Plasma cell Dyscrasias

Synonyms:
 Paraprotein aemias
 Monoclonal gammopathies

Plasma cell dyscrasias are a group of disorders characterized by neoplastic
proliferation of plasma cells and increased production of single homogenous
immunoglobulin( Paraprotein, monoclonal protein, M protein)

Disorder associated with paraprotein aemias : dg281.hp273p

Neoplastic:
 Multiple myeloma
 Plasmacytoma ( medullary / extra medullary)
 Plasma cell leukaemia
 WaldenStrom’s macroglobinaemia ( Lympho-plasmacytic lymphoma)
 Heavy chain disease ( these are now classified with non Hodgkin
lymphoma ) hf282p
 Immunoglobulin light chain amyloidosis
 Monoclonal gammopathy of uncertain significance
 Osteosclerotic multiple myeloma
 Some B-cell lymphocytic neoplasms
Benign :
 Chronic cold haemagglutinin disease
 Transient ( ig: with infections)
 HIV infection
 Gaucher’s disease
(Paraprotein is one type of immunoglobin molecule or one type of heavy chain or one
type of light chain of immunoglobulin( monoclonal protein)
It is produced under neoplastic proliferation of monoclonal cells of lymphoid tissue .)

Features of benign and malignant paraproteinaemia hf282p

Benign Malignant
Bence-jones protein Absent May be present
Serum paraprotein Usually < 30g/L Usually > 30g/L
concentration and Stationary and rising
Serum free light chain ratio Normal Abnormal
Underlying Absent Present
lymphoproliferative
disease or myeloma )
Bone lesions Absent Present
Plasma cells in marrow < 10% >10%
Plasma cell neoplasm (WHO -2008) hf273
o Monoclonal gammopathy of undetermined significance (MGUS)
o Plasma cell myeloma
 Asymptomatic myeloma
 Non secretory myeloma
 Plasma cell leukaemia
o Plamacytoma
o Solitary plasmacytoma of bone
o Extraosseous(Extramedullary) Plasmacytoma
o Immunoglobulin disease
Primary amyloidosis
systemic light and heavy chain deposition disease

o Osteosclerotic myeloma(POEMS syndrome)

Investigations in plasma cell dyscrasias : kh313p

Blood : CBC, Hb estimation, Blood smear (Rouleaux formation),

ESR – increase
o Bone marrow: Plasma cell number and morphology, demonsration of
clonality and immunophenotype.
In myeloma plasma cells are more than 10% . in
waldstrom’s macroglobinaemia , bone marrow shows
infiltration by lymphocytes , plasmacytoid lymphocytes
and plasma cells.
o Serum : albumin, immunoglobulins, serum protein electrophoresis
( Primary scrrening test for detection of paraproteins) immuno
fixation, serum free light chain assay, ?
o Urine : 24 hor protein, 24 hour protein electrophoresis, 24 hour
immuno fixation
o Skeletal radiological survey
Pathological effects of paraproteins: dg283p
 Raised serum globulin
 Hypoalbuminaemia
 Hyponatraemia
 Dilutional anemia
 Raised ESR , Rouleaux formation in blood
 Hyperviscosity
 Interference with platelet function and coagulation pathway
 Proteinuria
 Renal failure
 Amyloidosis

Multiple myeloma dg283

Myeloma is a chronic , progressive and fatal malignant condition in which the
fundamental abnormality is a neoplastic proliferation of plasma cells which
infiltrate the bone marrow and often other body tissue.
occurs mainly in older age.(50-70 years. uncommon under 40 years)

Characteristic features of symptomatic myeloma: hf273p

1. Monoclonal protein inserum and /or urine
2. Increased clonal plasma cells in the bone marrow and
3. Related organ or tissue impairment.

 Plasma cell are mixture of both normal and immature forms in

appearance .
 Occasionally plasma cells appear in the peripheral blood in large amount
( if more than 20% of all nucleated cells in peripheral blood or absolute
plasma cell counts >2000/cu mm blood) and the disorder referred as to
plasma cell leukaemia .
 When it occurs in aknown case of myeloma it is called secondary plasma
cell leukaemia. and if other wise is called primary plasma cell
leukaemia.

Types of myeloma ( as per type of immunoglobulin it produces )

 Ig M - 65%
 Ig A - 20%
 Light chain myeloma – 15 % producing either kappa or
lambda light chain.
Rare subtypes include non secratory or Ig D / Ig E myeloma.
 Pathogenesis Of Multiple Myeloma : kh319p

Antigen exposed post germinal center B cells

↓ ← Primary Ig H translocations

Monoclonal gammopathy of undetermined significans

Changes in bone marrow

microenvironment(increased

↓ ←secondary Ig H traslocation
angiogenesis, altered expression of cytokines,
growth factors and adhesion molecules),.
bone reabsorption

Multiple myeloma.

Aetiology: Unknown. Risk factors include exposure to pesticides and

herbicides ( in farm workers) Ionising radiation, prolong use of hair colouring
agent and chronic antigenic stimulation.

Pathophysiology:
Pathological and clinical features of myeloma are predominantly due to
 Monoclonal protein inserum and /or urine
 Increased clonal plasma cells in the bone marrow and
 Related organ or tissue impairment.
 Impairment of immunity
 Bone infiltration causes destruction of medullary and cortical bone due to
stimulation of osteoclast activity by osteoclast activating factor released
by myeloma cells.
 Hypercalcaemia- due to increased resorption of bone .
 Defective haemopoiesis due to abnormal cells from inra and extra osseous
tumours and infiltration of bone marrow
 Production of large amount of paraproteins.
Clinical features : jo292p, hf 275p
1. bone pain
2. Skeletal deformity
3. Sign and symptom of anaemia ( due to dilution effect of large amount of
paraprotein in circulation or insufficient production of erythropoietin in
chronic renal failure)
4. Neurological signs due to nervous system involvement
5. Renal insufficiency( Hypercalcaemia, polyuria, renal failure)
6. Bleeding manifestration( Myeloma protein may interfere with platelet
functions and coagulation factors; Thrombocytopaenia occurs in advance
stage)
7. Amyloidosis ( occurs in 5% with features such as macrolossia, carpal
tunnel syndrome and diarrhoea)
8. Infection ( releted to dificent anti body production, abnormal cell mediated
immunity and neutrophilia )
9. Cryglobulinaemia: 5% of myeloma proteins are cryoglobulins which
reversibly gen in cold and cause symptoms of cold intolerance.

 Bone pain due to pathological fracture , lysis and compression .

 Tumour formation is not uncommon and may occur on any bone, but
specially on the ribs.
 Tumour are generally firm and often tender. occasionally when the cortex
is very thin characteristic “ egg shell cracking ‘’ is felt.

 Nervous system involvement is common. frequently it is due to

compression by collapse vertebrae and spinal cords causes paraplegia or
quadriplegia

 ‘Myeloma kidney’- The most important pathological changes in kidney

take form of atrophy and dilation of tubles with cast formation in the
lumen .
The cast are composed of a mixture of a normal plasma protein and
precipitated Bence jones protein. Bence jones protein is also believed to
damage renal tubles directly.
Other factor of renal failure --- deposition of myeloma protein,
dehydration, local infections,hyper uricaemia, hyper calcaemia , plasma
cell infiltration In kidney and renal amyloidosis.

 Bleeding manifestation : An effect on platelets by paraprotein often leads

to abnormal platelet function, with prolongation of bleeding time and
defective adhesion and aggregation of platelet. Paraprotein also act as an
anticoagulant and inhibit some steps in coagulation pathway.
 Lab diagnosis of multiple myeloma :

ESR : Raised ( marked 100mm/hr to 150mm/hr)

PBF
 Red cell: anaemia, marked red cell rouleaux formation.
Abnormally Blue Stained background in the film.
 WBC: Moderate leucopenia ( may be normal/ raised), plasma cell
may appear in blood.
 Platelet: Reduced. ( advance disease)

Blood biochemistry :

1. Total serum protein : Often increased due to the presence of

paraproteins.. Total serum protein ranges from 70-120 g/l but may be
higher.
2. Serum albumin : Reduced
3. Serum normal gamma globulin : reduced
4. Serum calcium concentration : Increased ( due to osteolysis by
cytokines produced by myeloma cells.)

5. Serum alkaline phosphatase: is normal or slightly raised. ( a point of

importance in differentiation from hyperparathyroidism and secondary
carcinoma in bone , in which significant evelation is usual)
6. Serum uric acid : Incrased
7. Serum viscosity : Increased
8. Plasmaa volume : Increased.

Bone marrow :
Cellularity : Hypercellular .
Myeloma cells : 15-30% of the differential count may be higher.
 The cytoplasm of mature cells is basophilic,sometimes with aperinuclear
halo.
 The Nucleus is commonly eccentric
 Coarse Chromatin ( Show typical cartwheel arrangement )
 Cytoplasm of most immature cells is abundant, light blue and may show
perinuclear halo, vaculation and russell bodies. nucleoli is common in the
immature cells.
(( Increased proportion of plasma cell may present in the bone marrow in some other
disease-
 Aplasticanaemia
 kala azar
 Rheumatiod Arthritis
 SLE
 Hepatic cirrhosis
 Sarcoidosis
  Secondary carcinoma ))

Immunophenotyping : hf277p
 The characteristic Immunophenotyping of malignant plasma cell
is CD38 high , CD 138 high , CD 45 low .
 Anti CD138 is used to measure the number of plasma cells in the marrow
biopsy.

Free light chain ( FLC) : (serum and urine)

 immunoaasay method for assay of FLC.
 Normal range of serum κ: λ ration range is 0.26-1.65 for diagnosis of
monoclonal disease.
 Normally small amount of free κ ( kappa) and free λ (lamda) immunoglobulin
light chains are present in plasma. Though production of normal κ light chain is
more than that of λ (lamda) light chains , curiously serum λ (lamda) light chain
level is more than serum k level . Because λ (lamda) chains are present in dimeric
form and k light chains in monomeric form, So Urine clearance is more rapid for
k than λ (lamda).
 Urine : Bence jones protein are present. ( Free monoclonal κ or λ chain of
immunoglobulin) (( also may occationally occur in macroglobinaemia,
amyloidosis, Lymphoma and leukaemia)

Bone x ray : Bony change –

Diffuse decalcification
Localized area of bone destruction
Localized osteoclastic lesions usually appear as multiple, rounded,discrete,
punch out areas with no sclerosis at the margin. ( common in skill).

** any of the following investigation findings in diagnostic for multiple

myeloma-
1. Osteolytic lesion in bone in x ray
2. Evidence of para protein in blood or urine
3. Increased plasma cells ( >30%) in the bone marrow.
 Invevstigations for M protein : dg287p

1) Serum and urine protein electrophoresis : Light chain myeloma

proteins don’t have monoclonal protein in serum and there fore , these
cases are missed, if only serum and urine electrophoresis is done .

2) Immunofixation electrophoresis (IFE) in serum and urin : It is

more sensitive test than immunoelectrophoresis

3) Nephelometry : Is used for quantitative measurement of

immunoglobulin in serum. these does not distinguish normal and
abnormal immunoglobulins

4) Quantity of urinary light chain : It is measured from 24 hours urine

bt immunoelectrophoresis.

5) Serum free light chain assay :

Different type of Multiple myeloma : dg289p

Symptomatic multiple myeloma : The criteria for diagnosis of

symptomatic multiple myeloma as per international myeloma working group
(2003) include : .
I. M –protein inserum and or urine
II. Bone marrow (clonal) plasma cells or plastocytoma
III. Related organ or tissue impairment .
Therefore neither plasma cell number nor quantity of parapprotein is
important in diagnosis.
The criteria for myeloma –related organ or tissue impairment (
ROTI) due to plasma cell proliferative process
 Increased Calcium levels ( Serum calcium > 2.75
mmol/L)
 Renal insufficiency – ( Creatinine level > 173mmol/L)
 Anaemia
 Bone lesions – lytic lesions or osteoporesis with
compression fractures
 Other – symptomatic hyperviscosity, Amyloidosis,
Recurrent bacterial infections ( >2 episodes in 12
months)

CRAB – is a short form used for calcium, renal insufficieny, anaemia and
bone lesions in diagnosis of organ damage in symptomatic myeloma.

`
 Asymptomatic (Smoldering) Myeloma:
Diagnosis of asymptomatic multiple myeloma as per international myeloma
working group (2003) include :
o Serum M-protein - less than 30g/L
o Less than 10% bone marrow clonal plasma cells
o No ROTI or symptoms

Light chain myeloma : Light chain myeloma patients don’t have detectable heavy
chain ( Complete immunoglobulin) on immunofixation or immunoelectrophoresis of
serum and urine but either κ or λ light chain is detected by same tests. Bence jones
protein in urine is positive is most of the cases.

Non secretary myeloma : In about 2 5 patients of symptomatic myeloma , the serum

M-Protein is not measurable by conventional methods , although plasma cell in bone
marrow are >10% and there is evidence of ROTI. this condition is called non secretary
myeloma.

Walderstrom’s Macroglobulinaemia : dg291p

This is a unknown neoplastic proliferation of B lymphocytes, predominantly in bone
marrow which produce Ig M paraprotein , called macroglobulins because of their high
molecular weight .
The pathological and clinical features of the disorder due to
 Infiltration by the disease, causing marrow failure and enlargement of liver ,
spleen, lymphnode .
 Consequence of paraprotein in blood , which may markedly increase viscosity ,
interference with haemostasis.

Monoclonal gammopathy of uncertain significance ( MGUS) : dg292

 A serum paraprotein may be sometimes detected without any evidence of

myeloma or other underlying disease and is termed as MUGS
 The prevalence of MUGS is considerably greater than that of myeloma or malignant
lymphoplasacytic disorder.
 The internation myeloma working group (2003) has defined the criteria for
diagnosis of MUGS as
1. Serum M protein < 30g/L
2. Bone marrow clonal plasma cells < 10%
3. Low level of plasma infiltration in trephine biopsy (if done)
 There is no evidence of B cell proliferative disorders and no ROTI.
 There is no symptoms due to the presence of the monoclonal protein. the
liver , spleen , lymphnode are not enlarged. Osteolytic lesion are absent.

Solitary Plasmacytoma : These are isolated plasma cell tumours , usually of bone
or soft tissue ( e.g mucosa of the upper respiratory and gastrointestinal tracts or the
skin)
Amyloidosis : hf282
 Amyloidosis are a heterogeneous group of disorder characterized by the
extracellular deposition of protein in an abnormal fibrillar form .
 Amiloidosis May be hereditary or acquired and deposits may be focal,
localized or systemic in distribution .
 The amyloid is made form different amyliod fibril precursor proteins in each
type of disease .
 The classic diagnostic histological test is red green
birefringence after staining with Congo red and viewing
under polarized light .
Type Chemical Organs
nature Involved

Systemic AL amyloidosis (Associated Immunoglobu Tongue, skin,

with myeloma, Walderstrom’s lin Light heart, nerves,
Macroglobulinaemia or MUGS) May also chain ( AL) connective
occur on its own as primary amyloidosis tissue, kidney,
liver , spleen
Liver,
Reactive Systemic AA amyloidosis Protein A spleen,kidneys,
(AA) Bone marwow
Familial amyloidosis e.g – Trans Nerves, Hearts,
thyretin Eyes
abnormalities
Localized Amyloidosis -β Amyloid -Alzheimer’s
Central nervous system, Endocrine , Senile protein disease
-Peptic -Endocrine
hormone tumours
-Various -Heart, brain,
prostate etc