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Assays / Protein
Reference Units / Paraprotein Typing
Clinical use:
The term 'paraprotein' was introduced by Apitz in 1940 to describe
the proteins in blood, urine or tissues that are produced by myeloma
cells. However, the abnormally occurring protein in urine, later
identified as the monoclonal light chain component of the immunoglobulin
molecule was first described by William Maclntyre in 1846 and thereafter
called 'Bence-Jones protein'.
In a situation where there is proliferation of a single clone of
B-cells, the antibody product will consist of a single heavy chain
class and sub-class, light chain type and idiotype. Such antibody
will represent a homogenous protein migrating as a compact band
in electrophoretic separations. This is a paraprotein or monoclonal
immunoglobulin.
Paraproteins are thus the earliest described tumour markers and
remain an important diagnostic feature in multiple myeloma. However,
it has now become clear that paraproteins are found in many individuals
and are associated with a wide range of disorders, other than multiple
myeloma. When hospital populations are surveyed, the most frequent
association of paraproteinaemia is with the malignant conditions.
Surveys of symptomless populations have shown a low incidence of
paraproteinaemia increasing with age and in the majority of cases
this does not seem to signify early detection of malignancy, but
rather the chance finding of an idiopathic benign condition. Current
data would suggest a higher frequency than was recorded 20-30 years
ago, this probably represents increased sensitivity of the detection
methods rather than a true increased incidence. Significant studies
at extreme ages are difficult to document, but frequencies of up
to 10% in the tenth decade, and 20% in the twelfth decade, have
been recorded.
Whether a paraprotein indicates a benign or malignant condition
is important in patient management. In all cases of paraproteinaemia,
and in suspected cases of a B-cell malignancy, both serum and urine
analysis is essential. An important distinguishing feature is the
fairly frequent finding, in the malignant conditions, of immunoglobulin
fragments produced by tumour cells. These fragments, which may show
as only subtle changes in the serum electrophoretic pattern, are
usually of lower molecular weight than the complete immunoglobulin
molecule and may be clearly visible in the urine, due to the concentration
effect. The most frequently seen of these is the Bence-Jones protein
(BJP).
Myelomatosis
- Myelomatosis (multiple myeloma) is defined
by three major features:
- The production of paraproteins which can
be detected in serum or urine.
- The presence of increased plasma cells within
the bone marrow, usually 10% or more of the nucleated cell population.
- The destruction of bone, either in the form
of osteolytic lesions or as extreme osteoporosis.
A confident diagnosis can be made when only
two of these features are present.
In 20% of myeloma patients, BJP is the only tumour product and can
be missed if only the serum is examined. BJP may also be implicated
in deposition of amyloid and in the rare kappa chain disease, the
idiotype of the BJP shows an affinity for kidney and other tissues
without forming amyloid, so that diagnosis depends on immunochemical
studies on biopsies.
Apparently localised plasmacytoma can present in a single bone,
eg clavicle, femur or vertebra or in the soft tissues. In most patients
a serum paraprotein or urinary Bence-Jones provides a tumour marker.
In the absence of an immunoglobulin marker, serum b 2-microglobulin
estimations may be useful.
Waldenstrom's Macroglobulinaemia
This diagnosis should be a diagnosis reserved for those patients
with IgM paraproteins who present with viscosity syndrome.
The underlying tumour is so indolent ( only slowly infiltrating
the lymph nodes, spleen and bone marrow with lymphocytoid plasmacells,
typically of uniform size) that the protein product is allowed to
build up to a concentration above 30 g/L. It is this protein concentration,
rather than symptoms from tumour invasion, which brings the usually
elderly male patient to the doctor.
Heavy Chain Diseases
These are extremely rare in native Western populations - the
most commonly seen in the UK is Alpha chain disease in patients
from the Middle East. Clinically, it presents as a severe malabsorption
syndrome with a stove-pipe-like involvement of the small intestine
and an apparently high serum IgA concentration with almost absent
IgG and IgM. A few cases have presented with a segmental involvement
of the lung and similar serum findings.
Gamma chain disease
This was first described in association with oedema and redness
of the uvula and soft palate. As more cases were discovered, it
was apparent that less than 15% present in this way. The clinical
picture may resemble that of malignant lymphoma. The disease has
been described in association with a number of chronic conditions,
eg rheumatoid arthritis, Sjogren's syndrome, SLE, tuberculosis.
Mu chain disease
This occurs predominantly with Chronic Lymphatic Leukaemia and,
unlike gamma and alpha chain, is often accompanied by BJP. The defect
appears to be in the assembly of complete immunoglobulin, unlike
the other heavy chain diseases where evidence indicates deletion
of light chain synthesis.
The diagnosis of heavy chain disease remains the prerogative of
the laboratory and the term should be reserved for those conditions
in which the presence of free heavy chains can be clearly demonstrated.
Immunofixation can be used to detect free heavy chains. These may
then be confirmed by the technique of immunoselection electrophoresis.
Other B-Cell Malignancies
Paraproteins may be seen with any B-cell malignancy, eg lymphoma,
Chronic Lymphocytic Leukaemia and occasionally Kaposi's Sarcoma.
In most cases it is the effect of the tumour, rather than the paraprotein,
that produces clinical symptoms.
Benign Paraproteinaemia
This is the diagnosis made when all possible malignant conditions
have been excluded and there has been no progression for at least
five years, and preferably ten years, of follow-up. The term Monoclonal
Gammopathy of Uncertain Significance (MGUS) is used to denote
those cases where a monoclone has been identified but no other features
of myelomatosis are present, the condition has not been monitored
for a minimum five years and cannot, therefore, be defined as benign.
Transient Paraprotein
This is the most often seen against a background of immune suppression,
particularly with a superimposed infection, and probably represents
limited clonal expansion and/or immune imbalance. Some 80% of bone-marrow-transplant
patients will show such bands during the reconstitution period.
Paraprotein Detection and Typing
Paraproteins are most conveniently demonstrated as narrow bands
on electrophoresis. The method of choice for typing heavy and/or
light chains of paraproteins is immunofixation.
Investigation and typing of paraprotein is necessary
for:
- Diagnosis and prognosis in B-cell neoplasm.
- Assessing significance of the paraprotein.
- Monitoring of both benign and malignant paraproteinaemia.
Diagnosis and assessment of paraprotein
Quantitation and typing of a paraprotein, together with estimation
of the normal immunoglobulins, can help to assess whether the underlying
lesion is benign or malignant, and to establish the diagnosis. Unless
the isotype of the paraprotein is known the concentration cannot
be interpreted in terms of tumour bulk. The average serum concentrations
(g/L) at the time of presentation of patients with myelomatosis
are IgG 43; IgA 28; IgM 19; IgD 14; IgE 10. The IgM concentration
in Waldenstrom's macroglobulinaemia is usually greater than 30 g/L.
In most cases of benign paraproteinaemia the paraprotein concentration
is less than 10 g/L and in transient conditions, less than 5 g/L.,
although exceptions to both rules are recognised
Investigation of urine for BJP is important in diagnosis of BJ myeloma
and for distinguishing benign from malignant conditions. Bence Jones
Protein is very rarely seen with a benign condition.
See also b2microglobulin
for prognostic significance in myeloma.
Monitoring
If a diagnosis of malignant immunocytoma is made, it is important
to monitor the patient's serum and urine every three months so that
the patient's response, or lack of response, to treatment can be
assessed.
If the paraprotein disappears following treatment, measurement can
be repeated 6 or 12 monthly. If the paraprotein does not disappear,
this indicates residual disease particularly with solitary plasmacytoma.
Apparently benign paraproteinaemia should be monitored yearly if
the patient is elderly, but three monthly if the patient is less
than 50 years old. At this age, benign paraproteinaemia is rare
and if due to myeloma, this can be swift to evolve.
Sample requirement:
5 mL serum in a screw capped glass bottle. The sample must be
taken and separated at 37° C if the presence of cryoglobulins
is suspected. A 25 mL sample of a 24 hour collection of urine in
a screw capped universal container with 0.1% sodium azide should
be submitted.
Random urine samples are of limited value for quantitative assessment
of BJP although they can be used for screening purposes.
Centres offering this assay: Cardiff,
St.George’s,
Sheffield
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