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General Pathology > PLASMA CELL PROLIFERATIONS > Flashcards

PLASMA CELL PROLIFERATIONS Flashcards

1
Q

what are the plasma cell dyscriasias?

A

A group of conditions characterized by the abnormal proliferation of the same type of (monoclonal) plasma cell that may also secrete a monoclonal immunoglobulin and/or immunoglobulin fragment (e.g., light chain). Includes multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), and Waldenstrom macroglobulinemia.

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2
Q

why patients with plasma cell dyscrasias are immunologically suppressed if they secreted a lot of immunoglobulins?

A

immunoglobulins are monoclonal derived from 1 cell so don’t have antigenic diversity and are dysfunctional

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3
Q

what is the Bence Jones protein?

A

Polypeptide consisting of one or two immunoglobulin light chains. Its detection in urine is suggestive of plasma cell disorders such as multiple myeloma or Waldenstrom’s macroglobulinemia.

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4
Q

what is the classification of plasma cell dyscrasias

A

1) Multple Myeloma
2) SMoldering Multiplemyeloma
3) solitary myeloma (plasmacytoma)
4) MGUS
5) Waldenstrom’s macroglobulinemia
6) other

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5
Q

what is the multiple myeloma?

A

• Multifocal bone marrow disease characterised by malignant proliferation of plasma cells with skeletal destruction
– Monoclonal B cells produce a single type of Ig
• Most common primary malignancy of bone
• Accounts for 15% of haematological malignancies
• Causes 1% of cancer death
• Adults- usually >50 years
– M:F 3:1
– More common in Africans and African Americans
• Blacks >Whites (2:1)

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6
Q

what is the M spike?

A

An abnormal immunoglobulin fragment. Excess production of M protein by monoclonal plasma cells (as in patients with multiple myeloma) causes a peak in the gamma-globulin zone of serum or urine electrophoresis (SPEP or UPEP).

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7
Q

what is the pathophysiology of MM

A

1) Previous exposure to irradiation
2) Exposure to asbestos, petroleum products, rubber and plastic products
3) Human herpes virus 8
4) Cytogenetics (multiple and variable)
5) No common molecular pathogenies known

6)Myeloma cells bind to bone marrow stromal cells via cell surface adhesion moleculesà myeloma cell growth, survival, drug resistance and migration in the bone marrow milieu
7)Myeloma cells produce cytokines (eg., IL6)
– Growth of myeloma cells
– Interaction with bone marrow stromal cells àosteoclast activation (RANK receptors) and osteoblast inhibition
1)Neoplastic proliferation of plasma cells
–Bone marrow infiltration → suppression of hematopoiesis → leukopenia, thrombocytopenia, anemia
–Cell proliferation → osteolysis → hypercalcemia
2)Overproduction of monoclonal immunoglobulin and/or light chains
–Non-functioning antibodies → functional antibody deficiency
–↑ Serum viscosity → hyperviscosity syndrome
References

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8
Q

what is the osteoclast-activating factor?

A

IL-1
An interleukin released after immune system contact with lipopolysaccharides (e.g., the wall of gram-negative bacteria). Causes fever and acute inflammation, including chemokine secretion to recruit white blood cells. Induces vasodilation and promotes the adhesion and diapadesis of inflammatory cells by activating endothelium. Dysregulation of IL‑1 in cartilage leads to damage and osteoarthritis, as IL-1 activates osteoclasts.

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9
Q

what are the RANK and RANKL?

A

1) RANK (receptor activator of nuclear factor κB): receptor on osteoclasts and osteoclast precursors for interaction with osteoblasts
2) RANKL (receptor activator of nuclear factor κB ligand)
- -Membrane-bound protein of osteoblasts that interacts with RANK on osteoclasts
- -Ensures fusion and differentiation into activated osteoclasts and prevents their apoptosis

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10
Q

what is the osteoprotegerin?

A

Osteoprotegerin (OPG): a regulatory protein secreted by osteoblasts that binds to RANKL and inhibits its effect (i.e., inhibits osteoclasts)

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11
Q

what is the DKK1?

A

Inhibitor of osteocalst differentiation
Elevated levels of DKK1 in bone marrow, plasma and peripheral blood is associated with the presence of osteolytic bone lesions in patients with multiple myeloma

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12
Q

why in MM osteoblasts are not stimulated?

A

because fo DKK1

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13
Q

why in MM osteoclasts are activated?

A

1) osteoprotegerin is inhibited

2) IL-1 and 6 stimulate osteoclasts

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14
Q

what cytokines are oversecreted in MM

A

IL-1 and 6

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15
Q

what immunoglobulins are secreted by MM

A

Plasma cells produce intact monoclonal Ig
– Present in plasma (M component)
– High molecular weight (not present in urine without glomerular disease)
– IgG 55%, IgA 25%, light chain only 15%
– IgD, IgE, IgM uncommon

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16
Q

what type of immunoglobulin is primarily secreted in MM

A

IgG

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17
Q

light-chains excreted in the urine are called

A

Bence-Jones protein

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18
Q

what is the epidemiology of MM

A

Sex: ♂ > ♀ (3:2)

Peak incidence: 50–70 years

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19
Q

how MM is classified Based on immunoglobulin type

A

IgG: 50% of multiple myelomas
IgA: 25% of multiple myelomas
Bence Jones myeloma (free light chains excreted in urine): 20% of multiple myelomas

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20
Q

Abnormal production of IgM suggests

A

Abnormal production of monoclonal IgM suggests Waldenstrom’s macroglobulinemia rather than multiple myeloma!

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21
Q

what are the clinical features of MM

A 
Often asymptomatic
Bone pain- especially back pain (most common symptom), spontaneous fractures
Symptoms of hypercalcemia
Mild fever, night sweats, weight loss
Weakness and anemia
Increased risk of infection
Increased risk of petechial bleeding
Foamy urine, caused by Bence Jones proteinuria
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22
Q

Lymphadenopathy is typical to MM. True/False

A

False

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23
Q

how MM is diagnosed?

A
  • -Serum protein electrophoresis (best initial test)
  • -Urine protein electrophoresis
  • -Bone marrow biopsy (confirmatory test)
  • -Laboratory tests (CBC and biochemistry) to assess for –hypercalcemia, anemia, and renal insufficiency
  • -Imaging to assess for bone lesions
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24
Q

what is the best initial test of MM

A

SPEP

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25
Q

what is the confirmatory test of MM

A

BM biopsy

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26
Q

bone lesions in MM are characterized by

A

• Multifocal destructive lesions
– Axial skeleton
• Vertebrae, ribs and skull, pelvis and femur, clavicle and scapula
– Punched out lytic lesions/ Soap-bubble appearance

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27
Q

in MM bone marrow examinations shows

A

• Plasma cells are increased (>10% of BM)
• Perinuclear clearing and eccentric nucleus
• Atypical cells with bi-nucleated, tri-nucleated or multinucleated forms
• Immature blasts
• Intra-cytoplasmic inclusions (Russell bodies)
Mott cells (plasma cells that have spherical inclusions packed in their cytoplasm).
• Intra-nuclear inclusions (Dutcher bodies)
• Immunohistochemistry- a single type of Ig (Monoclonal, eg IgG only) and a single type of light chain (either kappa or lambda)

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28
Q

what are the Russel bodies?

A

Accumulation of immunoglobulins–Plasma cells in plasmacytoma or chronic inflammation

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29
Q

what are the Dutcher bodies?

A

Periodic acid-Schiff positive, intranuclear vacuoles composed of monoclonal IgM collections. Seen in Waldenstrom macroglobulinemia.

30
Q

what is the Mott cell?

A

An atypical plasma cell that has spherical inclusions filled with immunoglobulin (small Russell bodies) packed in its cytoplasm

31
Q

in MM serum and urine analysis shows

A 
•	Serum
–	Monoclonal globulin spike on serum electrophoresis 
–	(M spike)most commonly IgG or IgA 
–	>3g/dL for IgG 
•	Urine
–	Proteinuria (light chain) 
–	Either Kappa or lambda light chain
32
Q

The absence of Ig or its components from blood or urine does exclude myeloma. True/False

A

False

33
Q

what is the disadvantage of SPEP and UPEP?

A

quantifies M spike and light chains but does not which M protein of light chain are elvevated, quantiative but not qualiative

34
Q

what is the disadvantage of serum and urine immunofixation electrophoresis

A

specifies the M component and light chain but does not tell the quantity. Both are qualitative but not quantitative

35
Q

what is the CRAB?

A 
–	Calcium (elevated)
–	Renal (kidney) failure
–	Anaemia
–	Bone lesions
typical to MM but not to other gammopathies
36
Q

what are the cause of bone lesions in MM?

A
  • Proliferation of tumour cells which infiltrate the bone

* Production of IL6/ osteoclast activating factor

37
Q

what is the presentation of bone lesions in MM

A

– Bone pain (most common)
– “punched out” lytic lesions
– Pathologic fractures
– Diffuse osteoporosis
– Hypercalcemia (confusion, weakness, lethargy, abdominal pain constipation, polyuria, depression, renal stones). This is due to increased production of PTHrP or lytic skeletal metastases due to cytokines such as IL-1 and IL-6 being released form myeloma cells accelerating bone resorption.
– The lumbar vertebrae are one of the most common sites of pain àspinal cord compression

38
Q

what are the signs of hypercalcemia in MM?

A

confusion, weakness, lethargy, abdominal pain constipation, polyuria, depression, renal stones)

39
Q

what are the reasons for hypercalcemia in MM

A

increased production of PTHrP or lytic skeletal metastases due to cytokines such as IL-1 and IL-6 being released form myeloma cells accelerating bone resorption.

40
Q

what is the most common site of bone fracture in MM

A

lumbar spine

41
Q

what are the clinical features of bone marrow involvement

A

• Tumour cells replace the bone marrow à Anaemia, thrombocytopenia and leucopenia

42
Q

what are the reasons for anemia in MM?

A

• Anaemia: Normocytic and normochromic
• Due to:
a- replacement of normal bone marrow by tumour cells
b- inhibition of normal red blood cell production by cytokines
c- decrease in erythropoietin production
Note: Decrease charge of red blood cells (Rouleaux formation on blood smear)

43
Q

what is the Rouleaux formation

A

An aggregation of erythrocytes with the appearance of a stack of coins on peripheral blood smear. This aggregation is caused by increased concentrations of plasma proteins (e.g., fibrinogen, immunoglobulins). Associated with multiple myeloma but is not specific to this condition.

44
Q

what are the reasons for bleeding in MM?

A

– Monoclonal immune proteins interfere with normal coagulation
– Infiltration of the bone marrowà thrombocytopenia

45
Q

what are the reasons for hyperviscosity seen with MM

A

• High volume of monoclonal protein à blood viscosity increases à complications such as stroke, myocardial ischaemia or infarction

46
Q

what is the most common cause of death in MM?

A

• Recurrent infection
– The most common cause of death
– Decreased production of normal Igà recurrent bacterial infection (Encapsulated organisms, eg. Staph, Strep, E. Coli infections)
– Leukopenia

47
Q

what is the second most common cause of death in MM?

A 
Renal Failure
•	Occurs in up to 50% of patients  
•	2nd most common cause of death
•	Multifactorial
–Myeloma kidney= myeloma cast nephropathy
•	Bence-Jones toxic to renal tubular epithelial cells 
–	Amyloidosis- AL type
–	Light chain nephropathy
–	Hypercalcaemia and hyperuricaemia
–	Pyelonephritis
–	Drug induced
48
Q

what is the myeloma cast nephropathy?

A

A form of tubulointerstitial renal disease seen in patients with multiple myeloma. It occurs when excessive amounts of immunoglobulin light chains are produced and filtered into the primary urine, resulting in their precipitation within the renal tubules and leading to tubular obstruction and toxicity to renal tissue. Same as light chain cast nephropathy

49
Q

what are the features of amyloidosis seen with MM

A

• Systemic deposition of AL type (derived from light chain)
– Kidneys: Nephrotic syndrome
– Heart: Restrictive cardiomyopathy
– Tongue enlargement
• Requires tissue biopsy- rectum)
• Congo red staining with apple green birefringence under polarised light
• Treatment: TNF inhibitors, Hematopoietic stem cell transplantation, hemodialysis

50
Q

what are the causes of neurological symptoms in MM?

A

Hyperviscosity, hypercalcaemia, nerve compression

51
Q

what is the prognosis of MM?

A 
•	6-12 months if untreated
•	Median survival 4-7 years
•	Causes of death
–	Infection
–	Renal failure
52
Q

what is the treatment of MM

A

1)Asymptomatic patients: watch and wait
–unless patients have ≥ 60% clonal cells, excessive free –light chains or ≥ 1 bone lesion
–Symptomatic patients
2_Standard and intermediate-risk
–HSCT eligible: induction therapy followed by autologous HSCT
–HSCT ineligible: chemotherapy alone (e.g., dexamethasone and lenalidomide)

53
Q

what is the lenalidomide?

A

An anti-neoplastic agent used to treat multiple myeloma and some myelodysplastic syndromes. The mechanism of action is complex, but the end result is induction of apoptosis. Significant side effects include venous thromboembolism and Stevens-Johnson syndrome.

54
Q

what are the measures of supportive therapy in MM?

A

1) Osteolysis and bone pain
- -Bisphosphonates
- -Radiation therapy of osteolytic regions
2) Pancytopenia with anemia and increased risk of infection
- -Blood transfusions
- -Granulocyte-colony stimulating factor (G-CSF) and erythropoietin (EPO)

55
Q

what is the bortezomib

A

A proteasome inhibitor that arrests cell growth at the G2-M phase and causes apoptosis. Often used in the treatment of multiple myeloma and mantle cell lymphoma. Adverse effects include peripheral neuropathy and reactivation of herpes zoster (shingles).

56
Q

what is the treatment of plasmacytoma?

A

radiation

57
Q

what is the melphalan?

A

A chemotherapeutic agent (alkylating agent, nitrogen mustard) typically used in the treatment of multiple myeloma (in elderly, paliative) and ovarian cancer. Common side effects include fatigue, myelosuppression, hypokalemia, and peripheral edema.

58
Q

what is the cyclophosphamide?

A

An alkylating agent used to treat many solid tumors, leukemias, lymphomas, and multiple myeloma (in elderly, paliative) and as an immunosuppressant to treat autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus) and severe nephrotic syndrome. Adverse effects include myelosuppression, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and hemorrhagic cystitis (risk reduced with prophylactic administration of mesna and aggressive hydration).

59
Q

what is the smoldering multiple myeloma?

A
  • Patients are asymptomatic
  • Plasma cells make up 10%-60% of bone marrow
  • M protein > 3g/dL
  • 75% progress to multiple myeloma
60
Q

in plasmacytomas, serum immunoglobulins are also elevated. True/False

A

False
• Solitary lesions
– Osseous (bone)
– Extra-osseous (extra-medullary) (soft tissue)
• Serum immunoglobulin concentrations are usually within normal limits

61
Q

describe solitary plasmacytoma of bone

A
  • Patients are younger than patients with multiple myeloma
  • Involves spine, pelvis and femur
  • A single symptomatic area of bone destruction
  • Progression to multiple myeloma in 10-20 years
62
Q

describe extra-medullary plasmacytoma

A
  • Involves lung, oronasopharynx and nasal sinuses
  • Extra-osseous lesions can be cured by local resection or radiotherapy
  • Progression to multiple myeloma is rare
63
Q

what is the MGUS?

A
  • The most common cause of monoclonal gammopathy
  • Incidence: 3% in adults >50 years, 5% in >70
  • Asymptomatic
  • Increased serum protein with M spike on serum electrophoresis (<3g/dL)
  • Plasma cells less than 10%
  • No Bence-Jones protein
  • No bone lesions
  • No hypercalcaemia
  • No amyloid
  • Progression to multiple myeloma 1% per year
  • MGUS is an early stage of myeloma (Same chromosomal aberrations as MM, but generally follow a benign course)
64
Q

is there CRAB with MGUS?

A

no

65
Q

what are the diagnostic criteria of MGUS?

A

Paraproteins: monoclonal immunoglobulins detectable in serum < 30 g/L
Bone marrow: < 10% of plasma cells in bone marrow
No evidence of organ damage or multiple myeloma-associated disease (CRAB)

66
Q

is there a risk of progression to MM of MGSU?

A

Progression to multiple myeloma 1% per year

67
Q

what is the Waldenstrom’s macroglobulinemia (Lymphoplasmacytic lymphoma)

A

A type of non-Hodgkin lymphoma associated with abnormal production of monoclonal IgM antibodies. It mostly occurs in old age and has a good prognosis, as it is a type of indolent lymphoma. The clinical presentation includes hyperviscosity syndrome, platelet dysfunction, and Raynaud’s phenomenon.

68
Q

what type of immunoglobulins are produced in Waldenstrom’s?

A

IgM

69
Q

what are the hyperviscosity symptoms seen with Waldenstrom’s macroglobulinemia?

A

• Visual impairment
– Distension of retinal veins and hemorrhage
• Neurological symptoms
– Headaches, dizziness due to sluggish blood flow
• Bleeding
– Macroglobulins bind to clotting factors and interfere with platelet function)
• Cryoglobulinaemia
– Precipitation of Macroglobulins at low temperatureà Raynaud’s phenomenon

70
Q

what is the treatment of Waldenstrom’s macroglobulinemia?

A 
Plasmapheresis for hyperviscosity symptoms
 CD20 antibodies (e.g., rituximab)
71
Q

what is the heavy chain disease?

A

Heavy chain disease is a form of paraproteinemia and plasma cell dyscrasia that involves the proliferation of cells producing immunoglobulin heavy chains. This disease is characterized by an excessive production of heavy chains that are short and truncated.

General Pathology (9 decks)

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