IntroductionWaldenstrom Macroglobulinemia, or Waldenstrom syndrome, is a rare type of malignant lymphoma.
- Non-Hodgkin B Lymphomas (NHL) with indolent course
- 2% of all cases of non-Hodgkin Lymphoma (NHL)
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.
- 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
- Hepatitis C virus (HCV)
- Preceded by 2 clinically asymptomatic but progressively more pre-malignant phases:
- IgM monoclonal gammopathy of undetermined significance (IgM MGUS)
- Smoldering Waldenström’s macroglobulinemia
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%)
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
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
- Lymphoplasmacytic lymphoma (in bone marrow or other organs)
- Monoclonal IgM paraproteinemia
- Recurrent MYD88 L265P somatic mutation
- 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)
- Monoclonal gammopathy of undetermined significance (MGUS)
- Multiple myeloma (MM)
|Clinical features||Anaemia symptoms|
|Asymptomatic||Bone pain, fracture|
|Serum protein electrophoresis (SPEP)||Spike between β & γ regions||γ spike||γ spike|
|Bone marrow biopsy||Abnormal lymphocytic infiltration||< 10% plasma cells||> 10% plasma cells|
|Monitoring||CVAD + BMT & thalidomide/melphalan|
Thalidomide + melphalan
Treatment indicated for symptomatic cases only.
Plasmapheresis (IgM removal from the serum):
- Management of hyperviscosity
- Combination therapy utilizing:
- Anti-CD20 monoclonal antibodies (rituximab) (first-line therapy)
- Nucleoside analogues (fludarabine, cladribine, bendamustine)
- Alkylating agents (cyclophosphamide, chlorambucil)
- Proteasome inhibitors (bortezomib, carfilzomib)