108: Macroglobulinemia Flashcards
A lymphoid neoplasm resulting from the accumulation, in the marrow and other organs, of a clonal population of lymphocytes, lymphoplasmacytic cells, and plasma cells, which secrete a monoclonal immunoglobulin (Ig) M
Waldenström macroglobulinemia (WM)
WM corresponds to lymphoplasmacytic lymphoma (LPL)
Most cases of LPL are WM; less than 5% of cases can secrete IgA, IgG, κ or λ light chains, or be nonsecretory.
TRUE OR FALSE
Lymphocytosis in WM is uncommon.
TRUE
Lymphocytosis in WM is uncommon.
Immunophenotypic profile of WM lymphoplasmacytic cells
Positive:CD19, CD20 (including FMC7), CD22, and CD79
CD5, CD10, and CD23 :10% to 20%
CD25 and CD27*
CD22dim/CD25+/CD27+/IgM+ population may be present among clonal B lymphocytes in patients with essential monoclonal gammopathy (synonym: monoclonal gammopathy of unknown significance [MGUS]) of the IgM type who ultimately saw progression to WM.
TRUE OR FALSE
No recurrent translocations have been described in WM,
TRUE
No recurrent translocations have been described in WM,
In contrast to myeloma plasma cells, no recurrent translocations have been described in WM, which can help to distinguish WM from IgM myeloma cases, because IgM myeloma cases often exhibit t11;14 translocations.
The most recurrent cytogenetic finding in WM cases
Deletions in chromosome 6q21–23
Deletions in chromosome 6q21–23: half of WM patients, with concordant gains in 6p in about 40% of 6q-deleted patients.
In a series of 174 untreated WM patients, 6q deletions, followed by trisomy 18, 13q deletions, 17p deletions, trisomy 4, and 11q deletions, were observed.
Deletion of 6q and trisomy 4 were associated with adverse prognostic markers
The most recurrent somatic mutation in WM
MYD88L265P
By PCR assays, 50% to 80% of IgM MGUS patients also express MYD88L265P, and expression of this mutation was associated with increased risk for malignant progression.
The second most common somatic mutation after MYD88L265P
CXCR4
Present in 30% to 35% of WM patients and impact serine phosphorylation sites that regulate CXCR4 signaling by its only known ligand, CXCL12, otherwise called stromal cell–derived factor 1a.
The location of somatic mutations found in the C-terminus of CXCR4 in WM are similar to those observed in the germline of patients with_______ syndrome
WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome
A congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia.
MYD88 and CXCR4 mutations
Characteristics of WM patients with MYD88L265PCXCR4NS mutations
Higher marrow disease involvement, serum IgM levels, symptomatic disease requiring therapy, hyperviscosity syndrome, and acquired von Willebrand disease
MYD88 and CXCR4 mutations
MYD88L265PCXCR4FS or MYD88L265PCXCR4WT
Intermediate marrow and serum IgM levels
MYD88 and CXCR4 mutations
MYD88WTCXCR4WT
Lowest marrow disease burden
MYD88 and CXCR4 mutations
Despite the more aggressive clinical presentation associated with what genotype
CXCR4NS genotype
Risk of death was not affected by CXCR4 mutation status.
MYD88 and CXCR4 mutations
Genotype associated with risk of death and aggressive disease transformation
MYD88WT
TRUE OR FALSE
In contrast to most indolent lymphomas, splenomegaly and lymphadenopathy are common
FALSE
In contrast to most indolent lymphomas, splenomegaly and lymphadenopathy are uncommon (≤15%).
Purpura is frequently associated with cryoglobulinemia and in rare circumstances with light-chain amyloidosis (AL)
The morbidity associated with WM is caused by the concurrence of two main components:
Tissue infiltration by neoplastic cells
Physicochemical and immunologic properties of the monoclonal IgM
Syndrome that cause marked increase in the resistance to blood flow and the resulting impaired transit through the microcirculatory system
Hyperviscosity Syndrome
Monoclonal IgM increases red cell aggregation and red cell internal viscosity while reducing red cell deformability.
The presence of cryoglobulins contributes to increasing blood viscosity, as well as to the tendency to induce erythrocyte aggregation.
Serum viscosity is proportional to IgM concentration up to _____ g/L, then increases sharply at higher levels.
Renal synthesis of erythropoietin is inversely correlated with plasma viscosity.
30 g/L
Hyperviscosity Syndrome
Clinical manifestations are related to circulatory disturbances that can be best appreciated by
Ophthalmoscopy
Shows distended and tortuous retinal veins, hemorrhages, and papilledema
Hyperviscosity Syndrome
Symptoms usually occur when the monoclonal IgM concentration exceeds ___ g/L or when serum viscosity is greater than ____ centipoises (cp)
Monoclonal IgM: > 50 g/L
Serum viscosity: > 4.0 centipoises (cp)
But there is individual variability, with some patients showing no evidence of hyperviscosity even at 10 cp
The most common symptoms of hyperviscosity syndrome
Oronasal mucosal bleeding, visual disturbances because of retinal bleeding, and dizziness that rarely may lead to stupor or coma
TRUE OR FALSE
The monoclonal IgM can behave as a cryoglobulin in up to 20% of patients and is usually type II and asymptomatic in most cases.
FALSE
The monoclonal IgM can behave as a cryoglobulin in up to 20% of patients and is usually type I and asymptomatic in most cases.
Treatment of cryoglobulinemia
Plasmapheresis or plasma exchange
Symptoms of cryoglobulinemia
Result from impaired blood flow in small vessels
- Raynaud phenomenon; acrocyanosis and necrosis of the regions most exposed to cold, such as the tip of the nose, ears, fingers, and toes;
- Malleolar ulcers
- Purpura
- Cold urticaria
Renal manifestations are infrequent.
Viral infection associated with mixed cryoglobulins (type II) consisting of IgM-IgG complexes
Hepatitis C
The nerve damage in Immunoglobulin M–Related Neuropathy is mediated by diverse pathogenetic mechanisms:
- IgM antibody activity toward nerve constituents causing demyelinating polyneuropathies;
- Endoneurial granulofibrillar deposits of IgM without antibody activity, associated with axonal polyneuropathy;
- Occasionally by tubular deposits in the endoneurium associated with IgM cryoglobulin; and, rarely,
- By amyloid deposits or by neoplastic cell infiltration of nerve structures
Half of the patients with IgM neuropathy have a distinctive clinical syndrome that is associated with antibodies against a minor 100-kDa glycoprotein component of nerve known as
Myelin-associated glycoprotein (MAG)
Anti-MAG antibodies are generally monoclonal IgMκ and usually also exhibit reactivity with other glycoproteins or glycolipids that share antigenic determinants with MAG.
The anti– MAG-related neuropathy is typically distal and symmetrical, affecting both motor and sensory functions; it is slowly progressive with a long period of stability.
