1. Dr Samal Nauhria samal@windsor .edu
Plasma cell lesions
Dr Samal Nauhria
.edu

2. Plasma Cell Lesions Multiple Myeloma Solitary Plasmacytoma/myeloma.
Lympho-plasmacytic Lymphoma
Heavy-chain Disease
Primary Amyloidosis
MGUS

4. Multiple Myeloma Median age at diagnosis - 70 years
M/C in males and in people of African origin
Principally involves bone marrow and associated with lytic lesions throughout the skeletal system
Evidence of end-organ damage includes Calcium elevation, Renal insufficiency, Anemia, and Bone lesions (CRAB)

5. Multiple Myeloma
Most frequent M protein is IgG (60%), followed by IgA (20% to 25%)
In 15 to 20% cases, the plasma cells produce only κ or λ light chains
Bence-Jones proteins: free κ or λ light chains that are excreted in the urine

7. Pathogenesis of Myeloma
Dysregulation of D cyclins is common
IL-6 produced by fibroblasts, macrophages in the bone marrow stroma stimulates proliferation of myeloma cells
Myeloma Cells secrete IL-1β, TNF, IL-6 which stimulate production of RANK-ligand  increased osteoclast  bone resorption

8. Pathogenesis of Myeloma
Immunosuppression:
Although plasma contains increased Ig’s owing to M protein, the levels of functional antibodies are profoundly depressed, leaving patients at high risk for bacterial infections

9. Morphology Multifocal destructive skeletal lesions,
most commonly involving the VERTEBRAL COLUMN, ribs, skull, pelvis, femur, clavicle, and scapula
Punched-out defects 1 to 4 cm in diameter
Arise in medullary cavityerode cancellous bone progressively destroy the cortical bone
Pathologic fractures, mostly in vertebra or femur

10. Multiple myeloma with multiple vertebral fractures at the thoracic and lumbar levels

11. Microscopic examination
Increased numbers of plasma cells > 30% of the cellularity
Abnormal features
Prominent nucleoli
Abnormal cytoplasmic inclusions(Ig)
In terminal stages, a leukemic picture may emerge

12. PLASMA CELLS Terminally differentiated B-cells
Not normally found in peripheral blood
Account for < 3.5% of nucleated cells in the bone marrow

13. Oval cells with cart-wheel nucleus
Cytoplasm is basophilic blue
Nucleus is oval or round and typically placed eccentrically
A hof is present adjacent to the nucleus contains Golgi apparatus

14. 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

15. MOTT CELLS/MORULA CELLS
Plasma cells crowded with Russell bodies
An obstruction blocks the release of Golgi secretions
These cells can be found in any case of chronic plasmacytosis

16. FLAME CELLS Eosinophilic torn cytoplasm
Usually associated with IgA myeloma

17. DUTCHER BODIES
Immunoglobulin filled cytoplasm invaginating into the nucleus creating the appearance of an intranuclear inclusion
PAS +ve
Identified by Dutcher and Fahey

18. Clinical Features
Pathologic fractures
Bone Pain
Vertebral fracture may lead to spinal cord impingement
Hypercalcemia from bone resorption
Neurologic manifestations (confusion, lethargy)
Renal dysfunction
Symptoms related to hyperviscosity
Anemia: due to marrow replacement by tumor cells and suppression of hematopoiesis
Recurrent infections with bacteria
Common cause of death**

19. Renal findings Renal insufficiency (in 50% of patients)
Proteinaceous tubular casts
Casts are composed of BJ protein, which is nephrotoxic and damages tubular epithelium
Biopsy reveals an intratubular multinucleated giant cell reaction
Nephrocalcinosis
Hypercalcemia leads to metastatic calcification of the tubular basement membranes in the collecting ducts
Calcium deposits are a common cause of acute renal failure in multiple myeloma
AL-type amyloidosis (5% to 10% of patients)

21. Diagnosis
Clinically suspected when focal, punched-out skeletal defects are present - especially in vertebrae
Electrophoresis of the serum and urine - monoclonal complete Ig or monoclonal free Ig light chain
Examination of bone marrow: to confirm plasma cell proliferation

22. SERUM PROTEIN ELECTROPHORESIS
Useful in quantitating the M protein and shows a monoclonal spike
Does not specify which M protein is increased (e.g., IgG, IgA, IgM)

23. Other Tests- Serum immunofixation electrophoresis
Provides a characterization of the M protein (heavy and light chain subclass; e.g., IgGκ or IgGλ; IgMκ or IgMλ)
Urine protein electrophoresis
Identifies BJ protein (free light chains) and quantitates the amount of light chains in the urine
But not specify whether the light chains are κ or λ
Urine immunofixation electrophoresis
Characterizes whether BJ protein is κ or λ
Serum for free light chains
Detects and quantitates κ and λ light chains in serum
More sensitive for detecting light chains than any of the urine methodologies listed above

24. Treatment and Prognosis
Progressive disease, median survival of around 4 to 6 years
Not curable
Autologous stem cell transplantation - dramatically improved survival
New therapies
Proteasome inhibitors (induce plasma cell apoptosis)
Thalidomide analogues (alter the marrow microenvironment to inhibit myeloma cell growth and survival)

25. Solitary Plasmacytoma/myeloma
Low or no serum and urine M protein
No malignant plasma cells in the bone marrow
Skeletal Plasmacytoma
Occurs in same locations as multiple myeloma
Progresses to full-blown multiple myeloma over 5 to 10 years
Soft tissue Plasmacytoma
Most often in upper respiratory tract
Spreads infrequently, cured by local resection

26. Lymphoplasmacytic Lymphoma (Waldenström macroglobulinemia)
Affects older persons; peak incidence between 6 -7th decades
Tumor cells secrete an M protein (commonly IgM)
Mixture of B cells ranging from small lymphocytes to plasmacytic lymphocytes to plasma cells
Involves lymph nodes, bone marrow, and spleen at presentation

27. Lymphoplasmacytic Lymphoma
↑IgM causes viscous blood - Waldenström Macroglobulinemia
No free light chains or Bence Jones proteinuria
No lytic bone lesions
Renal disease and amyloidosis are rare

28. Waldenström Macroglobulinemia
Visual impairment: tortuosity and distention of retinal veins; retinal hemorrhages and exudates
Neurologic problems - headaches, dizziness, tinnitus, deafness, and stupor, (from sluggish blood flow and sludging)
Bleeding - formation of complexes between macroglobulins and clotting factors as well as interference with platelet function
Cryoglobulinemia - precipitation of macroglobulins at low temperatures - Raynaud phenomenon and cold urticaria

29. Heavy-Chain Disease
Proliferations in which only heavy chains are produced
IgA heavy-chain disease: more common, has a predilection for lymphoid tissues in which IgA normally is produced (Small intestine, Respiratory tract)
IgG heavy-chain disease: diffuse lymphadenopathy and hepatosplenomegaly

30. Primary Amyloidosis
Monoclonal proliferation of plasma cells that secrete free light chains underlies primary amyloidosis
Amyloid deposits (AL type) consist of partially degraded light chains

31. Monoclonal Gammopathy of Undetermined Significance(MGUS)
Asymptomatic monoclonal gammopathy
Serum M proteins in 1 to 3% of healthy persons > 50 years
< 3 g/dL of monoclonal protein in serum
No Bence Jones proteinuria
Precursor lesion with a tendency to evolve to multiple myeloma (rate of 1% per year)
Diagnosis made only after careful exclusion of other monoclonal gammopathies, particularly multiple myeloma
The clonal plasma cells in MGUS contain the same chromosomal translocations found in full-blown multiple myeloma