Chapter 21
Monoclonal
Gammopathies
Wu Jianmin
GUIDELINES FOR EVALUATING
MONOCLONAL GAMMOPATHIES
1.Which Patients Should be Evaluated for the Presence
of an M-Protein
2.What Types of Specimens Should be Studied, and
How Often Should They be Used to Follow Patients
with M-Proteins
3.Which Laboratory Methods should be used to Detect,
Identify, and Follow M-Proteins
DISEASE STATES
1.Myeloma
2.Immunoglobulin Isotypes in Multiple Myelorna
3.Waldenström's Macroglobulinemia
4.Monoclonal Gammopathy Of Undetermined
Significance.
5.B-Cell Neoplasms
6.Amyloidosis
A monoclonal gammopathy is the protein product of
a single clone of plasma cells.
Although the term "monoclonal gammopathy"
often has been used to designate the proteins produced
by the malignant cells in multiple myeloma and other
B-cell lymphoproliferative lesions, such as
Waldenström's macroglobulinemia, a monoclonal
gammopathy also may be the product of a "regulated"
cell.
Factors to consider when evaluating an M-protein
include the quantity of the M-protein, the fluid in
which it is found (serum versus urine), and the
chemical type of the M-protein (light chains will
more likely be found in the urine than in the serum).
The term M-protein is used in the literature to
describe the monoclonal gammopathy. Although it
has been variously used for "monoclonal component,
mveloma prorein, and macroglobulin protein," the
recently
published
guidelines
for
evaluating
monoclonal gammopathies recommend the use of the
term "M-protein".
Which Patients Should be Evaluated
for the Presence of an M-Protein
M-proteins are found in the serum and/or urine of
patients with a wide variety of clinical conditions.
The occurrence and clinical symptoms of these
conditions vary widely (Table 21-1).
TABLE 21-1 CONDITIONS ASSOCIATED WITH THE
PRESENCE OF AN M-PROTEIN
Condition
Multiple myeloma
Waldenström's
macroglobulinemia
B-Lymphoproliferative
disorders
Amyloid (AL), light chain
deposition disease
Neuropathy and M-protein
Monoclonal gammopathy of
undetermined significance
(MGUS)
Clinical Features
Back pain, osteolytic lesions, fatigue,
elevated sedimentation rate,
nephrotic syndrome, infections,
anemia, elevated calcium
Fatigue, elevated sedimentation rate,
dizziness, anemia, hyperviscosity
Fatigue, anemia, lymphadenopathy,
lymphocytosis
Nephrotic syndrome, congestive
heart failure,carpal tunnel syndrome
Peripheral sensory and/or motor
neuropathy
No symptoms related to the M-protein
Traditionally, the size of the M-protein has been helpful in
determining the significance for the patient. Typically, a large
quantity of M-protein (greater than 2 G/dL) is more likely to
be associated with myeloma, whereas, a small quantity of Mprotein may be associated with monoclonal gammopathy of
undetermined significance (MGUS) . Yet, several important
conditions associated with small quantities of M-proteins may
be overlooked if these M-proteins are not recognized (Table 21-
2).
TABLE 21-2 CONDITIONS WITH RELATIVELY SMALL
QUANTITIES OF M-PROTEIN IN SERUM
Condition
Light chain disease
Associated Feature
15% of cases of multiple myeloma
are light chain disease
Amyloid (AL)
20% have multiple myeloma or
Waldenström's macroglobulinemia
Heavy chain disease
Alpha chain disease is rare in United States
Gamma chain disease is associated with
B-lymphoproliferative disorders
M-protein associated neuropathy Must do Immunofixation of serum
to rule out
Cryoglobulin type II
Associated with Hepatitis C
Solitary plasmacytoma
Tiny or no M-protein in serum
B-Lymphoproliferative disorder Often with overall gamma suppression
MGUS
The most common cause of serum M-proteins
What Types of Specimens Should
be Studied, and How Often Should
They be Used to Follow Patients
with M-Proteins
The initial evaluation of a patient with clinical
features suggesting the presence of an M-protein
should include a serum and urine electrophoresis
using high-resolution methods (Fig. 21-1).
Fig. 21-1. Specimens and evaluation for detecting monoclonal gammopathies.
If the serum protein electrophoresis is negative, and
there is a low index of suspicion, one may wish to
look for other causes of the symptoms before
performing an immunofixation (IFE). However, if
the clinical suspicion is high, an IFE should be
performed even when no M-protein is seen on the
screening electrophoresis.
If an M-protein is found on the screening
electrophoresis, an IFE must be performed to
identify the M-protein. This identification serves
several purposes.
First, it rules out a false positive due to some
other protein that may mimic an M-protein on
serum protein electrophoresis (Table 21-3).
Table 21-3．proteins that may mimic an M-protein
Fibrinogon
C3 Variant
Transferrin variant
Beta-1 lipoprotein
Antibiotic band on capillary zone electrophoresis
Second, because IFE is more sensitive than screening
electrophoresis, it may identify a second M-protein (often a
monoclonal free light chain that accompanies the intact
molecule in the serum).
Third, it identifies the M-protein for comparison with
subsequent samples from the patient. If there is no change in
the migration of the identified M-protein on subsequent
samples, there is no need to perform further IFE studies.
For serum, the best measurement of the M-protein
is achieved by performing high-resolution
electrophoresis and measuring the amount of
protein below the spike (Fig. 21-2).
Fig.21-2. Capillary zone electropherogram with M-protein.
M-proteins should be measured integrating the area under the peak.
For the urine, it is important to follow the
monoclonal free light chains and not the intact Mprotein immunoglobulin that may be found in the
urine. The prognosis and threat to the kidney is
mainly due to the amount of monoclonal free light
chain and not due to the intact M-protein.
The panel agreed that the term "Bence Jones
protein" has been somewhat confusing in this
regard. Bence Jones protein only refers to the
monoclonal free light chains, not to the intact
monoclonal immunoglobulins.
Which Laboratory Methods should be
used to Detect, Identify, and Follow
M-Proteins
The panel was unanimous that the laboratory
should use a high-resolution electrophoretic method
in the initial evaluation of serum and urine. A high-
resolution method is one that permits a crisp
separation of transferrin and C3 in the beta region
(Fig. 21-3).
Fig.21-3. high-resolution electrophoresis with M-protein (top).normal (middle).
And polyclonal patterns. The gel or CZE pattern should provide crisp separation
of the beta-1 (transferrin) band from the beta-2 (C3) band.
immunofixation with an IgA kappa M-protein. Note the small M-protein
band (arrow) in the SPE lane. The IgA and kappa restrictions are obvious.
DISEASE STATES
Myeloma
Multiple myeloma is the most common malignant cause for
the presence of an M-protein in serum or urine. This disease
is because of a malignant proliferation of a clone of B
lymphocytes that manifests predominantly as plasma cells.
Note that multiple myeloma often is considered to be a
condition of malignant plasma cells. In fact, the malignancy
involves the entire B-cell lineage but manifests mainly as
malignant plasma cells.
Immnunoglobulin Isotypes in Multiple Myelorna
The isotypes of immunoglobulins seen in multiple myeloma
largely reflect their prevalence in normal serum.
IgG myeloma proteins predominate. They are almost always
monomers weighing 160,000 daltons. It is rare that IgG
myeloma proteins produce significant problems with
hyperviscosity.
IgE myeloma is extremely rare and can occur as monomers or
as polymers with variable molecular weight.
IgA myeloma may be difficult to diagnose on occasion
because IgA tends to migrate in the P region. Therefore,
early in its course, the other beta region bands may mask
the IgA myeloma. C3, transferrin, or fibrinogen from an
inadequately clotted sample of blood or an inadvertently
examined sample of plasma may obscure the presence of
an IgA myeloma M-protein.
IgD myelomas also may be missed because the amount of
M-protein may be relatively small. If one is using the older
five-band electrophoresis techniques, a normal alpha 2 or
beta region band may hide the small IgD component. Also,
as discussed later, when radial immunodiffusion plates
perform quantification, at least two dilutions of the
patient's serum must be performed to avoid antigen excess.
Alpha heavy-chain disease is extremely uncommon in the
western world. In the Middle East and Mediterranean
regions, an unusual disease called a heavy-chain disease
occurs. The tissue distribution of the plasma cells in this
lesion roughly parallels that for the normal distribution of
IgA along the gastrointestinal tract and other mucosal
surfaces.
Waldenström's Macroglobulinemia
Patients with Waldenström's macroglobulinemia suffer
from complications of hyperviscosity from the presence of
large amounts of circulating IgM. IgM almost always
circulates as a pentamer (19S). Therefore, when one
develops a monoclonal proliferation of cells producing IgM,
the increased concentration of large proteins in the blood
disturbs the normal circulation hemodynamics, resulting in
the hyperviscosity syndrome. This causes a variety of
neurologic complaints, cardiac insufficiency, and vascular
insufficiency throughout the body.
Monoclonal Gammopathy Of Undetermined Significance
In older textbooks, the term for this section would
have been "benign monoclonal gammopathies."
By this term, he referred to individuals who have a
monoclonal component demonstrated in the serum, but
who lack other key features for diagnosing a malignant
monoclonal gammopathy. These patients are not anemic,
they do not have lytic lesions, and they do not have
elevated serum calcium or serum enzymes.
B-Cell Neoplasms
A variety of B-cell neoplasms have been associated
with monoclonal gammopathies.
In fact, the
majority of these patients have a monoclonal
gammopathy in either their serum or their urine
when high-resolution electrophoresis and
immunofixation are combined to study these
samples. Monoclonal gammopathies also have been
demonstrated in patients with Burkitt's lymphoma
and B-cell ALL.
Amyloidosis
About 4% patients with plasma cell proliferation
will have amyloid deposition in their tissues. There
are two major biochemical types of amyloid.
One consists of an immunoglobulin light chain and
is termed AL.
The second is composed of protein A and is termed
AA.