HAEM4Backup:Lymphoplasmacytic Lymphoma
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)
Cancer Category/Type
Cancer Sub-Classification / Subtype
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. [1]
- 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. [4]
- 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. [5]
Synonyms / Terminology
Malignant lymphoma, lymphoplasmacytoid lymphoma.[1]
Epidemiology / Prevalence
- Lymphoplasmacytic lymphoma, in approximately 95% of cases, occurs in patients of Caucasian descent. [4]
- The median age is in the seventh decade of life. [1][4]
- 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. [2]
Clinical Features[1][4]
| 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:
|
| Laboratory Findings | IgM paraprotein
IgM and IgG paraprotein (minority of patients) Cold agglutinins Cryoglobulinemia |
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. [1][4]
- Patients with non-IgM LPL are more likely to present with extramedullary involvement such as lymphadenopathy, splenomegaly, or extranodal disease. [2]
- Bone marrow involvement is more common in patients with IgM-associated LPL (Waldenström macroglobulinemia) when compared to non-IgM LPL. [2]
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. [1]
- 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[4]
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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 |
Chromosomal Rearrangements (Gene Fusions)[1][4]
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 |
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 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
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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.
| |||
| 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).
| ||||
| 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
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Vardiman JW, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, 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, p232-235
- ↑ 2.0 2.1 2.2 2.3 Varettoni, Marzia; et al. (2019-11). "Clinical and molecular characteristics of lymphoplasmacytic lymphoma not associated with an IgM monoclonal protein: A multicentric study of the Rete Ematologica Lombarda (REL) network". American Journal of Hematology. 94 (11): 1193–1199. doi:10.1002/ajh.25600. ISSN 1096-8652. PMID 31378966. Check date values in:
|date=(help) - ↑ Vajdic, Claire M.; et al. (2014-08). "Medical history, lifestyle, family history, and occupational risk factors for lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia: the InterLymph Non-Hodgkin Lymphoma Subtypes Project". Journal of the National Cancer Institute. Monographs. 2014 (48): 87–97. doi:10.1093/jncimonographs/lgu002. ISSN 1745-6614. PMC 4155457. PMID 25174029. Check date values in:
|date=(help) - ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Wang, Wei; et al. (2020-01). "Lymphoplasmacytic lymphoma and Waldenström macroglobulinaemia: clinicopathological features and differential diagnosis". Pathology. 52 (1): 6–14. doi:10.1016/j.pathol.2019.09.009. ISSN 1465-3931. PMID 31767130. Check date values in:
|date=(help) - ↑ Hunter, Zachary R.; et al. (2017-03-20). "Genomics, Signaling, and Treatment of Waldenström Macroglobulinemia". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 35 (9): 994–1001. doi:10.1200/JCO.2016.71.0814. ISSN 1527-7755. PMID 28294689.
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Notes
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