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aldenström

’

macroglobulinemia

–

review

ssoc

ras

2014; 60(5):490-499

491

stimulation, such as infection with the hepatitis C virus

(HCV). Despite the high incidence of HCV infection in

these patients, a statistically significant association

between HCV infection and WM has not been found.

In relation to familial predisposition, an association

is estimated in 20% of cases.

6,7

In first degree family rela-

tions there is a high risk of developing lymphoprolifera-

tive diseases, which is twenty times higher for WM/LPL.

athophysiology

It is believed that WM originates in memory B-lymphocy-

tes.

9,10

These lymphocytes descend from B-lymphocytes

that proliferate in the germinal centers of lymph nodes

(post-germinal center B-lymphocytes), accumulating all

the genetic changes that occur in these centers. Thus, in

most cases, the neoplastic B cells present somatic hyper-

mutation in the genes coding the hypervariable regions of

the immunoglobulin heavy chains (V

genes).

11,12

Howe-

ver, in some cases, the neoplastic B-cells are derived from

B-lymphocytes which have undergone somatic mutation

outside of germinal centers.

In other cases, there is no

evidence of somatic mutations in the V

genes, which may

indicate that they are derived from pre-germinal center B-

-lymphocytes, such as “virgin” B-lymphocytes.

In relation to the mechanisms involved in the patho-

physiology of WM, the blocking of immunoglobulin isoty-

pe switching and the role of cytokines is noteworthy.

Most malignant cells in WM express surface IgM and

IgD, suggesting an intrinsic incapacity to switch isoty-

pes.

This “block” may be related to the absence/dysfunc-

tion of the activation-induced cytidine deaminase (AID)

enzyme, which is involved in somatic hypermutation and

the immunoglobulin isotype switching process.

11,13

Although isotype switching is rarely seen in WM, ac-

cording to some studies it is possible that it occurs

ex vivo

and

in vivo

. Kriangkum et al.

demonstrated that AID

may be induced

ex vivo

, by stimulation with CD40L and

interleukin-4 (IL-4). Another study showed the possibi-

lity of isotype switching occurring

in vivo

Mast cells and various cytokines play an important

role in the development of the disease.

Cytokines may

be important for angiogenesis, increased bone resorption,

proliferation, survival of malignant cells, and secretion

of monoclonal IgM.

In WM, malignant B-lymphocytes express the recep-

tor CD27,

which can be found in the membrane of me-

mory B-lymphocytes and in soluble form (sCD27) in high

concentrations in the serum.

sCD27 activates bone mar-

row mast cells by binding to CD70. Activated mast cells

secrete growth and survival factors for B-lymphocytes

such as CD40L and APRIL (proliferation-inducing li-

gand),

which may contribute to lymphoplasmocytoid

differentiation of malignant cells in the bone marrow.

linical

symptoms

The clinical presentation of WM varies. Most of the pa-

tients present clinical signs/symptoms related to IgM hy-

pergammaglobulinemia and/or LPL infiltration in or-

gans and tissues, especially bone marrow. However, some

patients do not exhibit any clinical symptoms when diag-

nosis is made.

Blood hyperviscosity determines hemorheological

changes and is one of the most important characteristics

of WM; however, it is observed in less than 15% of pa-

tients upon diagnosis. The large size of the monoclonal

IgM molecule and its high concentration contribute to

increased blood viscosity and vascular resistance, com-

promising the blood flow to oxygenate tissues.

The main clinical manifestations associated with the

hyperviscosity syndrome are bleeding (epistaxis, bleeding

gums and gastrointestinal bleeding), ocular changes (pa-

pilledema, blindness, blurred vision and retinal changes:

hemorrhage, exudates, dilatation and segmentation of

the retinal veins, venous thrombosis), neurological chan-

ges (headache, dizziness, syncope, deafness, ataxia, diplo-

pia, drowsiness and even seizures) and cardiac changes

(heart failure).

The symptoms of hyperviscosity generally manifest

when the concentration of monoclonal IgM is greater

than 5000 mg/dL or when the serum viscosity reaches 4-5

cP (reference range: 1.4 to 1.8 cP). However, the serum vis-

cosity is not always proportional to the concentration of

IgM and its relationship to symptoms is not linear.

Type I cryoglobulinemia (monoclonal IgM cryoglo-

bulinemia) is associated with lymphoproliferative disea-

ses such as WM, and is detected in approximately 20% of

patients, while symptomatic in only 5% of cases.

The

precipitation of monoclonal IgM cryoglobulin is also res-

ponsible for some clinical symptoms, such as Raynaud’s

phenomenon, acrocyanosis, purpura and necrosis of body

regions most exposed to the cold. It is also responsible

for the development of distal symmetrical sensorimotor

polyneuropathy or multiple mononeuropathy with axo-

nal degeneration.

20,21

Monoclonal IgM can cause platelet dysfunction by

binding to IIIa and Ib glycoproteins on the surface of pla-

telets or due to nonspecific interactions with platelets.

It may also neutralize the activity of several coagulation

factors (fibrinogen, prothrombin, factors V, VII, VIII, IX,

X, and Von Willebrand factor),

9,22

triggering hemostatic