PLASMA CELL DYSCRASIA

Dr A. Mousavi

PLASMA CELL DYSCRASIA

15 % of all malignant white cell diseases 1% of all cancer deaths

Group of lymphoid neoplasms of terminally

differentiated B-cells that have in common the

expansion of a single clone of

immunoglobulin(Ig)-secreting plasma cells and a

resultant increase in serum levels of a single

homogeneous(monoclonal) Ig or it’s fragments.

PLASMA CELL DYSCRASIA

Caused by malignant changes to plasma

cells or the B lymphocyte cell line.

Exhibit either:

Excessive amounts of normal

immunoglobulin proteins (Igs)

Accumulation of Igs in an abnormal

location

Structurally abnormal Igs

PLASMA CELL 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. A clear, colorless area adjacent to the nucleus

contains Golgi apparatus Russell bodies: Globules(2-3μm) of accumulated

immunoglobulins in the cytoplasm of plasma cells. Usually round.

Russell bodies may be found in normal bone marrow.

NORMAL PLASMA CELL

PLASMA CELL HOW WORKS

Develop from stem cells in bone marrow

Stem cells develop into B cells (B

lymphocytes)

Antigens enter body then B cells develop

into plasma cells

Produce antibodies

NORMAL PLASMA CELL

REVIEW OF THE BASIC STRUCTURE OF IMMUNOGLOBULINS

Which of these are the heavy chains?

Name the 5 classes of heavy chain.Gamma, mu, alpha,

delta and epsilon Which of these are the

light chains? Name the 2 classes of

light chain.Kappa and lambda

NH3+

COO-

REVIEW OF THE BASIC STRUCTURE OF

IMMUNOGLOBULINS

Where is the constant region of the molecule?

Where is the variable region?

Which region defines the specificity of the antibody? Variable

Which region is responsible for the physical properties of the antibody, such as ability to activate complement and binding to macrophages? Constant

NH3+

COO-

IMMUNOGLOBULINS

PATHOPHYSIOLOGY

Normally, plasma cells produce immunoglobulins

to fight infection 

However, in MM and MGUS a single cloned

plasma cell proliferate and overproduce the

same Ig ("M-protein" or “Paraprotein")

The M-protein is usually an IgG

MM cells can also just produce the light chain

component (Instead of the entire Ig)

PATHOPHYSIOLOGY

• Consequence of producing lots of

monoclonal Ig: 

o Hyperviscosity

o Kidney Damage (from light chains

only)

o Bone pain, hypercalcemia and

pathologic fractures from bone

lesions.

o Anemia/Pancytopenia from bone

marrow invasion

MONOCLONAL GAMMOPATHYEXCESS OF ANTIBODIES

Y

B Cell

Normal

Plasma Cell

Malignant Plasma Cell

YY Y

Y

Y

Y YY

Y

Y

Y

Y

Y

YY

Y

YYY

Y

Y

Y

Y

Y Y

MONOCLONAL GAMMOPATHY

Accumulation of a single protein that arises from

proliferation of a single plasma cell clone.

Since each B cell can respond to only one antigenic epitope,

a plasma cell derived from that B cell produces antibody that

is reactive against that unique epitope (monoclonal

antibody).

Malignant changes to that plasma cell result in uncontrolled

production of its specific antibody.

The specificity of the monoclonal antibody (M protein) varies

between patients, but each affected patient has only one M

protein specificity.

WHAT CAUSES MYELOMA CELLS TO GROW?

Adhesion molecules

Stromal cells

Interactions:

Cytokines (IL-6)

Growth factors that promote

angiogenesis (IGF-1, VEGF, SDF-1α)

Inactivated immune system

PLASMA CELL DYSCRASIA SYNONYMS

Gammopathy

Monoclonal gammopathy

Dysproteinemia

Paraproteinemia

CLASSIFICATION OF PLASMA CELL DYSCRASIA

MGUS (62%) Malignant Monoclonal gammopathies:

MM (18%) variants: smoldering myeloma (3%), non-secretory MM,

light chain myeloma

Plasmacytoma

Plasma cell leukemia

IgD myeloma

POEMS syndromes (Osteosclerotic myeloma)

Waldenstrom’s Macroglobulinemia

(Lymphoplasmacytic lymphoma)

CLASSIFICATION OF PLASMA CELL DYSCRASIA

Malignant lymphoproliferative disorders

Heavy chain diseases (Gamma HCD, Mu HCD,

Alpha HCD)

Immunoglobulin deposition diseases (Primary

Amyloidosis, Systemic light chain and heavy

chain deposition diseases)

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

INVESTIGATIONS

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.

INVESTIGATIONS Serum Protein Electrophoresis with

immunofixation if monoclonal

gammopathy is suspected.

24HR-Urine protein electrophoresis with

urine immunofixation (Serum Free Light

Chain assay(κ/λratio) may be used in

place of UPEP}

INVESTIGATIONS 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).

NORMAL SERUM PROTEIN ELECTROPHORESIS

MONOCLONAL SERUM PROTEIN

ELECTROPHORESIS

MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS)

Denotes presence of an M-protein in a patient without a plasma cell or lymphoproliferative disorder (i.e; Undetermined Significance)

M- protein < 3 gr/dl < 10% plasma cell in bone marrow No or small amounts of M- protein in urine Absence of lytic bone lesions, anemia,

hypercalcemia, renal insufficiency No evidence of B- cell lymphoproliferative disorder Stability of M- protein over time

MGUS

Incidence increases with age Significance: can progress to

monoclonal disease

IgA or IgG MGUS IgM MGUS

MMPrimary

AmyloidosisRelated Plasma

cell disorder

NHLCLL

Waldenstroms’Macroglobuline

mia

MULTIPLE MYELOMA & VARIANTS

Smoldering Myeloma:

Serum monoclonal protein ≥ 3

g/dl and/or bone marrow

plasma cells ≥ 10%

No end organ damage related

to plasma cell dyscrasia

MM: PLASMA CELLS IN BMA-B

MULTIPLE MYELOMA IN BMA-B

NON-SECRETORY MYELOMA

Rare variant: About 1% of Myelomas May present with Bone lesions (most common

presenting symptom bone pain) No serum or urine monoclonal protein(diagnosis

can be missed if one is not aware of this entity, NSMM).

Renal failure and hypercalcemia are generally lacking

Anemia may be present Bone marrow biopsy must be performed in

suspected cases: Immunostaining for a monoclonal protein on bone marrow sections may establish the diagnosis

Clonal plasma cell population in marrow. Must rule out IgD and IgE myeloma

SOLITARY PLASMACYTOMA

Localized plasma cell tumor Absence of a plasma cell infiltrate in

random marrow biopsies No evidence of other bone lesions by

radiographic examination Absence of renal failure, hypercalcemia

or anemia Younger median age at presentation

(55 y) Treatment: Radiation to site (5000 cGy) 50-60% will convert MM within 10 years Possible bone marrow collection/

storage

EXTRAMEDULLARY PLASMACYTOMA

Arise outside the bone marrow with no features of MM

Most common: Head and Neck region Less common: Lymph nodes, Salivary

glands, spleen, liver,… 25% have small monoclonal spike Rare dissemination, rare revolution to

myeloma Management: If completely resected during biopsy,no

further therapy If incompletely resected,radiation therapy

locally

MULTIPLE MYELOMA Three criteria:1.Presence of a serum or urinary monoclonal

protein2.Presence of 10 percent or more clonal plasma

cells in the bone marrow or a plasmacytoma3.Presence of end organ damage felt related to

the plasma cell dyscrasia, such as:M- CRAB: Monoclonal proteinHyperCalcemia (calcium >11.5 gm/dl) Renal Insufficiency Anemia (Hb < 10gm/dl) Lytic Bone lesions

MULTIPLE MYELOMA

Bone lesions:

Conventional Radiographs (Skeletal

Survey) is abnormal in 80% of MM

Focal lytic bone: 57%

Osteopenia or Osteoporosis: 20%

Pathologic fractures: 20%

Vertebral body compression fractures:

20%

MULTIPLE MYELOMA

Anemia:

Normochrome nomocyter in 75% of MM

Hb < 10 mg/dl

Renal insufficiency:

Serum creatinine increased in >50% at

diagnosis

Creatinine >2g/dL in 20% of patients

Renal failure may be presenting manifestation

MULTIPLE MYELOMA

Cytogenetic: 14 q 32 1 q 5, 8, 12,….

Deletion 17 p and Abnormalities

associated with chromosome13 carry a

particularly unfavorable prognosis and

respond poorly to therapy

MULTIPLE MYELOMA

Staging:International staging system: Stage I— B2M <3.5mg/L and serum

albumin ≥ 3.5g/dL Stage II— neither stage I nor stage III Stage III— B2M ≥ 5.5mg/L

Median overall survival

dicreases with increasing stages

MULTIPLE MYELOMA TREATMENT

Indications: presence of any of CRAB, High risk patients

Current frontline options: Conventional chemotherapy

Survival ≤ 3 yrs Stem Cell Transplantation

Prolongs survival 4- 5 yrs Novel agents targeting stromal interactions

and associated signaling pathways (Thalidomide, Lenalidomide, Bortezomib,…)have shown promise and improved survival

POEMS (OSTEOSCLEROTIC MYELOMA)

Polyneuropathy (Motor, 100%)

Organomegaly (Hepatosplenomegaly, 50%)

Endocrinopathy (Hypogonadism, Hypothyroidism, 66%)

Monoclonal gammopathy

Skin changes (Hyperpigmentation, Hypertrichosis)

Sclerotic bone lesions (related to cytokines, VEGF, 97%)

POEMS (DIAGNOSIS AND TREATMENT)

Diagnostic criteria: Two major+ at least one minor Major: Polyneuropathy, Monoclonal

plasma cell disorder Minor: Sclerotic bone lesions,

Organomegaly, castleman’s dis, Volume overload, Endocrinopathy, Skin changes, Papilledema

Treatment: Radiation to bone lesion

PLASMA CELL LEUKEMIA

>2 X 109/L plasma cells in blood(seen on peripheral smear)

Younger age Higher incidence of organomegaly

and lymphadenopathy More extensive bone marrow

infiltration Renal failure more common Less bone pain, fewer lytic lesions Poor response to therapy

PLASMA CELL LEUKEMIAPERIPHERAL SMEAR

WALDENSTROM’S MACROGLOBULINEMIA

Monoclonal gammopathy: IgM type Plasmacytoid lymphoma Median age at diagnosis: 60 yrs Presentation:

Hyperviscosity syndrome(15%): visual impairment, neurologic manifestations

Bleeding(Acquired VWD)CryoglobulinaemiaOrganomegaly, lymphadenopathy (20%- 40%)Autoimmune hemolysis: commonBone marrow involvement: 90%Lytic bone lesions: 2%Hypercalcemia: 4%

WALDENSTROM’S MACROGLOBULINEMIA- IGM

WALDENSTROM’S MACROGLOBULINEMIA MANAGEMENT

Asymptomatic patients not treated until

symptoms develop

If Hyperviscocity features: urgent

Plasmapheresis

Symptomatic WM: Rituximab based

therapy

AMYLOIDOSIS

Amyloidosis caused by extracellular deposition

of pathologic insoluble fibrillar proteins in organs

and tissues

M-protein: 89%, Lambda: 70%

M-protein > 3 mg/dl: 7%

Hypogammaglobulinemia: 20%

Median bone marrow plasma cells: 7%

(<10%)

Organ involvments: cardiac arrythmia, renal

failure, skin changes, macroglossia

AMYLOIDOSIS

Evaluate for amyloidosis in patients with a

monoclonal protein in serum or with a

monoclonal protein in serum or urine plus:

Nephrotic syndrome or renal insufficiency

Congestive heart failure

Peripheral neuropathy

Carpal tunnel syndrome

Hepatomegaly

Idiopathic malabsorption

AMYLOIDOSIS DIAGNOSIS

Diagnostic Criteria:

Tissue biopsy showing typical morphology

Apple green birefringence under polarized light

after Congo Red staining

Term amyloid first coined by Virchow in mid 19th

century (meaning starch or cellulose).

Typical fibrillar ultrastructure

Diagnostic methods and Sensitivity:

Bone marrow examination: 56%

Abdominal fat aspiration: 80%

Combined BM and fat aspirate: 89%

AMYLOIDOSIS KIDNEY- CONGO RED

SKIN-GREEN BIREFRINGENCEPOLARIZED MICROSCOPY

HEAVY CHAIN DISEASE

Heavy chain of Ig

Alpha type:

Younger patients

Mediterranean lymphoma (Intestinal

lymphoplasmacytoid Lymphoma)

Remission with antibiotics

HEAVY CHAIN DISEASE

Gamma Heavy Chain Disease – seen in elderly Symptoms –enlarged liver and spleen,

recurrent infections, and anemia Some patients experience no symptoms Treatment with anti-lymphoma drugs and

corticosteroids Mu Heavy Chain Disease – rare

Symptoms include enlarged spleen, liver and abdominal lymph nodes

Survival and response to treatment varies

HEAVY CHAIN DISEASE-IGA TYPE

Thank you for your attention