PLASMA CELL DYSCRASIAS PLASMA CELL DYSCRASIAS &

RELATED DISORDERSRELATED DISORDERS

Dr.CSBR.Prasad, M.D.

This patient came with

shoulder pain of 1month duration

This patient complained of generalized bone pain and weakness

This patient complained of

loss of HEIGHT and

bone pain

What is the main function of plasma cells?

• A group of disorders • Common feature:

– Clonal proliferation of Ig producing cells • Plasma cells / lymphocytes

• They produce single class of Ig – Monoclonal spike (M-protein) on electrophoresis

The plasma cell dyscraias

ClassificationThe most commonly recognized types are: 1-Multiple myeloma2-Monoclonal gammopathy of undetermined

significance (MGUS) 3-Waldenström macroglobulinemia

(lymphoplasmacytoid lymphoma)4-Heavy chain disease and 5-Primary amyloidosis

Multiple myelomaMultiple myeloma

Multiple myeloma• Definition. A neoplastic clonal proliferation of plasma

cells characterized by the production of a monoclonal immunoglobulin. The bone marrow is the site of origin of nearly all myelomas and in most cases there is disseminated marrow involvement. Other organs may be secondarily involved.

• Due to neoplastic proliferation of plasma cells• Immunosecretory disorder• Involves BM in multiple sites• Only neoplasm of terminally differentiated cells-plasma

cells• Secretes homogeneous product M-component

Multiple myeloma

• Multifocal involvement of the skeleton– axial skeleton– vertebral column, ribs, skull, pelvis,

femur, clavicle, and scapula• Disease of the elderly (65 to 70 years)

Never diagnose Myeloma below the age of 40yrs

• 1% of all cancers & 10% of hematological malignancies

• M:F = 3:2• usually >70yrs. Rare <35yrs, not seen in children• Presenting symptom is bone pain• Loss of height due to vertebral collapse• Generalized BM involvement (sites:

hemopoietically active areas)• Infections, renal failure, hypercalcemia• Anemia (replacement of marrow, <EPO production)

Multiple myeloma

Diagnostic criteriaThe diagnosis of myeloma requires • one major and one minor or• Three minor criteria which must include 1&2

Major criteria:1. Marrow plasmacytosis >30%2. Plasmacytoma on biopsy3. M-component (IgG >3.5, IgA>2)Minor criteria:1. Marrow plasmacytosis <10%2. M-component is present but, less than above3. Lytic bone lesions4. hypogammaglobulinemia

Clinical varients

• Non-secretory myeloma• Smouldering myeloma (like MGUS, M-component

as in MM, BM plasma cells 10-30%)

• Indolent myeloma (same as MM but, M-component <7, bone lesions<3, normal HGB, Ca, creatinine)

• Plasma cell leukemiaMGUS:

– M-component <MM– BM plasma cells <10%– No bone lesions– Asymtomatic

Plasma cell leukemia

• Involvement of PB occurs in 2% of MM• Def: circulating plasma cells >20% or PB plasma cells >2000/cumm• Likely to be light chain only disease• Osteolytic lesions are less frequent• Renal failure is more frequent• Clinically aggressive

Etiology

• 3-4x more common in cosmetologists, farmers & laxative users

• Pesticides, petroleum products, rubber, plastics and wood products

• Radiation (atomic bombs, radiologists, nuclear plant workers)

• Chronic infections (ostemyelitis, RA)• HHV8, EBV

Molecular Pathogenesis• Ig genes in myeloma cells always show evidence of

somatic hypermutation• the cell of origin is considered to be a post-germinal

center B cell that homes to the bone marrow and has differentiated into a plasma cell

• tumor originates in and is maintained by stem-like cells resembling small B lymphocytes that rely on signals generated by the “hedgehog” pathway for self-renewal

• The proliferation and survival of myeloma cells are dependent on several cytokines, most notably IL-6

Molecular Pathogenesis• rearrangements involving the Ig heavy-chain gene on

chromosome 14q32• Common translocation partners include FGFR3

(fibroblast growth factor receptor 3) on chromosome 4p16• cell cycle–regulatory genes cyclin D1 on chromosome

11q13 and • cyclin D3 on chromosome 6p21• The gene for the transcription factor c-MAF on

chromosome 16q23; and • The gene encoding the transcription factor MUM1/IRF4

on chromosome 6p25

Why bone destruction and hypercalcemia in MM?

• MIP1α• modulators of the Wnt pathway

• The net effect is a marked increase in bone resorption, which leads to hypercalcemia and pathologic fractures

Gross

• Osteolytic lesions on gross, filled with soft gelatinous material, fish-flesh appearance or hemorrhagic tissue.

Micro

• Plasma cells in BM >30%• Plasma cells occur in clusters and sheets• Myeloma cells vary from mature to immature

forms and may be frankly anaplastic• Clock face/spoke wheel chromatin• Perinuclear HOF• Mott cells, Russel bodies, Dutcher bodies,

flame cells, cytoplasmic crystals.

Immunophenotyping

• Cytoplasmic Ig• No sIg• Malignat plasma cells : CD19/20 neg CD56/58 pos• Normal plasma cells: CD19/20 pos CD56/58 neg

Plasmacytoma

• Localized myeloma• Can be osseous or extraosseous• In bone osteolysis

– (vanishing bone disease)• 5% of all plasma cell neoplasms• BM in active hemopoietic sites• Bone pain / #• No M-component

Bence-Jones proteins

• Light chains of Ig• Seen in MM, WSMG, lymphoma• >6gm in serum• BJ appear in urine• Diagnosis: heat coagulation test (40-60°-

appear; on boiling 100°-disappears; reappear on cooling)

immunofixation test• Damages the kidney

The "punched out" circular lytic lesions in the skull seen here are the result of multiple myeloma in a woman. The rounded lesions with central lucency are more subtle. These lesions consist of a neoplastic proliferation of plasma cells.

Multiple myeloma of the skull (lateral view). The sharply punched-out bone lesions (usually 1 to 4 cm in dia) are most obvious in the calvarium

The skull demonstrates the characteristic rounded "punched out" lesions of multiple myeloma. The plasma cell proliferation results in bone lysis to produce these lytic lesions. Such lesions can produce bone pain.

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

Here is a smear of bone marrow aspirate from a patient with multiple myeloma. Note that there are numerous well-differentiated plasma cells with eccentric nuclei and a perinuclear halo of clearer cytoplasm. There is also an abnormal plasma cell with a double nucleus.

MULTIPLE MYELOMA CASE-1 BM

MULTIPLE MYELOMA CASE-2 BM

MULTIPLE MYELOMA CASE-3

MULTIPLE MYELOMA CASE-12

PLASMA CELL LEUKEMIAA blood smear from a 59-year-old man with plasma cell leukemia. The total blood leukocyte count was slightly elevated. There were 50 percent plasma cells. Themonoclonal protein in this case was IgG kappa. (Wright-Giemsa stain)

INTRANUCLEAR INCLUSIONSBone marrow smear from a patient with IgA myeloma. Large nuclear inclusions (Dutcher bodies) are present in two of the plasma cells.

Two of the cells contain large cytoplasmic crystals. (Wright-Giemsa stain)

In this bone marrow biopsy section at medium power, there are sheets of plasma cells of multiple myeloma that are very similar to normal plasma cells, but the cells may also be poorly differentiated.

A plasma cell has prominent cytoplasmic smooth endoplasmic reticulum, an eccentrically placed nucleus with prominent radially arranged chromatin, and a prominent perinuclear Golgi apparatus (not seen in this plane of sectioning).

Normal serum electrophoresis

Multiple myeloma (BM). Normal marrow cells are largely replaced by plasma cells, including forms with multiple nuclei, prominent

nucleoli, and cytoplasmic droplets containing Ig.

Clinical features

Due to:

• The effects of plasma cell growth in tissues• The production of excessive Igs and • The suppression of normal HI

Bone pain & Fractures

Hypercalcemia

LethargyWeakness

ConstipationconfusionPolyuria

Clinical features

Due to:

• The effects of plasma cell growth in tissues• The production of excessive Igs and • The suppression of normal HI

Hyperviscosity

Clinical features

Due to:

• The effects of plasma cell growth in tissues• The production of excessive Igs and • The suppression of normal HI

Infections

Kidney

• BJ proteins accumulate • Resorption of BJ proteins by renal

tubules with resultant damage to tubular cells > kidney damage

• Known as myeloma kidney• Micro: tubules plugged with

proteinaceous material with giant cell reaction.

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