dr a. mousavi. 15 % of all malignant white cell diseases 1% of all cancer deaths group of...
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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