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Lymphoma & related disorders

Mature B cell neoplasms

Small B cell lymphomas with lymphoplasmacytic differentiation / marginal zone lymphomas

Lymphoplasmacytic lymphoma

Authors: Sanjay Bridgelall, M.D., Ling Zhang, M.D.

Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.

Last author update: 27 February 2020

Last staff update: 26 May 2023 (update in progress)

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Table of Contents

Cite this page: Bridgelall S, Zhang L. Lymphoplasmacytic lymphoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomalpl.html. Accessed May 30th, 2023.

Definition / general

Lymphoplasmacytic lymphoma (LPL) is a B cell neoplasm of small lymphocytes, plasmacytoid lymphocytes and plasma cells (Swerdlow: WHO Classification of Tumours of Haematopoeitic and Lymphoid Tissue, 4th Edition, 2017)
Usually involves bone marrow, sometimes lymph nodes and spleen
Does not fulfill the criteria for any other small B cell lymphoid neoplasm
Waldenström macroglobulinemia (WM): lymphoplasmacytic lymphoma involving the bone marrow associated with IgM monoclonal paraprotein of any concentration

Essential features

Lymphoplasmacytic lymphoma
- Spectrum of lymphocytes, plasmacytoid lymphocytes and plasma cells
- Flow cytometry: monoclonal B cells with typical immunophenotype and monoclonal plasma cells
- Monoclonal IgM paraprotein by serum and urine protein electrophoresis (SPEP / UPEP), minority with IgA or IgG paraprotein
- MYD88 L265P mutation present (Virchows Arch 2016;468:259)
Waldenström macroglobulinemia
- Serum IgM of any level
- Bone marrow involvement by small B cell lymphoma with plasmacytic differentiation
- Exclusion of other types of small B cell lymphoma

Terminology

Lymphoplasmacytic lymphoma
Waldenström macroglobulinemia

ICD coding

ICD-O: 9671/3 - lymphoplasmacytic lymphoma
ICD-O: 9761/3 - Waldenström macroglobulinemia

Epidemiology

Incidence: 3.8 per 1,000,000 per year (Cancer 2012;118:3793)
Median age: seventh decade
Slight male predominance
Higher in Caucasians compared to other races

Sites

Bone marrow
Some cases involving the blood, lymph node and extranodal sites manifested with splenomegaly, hepatomegaly or adenopathy, or cutaneous, gastrointestinal, lung and central nervous system (Bing-Neel syndrome) involvement

Pathophysiology

Genetic / molecular factors may contribute to pathogenesis of lymphoplasmacytic lymphoma
- Evidence of familial clustering in ~20% of patients
- MYD88 mutation in > 90% of cases (Blood 2014;123:1637)
  - Gene at 3p22.2
  - Most common mutation c794T>C results in switching of leucine to proline at codon 265 (pL265P)
  - Protein MYD88 plays significant role in Toll-like receptor and interleukin 1 (IL1) receptor signaling
  - Gain of function mutation product activates downstream transcription protein complex nuclear factor κ light chain enhancer of activated B cells (NFkB)
  - NFkB promotes cell proliferation and survival
  - MYD88 mutation is also present in significant proportion (50%) of IgM monoclonal gammopathy of unknown significance (IgM MGUS)
  - Present in ~30% of nongerminal center type diffuse large B cell lymphoma
  - Present in > 50% of primary cutaneous diffuse large B cell lymphoma, leg type
  - In many diffuse large B cell lymphoma at immune privileged sites (e.g. central nervous system, testicle)
- 6q deletion in 40 - 60% of lymphoplasmacytic lymphoma cases
  - Most common recurrent cytogenetic abnormality
  - Tumor suppressor genes B lymphocyte induced maturation protein 1 (PRDM1) and TNFα induced protein 3 (TNFAIP3) are deleted
- Other cytogenetic abnormalities identified (Blood 2014;123:1637)
  - Trisomy 18, 13q deletion, 17p (TP53) deletion, trisomy 4, trisomy 12 and 11q (ATM) deletion are seen in various proportions
- CXCR4 mutation in ~30% of lymphoplasmacytic lymphoma cases and 20% of IgM MGUS (Blood 2014;123:1637)
  - CXC chemokine receptor type 4 (CXCR4) plays critical role in lymphoplasmacytic lymphoma cells homing to bone marrow
  - Almost always coexists with MYD88 mutation
  - Mutation in CXCR4 gene is linked to disease progression and drug resistance
- ARID1A mutations 17%
- JAK-STAT signaling pathway may be involved
- MicroRNA-9, miRNA-155 and miRNA-206 abnormalities may contribute to pathogenesis of lymphoplasmacytic lymphoma
Chronic immune stimulation
- Lymphoplasmacytic lymphoma / Waldenström macroglobulinemia risk is elevated among individuals with autoimmune disorders, particularly Sjögren syndrome and autoimmune hemolytic anemia
- Lymphoplasmacytic lymphoma / Waldenström macroglobulinemia risk is elevated in persons with hepatitis, HIV infection and rickettsiosis
Predisposition
- MGUS of IgM type is associated with estimated annual progression rate of 1.5% to lymphoplasmacytic lymphoma
  - IgM MGUS is precursor lesion to lymphoplasmacytic lymphoma
  - MYD88 mutation is identified in 50% of IgM MGUS cases

Etiology

Post germinal center memory B cell is likely cell of origin
Hepatitis C is associated in some series (Swerdlow: WHO Classification of Tumours of Haematopoeitic and Lymphoid Tissue, 4th Edition, 2017)
- Hepatitis C associated lymphoplasmacytic proliferations are nonprogressive and may be similar to monoclonal B cell lymphocytosis
- Treating hepatitis C with antivirals may lead to regression to the lymphoplasmacytic proliferation
Autoimmune disorders: associated with an increased risk of occurrence

Clinical features

20 - 30% of patients: asymptomatic at diagnosis
Anemia related symptoms: fatigue, shortness of breath and chest pain
Thrombocytopenia related bleeding tendency
Constitutional symptoms, including weight loss and night sweats
Splenomegaly and adenopathy
- High concentration of IgM may form aggregates and may bind water
- IgM may cause red blood cell aggregation (rouleaux formation) and increase red cell internal viscosity
- Results in circulatory disturbances
- Most common symptoms include oronasal bleeding, headache, visual disturbances due to retinal bleeding and dizziness
Hyperviscosity
- 15 - 30% of patients with Waldenström macroglobulinemia have hyperviscosity (in particular when IgM level reaching ≥ 3 grams/dL)
- Worse clinical scenarios could occur when IgM ≥ 5 grams/dL
Hyperviscosity syndrome
- Due to IgMs large size and quantity
- Symptoms
  - Visual impairment (distended and tortuous retinal veins with hemorrhage and exudates)
  - Neurologic: slowing blood flow
  - Bleeding: IgM binding of clotting factors and cryoglobulinemia causing Raynaud phenomena and cold urticaria
The following findings can be associated with bone marrow infiltration, cryoprecipitation, autoimmune or nonautoimmune antibody activity
- Cytopenia
- Cold agglutinin hemolytic anemia (10% of cases) (IgM antibodies that bind at < 37 °C)
- Peripheral neuropathy
Primary amyloidosis
No lytic bone lesion, distinguishing it from plasma cell myeloma
May transform to diffuse large B cell lymphoma with Reed-Sternberg-like cells or immunoblasts
Reference: Blood Rev 2015;29:301

Diagnosis

Diagnostic criteria for Waldenström recommended by Second International Workshop (Semin Oncol 2003;30:110)
- IgM monoclonal gammopathy of any concentration
  - Bone marrow infiltration by small lymphocytes showing plasmacytoid or plasma cell differentiation
  - Intertrabecular pattern of bone marrow infiltration
Immunophenotype
- Positive: IgM, CD19, CD20, CD22, CD79a, CD25 and CD38 frequent expression
- Negative: CD5, CD10, CD103, CD23; however, CD23 expression not uncommon in some cases
- CD5 and CD10 positive but BCL6 negative seen in a minority of cases
- Plasma cells in lymphoplasmacytic lymphoma:
  - Positive: CD138, CD19, CD45 and sometimes MUM1 but can be negative
  - Can be PAX5 positive

Laboratory

IgM monoclonal paraprotein commonly present in serum, rarely IgG or IgA
- Lymphoplasmacytic lymphoma
  - IgM paraprotein not required for diagnosis
  - IgA or IgG paraprotein alone or coexists with IgM in serum (rare)
- Waldenström macroglobulinemia
  - IgM paraprotein required for diagnosis
  - No cutoff level for IgM in serum
Other abnormal tests with Waldenström macroglobulinemia
- Elevated erythrocyte sedimentation rate (ESR), cytopenia / anemia
- Elevated serum levels of lactate dehydrogenase (LDH) and beta 2 microglobulin
Reference: Blood 2015;126:721

Prognostic factors

An indolent clinical course but incurable
Adverse prognostic factors (International Prognostic Scoring System) (Blood 2009;113:4163)
- > 65 years old
- Hemoglobin < 11.5 g/dL
- Platelet count < 100 x 10⁹/L
- Monoclonal IgM > 7 g/dL
- Increased beta 2 microglobulin > 3 mg/L
Overall survival varies from 5 - 11 years depending on the study; median survival is 5 years, 40% survive 10 years or more or die of unrelated causes (Blood 2009;113:4163, Am J Hematol 2013;88:60)
- Low risk (≤ 65 years, 0 - 1 risk factor) 5 year survival rate of 87%
- High risk (> 65 years, > 2 risk factors) 5 year survival rate of 36%
Transformation to large cell lymphoma can occur (13%) (Blood Cancer J 2015;5:e394, Am J Clin Pathol 2003;120:246)
Relapse: inevitable, can occur years after initial treatment
Main disease related causes of death
- Disease progression
- Transformation to high grade lymphoma
- Complications of therapy

Case reports

39 year old woman and 56 year old man with Hodgkin disease (Am J Clin Pathol 2001;116:34)
43 year old woman with headaches; MRI revealed an abnormal homogeneously enhancing mass in the cerebellopontine angle (Medicine (Baltimore) 2016;95:e4627)
60 year old man with fatigue, sensory neuropathy and lab findings of anemia and elevated albumin globulin gap (Case Rep Hematol 2019;2019:4075960)

Treatment

No standardized treatment
Asymptomatic patients: watch and wait
Therapy initiated in patients with:
- Constitutional symptoms: fever, weight loss, night sweats, fatigue
- Hyperviscosity
- Severe neuropathy
- Amyloidosis
- Symptomatic cryoglobinemia
- Cold agglutinin disease
- Evidence of transformation
Treatment regimen / options (Leukemia 2014;28:1799, J Clin Oncol 2009;27:120):
- Single agent
- Combination therapy:
  - Monoclonal antibodies
  - Proteasome inhibitors
  - Immunomodulatory agents
  - Signaling pathway inhibitors
  - Histone deacetylase
- First line treatment:
  - Anti-CD20 antibody in combination with a purine analogs or alkylating agent
  - Rituximab in combination with thalidomide or bortezomib and dexamethasone
  - Rituximab with bendamustine
- Plasmaphoresis: reduce circulating IgM in hyperviscosity patients
- Splenectomy: chemoresistant patient
- Stem cell transplant (Blood 2015;126:721):
  - Autologous stem cell transplantation is feasible, safe and associated with significant cytoreduction in relapsed or refractory patient
  - Allogeneic stem cell transplantation is used only in patients with advanced and refractory disease for whom no other options are available
- Investigational therapies (Blood 2015;126:721):
  - Agents target MYD88, CXCR4, BCL2, CD27 / CD70 signaling
  - Novel proteasome inhibitors
  - Chimeric antigen receptor modified T cell therapy

Microscopic (histologic) description

Blood:
- Often shows lymphocytosis with spectrum of lymphocytes, plasmacytoid lymphocytes and plasma cells
- Rouleaux formation of red blood cells is routinely seen
- Cold agglutinin or cryoglobulin may be present
Bone marrow (Arch Pathol Lab Med 2013;137:580):
- Involvement in almost all cases
- Aspirate is most helpful sample in morphologic diagnosis
  - Predominantly small lymphocytes with variable number of plasmacytoid lymphocytes and plasma cells
  - Mast cells typically increased; most prominent within particles on aspirate smears
- Core biopsy (Am J Surg Pathol 2005;29:1549):
  - Most common pattern is combination of paratrabecular and nonparatrabecular lymphoid nodules
  - Less common patterns include paratrabecular or intrasinusoidal ± interstitial infiltrate
  - Pseudointranuclear (Dutcher bodies) and intracytoplasmic inclusions (Russell bodies) are most prominent on core biopsy section
  - Amyloid deposition may be present within vessel walls or interstitial deposits
Lymph node (Arch Pathol Lab Med 2013;137:580):
- Two main patterns of nodal involvement:
  - Classic pattern:
    - Subtotal architecture effacement
    - Retention of small primary or enlarged reactive follicles
    - Patent dilated sinuses
    - Interfollicular areas contain monomorphous infiltrate of small lymphocytes, plasmacytoid lymphocytes and plasma cells
    - Dutcher bodies, increase number of mast cells and hemosiderin deposition maybe present
  - Polymorphous pattern:
    - Complete architectural effacement
    - Nodular to diffuse polymorphous infiltrate
      - Small lymphocytes
      - Plasmacytoid lymphocytes
      - Plasma cells
    - Greater numbers of large transformed cells
    - Clusters of epithelioid histiocytes maybe conspicuous
      - Termed polymorphous immunocytoma
  - Extracellular immunoglobulin in the form of amyloid may be present
Spleen (Am J Surg Pathol 2003;27:1104):
- Not well described
- Older published series and review
  - Presence of nodular and diffuse infiltrates of lymphoplasmacytic cells involving red pulp
  - Spectrum of lymphoma cells analogous to bone marrow
  - Sparing of white pulp with absence of marginal zone growth pattern

Microscopic (histologic) images

Contributed by Ling Zhang, M.D.

Increased lymphoid cells

Round eccentrically located nuclei

Condensed chromatin, inconspicuous nucleoli

Small mature lymphoid cells

Intermingled plasma cells

Lymphoid cells negative for CD3

Diffuse CD20 positivity

Focal plasma cell positivity (CD138)

Immunoglobulin M positivity

Positive stains

CD19, CD20, CD22, CD79a, PAX5, FMC7, monoclonal surface light chain
Also variable CD20, CD22, CD38, variable CD43, CD138 and strong cytoplasmic immunoglobulin in plasma cell component (monoclonal kappa or lambda, not both)
Reference: Am J Clin Pathol 2015;143:797

Negative stains

CD5, CD10, CD23, CD103, CD56

Flow cytometry description

Positive: IgM, CD19, CD20, CD22, CD79a, CD27
Variable expression of CD25, CD11c, CD38
Negative: CD5, CD10, CD23, CD43 and CD103
Surface kappa or lambda light chain restriction
Minor subset: CD5+
Reference: Leukemia 2014;28:166

Flow cytometry images

Contributed by Ling Zhang, M.D. and Caroline An, M.D.

Flow cytometric findings of LPL

Scatter plots

Molecular / cytogenetics description

MYD88 mutation in > 90% of cases; increasingly used in diagnostic workup
CXCR4 mutation; not routinely tested
Cytogenetic study is not required for diagnosis; when done, 6q deletion is reported in 40 - 50% of patients
IGH gene rearranged
Biased VH3 and VH3-23 usage
Reference: Blood 2014;123:1637

Molecular / cytogenetics images

Contributed by Ling Zhang, M.D.

ISH clonal kappa light chain expression

Negative lambda light chain expression

Sample pathology report

Peripheral blood:
- Normocytic, normochromic red blood cells
- A small population of atypical lymphocytes identified
- Mild thrombocytopenia
Bone marrow, right posterior iliac crest, aspirate and biopsy:
- Hypercellular marrow with extensive involvement by lymphoplasmacytic lymphoma (see comment)
- Peripheral blood: The red blood cells are normocytic and normochromic with mildly decreased hemoglobin level (11.8 g/dL). The reticulocyte count is adequate. There is no overt rouleaux formation. The white blood cell count is within normal range. Lymphocytes are not increased. However, few atypical lymphocytes are seen, which are mostly small in size, with slightly irregular nuclear contour and mature chromatin or plasmacytoid morphology. Platelets are mildly decreased in number with normal morphology.
- Aspirate smear: The Wright stained bone marrow aspirate smears are cellular, with adequate spicules included for evaluation. Megakaryocytes are decreased in number, when identified, showing normal morphology. Myeloid and erythroid precursors show progressive maturation but are relatively decreased in number. The estimated M:E ratio is 4:1. The cellularity is composed of mostly atypical lymphocytes (84% of differential count). These atypical lymphocytes are predominantly small in size, with oval or slightly irregular nuclear contours, mature chromatin and small amount of basophilic cytoplasm. Rare atypical lymphocytes are medium in size, with plasmacytoid differentiation. Plasma cells account for 4.8% of the differential count. Scattered mature mast cells are present in the background.
- Core biopsy and cell clot: The bone marrow core biopsy includes normal appearing trabecular bone and marrow, adequate for morphologic evaluation. The marrow cellularity is very high, up to 95%. Megakaryocytes are essentially normal in number with normal morphology. Myeloid and erythroid precursors are markedly decreased in number. The marrow is diffusely infiltrated by atypical lymphocytes, accounting for approximately 80% of total cellularity, a small subset of which shows plasmacytoid differentiation. Mature plasma cells are identified. Iron stain shows adequate stainable storage iron. Reticulin stain highlights mild reticulin fibrosis. The clot section contains a few small cellular particles including predominantly atypical lymphoid cells, with findings similar to the core biopsy.
- Immunohistochemical study: Immunohistochemical stains and in situ hybridization stains are performed on the core biopsy with adequate controls. CD20 and PAX5 highlight a diffuse infiltration of neoplastic B cells, occupying 80% of total cellularity. CD3 highlights scattered interstitial T lymphocytes, ranging from 2% to 5%. CD138 highlights scattered plasma cells, focally forming small clusters, accounting for approximately 5% of the total cells. By in situ hybridization (ISH), the plasma cells are positive for kappa light chain and negative for lambda light chain.

Differential diagnosis

IgM MGUS, closely related to lymphoplasmacytic lymphoma, likely a precursor lesion (Leukemia 2014;28:1698):
- MYD88 mutation is found in 50% of cases
- Serum M protein < 3 g/dL
- Bone marrow clonal plasma cells < 10%
- No end organ damage
IgG and IgA MGUS:
- More closely related to plasma cell myeloma
- Negative for MYD88
Marginal zone lymphoma
Chronic lymphocytic leukemia / small Lymphocytic Lymphoma

Additional references

Arch Pathol Lab Med 2013;137:580

Board review style question #1

Which of the following immunoglobulins is more commonly seen in lymphoplasmacytic lymphoma?

Board review style answer #1

E. IgM

Comment Here

Reference: Lymphoplasmacytic lymphoma

Board review style question #2

What somatic mutation is associated with lymphoplasmacytic lymphoma that can aid in diagnosis?

BCL2
BRAF
KRAS
MYD88 L265P

Board review style answer #2

D. MYD88 L265P

Comment Here

Reference: Lymphoplasmacytic lymphoma