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Internal Medicine

Waldenström macroglobulinemia (WM)

Introduction

Waldenstrom Macroglobulinemia, or Waldenstrom syndrome, is a rare type of malignant lymphoma.

B-cell lymphoplasmacytic lymphoma characterized by monoclonal immunoglobulin M protein in the serum and infiltration of bone marrow with lymphoplasmacytic cells.

  • Non-Hodgkin B Lymphomas (NHL) with indolent course
  • 2% of all cases of non-Hodgkin Lymphoma (NHL)

History:

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Jan Gösta Waldenström (1906 – 1996) was a Swedish doctor of internal medicine, who first described the disease which bears his name, Waldenström’s macroglobulinemia.

WM was first described by Jan G. Waldenström (1906–1996) in 1944 in two patients with bleeding from the nose and mouth, anaemia, decreased levels of fibrinogen in the blood (hypofibrinogenemia), swollen lymph nodes, neoplastic plasma cells in bone marrow, and increased viscosity of the blood due to increased levels of a class of heavy proteins called macroglobulins.

For a time, WM was considered to be related to multiple myeloma because of the presence of monoclonal gammopathy and infiltration of the bone marrow and other organs by plasmacytoid lymphocytes. The new World Health Organization (WHO) classification, however, places WM under the category of lymphoplasmacytic lymphomas, itself a subcategory of the indolent (low-grade) non-Hodgkin lymphomas.

Aetiology

Genetic mutations:

  • MYD88 gene (M/C): Adaptor protein for toll-like receptor 4 (TLR-4) and interleukin-1 and -2 receptors (IL-1R and IL-2R).
  • CXCR4 gene: G-protein coupled receptor and was shown to play a pivotal role in cytokine release and chemotaxis
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MYD88 allele burden in patients with IgM monoclonal gammopathy of undetermined significance, asymptomatic and symptomatic Waldenström macroglobulinemia. | Varettoni, M., Zibellini, S., Defrancesco, I., Ferretti, V. V., Rizzo, E., Malcovati, L., … Cazzola, M. (2017). Pattern of somatic mutations in patients with Waldenström macroglobulinemia or IgM monoclonal gammopathy of undetermined significance. Haematologica, 102(12), 2077 LP – 2085. https://doi.org/10.3324/haematol.2017.172718

Viral infection:

  • Hepatitis C virus (HCV)

Pathophysiology

  • Preceded by 2 clinically asymptomatic but progressively more pre-malignant phases:
    • IgM monoclonal gammopathy of undetermined significance (IgM MGUS)
    • Smoldering Waldenström’s macroglobulinemia

Clinical features

Extremely heterogeneous presentation.

Neoplasmic organ involvement:

  • BM involvement:
    • Anaemia (M/C presenting symptom is fatigue related to normocytic anemia)
    • Nonspecific B-symptoms: Fever, weight loss, fatigue, and drenching night sweat
  • Hepatomegaly (20%)
  • Splenomegaly (15%)
  • Lymphadenopathy (15%)

IgM paraprotein-related symptoms:

  • Hyperviscosity syndrome (5–10%):
    • Spontaneous epistaxis, ocular and hearing disorder, such as blurred vision, headache, tinnitus and vertigo
    • CNS: Strokes
  • IgM‐associated peripheral neuropathy (20-25%)
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Complications

Deposition of IgM-secreting lymphoplasmacytic elements:

  • Type I and II cryoglobulinemia:
    • Skin alterations (purpura, ulcers and livedo), especially in the lower extremities.
    • Can also worsen hyperviscosity manifestations
  • Amyloidosis (rare and severe complication):
    • M/C involved organs: Kidneys, heart, liver and peripheral nerves
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Fundoscopic appearance of a patient with WM and mixed cryoglobulinemia. Note the marked retinal venous engorgement and “sausaging.” The white material at the edge of the veins may be cryoglobulin. | Stone, M. J., & Pascual, V. (2010). Pathophysiology of Waldenström’s macroglobulinemia. Haematologica, 95(3), 359 LP – 364. https://doi.org/10.3324/haematol.2009.017251

Central nervous system (CNS) involvement:

  • Bing-Neel syndrome (1%): Heterogeneous neurological signs and symptoms may be investigated by the brain and whole spine imaging and cerebrospinal fluid tests.
  • Schnitzler syndrome: Chronic autoimmune urticaria associated with IgM gammopathy and other rheumatic manifestations, such as recurrent fever, joint and bone pain, characterized this autoinflammatory disorder

Diagnosis

Diagnostic criteria:

  • Lymphoplasmacytic lymphoma (in bone marrow or other organs)
  • Monoclonal IgM paraproteinemia
  • Recurrent MYD88 L265P somatic mutation

Blood tests:

  • Serum protein electrophoresis (SPEP) (Best initial test): Monoclonal IgM spike
  • Normocytic anaemia (80% cases)
  • Thrombocytopenia (50% cases)

Bone marrow biopsy:

  • Lymphoplasmocytic cell proliferation
  • Dutcher bodies (intranuclear vacuoles containing IgM protein)
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Bone marrow findings in Waldenström macroglobulinaemia (WM). Panels (A) and (B) show a hypercellular bone marrow aspirate with a prominent infiltrate of small mature lymphocytes and lymphoplasmacytoid cells. A mast cell is seen in panel (B); these are often increased in WM. Panels (C) and (D) shows a similar infiltrate on the trephine biopsy. | Talaulikar, D., Tam, C. S., Joshua, D., Ho, J. P., Szer, J., Quach, H., … Prince, H. M. (2017). Treatment of patients with Waldenström macroglobulinaemia: clinical practice guidelines from the Myeloma Foundation of Australia Medical and Scientific Advisory Group. Internal Medicine Journal, 47(1), 35–49. https://doi.org/10.1111/imj.13311

Differential diagnosis:

  • Monoclonal gammopathy of undetermined significance (MGUS)
  • Multiple myeloma (MM)
 WMMGUSMM
Clinical featuresAnaemia symptoms
Thrombocytopenia symptoms
Hyperviscosity symptoms
Other symptoms		AsymptomaticBone pain, fracture
Anaemia symptoms
Age 60s-70s
InvestigationsNormocytic anaemia
Uremia (rare)		NoneNormocytic anaemia
Hypercalcemia
Uremia
Serum protein electrophoresis (SPEP)Spike between β & γ regionsγ spikeγ spike
Bone marrow biopsyAbnormal lymphocytic infiltration< 10% plasma cells> 10% plasma cells
ManagementRituximab
Plasmapheresis		MonitoringCVAD + BMT & thalidomide/melphalan
or
Thalidomide + melphalan

Management

Treatment indicated for symptomatic cases only.

Plasmapheresis (IgM removal from the serum):

  • Management of hyperviscosity

Chemotherapy:

  • Combination therapy utilizing:
    • Anti-CD20 monoclonal antibodies (rituximab) (first-line therapy)
    • Nucleoside analogues (fludarabine, cladribine, bendamustine)
    • Alkylating agents (cyclophosphamide, chlorambucil)
    • Proteasome inhibitors (bortezomib, carfilzomib)
Diagnosis and Management of Waldenström MacroglobulinemiaMayo St
Consensus for Waldenström Macroglobulinemia (WM): BDR indicates bortezomib (weekly) + dexamethasone + rituximab; BR, bendamustine + rituximab; DRC, dexamethasone-rituximab-cyclophosphamide; MGUS, monoclonal gammopathy of undetermined significance. | Kapoor, P., Ansell, S. M., Fonseca, R., Chanan-Khan, A., Kyle, R. A., Kumar, S. K., … Reeder, C. B. (2017). Diagnosis and Management of Waldenström Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines 2016. JAMA Oncology, 3(9), 1257–1265. https://doi.org/10.1001/jamaoncol.2016.5763

Summary

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