PARAPRTEINEMI

A
A/P Dr. T. Prasad
Contents:
1. Multiple myeloma
 Definition
 Aetio-pathogenesis

2. Clinical features
3. Complications
4. Blood and bone marrow
findings
5. Laboratory diagnosis
 Urine and electrophoresis
 The common feature of this collection of entities is the proliferation of a
B-cell clone that synthesizes and secretes a single homogeneous
immunoglobulin or its fragments.

 In many (but not all) cases, these proliferations (often referred to as

dyscrasia) are malignant.

 Collectively, the plasma cell dyscrasia account for about 15% of deaths
from white cell neoplasms.

 The monoclonal immunoglobulin identified in the blood is referred to as

an M component, in reference to myeloma.

 neoplastic plasma cells often synthesize excess L or H chains along

with complete immunoglobulins. Occasionally, only L chains or H chains
are produced.

 The free L chains, known as Bence Jones proteins, are small enough to
be rapidly excreted in the urine.
Origins of plasma cells. Like most blood Normal immunoglobulin molecule
cells, plasma cells develop from stem cells containing paired heavy chains with
in the bone marrow. Stem cells can one smaller light chain attached to
develop into B cells (B lymphocytes), which each
travel to the lymph nodes, mature, and
then travel throughout the body. When
foreign substances (antigens) enter the
body, B cells develop into plasma cells that
produce immunoglobulins (antibodies) to
help fight infection and disease.
A monoclonal immunoglobulin or
immunoglobulin light chain in the blood or urine
- resulting from a clonal proliferation of
plasma cells or B- lymphocytes
 Synonyms: M-band, Monoclonal band,
Monoclonal spikes, monoclonal protein

 Three major disorders associated with

para-proteinemia :
1.Monoclonal gammopathy of undetermined
significance(MGUS).
2.Multiple Myeloma
3.Waldenstroms macroglobulinemia.
Other minor disorders :
4.Solitary Myeloma
a.Extraosseous
b.Osseous

5.Heavy chain disease

6.B-NHL

7.Pr Amyloidosis

8.Monoclonal immunoglobulin deposition

disease
Multiple Myeloma:
Neoplasm of mature and immature plasma cells.

Lethal,
Neoplastic expansion,
Triad of :
Anemia
Plasma cell accumulation
Granulopenia
Hypercalcemia
Osteolytic lesions
# and bone pains
Myeloma Kidney
M component Amyloidosis
Hyperviscosity
Cryoglobulinemia
Other Effects:
 1. Hypoglobulinemia

 2. Suppression of normal Ig Synthesis

- PIMS (Pims are a small family of serine/threonine

kinases with increased expression across the hematological
malignancies. )

-T suppressor effect

 3.Tissue deposits
Etiology:
 Environmental exposure

 Chronic antigenic stimulation

 Radiations

 Family history of haematologic & lymphoid

malignancy.

 Viruses : HIV, Hep A,B,C, Kaposi Sa

 SV – 40 virus : on Chromosome 22 close to

lamda chain
Pathogenesis:
 1.The most frequent karyotypic abnormalities :Molecular
biology.

• deletions of 13q and translocations involving the Ig heavy

chain( Ig H) locus on 14q32.

• Common translocation partners with Ig H are FGFR3

(fibroblast growth factor receptor 3) on chromosome 4p16, a
gene encoding a type of tyrosine kinase receptor implicated in
control of cellular proliferation ;

• the cell cycle regulatory genes cyclin D1 on chromosome 11q13

and cyclin D3 on chromosome 6p21;

• the gene for the transcription factor cMAF on chromosome 16

q23;

• and MUM1/IRF4, a gene for an interferon regulatory factor, on

chromosome 6p25.
 2. IL-6 is produced by neoplastic plasma cells and normal
stromal cells in the marrow:

- Serum levels of this cytokine are increased in patients with

active disease,

- and high serum IL-6 levels are associated with a poor

prognosis.

 3. Cytokines , MIP1α and the receptor activator of NF-κB

ligand (RANKL), serve as osteoclast-activating factors.
 presents most often as multifocal destructive bone tumors composed
of plasma cells (plasmacytomas) throughout the skeletal system.

 Bones in the axial skeleton are affected most commonly.

 The following distribution was found in a large series of cases:

 vertebral column, 66%;

ribs, 44%;
skull, 41%;
pelvis, 28%;
femur, 24%;
clavicle, 10%; and
scapula, 10%.

 focal lesions generally begin in the medullary cavity, erode cancellous bone,
and progressively destroy the bony cortex, often leading to pathologic
fractures.
 The bone lesions appear radiographically as punched-out defects,
usually 1 to 4 cm in diameter.
Gross :
consist of gelatinous, soft, red tumor masses.
Less commonly, widespread myelomatous bone disease can produce diffuse
demineralization (osteopenia) rather than focal defects.

Microscopic :
- an increased number of plasma cells, which usually constitute more than 30%
of the marrow cellularity.

- diffusely or be present in sheet like masses - completely replace normal

marrow.
- neoplastic plasma cells: a perinuclear clearing (due to a prominent Golgi
apparatus) and an eccentrically placed nucleus .

- plasmablasts, with vesicular nuclear chromatin and a prominent single

nucleolus, binucleated, trinucleated or bizarre multinucleated cells seen.

Other cytologic variants:

intracellular accumulation of intact or partially degraded Ig.
 flame cells, with fiery red cytoplasm;
 Mott cells having multiple blue grapelike cytoplasmic droplets; and cells
containing a variety of other inclusions, including fibrils, crystalline rods, and
globules, sometimes Russell bodies (cytoplasmic) or Dutcher bodies (intra
nuclear inclusion).
Dutcher bodies (arrow) are intranuclear inclusions
found in plasma cells.
Flame Cells: These are plasma cells
with vermillion-staining glycogen-rich
overstuffed fibrils
A mott cell (a plasma cell with immunoglobulin globules)
 the high level of serum M proteins causes red cells in smears of
peripheral blood to stick to one another in linear arrays, a finding referred
to as rouleaux formation

 With progressive disease, plasma cell infiltrations can be encountered in

the spleen, liver, kidneys, lungs, lymph nodes, or other soft tissues.

 Bence Jones proteins - excreted in the kidney and contribute to a form

of renal disease called myeloma kidney that is one of the more
distinctive features of multiple myeloma.

rouleaux formation
Lab Features:
 Normocytic& nromochromic anaemia& rouleaux formation

 ESR  ; neutropenia, immature plasma cells

 BM: 5-10%, exceeds 15-20% highly probable

 Myeloma cell: large 2-3 nuclei & nucleoli

 N:C asynchrony : nuclear immaturity in face of cytoplasmic

maturity

 99% of patients with multiple myeloma, laboratory analyses reveal

increased levels of immunoglobulins in the blood and/or light chains
(Bence-Jones proteins) in the urine.

 The monoclonal immunoglobulins are usually first detected as

abnormal protein "spikes" in serum or urine electrophoresis and then
further characterized by immunofixation .
  The most common serum monoclonal immunoglobulin ("M protein")
- IgG, which is found in 55% of patients.
- An additional 25% of cases, associated with an IgA M protein.

 . Excessive production and aggregation of M proteins hyperviscosity

syndrome (described under lymphoplasmacytic lymphoma) in
approximately 7% of patients, mostly associated with tumors that secrete
IgA and or IgG3.

Polyclonal IgG
Polyclonal IgG

Polyclonal IgG in normal serum (denoted by the arrow) appears as a broad band; in contrast, serum from a patient with
multiple myeloma contains a single sharp protein band in this region of the electropherogram. The suspected monoclonal
immunoglobulin is confirmed and characterized by immunofixation. Note the sharp band in the immunoglobulin region of
the patient SP that is recognized by antisera against IgG heavy chain (G) and kappa light chain (κ), indicating the
presence of a Ig Gκ M protein. Levels of polyclonal Ig G, IgA (A), and lambda light chain (λ) are also decreased in the
patient serum relative to normal, a common finding in multiple myeloma.
Diagnosis: Durie & Salmon
Criteria based:
Major Criteria
1. Plasmacytoma on tissue biopsy

2. Marrow plasma cells>30%

3. M component
- Serum IgG>3.5g/dl, IgA>2g/dl,
- urinary M component ≥ 1g/day (no amyloidosis)
Minor
a. Marrow plasma cells 10 – 30%

b. Smaller M component

c. Osteolytic lesions

d. Hypoglobulinemia
- Ig G < 600mg/dl, IgA < 100mg/dl, Ig M < 50mg/dl

Diagnosis: One major + One minor or three minor with

both a& b being compulsory
Clinical features/ complications :
effects of
(1) infiltration of organs, particularly bones, by the neoplastic plasma cells;

(2) the production of excessive immunoglobulins, which often have abnormal

physicochemical properties; and

(3) the suppression of normal humoral immunity. (DCRAB)

 Bone resorption -- pathologic fractures and chronic pain, spinal cord

compression.

 Hypercalcemia - neurologic manifestations such as confusion,

weakness, lethargy, constipation, and polyuria and can contribute to renal
disease.
 Decreased production of normal immunoglobulins - recurrent infections
with bacteria such as Streptococcus pneumoniae, Staphylococcus aureus,
and Escherichia coli.

 Of great significance is renal insufficiency, which is second only to

infections as a cause of death, the single most important factor appears to
be Bence Jones proteinuria, as excreted light chains are toxic to renal tubular
epithelial cells.
 Amyloidosis of the AL (amyloid light chain) type occurs in some patients
owing to secretion of amyloidogenic Ig light chains.

 The prognosis for this condition is variable but generally poor.

Solitary Myeloma (Plasmacytoma):

 3% to 5% of plasma cell neoplasms present as a solitary lesion of
either bone or soft tissue.

 the bony lesions tend to occur in the same locations as in multiple

myeloma.

 extraosseous lesions are often located in the lungs, oronasopharynx,

or nasal sinuses.

 modest elevations of M proteins in the blood or urine may be found in

a minority of patients
Progression to classic multiple myeloma is common in patients with solitary
osseous plasmacytoma, whereas extraosseous plasmacytomas disseminate
in only a minor fraction of patients.
..
Waldenstroms macroglobulinemia (WM)
is a malignant B-cell neoplasm characterized by
lymphoplasmacytic infiltration of the bone marrow and hypersecretion of
monoclonal immunoglobulin M (Ig M) protein.

6th or 7th deacade of life.

Patients with IgM MGUS can progress to develop WM, at the rate of 1.5%
to 2% per year .

Genetic Heterogeneity of Waldenstrom Macroglobulinemia

One locus for susceptibility to Waldenstrom macroglobulinemia (WM1)

maps to chromosome 6p21.3. Another locus (WM2; 610430) maps to
chromosome 4q.
Clinical features:
due to hyper-viscocity of blood.
o Bleeding

o Headache

o Weakness

o Visual disturbance.

Morphology :
the bone marrow contains :
- a diffuse, sparse-to-heavy infiltrate of lymphocytes, plasma cells, and
intermediate plasmacytoid lymphocytes, often accompanied by a reactive
hyperplasia of mast cells.

- PAS-positive inclusions containing immunoglobulin are frequently seen

in the cytoplasm (Russell bodies) or nucleus (Dutcher bodies) of
plasmacytoid cells.
 Tumorous masses causing bony erosions, a hallmark of multiple
myeloma, are absent.

 In addition to almost invariable involvement of marrow, the tumor is often

disseminated to the lymph nodes, spleen, and liver at diagnosis.

 Infiltration of the nerve roots, meninges, and more rarely the brain can
also occur with disease progression.

Diagnosis :
only after careful exclusion of other causes of monoclonal gammopathy,
particularly indolent multiple myeloma.
On completion of this topic, you should be able to
1. define paraproteins.
2. define multiple myeloma.
3. describe the aetio-pathogenesis of multiple myeloma.
4. describe the clinical features of multiple myeloma.
5. describe the peripheral blood smear and bone marrow
findings in myeloma.
6. enumerate the the effects and complications of multiple
myeloma.
7. discuss Bence-jones proteinuria.
8. discuss the urinary and serum diagnosis in myeloma