HAEM5:Plasmablastic lymphoma

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:Plasmablastic Lymphoma.

(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)*

Mark Evans, MD (University of California, Irvine)

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

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	B-cell lymphoid proliferations and lymphomas
Family	Mature B-cell neoplasms
Type	Large B-cell lymphomas
Subtype(s)	Plasmablastic lymphoma

Definition / Description of Disease

In 1997, Delecluse et al. described a series of large B-cell lymphomas occurring within the jaw and oral cavities of HIV-positive individuals. The cells were blastic in appearance and did not express CD20, but did demonstrate plasmacytic antigens. Plasmablastic lymphoma (PBL) is recognized by the World Health Organization (WHO) as an aggressive proliferation of large B cells with immunoblastic or plasmablastic morphology and plasmacytic phenotype. This entity is distinguished from other large B-cell lymphomas with similar immunoprofiles, such as ALK-positive large B-cell lymphoma and HHV-8-associated lymphoproliferative disorders.

Synonyms / Terminology

Monomorphic plasmablastic lymphoma; plasmablastic lymphoma with plasmacytic differentiation

Epidemiology / Prevalence

• Plasmablastic lymphoma typically occurs in adults with human immunodeficiency virus (HIV) infection (approximately 73% of cases).

• It is also seen in the setting of iatrogenic immunosuppression (autoimmune disease or post-transplant).

• PBL has been observed in older immunocompetent adults and in children, typically with HIV or immunodeficiency.

Clinical Features

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Signs and Symptoms	EXAMPLE: Asymptomatic (incidental finding on complete blood counts) EXAMPLE: B-symptoms (weight loss, fever, night sweats) EXAMPLE: Fatigue EXAMPLE: Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE: Cytopenias EXAMPLE: Lymphocytosis (low level)

editv4:Clinical Features

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An extranodal mass is the most typical presentation, and nodal disease is more common in post-transplant PBL. Paraproteins may be detected in some cases. Greater than 50% of cases associated with some form of immunodeficiency present with stage III/IV disease with bone marrow involvement.

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Sites of Involvement

Typically head and neck regions, particularly the oral cavity. Other less commonly involved sites include the gastrointestinal tract, skin, soft tissue, lung, bone, and rarely lymph nodes.

(PBL, monomorphic variant; image courtesy of Mark Evans, MD)

Morphologic Features

Two histologic variants have been described:

• The monomorphic variant features large immunoblast-like cells with fine nuclear chromatin, prominent nucleoli, and little or no plasmacytic differentiation; a starry sky pattern is common.

• The variant with plasmacytic differentiation is composed of cells with course nuclear chromatin, basophilic cytoplasm, eccentric nuclei, and paranuclear hof.

• Some cases demonstrate features of both variants.

Immunophenotype

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Finding	Marker
Positive (universal)	EXAMPLE: CD1
Positive (subset)	EXAMPLE: CD2
Negative (universal)	EXAMPLE: CD3
Negative (subset)	EXAMPLE: CD4

editv4:Immunophenotype

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(PBL strongly positive for CD138 by immunohistochemistry; image courtesy of Mark Evans, MD)

The cells express plasmacytic antigens (CD138, VS38c, IRF4/MUM1, BLIMP1, XBP1, and CD38). CD45, PAX-5, and CD20 are typically negative or weakly positive. Cytoplasmic IgG, as well as kappa and lambda light chains are common. CD79a is present in approximately 40% of cases, and CD56 in about 25%. The cells are typically positive for Epstein-Barr virus-encoded RNA (EBER). Ki-67 proliferation index is usually >90%.

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WHO Essential and Desirable Genetic Diagnostic Criteria

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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

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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

editv4:Chromosomal Rearrangements (Gene Fusions)

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MYC (8q24) up-regulation occurs via translocations, frequently between MYC and immunoglobulin (IG) heavy chain [t(8;14)] and immunoglobulin light chain genes [t(2;8) or t(8;22)], which are also seen in Burkitt lymphoma. These translocations are more common in EBV-positive tumors (74%), and have been associated with poorer prognosis.

(Rearrangement of MYC by FISH (yellow signals); image courtesy of Fabiola Quintero-Rivera, MD)

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editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

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• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

• The prognosis of PBL is very poor, with three quarters of patients dying with a median survival of 6-11 months.

• There is currently no standard therapy for PBL. CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) have been generally considered inadequate, and the National Comprehensive Cancer Network (NCCN) favors Hyper-CVAD-MA (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, and high-dose methotrexate and cytarabine), CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine), COMB (cyclophosphamide, Oncovin, methyl-CCNU, and bleomycin), and infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin).

• Patients with localized disease have a better prognosis, and these individuals can be managed by radiotherapy and doxorubicin-based chemotherapy with radiation therapy.

• Polychemotherapy is required for patients with disseminated disease; more than 50% achieve complete remissions (CRs), but approximately 70% die of progressive disease, with an event-free survival of 22 months, and an overall survival of 32 months.

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Individual Region Genomic Gain/Loss/LOH

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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.

editv4:Genomic Gain/Loss/LOH

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One study of 12 PBL cases showed recurrent gains of 1q31.1q44, 5p15.33p13.1, 7q11.2q11.23, 8q24.13q24.3, 11p and 11q terminal regions, 15q15q26.3, 19p13.3p13.12 and chromosomes 3, 7, 11, and 15, as well as losses of 1p36.33p35.1, 6q25.1q27, 8p23.3p22.14 and 18q21.32q23. Additionally, 54% of the cases had either deletion or copy neutral loss of heterozygosity (CN-LOH) involving the tumor suppressor gene CDKN2C at 1p32.3. Furthermore, recurrent copy number losses involving the immunoglobulin genes IGH and IGKV were documented.

(Reciprocal translocation between the MYC and IGH loci by FISH (yellow signals); image courtesy of Fabiola Quintero-Rivera, MD)

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Characteristic Chromosomal or Other Global Mutational Patterns

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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

editv4:Characteristic Chromosomal Aberrations / Patterns

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In addition to the MYC/IG rearrangements, complex karyotypes are also frequently observed. PBL often demonstrates chromosomal changes seen in plasma cell myeloma, including gain of 1q, loss of 1p, deletions 13q and/or 17p, and gains of odd-numbered chromosomes, such as +3, +5, +7, +9, +11, and/or +15.

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Gene Mutations (SNV/INDEL)

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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.

editv4:Gene Mutations (SNV/INDEL)

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• IGHV may be unmutated or demonstrate somatic hypermutation.

• Montes-Moreno et al. demonstrated somatic mutations in PRDM1(BLIMP1) in 50% of cases.

• The largest series of transplant-associated PBL analyzed by next-generation sequencing detected genetic aberrations of the RAS/MAPK, TP53, and NOTCH signaling pathways.

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Epigenomic Alterations

Hypermethylation of p16 has been reported in a case of PBL.

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations	EXAMPLE: Histone modification, chromatin remodeling	EXAMPLE: Abnormal gene expression program

editv4:Genes and Main Pathways Involved

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• MYC expression is suppressed by PRDM1 (BLIMP1) in terminally differentiated B cells; BLIMP1 encodes a transcriptional factor responsible for plasma cell differentiation.

• The MYC activation present in PBL (by gene amplification or translocation) results in cellular proliferation and survival upon overcoming PRDM1 (BLIMP1) repression.

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Genetic Diagnostic Testing Methods

• Diagnosis is usually dependent on morphologic examination and immunohistochemistry demonstrating expression for plasmacytic antigens.

• Conventional cytogenetics has utility in detecting MYC rearrangement and amplification. Most common translocation involves MYC -IGH.

• Next-generation sequencing is helpful for identifying single nucleotide variants of PRDM1 and of genes in the of the RAS/MAPK, TP53, and NOTCH signaling pathways.

Familial Forms

Not applicable.

Additional Information

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Links

HAEM4:Lymphomas Associated with HIV Infection

MYC in COSMIC (https://cancer.sanger.ac.uk/cell_lines/gene/analysis?ln=MYC)

References

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Notes

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Prior Author(s):

*Citation of this Page: “Plasmablastic lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/10/2025, https://ccga.io/index.php/HAEM5:Plasmablastic_lymphoma.