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

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), 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 in a table, click nearby within the table and select the > symbol that appears. 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 Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

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

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

WHO Essential and Desirable Genetic Diagnostic Criteria

(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)

WHO Essential Criteria (Genetics)*
WHO Desirable Criteria (Genetics)*
Other Classification

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

(Instructions: The table will have the related terminology from the WHO autocompleted.)

Acceptable
Not Recommended

Gene Rearrangements

Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Driver Gene Fusion(s) and Common Partner Genes Molecular Pathogenesis Typical Chromosomal Alteration(s) Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE: ABL1 EXAMPLE: BCR::ABL1 EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1. EXAMPLE: t(9;22)(q34;q11.2) EXAMPLE: Common (CML) EXAMPLE: D, P, T EXAMPLE: Yes (WHO, NCCN) EXAMPLE:

The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).

EXAMPLE: CIC EXAMPLE: CIC::DUX4 EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5. EXAMPLE: t(4;19)(q25;q13) EXAMPLE: Common (CIC-rearranged sarcoma) EXAMPLE: D EXAMPLE:

DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).

EXAMPLE: ALK EXAMPLE: ELM4::ALK


Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1

EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18. EXAMPLE: N/A EXAMPLE: Rare (Lung adenocarcinoma) EXAMPLE: T EXAMPLE:

Both balanced and unbalanced forms are observed by FISH (add references).

EXAMPLE: ABL1 EXAMPLE: N/A EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways. EXAMPLE: N/A EXAMPLE: Recurrent (IDH-wildtype Glioblastoma) EXAMPLE: D, P, T

Cytogenetic abnormalities are uncommon in P-PTLD being present in approximately 15% of cases. [1]

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 [2]
ins(11;?)(q23.1;?) Unknown Unknown Unknown [2]
t(1;17)(q21.3;p13) Unknown Unknown Unknown [1]
Inv(9)(p11q13) Unknown Unknown Unknown [1]

Individual Region Genomic Gain/Loss/LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)

Chr # Gain, Loss, Amp, LOH Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] Relevant Gene(s) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:

7

EXAMPLE: Loss EXAMPLE:

chr7

EXAMPLE:

Unknown

EXAMPLE: D, P EXAMPLE: No EXAMPLE:

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).

EXAMPLE:

8

EXAMPLE: Gain EXAMPLE:

chr8

EXAMPLE:

Unknown

EXAMPLE: D, P EXAMPLE:

Common recurrent secondary finding for t(8;21) (add references).

EXAMPLE:

17

EXAMPLE: Amp EXAMPLE:

17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]

EXAMPLE:

ERBB2

EXAMPLE: D, P, T EXAMPLE:

Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

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 [3]
3 trisomy Whole chromosome Possibly a recurrent finding Favorable, possibly Favorable, possibly [4] [5]
5 Gain 5p Unknown Unknown Unknown [3]
17 Loss 17q23-q25 [3]
X Loss Xp Unknown Unknown Unknown [3]
X trisomy Whole chromosome Unknown Unknown Unknown [1]

Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Chromosomal Pattern Molecular Pathogenesis Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:

Co-deletion of 1p and 18q

EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). EXAMPLE: Common (Oligodendroglioma) EXAMPLE: D, P
EXAMPLE:

Microsatellite instability - hypermutated

EXAMPLE: Common (Endometrial carcinoma) EXAMPLE: P, T

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 [5][4]

Gene Mutations (SNV/INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Gene Genetic Alteration Tumor Suppressor Gene, Oncogene, Other Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T   Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:EGFR


EXAMPLE: Exon 18-21 activating mutations EXAMPLE: Oncogene EXAMPLE: Common (lung cancer) EXAMPLE: T EXAMPLE: Yes (NCCN) EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE: TP53; Variable LOF mutations


EXAMPLE: Variable LOF mutations EXAMPLE: Tumor Supressor Gene EXAMPLE: Common (breast cancer) EXAMPLE: P EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations EXAMPLE: Activating mutations EXAMPLE: Oncogene EXAMPLE: Common (melanoma) EXAMPLE: T

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

The frequency of mutations in P-PTLD is lower, and variants seen are less deleterious, when compared to those seen in monomorphic PTLD. [6] [7] Mutations in BCL6 are reported in up to 50% of P-PTLD cases. [8]

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] [10] [11]
BCL11B NM_0138576.3 H317Y Unknown Unknown Unknown [12]
IRS4 NM_003604.2 P930Q Unknown Unknown Unknown [13]
PAX5 Oncogene Unknown Unknown Unknown [14]
NOTCH1 Oncogene Unknown Unknown Unknown [15]
KRAS Oncogene Unknown Unknown Unknown [16]
JAK3 Oncogene Unknown Unknown Unknown [17]
TET2 TSG Unknown Unknown Unknown [18]
PTPN1 TSG Unknown Unknown Unknown [19]

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 [20]. MGMT is involved in DNA repair.

Hypermethylation of SHP1 is observed in 75% of P-PTLD. [20] 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. [21]

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. [1][2]

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. ↑ Jump up to: 1.0 1.1 1.2 1.3 1.4 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.
  2. ↑ Jump up to: 2.0 2.1 2.2 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)
  3. ↑ Jump up to: 3.0 3.1 3.2 3.3 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.
  4. ↑ Jump up to: 4.0 4.1 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.
  5. ↑ Jump up to: 5.0 5.1 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)
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  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. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ Jump up to: 20.0 20.1 Ibrahim, Hazem A. H.; et al. (2012). "Posttransplant Lymphoproliferative Disorders". Advances in Hematology. 2012: 1–11. doi:10.1155/2012/230173. ISSN 1687-9104.
  21. ↑ 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.

Notes

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*Citation of this Page: “Polymorphic lymphoproliferative disorders arising in immune deficiency / dysregulation”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/13/2025, https://ccga.io/index.php/HAEM5:Polymorphic_lymphoproliferative_disorders_arising_in_immune_deficiency_/_dysregulation.

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