Lymphoplasmacytic Lymphoma and Waldenstrom Macroglobulinemia

Lymphoplasmacytic Lymphoma and Waldenstrom Macroglobulinemia

Pei Lin, MD

Lymphoplasmacytic lymphoma and Waldenström macroglobulinemia (LPL/WM) involving lymph node. Low-power view shows a diffuse pattern of growth with patent sinuses image that contain histiocytes.

LPL/WM involving lymph node. The proliferating cells are small lymphocytes, and a subset of cells has plasmacytoid features.



  • Lymphoplasmacytic lymphoma (LPL)

  • Waldenström macroglobulinemia (WM)


  • Terms used in earlier lymphoma classification systems are not exact synonyms as the definition of LPL has been refined over the years

  • Older terms that included LPL along with other B-cell lymphomas include

    • Well-differentiated lymphocytic, plasmacytoid (Rappaport classification)

    • Immunocytoma, lymphoplasmacytic type (Kiel classification)

    • Malignant lymphoma, small lymphocytic, plasmacytoid (Working Formulation)

    • Lymphoplasmacytoid lymphoma (REAL classification)

  • Terms “LPL” and “WM” are often used interchangeably, but the 2 are not identical

    • WM represents great majority of LPL cases


  • LPL is a neoplasm of small B lymphocytes, plasmacytoid lymphocytes, and plasma cells that does not meet criteria for any other type of small B-cell lymphoma showing plasmacytic differentiation

    • LPL is usually associated with serum monoclonal paraprotein

      • Usually IgM; rarely IgG or IgA

      • Monoclonal paraprotein is not required for diagnosis of LPL

  • WM is LPL involving bone marrow associated with an IgM paraprotein

    • No specific cutoff level of IgM is required


Infectious Agents

  • Hepatitis C is implicated in some cases of LPL; data are controversial

Genetic Predisposition

  • Familial cases of WM are reported

    • Usually occurs in younger patients

  • Monoclonal gammopathy of unknown significance (MGUS) is most likely a precursor of WM



  • Incidence

    • ˜ 1% of non-Hodgkin lymphomas

  • Age

    • Median age: 63 to 71 years

  • Gender

    • Male to female ratio = 2:1

  • Ethnicity

    • Whites are more frequently affected than African Americans or Asians


  • Relatively little data are available for patients with LPL that do not also have WM

  • About 25% of patients with WM are asymptomatic, so-called smoldering WM

  • Symptoms and signs of patients with WM are related to

    • Tissue infiltration by neoplastic cells or

    • Effects of elevated IgM paraprotein

  • Anemia due to bone marrow infiltration is common and causes fatigue and weakness

    • Bilineage cytopenia or pancytopenia can occur if infiltration by WM is extensive

  • Hepatomegaly occurs in ˜ 20% and splenomegaly in ˜ 15% of WM patients

    • WM can involve gastrointestinal tract, kidney, and other extramedullary sites

  • Lymphadenopathy in ˜ 15% of WM patients

    • Lymphadenopathy is usually mild compared with other types of non-Hodgkin lymphoma

  • Elevated serum IgM paraprotein levels can cause variety of symptoms

    • Hyperviscosity syndrome occurs in 5-15% of cases

      • Headache, vision disturbance (retinopathy), neurologic changes, and cardiac failure

      • Bing-Neel syndrome is central nervous system manifestation

    • Cryoglobulinemia, cold agglutinin hemolysis, autoimmune thrombocytopenia

      • Type II cryoglobulinemia associated with HCV may cause Raynaud phenomenon, arthralgia, skin purpura, and vasculitis

      • IgM-associated neuropathy is autoimmune mediated and tends to be distal, sensory, and symmetric

    • Deposition of IgM in skin and gastrointestinal tract causes related symptoms

  • Rare manifestations include amyloidosis or light-chain deposition disease

    • Any site: Most common in kidney, skin, or bone marrow

Laboratory Tests

  • IgM monoclonal protein is usually present in serum

    • WM

      • IgM paraprotein is required for diagnosis

      • No cutoff level for IgM in serum

    • LPL

      • IgM paraprotein not required for diagnosis

      • Rarely, IgA or IgG paraprotein alone or coexisting with IgM in serum

  • Other laboratory abnormalities well described in WM patients

    • Elevated erythrocyte sedimentation rate, cytopenia (usually anemia)

    • Elevated serum levels of LDH or β-2 microglobulin


  • Treatment regimens are best defined for WM patients

    • Alkylating agents (chlorambucil), nucleoside analogs (cladribine or fludarabine), or single-agent rituximab is used

    • Autologous or allogeneic stem cell transplantation in eligible candidates

    • Plasmapheresis for hyperviscosity syndrome, cryoglobulinemia, neuropathy, amyloidosis, and light chain nephropathy

    • Corticosteroids for autoimmune hemolytic anemia or thrombocytopenia

  • No consensus on optimal therapy of LPL patients without WM or serum IgM paraprotein

    • For cases without serum paraprotein: Patients often treated with low-grade B-cell lymphoma regimens


  • WM

    • Usually indolent; median overall survival: 5-10 years

    • International prognostic scoring system designed to stratify patients into low-, intermediate-, and highrisk groups

      • Age > 65 years

      • Hemoglobin ≤ 11.5 g/dL

      • Platelet count ≤ 100 X 109

      • Serum β-2 microglobulin > 3 mg/L

      • Serum M protein concentration > 7 g/dL

      • 5-year survival rates are 87%, 68%,and 36%, respectively, for low-, intermediate- and high-risk groups

    • Poor performance status and elevated serum LDH level also predict poorer prognosis



  • Lymph nodes are usually only modestly enlarged


Histologic Features

  • Lymph node

    • Involvement is usually total or subtotal, extending through capsule into perinodal adipose tissue

    • Pattern of growth is diffuse, but sinuses often are patent

    • Small residual follicles, usually in subcortical areas

    • Lymphoma cells are small ± plasmacytoid differentiation; monocytoid B cells can be seen

    • Blood vessels and sinuses may appear to be markedly dilated

    • Epithelioid histiocytes may be abundant or form scattered clusters

    • Hemosiderin or amyloid deposition

    • Scattered mast cells

  • Bone marrow involvement is constant in WM

    • Pattern of infiltration can be diffuse, interstitial, and nodular

  • 3 subtypes of WM are recognized

    • Lymphoplasmacytoid: Usually composed of monotonous small mature lymphocytes with varying degrees of plasmacytoid differentiation

    • Lymphoplasmacytic: Usually composed of lymphocytes and plasmacytic (Marschalko) cells; ± Dutcher or Russell bodies

    • Polymorphous: Has increased (5-10%) large cells; likely represents initial progression to large B-cell lymphoma

    • Subtypes do not predict level of serum IgM

  • Peripheral blood smear

    • Rouleaux formation is common if IgM paraprotein level is high

    • Leukemic involvement (i.e., high leukocyte count) is unusual

    • Occasional neoplastic cells can be present

  • WM and LPL can be associated with so-called crystalstoring histiocytosis

  • Transformation of WM to diffuse large B-cell lymphoma (DLBCL) occurs in small subset of patients

    • WM and DLBCL components are usually of identical light chain type, suggesting clonal relationship

    • Serum IgM levels may paradoxically decrease

    • EBV is not usually implicated in transformation

  • Rare patients with WM can develop classical Hodgkin lymphoma (CHL)

    • Clonal relationship between WM and CHL is unknown



  • LPL and WM have 2 components: B cells and plasmacytoid/plasma cells

  • B cells

    • pax-5(+), CD19(+), CD20(+), CD22(+)

    • CD45/LCA(+), Bcl-2(+), cytoplasmic Ig(-)

    • CD5(-), CD10(-), Cyclin-D1(-), Bcl-6(-)

  • Plasmacytoid/plasma cells

    • CD38(+), CD138(+), CD20(-), pax-5(-/+)

    • Monotypic cytoplasmic Ig light chain (+), IgM(+)

    • Monotypic plasma cells may not be demonstrable in lymphoplasmacytoid subtype

  • Ki-67 typically low, p53(-), CD3(-)

Flow Cytometry

  • B cells

    • Surface IgM(+), Ig light chain (+), CD19(+), CD20(+)

    • Usually CD5(-), CD10(-), CD23(-)

    • Subset of cases may express CD5, CD10, or CD23

      • CD5 expression can be distinct or variable

      • CD10(+) cases are usually Bcl-6(-)

      • CD23 expression is usually dim/partial

    • CD11c(+/-), CD22(+/- dim), FMC-7(+/-), CD43(+/-)

    • CD25(-/+), CD103(-)

  • Plasma cells

    • Cytoplasmic IgM(+), Ig light chain (+)

    • CD19(+), CD38(+), CD138(+)

    • IgG type of LPL may not coexpress CD19 and CD138

    • Monotypic plasma cells may be only evidence of persistent disease after chemotherapy


  • Cytogenetic data are available for WM

    • Deletion of 6q in 40% of cases

    • Trisomy 4 in 20% of cases

    • Deletion of 13q in subset

    • Trisomy 3 is rare

    • Frequency of these abnormalities has not been confirmed in lymph node

  • IgH translocations are uncommon in WM

  • PAX5-IgH/t(9;14) is neither specific nor common in WM

In Situ Hybridization

  • EBER(-)

Array CGH

  • Deletions of 6q23 and 13q14

  • Gains of 3q13-q28, 6p, and 18q

  • Gains of 4q and 8q occur in 12% and 10% of WM cases, respectively

Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Lymphoplasmacytic Lymphoma and Waldenstrom Macroglobulinemia

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