View source for HAEM5:Polymorphic lymphoproliferative disorders arising in immune deficiency / dysregulation

{{DISPLAYTITLE:Polymorphic lymphoproliferative disorders arising in immune deficiency / dysregulation}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]

{{Under Construction}}

<blockquote class='blockedit'>{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Polymorphic Post-Transplant Lymphoproliferative Disorders]].

Note: encompassing polymorphic PTLD, other iatrogenic immunodef-assoc lympho disorders, among others
}}</blockquote>

<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column to a table, click within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>

==Primary Author(s)*==

Anna Shestakova, MD, PhD, Fellow, University of Utah/ARUP Laboratories

Fabiola Quintero-Rivera, MD, Professor, University of California Irvine (UCI)

__TOC__

==WHO Classification of Disease==

{| class="wikitable"
!Structure
!Disease
|-
|Book
|Haematolymphoid Tumours (5th ed.)
|-
|Category
|B-cell lymphoid proliferations and lymphomas
|-
|Family
|Mature B-cell neoplasms
|-
|Type
|Lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation
|-
|Subtype(s)
|Polymorphic lymphoproliferative disorders arising in immune deficiency / dysregulation
|}

==Definition / Description of Disease==

Polymorphic PTLD is a distinct entity in the 4<sup>th</sup> edition of the World Health Organization (WHO) classification system<ref>Swerdlow SH, et al., (2017). Polymorphic post-transplant lymphoproliferative disorders, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p457-459.</ref>. 

There are six types of PTLD, divided further into non-destructive and destructive subtypes. 

Non-destructive PTLD (strong association with EBV)

1) Plasmacytic hyperplastic PTLD

2) Infectious mononucleosis-like PTLD

3) Florid follicular hyperplasia PTLD

Destructive PTLD

4) Polymorphic PTLD (P-PTLD) 

5) Monomorphic PTLD (B- and T/NK-cell types)

6) Classic Hodgkin lymphoma PTLD

Polymorphic post-transplant lymphoproliferative disorders (P-PTLD) are characterized by the effacement of the nodal architecture, or destructive extra-nodal masses consisting of a heterogeneous cellular proliferation that comprises the full spectrum of B-cell maturation (immunoblasts, plasma cells, and small and intermediate-sized lymphocytes).

==Synonyms / Terminology==

P-PTLDs, polymorphous PTLD 

==Epidemiology / Prevalence==

P-PTLD develop because of immunosuppression following solid organ, or allogeneic stem cell transplant, and the majority of cases are associated with Epstein-Barr virus (EBV) infection. <ref name=":0">{{Cite journal|last=Webber|first=Steven A|last2=Naftel|first2=David C|last3=Fricker|first3=F Jay|last4=Olesnevich|first4=Pamela|last5=Blume|first5=Elizabeth D|last6=Addonizio|first6=Linda|last7=Kirklin|first7=James K|last8=Canter|first8=Charles E|date=2006-01|title=Lymphoproliferative disorders after paediatric heart transplantation: a multi-institutional study|url=http://dx.doi.org/10.1016/s0140-6736(06)67933-6|journal=The Lancet|volume=367|issue=9506|pages=233–239|doi=10.1016/s0140-6736(06)67933-6|issn=0140-6736}}</ref> <ref>{{Cite journal|last=Uhlin|first=M.|last2=Wikell|first2=H.|last3=Sundin|first3=M.|last4=Blennow|first4=O.|last5=Maeurer|first5=M.|last6=Ringden|first6=O.|last7=Winiarski|first7=J.|last8=Ljungman|first8=P.|last9=Remberger|first9=M.|date=2013-09-20|title=Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation|url=http://dx.doi.org/10.3324/haematol.2013.087338|journal=Haematologica|volume=99|issue=2|pages=346–352|doi=10.3324/haematol.2013.087338|issn=0390-6078}}</ref> <ref name=":1">{{Cite journal|last=Natkunam|first=Yasodha|last2=Gratzinger|first2=Dita|last3=Chadburn|first3=Amy|last4=Goodlad|first4=John R.|last5=Chan|first5=John K. C.|last6=Said|first6=Jonathan|last7=Jaffe|first7=Elaine S.|last8=de Jong|first8=Daphne|date=2018-11-01|title=Immunodeficiency-associated lymphoproliferative disorders: time for reappraisal?|url=http://dx.doi.org/10.1182/blood-2018-04-842559|journal=Blood|volume=132|issue=18|pages=1871–1878|doi=10.1182/blood-2018-04-842559|issn=0006-4971}}</ref>

P-PTLD are more common in pediatric patients than adults, although overall P-PTLD account for the minority of PTLDs.

In children, P-PTLD usually develops during the first year; the vast majority are EBV-driven. <ref>{{Cite journal|last=Dharnidharka|first=Vikas R.|date=2018-01-10|title=Comprehensive review of post-organ transplant hematologic cancers|url=http://dx.doi.org/10.1111/ajt.14603|journal=American Journal of Transplantation|volume=18|issue=3|pages=537–549|doi=10.1111/ajt.14603|issn=1600-6135}}</ref> <ref name=":0" /> <ref name=":1" /> <ref>{{Cite journal|last=Nijland|first=Marieke L.|last2=Kersten|first2=Marie José|last3=Pals|first3=Steven T.|last4=Bemelman|first4=Frederike J.|last5=Ten Berge|first5=Ineke J. M.|date=2016-01|title=Epstein-Barr Virus-Positive Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation: Pathogenesis, Clinical Manifestations, Diagnosis, and Management|url=https://pubmed.ncbi.nlm.nih.gov/27500242|journal=Transplantation Direct|volume=2|issue=1|pages=e48|doi=10.1097/TXD.0000000000000557|issn=2373-8731|pmc=4946499|pmid=27500242}}</ref>
==Clinical Features==

The clinical presentation of P-PTLD is similar to other types of PTLD, with predominantly destructive extra-nodal masses. Reduction in immunosuppression can lead to regression.

Positive EBV serology or serum EBV polymerase chain reaction (PCR) is often seen in association with P-PTLD. 
{| class="wikitable"
|'''Signs and Symptoms'''
|Enlarged lymph nodes
B-symptoms (weight loss, fever, night sweats)
|-
|'''Laboratory Findings'''
|EBV viremia
|}

==Sites of Involvement==

P-PTLD commonly involves lymph nodes, and extra-nodal sites, including but not limited to, lungs and gastrointestinal tract. <ref name=":0" /> P-PTLD involves the bone marrow in ~20% of cases. <ref>{{Cite journal|last=Montanari|first=Francesca|last2=O'Connor|first2=Owen A.|last3=Savage|first3=David G.|last4=Zain|first4=Jasmine M.|last5=Venkatraman|first5=Seshan|last6=McCormick|first6=Erin K.|last7=Crook|first7=Meaghan T.|last8=Tsao|first8=Lawrence|last9=Sevilla|first9=Deborah W.|date=2010-08|title=Bone marrow involvement in patients with posttransplant lymphoproliferative disorders: incidence and prognostic factors|url=http://dx.doi.org/10.1016/j.humpath.2009.11.016|journal=Human Pathology|volume=41|issue=8|pages=1150–1158|doi=10.1016/j.humpath.2009.11.016|issn=0046-8177}}</ref> 

==Morphologic Features==

P-PTLD shows a destructive growth pattern, characterized by the effacement of the underlying tissue or lymph node architecture. Unlike most lymphomas, there is a heterogeneous proliferation of the full spectrum of B-cells (immunoblasts, small B-cells and plasma cells) with an admixed population of small T-cells. Areas of geographic necrosis, mitotic figures and Reed-Sternberg-like cells (atypical immunoblasts) can be seen. Aggregates of plasma cells can be seen. <ref>{{Cite journal|last=Koeppen|first=Hartmut|last2=Newell|first2=Kenneth|last3=Baunoch|first3=David A.|last4=Vardiman|first4=James W.|date=1998-02|title=Morphologic Bone Marrow Changes in Patients With Posttransplantation Lymphoproliferative Disorders|url=http://dx.doi.org/10.1097/00000478-199802000-00009|journal=The American Journal of Surgical Pathology|volume=22|issue=2|pages=208–214|doi=10.1097/00000478-199802000-00009|issn=0147-5185}}</ref>

==Immunophenotype==

Immunophenotyping demonstrates an heterogeneous population comprised of the full spectrum of B-cell maturation, including immunoblasts, small B-cells, and plasma cells, admixed with small T-cells. 25% of P-PTLD expresses the BCL6<sup>+</sup>/multiple myeloma oncogene-1 protein (MUM1<sup>-/+</sup>)/CD138<sup>-</sup> profile and mimics B cells undergoing the germinal center reaction; 67% of P-PTLD displays a BCL6<sup>-</sup>/MUM1<sup>+</sup>/CD138<sup>-</sup> phenotype and mimic B cells that have completed the germinal center reaction. <ref name=":2">{{Cite journal|last=Capello|first=D.|date=2003-07-31|title=Molecular histogenesis of posttransplantation lymphoproliferative disorders|url=http://dx.doi.org/10.1182/blood-2003-05-1683|journal=Blood|volume=102|issue=10|pages=3775–3785|doi=10.1182/blood-2003-05-1683|issn=0006-4971}}</ref>

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (vast majority)||EBV by EBV-encoded small RNA (EBER) in situ hybridization
|-
|Positive (subset)||CD20 (B-cells), CD3 (T-cells), CD30 (atypical immunoblasts)
|-
| ||Light chain restriction, different clonal populations can be present  <ref>{{Cite journal|last=Nalesnik|first=M. A.|last2=Jaffe|first2=R.|last3=Starzl|first3=T. E.|last4=Demetris|first4=A. J.|last5=Porter|first5=K.|last6=Burnham|first6=J. A.|last7=Makowka|first7=L.|last8=Ho|first8=M.|last9=Locker|first9=J.|date=1988-10|title=The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression|url=https://pubmed.ncbi.nlm.nih.gov/2845789|journal=The American Journal of Pathology|volume=133|issue=1|pages=173–192|issn=0002-9440|pmc=1880655|pmid=2845789}}</ref>
|-
|Negative (universal)||CD15 (atypical immunoblasts)
|}

==Chromosomal Rearrangements (Gene Fusions)==

Cytogenetic abnormalities are uncommon in P-PTLD being present in approximately 15% of cases. <ref name=":3">{{Cite journal|last=Djokic|first=Miroslav|last2=Le Beau|first2=Michelle M.|last3=Swinnen|first3=Lode J.|last4=Smith|first4=Sonali M.|last5=Rubin|first5=Charles M.|last6=Anastasi|first6=John|last7=Carlson|first7=Katrin M.|date=2005|title=Post-transplant lymphoproliferative disorder subtypes correlate with different recurring chromosomal abnormalities|url=http://dx.doi.org/10.1002/gcc.20287|journal=Genes, Chromosomes and Cancer|volume=45|issue=3|pages=313–318|doi=10.1002/gcc.20287|issn=1045-2257}}</ref>

Clonally rearranged Immunoglobulin (IG) genes IGH / IGK / IGL may be detected.
{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|IGH (heavy chain on  chromosome 14q32.13)    
|IGH
|
|
|Yes
|Unknown
|Unknown
|
|-
|IGK (kappa light  chain on chromosome 2p11)
|IGK
|
|
|Yes
|Unknown
|Unknown
|
|-
|IGL (lambda light  chain on chromosome 22q11)
|IGL
|
|
|Yes
|Unknown
|Unknown
|
|-
|t(1;3)(p36;p21)
|
|
|
|Unknown
|Unknown
|Unknown
|<ref name=":4">{{Cite journal|last=Vakiani|first=Efsevia|last2=Basso|first2=Katia|last3=Klein|first3=Ulf|last4=Mansukhani|first4=Mahesh M.|last5=Narayan|first5=Gopeshwar|last6=Smith|first6=Paula M.|last7=Murty|first7=Vundavalli V.|last8=Dalla-Favera|first8=Riccardo|last9=Pasqualucci|first9=Laura|date=2008-12|title=Genetic and phenotypic analysis of B-cell post-transplant lymphoproliferative disorders provides insights into disease biology|url=http://dx.doi.org/10.1002/hon.859|journal=Hematological Oncology|volume=26|issue=4|pages=199–211|doi=10.1002/hon.859|issn=0278-0232}}</ref>
|-
|ins(11;?)(q23.1;?)
|
|
|
|Unknown
|Unknown
|Unknown
|<ref name=":4" />
|-
|t(1;17)(q21.3;p13)
|
|
|
|Unknown
|Unknown
|Unknown
|<ref name=":3" />
|-
|Inv(9)(p11q13)
|
|
|
|Unknown
|Unknown
|Unknown
|<ref name=":3" />
|}        
            
==Individual Region Genomic Gain / Loss / LOH==

Cytogenetic abnormalities are rare in P-PTLD. Trisomy X and trisomy 3 have been reported in the context of P-PTLD. 

{| class="wikitable sortable"
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|1
|Loss
|
|1q31-q44
|
|
|
|<ref name=":5">{{Cite journal|last=Poirel|first=Hélène A.|last2=Bernheim|first2=Alain|last3=Schneider|first3=Anouck|last4=Meddeb|first4=Mounira|last5=Choquet|first5=Sylvain|last6=Leblond|first6=Véronique|last7=Charlotte|first7=Frédéric|last8=Davi|first8=Frédéric|last9=Canioni|first9=Danielle|date=2005-07-27|title=Characteristic Pattern of Chromosomal Imbalances in Posttransplantation Lymphoproliferative Disorders: Correlation with Histopathological Subcategories and EBV Status|url=http://dx.doi.org/10.1097/01.tp.0000163288.98419.0d|journal=Transplantation|volume=80|issue=2|pages=176–184|doi=10.1097/01.tp.0000163288.98419.0d|issn=0041-1337}}</ref>
|-
|3
|trisomy
|
|Whole chromosome
|Possibly a recurrent  finding
|Favorable, possibly
|Favorable, possibly
|<ref name=":6">{{Cite journal|last=Gallego|first=Marta S.|last2=Bernasconi|first2=Andrea|last3=Dávila|first3=María T.|last4=Rampazzi|first4=Alejandra|last5=Chantada|first5=Guillermo|last6=Gallo|first6=Guillermo|last7=Rossi|first7=Jorge|last8=Barreiro|first8=Cristina Z.|date=2002-05-19|title=Trisomy 3 in two paediatric post-transplant lymphomas|url=http://dx.doi.org/10.1046/j.1365-2141.2002.03481.x|journal=British Journal of Haematology|volume=117|issue=3|pages=558–562|doi=10.1046/j.1365-2141.2002.03481.x|issn=0007-1048}}</ref> <ref name=":7">{{Cite journal|last=Shestakova|first=Anna|last2=Grove|first2=Narina|last3=Said|first3=Jonathan|last4=Song|first4=Sophie|last5=Quintero-Rivera|first5=Fabiola|date=2020-10|title=Trisomy 3, a sole recurrent cytogenetic abnormality in pediatric polymorphic post-transplant lymphoproliferative disorder (PTLD)|url=http://dx.doi.org/10.1016/j.cancergen.2020.09.006|journal=Cancer Genetics|volume=248-249|pages=39–48|doi=10.1016/j.cancergen.2020.09.006|issn=2210-7762}}</ref>
|-
|5
|Gain
|
|5p
|Unknown
|Unknown
|Unknown
|<ref name=":5" />
|-
|17
|Loss
|
|17q23-q25
|
|
|
|<ref name=":5" />
|-
|X
|Loss
|
|Xp
|Unknown
|Unknown
|Unknown
|<ref name=":5" />
|-
|X
|trisomy
|
|Whole chromosome
|Unknown
|Unknown
|Unknown
|<ref name=":3" />
|}
==Characteristic Chromosomal Patterns==

Trisomy 3 may be a recurrent aberration.

{| class="wikitable sortable"
|-
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|Trisomy 3
|Unknown
|Favorable, possibly
|Favorable, possibly
|<ref name=":7" /><ref name=":6" />
|}
==Gene Mutations (SNV / INDEL)==

The frequency of mutations in P-PTLD is lower, and variants seen are less deleterious, when compared to those seen in monomorphic PTLD. <ref>{{Cite journal|last=Menter|first=Thomas|last2=Juskevicius|first2=Darius|last3=Alikian|first3=Mary|last4=Steiger|first4=Juerg|last5=Dirnhofer|first5=Stephan|last6=Tzankov|first6=Alexandar|last7=Naresh|first7=Kikkeri N.|date=2017-04-17|title=Mutational landscape of B-cell post-transplant lymphoproliferative disorders|url=http://dx.doi.org/10.1111/bjh.14633|journal=British Journal of Haematology|volume=178|issue=1|pages=48–56|doi=10.1111/bjh.14633|issn=0007-1048}}</ref>  <ref>{{Cite journal|last=Butzmann|first=Alexandra|last2=Sridhar|first2=Kaushik|last3=Jangam|first3=Diwash|last4=Song|first4=Hanbing|last5=Singh|first5=Amol|last6=Kumar|first6=Jyoti|last7=Chisholm|first7=Karen M.|last8=Pinsky|first8=Benjamin|last9=Huang|first9=Franklin|date=2022-01-17|title=Mutations in JAK/STAT and NOTCH1 Genes Are Enriched in Post-Transplant Lymphoproliferative Disorders|url=http://dx.doi.org/10.3389/fonc.2021.790481|journal=Frontiers in Oncology|volume=11|doi=10.3389/fonc.2021.790481|issn=2234-943X}}</ref> Mutations in BCL6 are reported in up to 50% of P-PTLD cases. <ref>{{Cite journal|last=Cesarman|first=E.|last2=Chadburn|first2=A.|last3=Liu|first3=Y. F.|last4=Migliazza|first4=A.|last5=Dalla-Favera|first5=R.|last6=Knowles|first6=D. M.|date=1998-10-01|title=BCL-6 gene mutations in posttransplantation lymphoproliferative disorders predict response to therapy and clinical outcome|url=https://pubmed.ncbi.nlm.nih.gov/9746767|journal=Blood|volume=92|issue=7|pages=2294–2302|issn=0006-4971|pmid=9746767}}</ref>

{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!'''Diagnostic Significance (Yes, No or Unknown)'''
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|BCL6
|Oncogene
|NM_001130845.1 

449T>C,  645G>C, 823T>A, 978G>A,   445C>G, 477T>C, 564T>C, 863A>G ,

443A>T,  506A>G, 668A>G, 802A>G, 803C>G, 837T>G  
|
|
|Unknown
|Aggressive disease
|Aggressive disease
|<ref name=":2" /> <ref>{{Cite journal|last=Cesarman|first=Ethel|last2=Chadburn|first2=Amy|last3=Liu|first3=Yi-Fang|last4=Migliazza|first4=Anna|last5=Dalla-Favera|first5=Riccardo|last6=Knowles|first6=Daniel M.|date=1998-10-01|title=BCL-6 Gene Mutations in Posttransplantation Lymphoproliferative Disorders Predict Response to Therapy and Clinical Outcome|url=http://dx.doi.org/10.1182/blood.v92.7.2294|journal=Blood|volume=92|issue=7|pages=2294–2302|doi=10.1182/blood.v92.7.2294|issn=1528-0020}}</ref> <ref>{{Cite journal|last=Morscio|first=J.|last2=Dierickx|first2=D.|last3=Tousseyn|first3=T.|date=2013|title=Molecular Pathogenesis of B-Cell Posttransplant Lymphoproliferative Disorder: What Do We Know So Far?|url=http://dx.doi.org/10.1155/2013/150835|journal=Clinical and Developmental Immunology|volume=2013|pages=1–13|doi=10.1155/2013/150835|issn=1740-2522}}</ref>
|-
|BCL11B
|
|NM_0138576.3 H317Y
|
|
|Unknown
|Unknown
|Unknown
|<ref>{{Cite journal|last=Butzmann|first=Alexandra|last2=Sridhar|first2=Kaushik|last3=Jangam|first3=Diwash|last4=Song|first4=Hanbing|last5=Singh|first5=Amol|last6=Kumar|first6=Jyoti|last7=Chisholm|first7=Karen M.|last8=Pinsky|first8=Benjamin|last9=Huang|first9=Franklin|date=2022-01-17|title=Mutations in JAK/STAT and NOTCH1 Genes Are Enriched in Post-Transplant Lymphoproliferative Disorders|url=http://dx.doi.org/10.3389/fonc.2021.790481|journal=Frontiers in Oncology|volume=11|doi=10.3389/fonc.2021.790481|issn=2234-943X}}</ref>
|-
|IRS4
|
|NM_003604.2 P930Q
|
|
|Unknown
|Unknown
|Unknown
|<ref>{{Cite journal|last=Butzmann|first=Alexandra|last2=Sridhar|first2=Kaushik|last3=Jangam|first3=Diwash|last4=Song|first4=Hanbing|last5=Singh|first5=Amol|last6=Kumar|first6=Jyoti|last7=Chisholm|first7=Karen M.|last8=Pinsky|first8=Benjamin|last9=Huang|first9=Franklin|date=2022-01-17|title=Mutations in JAK/STAT and NOTCH1 Genes Are Enriched in Post-Transplant Lymphoproliferative Disorders|url=http://dx.doi.org/10.3389/fonc.2021.790481|journal=Frontiers in Oncology|volume=11|doi=10.3389/fonc.2021.790481|issn=2234-943X}}</ref>
|-
|PAX5
|Oncogene
|
|
|
|Unknown
|Unknown
|Unknown
|<ref>{{Cite journal|last=Menter|first=Thomas|last2=Juskevicius|first2=Darius|last3=Alikian|first3=Mary|last4=Steiger|first4=Juerg|last5=Dirnhofer|first5=Stephan|last6=Tzankov|first6=Alexandar|last7=Naresh|first7=Kikkeri N.|date=2017-04-17|title=Mutational landscape of B-cell post-transplant lymphoproliferative disorders|url=http://dx.doi.org/10.1111/bjh.14633|journal=British Journal of Haematology|volume=178|issue=1|pages=48–56|doi=10.1111/bjh.14633|issn=0007-1048}}</ref>
|-
|NOTCH1
|Oncogene
|
|
|
|Unknown
|Unknown
|Unknown
|<ref>{{Cite journal|last=Menter|first=Thomas|last2=Juskevicius|first2=Darius|last3=Alikian|first3=Mary|last4=Steiger|first4=Juerg|last5=Dirnhofer|first5=Stephan|last6=Tzankov|first6=Alexandar|last7=Naresh|first7=Kikkeri N.|date=2017-04-17|title=Mutational landscape of B-cell post-transplant lymphoproliferative disorders|url=http://dx.doi.org/10.1111/bjh.14633|journal=British Journal of Haematology|volume=178|issue=1|pages=48–56|doi=10.1111/bjh.14633|issn=0007-1048}}</ref>
|-
|KRAS
|Oncogene
|
|
|
|Unknown
|Unknown
|Unknown
|<ref>{{Cite journal|last=Menter|first=Thomas|last2=Juskevicius|first2=Darius|last3=Alikian|first3=Mary|last4=Steiger|first4=Juerg|last5=Dirnhofer|first5=Stephan|last6=Tzankov|first6=Alexandar|last7=Naresh|first7=Kikkeri N.|date=2017-04-17|title=Mutational landscape of B-cell post-transplant lymphoproliferative disorders|url=http://dx.doi.org/10.1111/bjh.14633|journal=British Journal of Haematology|volume=178|issue=1|pages=48–56|doi=10.1111/bjh.14633|issn=0007-1048}}</ref>
|-
|JAK3
|Oncogene
|
|
|
|Unknown
|Unknown
|Unknown
|<ref>{{Cite journal|last=Menter|first=Thomas|last2=Juskevicius|first2=Darius|last3=Alikian|first3=Mary|last4=Steiger|first4=Juerg|last5=Dirnhofer|first5=Stephan|last6=Tzankov|first6=Alexandar|last7=Naresh|first7=Kikkeri N.|date=2017-04-17|title=Mutational landscape of B-cell post-transplant lymphoproliferative disorders|url=http://dx.doi.org/10.1111/bjh.14633|journal=British Journal of Haematology|volume=178|issue=1|pages=48–56|doi=10.1111/bjh.14633|issn=0007-1048}}</ref>
|-
|TET2
|TSG
|
|
|
|Unknown
|Unknown
|Unknown
|<ref>{{Cite journal|last=Menter|first=Thomas|last2=Juskevicius|first2=Darius|last3=Alikian|first3=Mary|last4=Steiger|first4=Juerg|last5=Dirnhofer|first5=Stephan|last6=Tzankov|first6=Alexandar|last7=Naresh|first7=Kikkeri N.|date=2017-04-17|title=Mutational landscape of B-cell post-transplant lymphoproliferative disorders|url=http://dx.doi.org/10.1111/bjh.14633|journal=British Journal of Haematology|volume=178|issue=1|pages=48–56|doi=10.1111/bjh.14633|issn=0007-1048}}</ref>
|-
|PTPN1
|TSG
|
|
|
|Unknown
|Unknown
|Unknown
|<ref>{{Cite journal|last=Menter|first=Thomas|last2=Juskevicius|first2=Darius|last3=Alikian|first3=Mary|last4=Steiger|first4=Juerg|last5=Dirnhofer|first5=Stephan|last6=Tzankov|first6=Alexandar|last7=Naresh|first7=Kikkeri N.|date=2017-04-17|title=Mutational landscape of B-cell post-transplant lymphoproliferative disorders|url=http://dx.doi.org/10.1111/bjh.14633|journal=British Journal of Haematology|volume=178|issue=1|pages=48–56|doi=10.1111/bjh.14633|issn=0007-1048}}</ref>
|}
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

==Epigenomic Alterations==

Hypermethylation of O6-Methylguanine-DNA Methyl-Transferase (MGMT) is reported in 75% of P-PTLD <ref name=":8">{{Cite journal|last=Ibrahim|first=Hazem A. H.|last2=Naresh|first2=Kikkeri N.|date=2012|title=Posttransplant Lymphoproliferative Disorders|url=http://dx.doi.org/10.1155/2012/230173|journal=Advances in Hematology|volume=2012|pages=1–11|doi=10.1155/2012/230173|issn=1687-9104}}</ref>. MGMT is involved in DNA repair.

Hypermethylation of SHP1 is observed in 75% of P-PTLD. <ref name=":8" /> The SHP1 gene is located on chromosome 12p13 and encodes the ''SHP1'' protein. The protein is expressed in hematopoietic cells and potentiates its negative effect on cell cycle regulation by inhibiting the JAK/STAT pathway.

==Genes and Main Pathways Involved==

Put your text here and fill in the table
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|BCL6, mutation
|BCL6 is a transcription factor,  prevents apoptosis
|Lymphoma, shuts of normal  differentiation in B-cells.
|-
|Hypermethylation of O6-Methylguanine-DNA Methyl-Transferase (MGMT)
|MGMT is one of the DNA repair genes  that serves to protect against DNA damage
|Damage of DNA.
|-
|Hypermethylation of SHP1 
<br />
|The SHP1 protein is  expressed in hematopoietic cells and potentiates its negative effect on cell  cycle regulation by inhibiting the JAKs/STATs pathway
|Activation of JAK/STAT pathway
|}
==Genetic Diagnostic Testing Methods==

Conventional cytogenetics, FISH, NGS

==Familial Forms==

Not known

==Additional Information==

Separate lesions may contain distinct and different clonal populations. <ref>{{Cite journal|last=Chadburn|first=Amy|last2=Cesarman|first2=Ethel|last3=Liu|first3=Yi Fang|last4=Addonizio|first4=Linda|last5=Hsu|first5=Daphne|last6=Michler|first6=Robert E.|last7=Knowles|first7=Daniel M.|date=1995-06-01|title=Molecular genetic analysis demonstrates that multiple posttransplantation lymphoproliferative disorders occurring in one anatomic site in a single patient represent distinct primary lymphoid neoplasms|url=http://dx.doi.org/10.1002/1097-0142(19950601)75:11<2747::aid-cncr2820751119>3.0.co;2-3|journal=Cancer|volume=75|issue=11|pages=2747–2756|doi=10.1002/1097-0142(19950601)75:11<2747::aid-cncr2820751119>3.0.co;2-3|issn=0008-543X}}</ref>

Significant T-cell clones are not expected.

EBV terminal repeat analysis is the most sensitive method for detection of clonal populations in EBV+ cases.

P-PTLD is similar to non-germinal center monomorphic PTLD, when assessed using gene expression profiling. <ref name=":3" /><ref name=":4" />
==Links==

Note: A more extensive list of mutations can be found in:

cBioportal https://www.cbioportal.org/<nowiki/>(<nowiki>https://www.cbioportal.org/</nowiki>),

COSMIC (https://cancer.sanger.ac.uk/cosmic), 

ICGC [https://dcc.icgc.org/] (<nowiki>https://dcc.icgc.org/</nowiki>) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

BCL6 https://cancer.sanger.ac.uk/cosmic/gene/analysis?all_data=y&coords=AA%3AAA&dr=&end=707&gd=&genome=37&id=1369&ln=BCL6&seqlen=707&sn=large_intestine&src=gene&start=1

BCLB11B https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=BCL11B

IRS4 https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=irs4

==References==
<references />

==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.


<nowiki>*</nowiki>''Citation of this Page'': “Polymorphic lymphoproliferative disorders arising in immune deficiency / dysregulation”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Polymorphic_lymphoproliferative_disorders_arising_in_immune_deficiency_/_dysregulation</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases P]]