Epidemiology, Etiopathogenesis, Pathology, Staging of Plasma Cell Dyscrasias.pptx

Epidemiology, Etiopathogenesis,
Pathology, Staging of Plasma Cell
Dyscrasias

Intoduction
Plasma cell dyscrasias are a spectrum of progressively more severe monoclonal gammopathies in
which a clone or multiple clones of pre-malignant or malignant plasma cells (sometimes in
association with lymphoplasmacytoid cells or B lymphocytes) over-produce and secrete into the
blood stream, a myeloma protein.
Plasma cells are differentiated B-lymphocyte white blood cells capable of secreting immunoglobulin, or
antibody.
These develop from antigen-activated B lymphocytes in secondary lymphoid organs, such as the
spleen and lymph nodes, after encountering the appropriate antigen.

PLASMA CELLS
Each clonal plasma cell line is committed to synthesizing
one specific immunoglobulin antibody that consists of 2
identical heavy chains (gamma [γ], mu [μ], alpha [α], delta
[δ], or epsilon [ε]) and 2 identical light chains (kappa [κ]
or lambda [λ]).
 A slight excess of light chains is normally produced, and
urinary excretion of small amounts of free polyclonal light
chains (≤ 40 mg/24 hours) is normal.

The most immature blood cell of plasma cell lineage is the plasmablast.
Plasmablasts  Proliferate
 Secrete small amounts of antibodies.
Mature plasma cells  Terminally differentiated
 Non-proliferating, larger than B cells
 Secrete large amounts of antibodies
Plasma cells  are important contributors to humoral immunity.

HISTORY
Earliest  Egyptian mummies
1845  Dr. William Macintrye, London
patient presented with c/o fatigue, bone pain and urinary frequency
detected a urinary protein with peculiar heat properties
named “mollities and fragilitas ossium”, published report in 1850
1845  Dr. Bence Jones  examined the urinary proteins and published the report
1846  surgeon Dr. John Dalrymple
◦ examined several bones
◦ gross and microscopic examination consistent with presence of myeloma cells

1873  Rustizky coined the term ‘multiple myeloma’
1889  Kahler published review  popular in Europe as ‘Kahler’s disease’
1899  Ellenger described increased serum proteins and ESR in myeloma
1900  Wright described involvement of plasma cells and also described the X ray
findings which till date are hallmark of the disease

1929  bone marrow aspiration
1937  protein electrophoresis  later report of the γ globulin region spike
1953  Graber confirmed the monoclonality of the cells by detection of monoclonal
proteins via immunoelectrophoresis

.
In the second half of last century much came to be known regarding the pathogenesis of MM; important among them
were the role of the bone marrow microenvironment in myeloma cell growth, survival and antiapoptosis properties of
plasma cells and development of drug resistance through cell–cell interaction and activation of cytokine networks.

 Recent advances which improved understanding of the disease and development of
various treatment modalities:
 Marrow micro-environment
 Development of resistance by cell – cell interactions
 Role of chromosomal translocations
 Gene expression profiling and genome sequencing  molecular pathobiology of disease

The worldwide Age Standardized Rate (ASR) for incidence of MM as per the GLOBOCAN/IARC data
is 1.4/1,00,000 population accounting to 1,00,000 new cases every year.
In the US as per the SEER data, the ASR for incidence is higher at 5.8/1,00,000 population
accounting for 21,000 new cases each year.
The ASR for MM incidence in India is 0.7/1,00,000 population amounting to about 6,800 new
cases a year
*Swerdlow SH, Campo E, Harris NL. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC; 2008:200-213. 4th ed. Lyon, France: IARC; 2008.
GLOBOCAN Country Fast Stat.htm.

Worldwide the 5 year prevalence of the disease is 2,10,697 or 4.3/1,00,000 population.
In India it is 11,602 or 1.4/1,00,000 population.
As per the SEER data the complete prevalence of MM in USA is around 71,000 cases.
The estimated mortality rate from MM worldwide is 72,453 which accounts for 1% of all cancer
related deaths.
In India it accounts for around 5,900 deaths every year.
*seer_cancer_gov.html. 2020.
**P Gupta. A twelve year study of multiple myeloma at the all india institute of medical sciences, new delhi, india. Indian Journal of Medical and Paediatric Oncology. 1995 Jun;16(2):108–14.
Rasool MT, Lone MM, Wani ML, Afroz F, Zaffar S, Mohib-ul Haq M. Cancer in Kashmir, India: burden and pattern of disease. J Cancer Res Ther. 2012 Jun;8(2):243–6.

The USA SEER data shows that the Age Adjusted Death Rate was 3.4/1,00,000 population.
The disease is slightly more prevalent in males with an M:F ratio of 1.2:1(SEER data) and 1.1:1
worldwide.
In India it is 1.3:1. But other single institution studies from India showed a higher M:F ratio of
2.2:1
The disease is more common among the black Americans than the white in USA(14.3 vs.
6.9/1,00,000 new cases every year.

The median age in USA is 74 years as per SEER data, whereas in various single institute data across
India it is 1-2 decades lower at around 52-61 years.
The incidence of MM increases with age. More than 75% cases occurring between the age group of 55-
85 years.
There are only few cases reported below 20 years of age.
The Annual Percentage Change (APC) of Incidence of MM from 2000 to 2009 is an insignificant -0.1%
indicating very minimal change, whereas the APC in mortality over the same period is a very significant
-1.8% indicating better survival from newer modalities of treatment.

ETIOPATHOGENESIS
 Exposure to ionizing radiation  strongest single factor linked to an increased risk of
multiple myeloma.
 People exposed to low levels of radiation also demonstrate an increased incidence of
myeloma, including radiologists, employees in the nuclear industry, or those handling
radioactive materials.

 Potential risk factors  metals, especially nickel; agricultural chemicals; benzene and
petroleum products; other aromatic hydrocarbons; agent orange; and silicon
 Alcohol and tobacco consumption has not been clearly linked to myeloma
 Mineral oil used as a laxative has been reported to be associated with an increased
risk of multiple myeloma in some patients

 Hereditary and genetic factors may predispose patients to myeloma development  direct genetic
linkage has not been established
 Myeloma risk also appears to be enhanced by the presence of HLA-Cw2 in both African American
and Caucasian populations
 A meta-analysis of two genome wide association studies (GWAS) in myeloma  showed that the
t(11;14)(q13;q32) translocation is associated with a constitutive genetic factor.

 MGUS has been considered to be a premalignant condition  rate of conversion to myeloma
remains extremely low  often associated with additional genetic changes.
 Recent study indicates that the diagnosis of symptomatic MM is always preceded by MGUS by 2 or
more years
 Development of MGUS has also been reported with T-cell deficiency disorders as in AIDS
 Repeated infections or antigenic stimulation of the plasma cell compartment  proposed as a
possible predisposing condition for developing myeloma

ETIOPATHOGENESIS
 Transition of normal plasma cells to mgus  malignancy
 Antigenic stimulation
 Unlike normal plasma cells, human myeloma cell lines and primary myeloma cells
express a broad range of toll-like receptors (tlrs).
 Tlrs are normally expressed by b lymphocytes  essential for these cells to recognize
infectious agents and pathogen-associated molecular patterns (pamp)  initiates the host-
defense response.

Aberrant expression of TLRs
cells respond to specific ligands
abnormal and sustained response to infection
TLR specific ligands cause increased myeloma
proliferation, survival and resistance to dexamethasone induced
apoptosis
Autocrine IL-6 also plays imp role in mediating these effects (growth
factor for myeloma cells)

Immunosuppression
By promoting evasion of tumor surveillance or by promoting antigenic stimulation may
also contribute to the initiation of monoclonal gammopathies.
Monoclonal proteins have been reported in the context of immunosuppressive states
such as bone marrow/stem cell transplantation, organ transplantation, and HIV
infection.
Patients undergoing renal transplantation develop M proteins depending on the level of
immunosuppression to which they are subjected.

Cytogenetic abnormalities
 The pathogenesis is associated with frequent rearrangements involving the IgH
locus and various proto-oncogenes
 Loci that are recurrently involved in translocations with the Ig heavy-chain gene
on chromosome 14q32 are the cell cycle-regulatory genes cyclin D1 on chromosome
11q13 and cyclin D3 on chromosome 6p21.
 Deletions of chromosome 17p that involve the TP53 tumor suppressor locus also
occur and are associated with a poor outcome.

 By conventional cytogenetics, the 14q32 region is involved in translocation in 20% to
40% of cases, and by molecular and FISH techniques it is detectable at higher frequency,
ranging from 50% in MGUS to 90% in advanced myeloma.
 Approximately 45% of cases of MGUS are associated with trisomies, usually of the odd
numbered chromosomes with the exception of 13

Late-stage, highly aggressive forms of the disease such as plasma cell leukemia are
associated with acquisition of rearrangements involving MYC.
More recent deep sequencing of myeloma genomes has identified frequent mutations
involving components of the NF-κB pathway, which supports B-cell survival.

PATHOGENESIS OF BONE
LESIONS
The complex pathogenetic mechanisms involve a combination of osteoclast activation
coupled with osteoblast inhibition.
 increase in the receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) expression
by osteoblasts and possibly plasma cells.
 accompanied by decreased stromal cell secretion of the RANKL decoy receptor
osteoprotegerin (OPG)
 the binding of OPG to RANKL is also inhibited by syndecan-1 (CD138) secreted and or
shed by myeloma cells  increase in the RANKL/OPG ratio  increased osteoclast
activation mediated through the NF-KB pathway.

Second factor  release of macrophage inflammatory protein (MIP)- 1α and MIP-1β by
myeloma cells  osteoclast activation
Also increased expression of stromal derived factor1α (SDF-1α) by stromal cells and
myeloma cells  increased osteoclast activity
Osteoblast inhibition in myeloma is believed to be primarily related to increased DKK1
expression by myeloma cells  inhibition of Wnt signaling  preventing stabilization and
promoting degradation of β-catenin  osteoblast activator

Symptomatology
Around one third of patients may have another PCD before the diagnosis of MM, in the form of
MGUS(20%), SMM(9%), and the rest being plasmacytomas and amyloidosis.
• Bone pain, Fatigue and recurrent infections are the most common symptoms of MM.
• Bone pains are present in around 60-90% of patients.
• Anaemia and fatigue was present in about 70% of the patients with the median Hemoglobin (Hb)
of around 10gm%.
• Mild elevation of Serum Creatinine is found in around 50% patients while levels above 2mg/dl
are found in 20% patients.
• Hypercalcemia is found in 25%. Conventional skeletal survey is abnormal in about 80% patients.

Investigations
Investigations in any suspected Monoclonal Gammopathy should include to accurately classify the
disorder:
• Complete Blood Count ( look for anemia)
• Comprehensive Metabolic Panel – Look for renal insufficiency, hypercalcemia and subtle clues like
decreased anion gap .
– Total protein and albumin level.
- Determine Globulin component.
- Too low globulin ( < 2gm%) or Elevated Globulin ( > 3.5gm%) is concerning :
Determine if Polyclonal vs. Monoclonal.
Evaluate further with : » Quantitative Immunoglobulins : Increase in all components usually,
polyclonal.
Increase in single component with reciprocal decrease of uninvolved globulin usually may suggest
monoclonal .

Serum Protein Electrophoresis with immunofixation if monoclonal gammopathy is suspected.
» 24Hr-Urine protein electrophoresis with urine immunofixation ( Serum Free Light Chain assay (κ/λ
ratio) may be used in place of UPEP}
» Bone marrow biopsy to evaluate % plasma cells if there is monoclonal protein or abnormal UPEP or
Light chain assay or if strong clinical picture of myeloma.
» Skeletal survey if monoclonal gammopathy has been established ( Bone scans are usually, negative
in MM)
» Beta-2 microglobulin and Albumin for staging and prognosis in MM ( once diagnosis is made).

IHC of PLASMA CELLS
• All plasma cells, whether normal or malignant, are distinguished by their expression of CD38 and
CD138, also CD79a.
• CD38
 Catalyzes synthesis and hydrolysis of cyclic ADP-ribose, resulting in the maintenance of intracellular
calcium levels.
• CD138/ syndecan-1
 Allows for the plasma cell to attach to extracellular matrix proteins.
 Recent research has found it plays a further role in acting as a co-receptor for epithelial growth factor
(EGF), particularly in the context of multiple myeloma.

A distinguishing characteristic unique to malignant plasma cells is the loss of CD19
expression alongside the possible aberrant expression of CD56, a marker characteristic of
natural killer (NK) cells.
CD79a  plays a critical role in B-lymphocyte antigen signal transduction and overall B-
lymphocyte development and stabilization.
Though CD79a is present in the cytoplasm of both precursor B-lymphocytes and mature,
differentiated plasma cells, its aberrant loss of expression has been noted in certain samples
of plasma cell neoplasms.

Plasma cell neoplasms represent a spectrum of diseases characterized by clonal proliferation and the
accumulation of immunoglobulin-producing terminally differentiated B cells.
It considered to originate from a single B cell  resultnt monoclonal protein secretion that characterizes
its type.
The plasma cells sectrete 5 major Ig  IgA, IgG, IgM, IgD and IgE
Dysfunctional plasma cells secrete one of these intact Ig molecules  there may be discrepancy in
heavy chain and light chain production  imbalance with excess κ or λ light chains  which are
excreted in urine  bence jones proteins or only production of excess κ or λ light chains
There can also be production of no paraproteins  non – secretory myeloma

Type of Monoclonal Paraproteins and Percentage
IgG 52%
IgA 21%
IgD 2%
IgE <0.01 L chains ( K or L) only 11%
H chain (G or A) only <12%
No monoclonal paraprotein 1%
IgM 12%

Serum Protein Electrophoresis
• Serum is placed on special paper treated with
agarose gel and exposed to an electric current.
- This separates the serum protein components into
five classifications by size and electrical charge :
serum albumin, alpha-1 globulins, alpha-2 globulins,
beta globulins, and gamma globulins.
• Immunoglobulins ( IgG, IgM, IgA) usually migrate to
gamma region but may sometimes extend to beta
region.
• SPEP should always be performed in combination
with serum immunofixation in order to determine
clonality

•SPEP showing Monoclonal Gammopathy
• Shows a tall “narrow” band in gamma region –
“M-Spike”
• Also, note reduction in the normal polyclonal
gamma band

SPEP showing Polyclonal Gammopathy
• Shows a broadbased peak in gamma
region .
• Seen in chronic infections,
inflammation, connective tissue
disease, lymphoproliferative disease.

Immunofixation
• More sensitive than SPEP
• Immunofixation is performed when SPEP shows a
sharp “peak” or a plasma cell disorder is suspected
despite a normal SPEP
• Immunofixation always done to confirm the presence of
M-Protein and to determine the type (IgM or IgG etc and
the light chain restriction : k or λ)
• Why do both SPEP and IF ? Why not just IF in initial
diagnosis ?
• Unlike SPEP, immunofixation does not give an estimate
of the size of the M protein (ie, its serum concentration),
and thus should be done in conjunction with
electrophoresis.

Evaluation of bone marrow (BM) plasma cell infiltration by BM aspiration and/or biopsy.
- BM for cytogenetic/fluorescence in situ hybridization (FISH) studies
- Evaluation of lytic bone lesions: a radiological skeletal bone survey, including spine, pelvis, skull, humeri and femurs.
- MRI or computed tomography (CT) scan may be needed to evaluate symptomatic bony sites, even if the skeletal
survey is negative and the patient has symptoms suggesting bone lesions.
- MRI provides greater detail and is recommended whenever spinal cord compression is suspected.
- FDG PET scan is currently under evaluation and should be used fro evaluation of all patients

Classification of Plasma Cell Dyscrasias (W.H.O)
- Monoclonal Gammopathy of Undetermined Significance (MGUS) ( 62%)
– Malignant Monoclonal Gammopathies
• Multiple Myeloma (18%)
◦ • Variants : Smoldering Myeloma (3%) , Non Secretory Multiple Myeloma, Indolent Myeloma, Light Chain Myeloma
• Plasmacytoma (2.5%) : Solitary Plasmacytoma of the bone, Extramedullary/ Extraosseous Plasmacytoma
• Plasma cell leukemia
• IgD myeloma
• POEMS syndrome (Osteosclerotic Myeloma)
• Waldenstrom’s Macroglobulinemia (Lymphoplasmacytic Lymphoma )
– Malignant Lymphoproliferative disorders
– Heavy Chain disease ( Gamma HCD, Mu HCD, Alpha HCD)
– Immunoglobulin Deposition diseases : Primary Amyloidosis, Systemic light chain and Heavy chain deposition
diseases

MGUS (Monoclonal gammopathy of unknown significance)
In almost all cases multiple myeloma is preceded by a premalignant asymptomatic stage termed as monoclonal
gammopathy of undetermined significance.
In population over the age of 50 year MGUS is present in 3-4% cases.
MGUS can progress to multiple myeloma at the rate of 1% per year.
Diagnosis of MGUS requires the absence of hypercalcaemia, renal failure, anaemia, and bone lesions (referred to
(referred to as CRAB features) that can be attributed to the underlying plasma cell disorder

Diagnostic criteria for MGUS
All three criteria must be met:
• _ Serum monoclonal protein <3 gm/dL
• _ Clonal bone marrow plasma cells <10%,
• _ Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone
lesions (CRAB) that can be attributed to the plasma cell proliferative disorder; or in the case of IgM
MGUS no evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or
hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.
Considering this high risk of plasma cell disorder, persons found to have MGUS should be
monitored stringently lifelong.

Various studies from Asian countries have documented a similar percentage (varying from 2.3-
6.3%) of MGUS among the general population but are yet to publish their results regarding
progression to Plasma cell dyscrasias (PCD).
Data from India regarding MGUS is not available.
There was an increased incidenceof MGUS among people exposed to radiation after the Nagasaki
atom bomb explosion especially those living within 1.5 km of the epicentre.
But this study did not reveal an increased rate of progression to PCD

IgM MGUS
All three criteria must be met:
◦ Serum IgM M protein < 3 g/dL
◦ Bone marrow lymphoplasmacytic infiltration < 10%
◦ No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or
hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder

Multiple Myeloma
Bone marrow plasma cells ≥10% or bony or biopsy proven extramedullary plasmacytoma and
any one or more of myeloma defining evens including:
• Myeloma defining events: •
• Clonal bone marrow plasma cells ≥ 60%
• Free light chain ratio ≥ 100
•>1 focal lesions on MRI

•Evidence of end organ damage due to underlying plasma cell proliferative disorder (CRAB)
• Hypercalcemia: Calcium>1 mg/dl higher than upper limit or >11 mg/dl
• Renal insufficiency:
•Serum creatinine increased in > 50% at diagnosis Creatinine >2g/dL in 20% of patients
•Renal failure may be presenting manifestation
•Major Causes : –
•Myeloma cast nephropathy
•Hypercalcemia
•Amyloidosis

•Anemia :
•hb < 10gm%, Normochromic /normocytic anemia occurs in 75% patients
• Bone lesion:
•one or more osteolytic lesions skeletal radiography, CT or PET-CT •

Bone Lesions :
Conventional radiographs (Skeletal Survey) abnormal in 80% of patients who present with
multiple myeloma.
Focal lytic lesions – 57%
Osteopenia, osteoporosis – 20%
Pathologic fractures – 20%
Vetebral body comression fractures – 20%

Round lesions filled with a soft
reddish material are indicative of
foci of myeloma in this section of
vertebral bone.

Skull showing characteristic,
rounded, punched out lesions

PLASMABLAST
• Diffuse chromatin pattern
• Nucleus >10 μm
• Nucleolus greater than 2 μm
• Concentrically placed nucleus with little or
no hof

Plasma Cell:
• Plasma Cell Plasma cells
• Terminally differentiated B- cells
• Not normally found in peripheral blood .
• Account for less than 3.5% of nucleated cells in
the bone marrow
• Oval cells with low N:C ratio.
Cytoplasm is basophilic blue.
Nucleus (30-40% of the cell) is oval or round and
typically placed eccentrically (to one side) of the
cell. .

Russell bodies :
Globules (2-3 μm) of accumulated immunoglobulins
in the cytoplasm of plasma cells
• Usually round
• May be found in normal bone marrow
• 1st described by William Russell

Flame Cell
Eosinophilic torn cytoplasm
Usually associated with IgA myeloma

Pathologic rouleaux
formation seen in Multiple
myeloma

BONE MARROW
 At low power, the abnormal
plasma cells of multiple myeloma
fill the marrow.
BONE MARROW
 At high power, the plasma cells
of multiple myeloma here are very
similar to normal plasma cells, but
they may also be poorly
differentiated.

PATTERNS OF BONE MARROW INVOLVEMENT IN MYELOMA
• Interstitial
• Focal
• Mixed
• Diffuse

MM & Skeletal Complications
~ 80% of patients with multiple
myeloma will have evidence of skeletal
involvement on skeletal survey
– Vertebrae: 65%
– Ribs: 45%
– Skull: 40%
– Shoulders: 40%
– Pelvis: 30%
– Long bones: 25%
* Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu
Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM. Long-term follow-up on overall survival
from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in
patients with relapsed or refractory multiple myeloma. Leukemia. 2009 Nov;23(11):2147-52.
doi: 10.1038/leu.2009.147. Epub 2009 Jul 23. PMID: 19626046.

Smoldering multiple myeloma (asymptomatic)
This is an intermediate during the transition from MGUS to frank symptomatic MM.
The monoclonal plasmacytosis and gammopathy has increased to MM levels but the end
organ damage that defines MM has not yet occurred.
The accepted diagnostic criteria for SMM is:
• Serum monoclonal protein (IgG or IgA) ≥ 3gm/dl or 24 hr urinary monoclonal protein ≥500
mg and/ or bone marrow plasma cells 10-60%
• Absence of myeloma defining event or amyloidosis

Solitary Plasmacytoma
This occurs around a decade younger than MM and is more common in males.
The sites commonly affected are the axial skeleton more than the appendicular skeleton.
It should be accompanied with a normal skeletal radiograph.
SPEP is ideally negative but in around 50% patients a low level of M protein might be present.
BM should not show increased plasma cells.
Care should be taken not to do a BM biopsy from an iliac crest or sternum if they are the
involved area for the plasmacytoma.
MRI might show 9 Consensus Document for Management of Multiple Myeloma other
asymptomatic lesions, but still it needs to be taken as a solitary plasmacytoma if X-ray doesn’t
show any other lesions.

Rate of progression to multiple myeloma is 10% in 3 years.
Solitary plasmacytoma is diagnosed by:
• Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
• Normal bone marrow with no evidence of clonal plasma cells
• Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
• Absence of end-organ damage such as hypercalcaemia, renal insuffi ciency, anaemia, or bone
lesions (CRAB) that can be attributed to a lymphoplasma cell proliferative disorder

Extramedullary Plasmacytoma
The common sites of involvement are the nasal cavity, nasopharynx, larynx and sinuses.
It can happen in any location in the body and is commonly of the IgA subtype.
Other evidence of systemic MM should not be present.
The diagnostic criteria is:
• No M-protein in serum and/or urine
• Extramedullary tumour of clonal plasma cells
• Normal bone marrow
• Normal skeletal survey
• No related organ or tissue impairment (end organ damage including bone lesions)

Multiple Solitary Plasmacytomas:
This entity constitutes less than 5% of all PCDs.
The diagnostic criteria for this entity are as follows:
• No M-protein in serum and/or urine
• More than one localized area of bone destruction or extramedullary tumour of clonal plasma
cells which may be recurrent
• Normal bone marrow
• Normal skeletal survey and MRI of spine and pelvis if done
• No related organ or tissue impairment (no end organ damage other than the localized bone
lesions)
* Small elevation of M protein may be seen

Waldenström macroglobulinemia
All criteria must be met:
◦ IgM monoclonal gammopathy (regardless of the size of the M protein)
◦ ≥ 10% bone marrow lymphoplasmacytic infiltration (usually intertrabecular) by small lymphocytes
that exhibit plasmacytoid or plasma cell differentiation and a typical immunophenotype (e.g.,
surface IgM+, CD5±, CD10−, CD19+, CD20+, CD23−) that satisfactorily excludes other
lymphoproliferative disorders, including CLL and mantle cell lymphoma
◦ Evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or
hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorde

Smoldering Waldenström macroglobulinemia (also referred to as indolent or asymptomatic
Waldenström macroglobulinemia)
Both criteria must be met:
◦ Serum IgM M protein ≥ 3 g/dL and/or bone marrow lymphoplasmacytic infiltration ≥ 10%
◦ No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or
hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorde

Light Chain MGUS
All criteria must be met:
◦ Abnormal free light chain (FLC) ratio ( 1.65)
◦ Increased level of the appropriate involved light chain (increased κ FLC in patients with ratio >
1.65 and increased λ FLC in patients with ratio < 0.26)
◦ No immunoglobulin heavy-chain expression on immunofixation
◦ Absence of end organ damage such as hypercalcemia, renal insufficiency, anemia, and bone
lesions (CRAB) that can be attributed to the plasma cell proliferative disorder

Systemic AL Amyloidosis
All four criteria must be met:
◦ Presence of an amyloid-related systemic syndrome (e.g., renal, liver, heart, gastrointestinal
tract, or peripheral nerve involvement)
◦ Positive amyloid staining by Congo red in any tissue (e.g., fat aspirate, bone marrow, or organ
biopsy)
◦ Evidence that amyloid is light-chain related established by direct examination of the amyloid
(possibly using mass spectrometry (MS)–based proteomic analysis, or immunoelectron
microscopy
◦ Evidence of a monoclonal plasma cell proliferative disorder (serum or urine M protein,
abnormal free light chain ratio, or clonal plasma cells in the bone marrow)
◦ Note: 2 to 3% of patients with AL amyloidosis will not meet the requirement for evidence of a
monoclonal plasma cell disorder listed above; the diagnosis of AL amyloidosis must be made
with caution in these patients.

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein,
skin changes)
All four criteria must be met
◦ Polyneuropathy
◦ Monoclonal plasma cell proliferative disorder (almost always λ)
◦ Any one of the following three other major criteria:
1. Sclerotic bone lesions
2. Castleman disease
3. Elevated levels of vascular endothelial growth factor (VEGF)
• Any one of the following six minor criteria:
1. Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)
2. Extravascular volume overload (edema, pleural effusion, or ascites)
3. Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic)
4. Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing,
white nails)
5. Papilledema
6. Thrombocytosis/polycythemia

The DSS provides a good estimate of tumor burden but has some limitations, especially in
the categorization of bone lesions.
Greipp and colleagues subsequently developed an International Staging System (ISS) 
overcomes the limitations of the DSS and divides patients into three distinct stages and
prognostic groups based solely on the β2-microglobulin and albumin levels in the serum.
The ISS cannot be considered a true staging system, because it is influenced by overall
health and comorbidities, tumor burden, as well as renal function.

PROGNOSTIC FACTORS
Major Independent Prognostic Factors
◦ Performance status
◦ Stage (International Staging System)
◦ Cytogenetic changes
◦ Abnormal cytogenetics by karyotyping (especially deletion 13 or hypodiploidy)
◦ Translocations t(4;14) or t(14;16) or t(14;20) on fluorescent in-situ hybridization
◦ Deletion 17p on fluorescent in-situ hybridization
◦ Serum lactate dehydrogenase
◦ Plasmablastic morphology
◦ Increased plasma cell proliferative rate
◦ Plasma cell leukemia
◦ Other Prognostic
Markers
◦ Advanced age
◦ Stage (Durie-Salmon
stage)
◦ C-reactive protein
◦ Serum creatinine
◦ Platelet count
◦ Increased circulating
plasma cells by flow
cytometry

Epidemiology, Etiopathogenesis, Pathology, Staging of Plasma Cell Dyscrasias.pptx

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