Polymorphic lymphoproliferative disorders arising in immune deficiency / dysregulation

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Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent 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

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Primary Author(s)*

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

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

WHO Classification of Disease

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 4th edition of the World Health Organization (WHO) classification system[1].

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. [2] [3] [4]

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. [5] [2] [4] [6]

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.

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. [2] P-PTLD involves the bone marrow in ~20% of cases. [7]

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. [8]

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+/multiple myeloma oncogene-1 protein (MUM1-/+)/CD138- profile and mimics B cells undergoing the germinal center reaction; 67% of P-PTLD displays a BCL6-/MUM1+/CD138- phenotype and mimic B cells that have completed the germinal center reaction. [9]

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  [10]
Negative (universal) CD15 (atypical immunoblasts)

Chromosomal Rearrangements (Gene Fusions)

Cytogenetic abnormalities are uncommon in P-PTLD being present in approximately 15% of cases. [11]

Clonally rearranged Immunoglobulin (IG) genes IGH / IGK / IGL may be detected.

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 [12]
ins(11;?)(q23.1;?) Unknown Unknown Unknown [12]
t(1;17)(q21.3;p13) Unknown Unknown Unknown [11]
Inv(9)(p11q13) Unknown Unknown Unknown [11]

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.

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 [13]
3 trisomy Whole chromosome Possibly a recurrent finding Favorable, possibly Favorable, possibly [14] [15]
5 Gain 5p Unknown Unknown Unknown [13]
17 Loss 17q23-q25 [13]
X Loss Xp Unknown Unknown Unknown [13]
X trisomy Whole chromosome Unknown Unknown Unknown [11]

Characteristic Chromosomal Patterns

Trisomy 3 may be a recurrent aberration.

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 [15][14]

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. [16] [17] Mutations in BCL6 are reported in up to 50% of P-PTLD cases. [18]

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 [9] [19] [20]
BCL11B NM_0138576.3 H317Y Unknown Unknown Unknown [21]
IRS4 NM_003604.2 P930Q Unknown Unknown Unknown [22]
PAX5 Oncogene Unknown Unknown Unknown [23]
NOTCH1 Oncogene Unknown Unknown Unknown [24]
KRAS Oncogene Unknown Unknown Unknown [25]
JAK3 Oncogene Unknown Unknown Unknown [26]
TET2 TSG Unknown Unknown Unknown [27]
PTPN1 TSG Unknown Unknown Unknown [28]

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 [29]. MGMT is involved in DNA repair.

Hypermethylation of SHP1 is observed in 75% of P-PTLD. [29] 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

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


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. [30]

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. [11][12]

Links

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

cBioportal https://www.cbioportal.org/(https://www.cbioportal.org/),

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

ICGC [1] (https://dcc.icgc.org/) 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

  1. ↑ 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.
  2. ↑ 2.0 2.1 2.2 Webber, Steven A; et al. (2006-01). "Lymphoproliferative disorders after paediatric heart transplantation: a multi-institutional study". The Lancet. 367 (9506): 233–239. doi:10.1016/s0140-6736(06)67933-6. ISSN 0140-6736. Check date values in: |date= (help)
  3. ↑ Uhlin, M.; et al. (2013-09-20). "Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation". Haematologica. 99 (2): 346–352. doi:10.3324/haematol.2013.087338. ISSN 0390-6078.
  4. ↑ 4.0 4.1 Natkunam, Yasodha; et al. (2018-11-01). "Immunodeficiency-associated lymphoproliferative disorders: time for reappraisal?". Blood. 132 (18): 1871–1878. doi:10.1182/blood-2018-04-842559. ISSN 0006-4971.
  5. ↑ Dharnidharka, Vikas R. (2018-01-10). "Comprehensive review of post-organ transplant hematologic cancers". American Journal of Transplantation. 18 (3): 537–549. doi:10.1111/ajt.14603. ISSN 1600-6135.
  6. ↑ Nijland, Marieke L.; et al. (2016-01). "Epstein-Barr Virus-Positive Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation: Pathogenesis, Clinical Manifestations, Diagnosis, and Management". Transplantation Direct. 2 (1): e48. doi:10.1097/TXD.0000000000000557. ISSN 2373-8731. PMC 4946499. PMID 27500242. Check date values in: |date= (help)
  7. ↑ Montanari, Francesca; et al. (2010-08). "Bone marrow involvement in patients with posttransplant lymphoproliferative disorders: incidence and prognostic factors". Human Pathology. 41 (8): 1150–1158. doi:10.1016/j.humpath.2009.11.016. ISSN 0046-8177. Check date values in: |date= (help)
  8. ↑ Koeppen, Hartmut; et al. (1998-02). "Morphologic Bone Marrow Changes in Patients With Posttransplantation Lymphoproliferative Disorders". The American Journal of Surgical Pathology. 22 (2): 208–214. doi:10.1097/00000478-199802000-00009. ISSN 0147-5185. Check date values in: |date= (help)
  9. ↑ 9.0 9.1 Capello, D. (2003-07-31). "Molecular histogenesis of posttransplantation lymphoproliferative disorders". Blood. 102 (10): 3775–3785. doi:10.1182/blood-2003-05-1683. ISSN 0006-4971.
  10. ↑ Nalesnik, M. A.; et al. (1988-10). "The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression". The American Journal of Pathology. 133 (1): 173–192. ISSN 0002-9440. PMC 1880655. PMID 2845789. Check date values in: |date= (help)
  11. ↑ 11.0 11.1 11.2 11.3 11.4 Djokic, Miroslav; et al. (2005). "Post-transplant lymphoproliferative disorder subtypes correlate with different recurring chromosomal abnormalities". Genes, Chromosomes and Cancer. 45 (3): 313–318. doi:10.1002/gcc.20287. ISSN 1045-2257.
  12. ↑ 12.0 12.1 12.2 Vakiani, Efsevia; et al. (2008-12). "Genetic and phenotypic analysis of B-cell post-transplant lymphoproliferative disorders provides insights into disease biology". Hematological Oncology. 26 (4): 199–211. doi:10.1002/hon.859. ISSN 0278-0232. Check date values in: |date= (help)
  13. ↑ 13.0 13.1 13.2 13.3 Poirel, Hélène A.; et al. (2005-07-27). "Characteristic Pattern of Chromosomal Imbalances in Posttransplantation Lymphoproliferative Disorders: Correlation with Histopathological Subcategories and EBV Status". Transplantation. 80 (2): 176–184. doi:10.1097/01.tp.0000163288.98419.0d. ISSN 0041-1337.
  14. ↑ 14.0 14.1 Gallego, Marta S.; et al. (2002-05-19). "Trisomy 3 in two paediatric post-transplant lymphomas". British Journal of Haematology. 117 (3): 558–562. doi:10.1046/j.1365-2141.2002.03481.x. ISSN 0007-1048.
  15. ↑ 15.0 15.1 Shestakova, Anna; et al. (2020-10). "Trisomy 3, a sole recurrent cytogenetic abnormality in pediatric polymorphic post-transplant lymphoproliferative disorder (PTLD)". Cancer Genetics. 248-249: 39–48. doi:10.1016/j.cancergen.2020.09.006. ISSN 2210-7762. Check date values in: |date= (help)
  16. ↑ Menter, Thomas; et al. (2017-04-17). "Mutational landscape of B-cell post-transplant lymphoproliferative disorders". British Journal of Haematology. 178 (1): 48–56. doi:10.1111/bjh.14633. ISSN 0007-1048.
  17. ↑ Butzmann, Alexandra; et al. (2022-01-17). "Mutations in JAK/STAT and NOTCH1 Genes Are Enriched in Post-Transplant Lymphoproliferative Disorders". Frontiers in Oncology. 11. doi:10.3389/fonc.2021.790481. ISSN 2234-943X.
  18. ↑ Cesarman, E.; et al. (1998-10-01). "BCL-6 gene mutations in posttransplantation lymphoproliferative disorders predict response to therapy and clinical outcome". Blood. 92 (7): 2294–2302. ISSN 0006-4971. PMID 9746767.
  19. ↑ Cesarman, Ethel; et al. (1998-10-01). "BCL-6 Gene Mutations in Posttransplantation Lymphoproliferative Disorders Predict Response to Therapy and Clinical Outcome". Blood. 92 (7): 2294–2302. doi:10.1182/blood.v92.7.2294. ISSN 1528-0020.
  20. ↑ Morscio, J.; et al. (2013). "Molecular Pathogenesis of B-Cell Posttransplant Lymphoproliferative Disorder: What Do We Know So Far?". Clinical and Developmental Immunology. 2013: 1–13. doi:10.1155/2013/150835. ISSN 1740-2522.
  21. ↑ Butzmann, Alexandra; et al. (2022-01-17). "Mutations in JAK/STAT and NOTCH1 Genes Are Enriched in Post-Transplant Lymphoproliferative Disorders". Frontiers in Oncology. 11. doi:10.3389/fonc.2021.790481. ISSN 2234-943X.
  22. ↑ Butzmann, Alexandra; et al. (2022-01-17). "Mutations in JAK/STAT and NOTCH1 Genes Are Enriched in Post-Transplant Lymphoproliferative Disorders". Frontiers in Oncology. 11. doi:10.3389/fonc.2021.790481. ISSN 2234-943X.
  23. ↑ Menter, Thomas; et al. (2017-04-17). "Mutational landscape of B-cell post-transplant lymphoproliferative disorders". British Journal of Haematology. 178 (1): 48–56. doi:10.1111/bjh.14633. ISSN 0007-1048.
  24. ↑ Menter, Thomas; et al. (2017-04-17). "Mutational landscape of B-cell post-transplant lymphoproliferative disorders". British Journal of Haematology. 178 (1): 48–56. doi:10.1111/bjh.14633. ISSN 0007-1048.
  25. ↑ Menter, Thomas; et al. (2017-04-17). "Mutational landscape of B-cell post-transplant lymphoproliferative disorders". British Journal of Haematology. 178 (1): 48–56. doi:10.1111/bjh.14633. ISSN 0007-1048.
  26. ↑ Menter, Thomas; et al. (2017-04-17). "Mutational landscape of B-cell post-transplant lymphoproliferative disorders". British Journal of Haematology. 178 (1): 48–56. doi:10.1111/bjh.14633. ISSN 0007-1048.
  27. ↑ Menter, Thomas; et al. (2017-04-17). "Mutational landscape of B-cell post-transplant lymphoproliferative disorders". British Journal of Haematology. 178 (1): 48–56. doi:10.1111/bjh.14633. ISSN 0007-1048.
  28. ↑ Menter, Thomas; et al. (2017-04-17). "Mutational landscape of B-cell post-transplant lymphoproliferative disorders". British Journal of Haematology. 178 (1): 48–56. doi:10.1111/bjh.14633. ISSN 0007-1048.
  29. ↑ 29.0 29.1 Ibrahim, Hazem A. H.; et al. (2012). "Posttransplant Lymphoproliferative Disorders". Advances in Hematology. 2012: 1–11. doi:10.1155/2012/230173. ISSN 1687-9104.
  30. ↑ Chadburn, Amy; et al. (1995-06-01). <2747::aid-cncr2820751119>3.0.co;2-3 "Molecular genetic analysis demonstrates that multiple posttransplantation lymphoproliferative disorders occurring in one anatomic site in a single patient represent distinct primary lymphoid neoplasms". Cancer. 75 (11): 2747–2756. doi:10.1002/1097-0142(19950601)75:11<2747::aid-cncr2820751119>3.0.co;2-3. ISSN 0008-543X.

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