HAEM5:Lymphoplasmacytic 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:Lymphoplasmacytic Lymphoma.

Other relevent pages include: HAEM4:Waldenstrom Macroglobulinemia

Note: author needs to coorelate with Waldenstrom Macroglobulinemia

(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)*

Kapitolina Semenova, MD, Jack Reid, MD, Fabiola Quintero-Rivera, MD

Departments of Pathology, Laboratory Medicine, and *Pediatrics, Division of Genetic and Genomic Medicine, 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	N/A
Subtype(s)	Lymphoplasmacytic lymphoma

Definition / Description of Disease

• Lymphoplasmacytic lymphoma (LPL) is a neoplasm of small B lymphocytes, plasmacytoid lymphocytes, and plasma cells, usually involving bone marrow and spleen, which does not fulfil the criteria for any of the other small B-cell lymphoid neoplasms, that can have plasmacytic differentiation.
• Based on the presence of the bone marrow involvement and the presence of paraprotein, LPL is categorized into Waldenström macroglobulinemia and LPL of non-Waldenström macroglobulinemia.
• The majority of cases of LPL lymphoma are associated with IgM paraprotein secretion (Waldenström macroglobulinemia), with less than 5% of cases attributed to IgA, IgG, and nonsecreting cases of LPL.

Synonyms / Terminology

Malignant lymphoma, lymphoplasmacytoid lymphoma.

Epidemiology / Prevalence

• Lymphoplasmacytic lymphoma, in approximately 95% of cases, occurs in patients of Caucasian descent.
• The median age is in the seventh decade of life.
• Approximately 1000-1500 new cases are diagnosed yearly in the United States.
• LPL associated with IgM (Waldenström macroglobulinemia) is more commonly occurs in male patients, while LPL with a non-IgM is reported more frequently in females.

Clinical Features

Signs and Symptoms

Weakness (usually related to anemia) Fatigue Hyperviscosity (in 30% of cases) Lymphadenopathy and splenomegaly (in 10-20% of patient at time of diagnosis) Paraprotein deposition in tissues with organ-specific dysfunction: Neuropathy (minority of patients; may be related to the IgM paraprotein with myelin sheath antigens) Diarrhea (rare, due to paraprotein deposition in gastrointestinal tract) Coagulopathy (may be cause by IgM binding to clotting factors) Bullae or papules in the skin Proteinuria and renal failure

Laboratory Findings

IgM paraprotein IgM and IgG paraprotein (minority of patients) Cold agglutinins Cryoglobulinemia

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Sites of Involvement

• Bone marrow (most of cases), lymph nodes, spleen, liver, and other extranodal sites. The peripheral blood may also be involved.
• Rare involvement of CNS associated with Waldenström macroglobulinemia (known as Bing-Neel syndrome). Lymphoplasmacytic lymphoma may occur at sites typically involved by extranodal marginal zone lymphoma (MZL) of mucosal-associated lymphoid tissue (MALT lymphoma), such as the ocular adnexa.
• Patients with non-IgM LPL are more likely to present with extramedullary involvement such as lymphadenopathy, splenomegaly, or extranodal disease.
• Bone marrow involvement is more common in patients with IgM-associated LPL (Waldenström macroglobulinemia) when compared to non-IgM LPL.

Morphologic Features

• Bone marrow involvement is characterized by diffuse, interstitial, and nodular infiltration patterns. Paratrabecular can also be present; however, it has been observed more frequently in cases of marginal zone lymphoma.
• The infiltrate is characterized by small monotonous lymphocytes admixed with a variable amount of plasmacytoid lymphocytes and plasma cells. Although nonspecific, variable amount of reactive mast cell and hemosiderin deposits are frequently observed. Dutcher bodies (nuclear vacuoles containing IgM protein) and Russell bodies (cytoplasmic inclusion) are often seen similarly in multiple myeloma cases.

• Peripheral blood often demonstrates lymphoma cells with similar morphology. Leukocytosis is not typically observed. Peripheral blood may also demonstrate a rouleaux formation due to increased IgM paraprotein.

Immunophenotype

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Finding	Marker
Positive (subset)	IgM
Positive (subset)	IgG
Positive (subset)	IgA
Positive (universal)	CD19
Positive (universal)	CD20
Positive (universal)	CD22 (dim)
Positive (universal)	CD25
Positive (universal)	CD79a
Positive (universal)	CD45
Positive (variable)	CD38
Positive (universal)	PAX5
Positive (subset)	CD5
Positive (subset)	CD10
Positive (subset)	TCL1
Negative (universal)	Cyclin D1
Negative (universal)	LEF1
Negative (universal)	EBV stain
Negative (universal)	CD56
Negative (universal)	CD117

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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

No specific chromosomal abnormalities are identified in LPL.

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
t(9:14)(p13:q32)	IGH/PAX5		rare	Yes	No	No

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Individual Region Genomic Gain/Loss/LOH

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
EXAMPLE:

Characteristic Chromosomal or Other Global Mutational Patterns

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Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE:

Gene Mutations (SNV/INDEL)

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
MYD88 L265; Activating mutation		>90%			Yes	Yes	Yes	This is also seen in some non-germinal centre subtype DLBCL, NOS, primary cutaneous DLBCL, leg type, and primary CNS and testicular DLBCL cases. Cases lacking MYDBB L265P mutation are reported to have an adverse prognosis and a lower response to ibrutinib.
CXCR4 S338X or or frameshift mutations		30%			Yes		Yes	Cases with nonsense mutations, has been associated with more symptomatic/active disease, other clinical and laboratory findings, and greater resistance to ibrutinib and possibly other therapeutic agents. Mutations are similar to those seen in the syndrome of warts, hypogammaglobulinaemia, immunodeficiency, and myelokathexis (WHIM syndrome). Mutations in this gene are also present in a very small proportion of other small B-cell lymphomas.
ARID1A		17%

Less commonly, other somatic mutations, such as mutations of TP53, CD79B, KMT20 (previously designated MLL2), and MYBBP1A

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

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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

Genetic Diagnostic Testing Methods

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Familial Forms

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Additional Information

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Links

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References

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Notes

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