (2013). "Foreword: Guidelines 3". American Journal of Transplantation. 13 (s4): 1–2. doi:10.1111/ajt.12129. ISSN 1600-6135.
  60. ↑ "European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.6.1. Cancer risk after renal transplantation. Post-transplant lymphoproliferative disease (PTLD): prevention and treatment". Nephrol. Dial. Transplant. 17 Suppl 4: 31–3, 35–6. 2002. PMID 12091638.
  61. ↑ Allen U, Hébert D, Moore D, Dror Y, Wasfy S (June 2001). "Epstein-Barr virus-related post-transplant lymphoproliferative disease in solid organ transplant recipients, 1988-97: a Canadian multi-centre experience". Pediatr Transplant. 5 (3): 198–203. PMID 11422823.
  62. ↑ 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
  63. ↑ Ganschow R, Schulz T, Meyer T, Broering DC, Burdelski M (February 2004). "Low-dose immunosuppression reduces the incidence of post-transplant lymphoproliferative disease in pediatric liver graft recipients". J. Pediatr. Gastroenterol. Nutr. 38 (2): 198–203. PMID 14734884.
  64. ↑ Jagadeesh D, Woda BA, Draper J, Evens AM (March 2012). "Post transplant lymphoproliferative disorders: risk, classification, and therapeutic recommendations". Curr Treat Options Oncol. 13 (1): 122–36. doi:10.1007/s11864-011-0177-x. PMID 22241590.
  65. ↑ Evens AM, Roy R, Sterrenberg D, Moll MZ, Chadburn A, Gordon LI (November 2010). "Post-transplantation lymphoproliferative disorders: diagnosis, prognosis, and current approaches to therapy". Curr Oncol Rep. 12 (6): 383–94. doi:10.1007/s11912-010-0132-1. PMID 20963522.
  66. ↑ Singavi AK, Harrington AM, Fenske TS (2015). "Post-transplant lymphoproliferative disorders". Cancer Treat. Res. 165: 305–27. doi:10.1007/978-3-319-13150-4_13. PMID 25655616.
  67. ↑ Al-Mansour Z, Nelson BP, Evens AM (September 2013). "Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies". Curr Hematol Malig Rep. 8 (3): 173–83. doi:10.1007/s11899-013-0162-5. PMC 4831913. PMID 23737188.
  68. ↑ Trappe R, Oertel S, Leblond V, Mollee P, Sender M, Reinke P, Neuhaus R, Lehmkuhl H, Horst HA, Salles G, Morschhauser F, Jaccard A, Lamy T, Leithäuser M, Zimmermann H, Anagnostopoulos I, Raphael M, Riess H, Choquet S (February 2012). "Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial". Lancet Oncol. 13 (2): 196–206. doi:10.1016/S1470-2045(11)70300-X. PMID 22173060.
  69. ↑ Styczynski J, Gil L, Tridello G, Ljungman P, Donnelly JP, van der Velden W, Omar H, Martino R, Halkes C, Faraci M, Theunissen K, Kalwak K, Hubacek P, Sica S, Nozzoli C, Fagioli F, Matthes S, Diaz MA, Migliavacca M, Balduzzi A, Tomaszewska A, Camara Rde L, van Biezen A, Hoek J, Iacobelli S, Einsele H, Cesaro S (September 2013). "Response to rituximab-based therapy and risk factor analysis in Epstein Barr Virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation". Clin. Infect. Dis. 57 (6): 794–802. doi:10.1093/cid/cit391. PMID 23771985.
  70. ↑ "European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.6.1. Cancer risk after renal transplantation. Post-transplant lymphoproliferative disease (PTLD): prevention and treatment". Nephrol. Dial. Transplant. 17 Suppl 4: 31–3, 35–6. 2002. PMID 12091638.
  71. ↑ Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, Marcus R, Parameshwar J, Ramsay A, Newstead C (June 2010). "Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients - BCSH and BTS Guidelines". Br. J. Haematol. 149 (5): 693–705. doi:10.1111/j.1365-2141.2010.08160.x. PMID 20408848.
  72. ↑ Tsai DE, Hardy CL, Tomaszewski JE, Kotloff RM, Oltoff KM, Somer BG, Schuster SJ, Porter DL, Montone KT, Stadtmauer EA (April 2001). "Reduction in immunosuppression as initial therapy for posttransplant lymphoproliferative disorder: analysis of prognostic variables and long-term follow-up of 42 adult patients". Transplantation. 71 (8): 1076–88. PMID 11374406.
  73. ↑ Elstrom RL, Andreadis C, Aqui NA, Ahya VN, Bloom RD, Brozena SC, Olthoff KM, Schuster SJ, Nasta SD, Stadtmauer EA, Tsai DE (March 2006). "Treatment of PTLD with rituximab or chemotherapy". Am. J. Transplant. 6 (3): 569–76. doi:10.1111/j.1600-6143.2005.01211.x. PMID 16468968.
  74. ↑ Cook RC, Connors JM, Gascoyne RD, Fradet G, Levy RD (November 1999). "Treatment of post-transplant lymphoproliferative disease with rituximab monoclonal antibody after lung transplantation". Lancet. 354 (9191): 1698–9. doi:10.1016/S0140-6736(99)02058-9. PMID 10568575.
  75. ↑ Zilz ND, Olson LJ, McGregor CG (July 2001). "Treatment of post-transplant lymphoproliferative disorder with monoclonal CD20 antibody (rituximab) after heart transplantation". J. Heart Lung Transplant. 20 (7): 770–2. PMID 11448808.
  76. ↑ Blaes AH, Peterson BA, Bartlett N, Dunn DL, Morrison VA (October 2005). "Rituximab therapy is effective for posttransplant lymphoproliferative disorders after solid organ transplantation: results of a phase II trial". Cancer. 104 (8): 1661–7. doi:10.1002/cncr.21391. PMID 16149091.
  77. ↑ Choquet S, Leblond V, Herbrecht R, Socié G, Stoppa AM, Vandenberghe P, Fischer A, Morschhauser F, Salles G, Feremans W, Vilmer E, Peraldi MN, Lang P, Lebranchu Y, Oksenhendler E, Garnier JL, Lamy T, Jaccard A, Ferrant A, Offner F, Hermine O, Moreau A, Fafi-Kremer S, Morand P, Chatenoud L, Berriot-Varoqueaux N, Bergougnoux L, Milpied N (April 2006). "Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study". Blood. 107 (8): 3053–7. doi:10.1182/blood-2005-01-0377. PMID 16254143.
  78. ↑ Swinnen LJ, Mullen GM, Carr TJ, Costanzo MR, Fisher RI (November 1995). "Aggressive treatment for postcardiac transplant lymphoproliferation". Blood. 86 (9): 3333–40. PMID 7579436.
  79. ↑ Smets F, Vajro P, Cornu G, Reding R, Otte JB, Sokal E (March 2000). "Indications and results of chemotherapy in children with posttransplant lymphoproliferative disease after liver transplantation". Transplantation. 69 (5): 982–4. PMID 10755561.
  80. ↑ Mamzer-Bruneel MF, Lomé C, Morelon E, Levy V, Bourquelot P, Jacobs F, Gessain A, Mac Intyre E, Brousse N, Kreis H, Hermine O (November 2000). "Durable remission after aggressive chemotherapy for very late post-kidney transplant lymphoproliferation: A report of 16 cases observed in a single center". J. Clin. Oncol. 18 (21): 3622–32. doi:10.1200/JCO.2000.18.21.3622. PMID 11054435.
  81. ↑ Knight JS, Tsodikov A, Cibrik DM, Ross CW, Kaminski MS, Blayney DW (July 2009). "Lymphoma after solid organ transplantation: risk, response to therapy, and survival at a transplantation center". J. Clin. Oncol. 27 (20): 3354–62. doi:10.1200/JCO.2008.20.0857. PMID 19451438.
  82. ↑ Oertel S, Trappe RU, Zeidler K, Babel N, Reinke P, Hummel M, Jonas S, Papp-Vary M, Subklewe M, Dörken B, Riess H, Gärtner B (July 2006). "Epstein-Barr viral load in whole blood of adults with posttransplant lymphoproliferative disorder after solid organ transplantation does not correlate with clinical course". Ann. Hematol. 85 (7): 478–84. doi:10.1007/s00277-006-0109-1. PMID 16586109.
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