Immunoproliferative disorders Qs

Which of the following is a type of B-cell tumor that arises from a germinal center **B cell** and does not express **antigen receptor**?

a. multiple myeloma

b. acute lymphoblastic leukemia (ALL)

c. Hodgkin’s lymphoma

d. follicular center cell lymphoma

c

You are a researcher interested in learning more about B-cell **anergy**. You would like to obtain a B-cell line from a tumor that has a single receptor specificity and resembles a **naive B cell**. Which tumor type would most likely serve your needs?

a. acute lymphoblastic leukemia (ALL)

b. mantle cell lymphoma

c. multiple myeloma

d. Hodgkin’s lymphoma

b

Which fit the following description non-germline B-cell receptor gene, with CD19, Igα/Igβ, and Pax-5 expression, and surface IgM molecules?

a. chronic lymphocytic leukemia

b. pre-B-cell leukemia

c. acute lymphoblastic lymphoma (ALL)

d. Burkitt’s lymphoma

a, d

An individual presents in the clinic with complaints of general achiness and fatigue. When her blood is checked for infection, it is found that her antibodies are overwhelmingly targeting a single antigen. What would you expect to find in her B-cell populations?

a. only cells that express IgM isotypes

b. a repertoire of normal depth and breadth

c. clonal population derived from a single ancestral cell

d. circulating pro-B cells

c

Which one of the following statements about the types of monoclonal M bands found by electrophoresis of serum indicates multiple myeloma?

a. An M band that moves in the beta position on protein electrophoresis

b. M band found in alpha position

c. Heavy deposit at the original suggesting large load of monoclonal protein

d. All of the above

e. None of the above

d

What is multiple myeloma?

a.      Cancer of the bone marrow

b.      Cancer of the plasma cells

c.       Cancer of the blood

d.      Cancer of the lymphatic system

e. Cancer of the bone

b

Bence Jones proteins are:

a.      Fragments of transferrin

b.      Polyclonal free light chains

c.       Monoclonal free light chains

d.      Beta 2-microglobulin

e.      Prostaglandins

c

Which one of the following statements about patients with monoclonal serum bands is true?

a.      All will develop a lymphoid malignancy within 3 years

b.      All should be followed up once a year, with quantitation of the band and examination of the urine

c.       All should have a skull X-ray

d.      Over 90% will have frank myeloma

e.      Only those with renal failure need urine examination for monoclonal free light chains

b

How is multiple myeloma diagnosed?

a.      Bone Marrow

b.      Serum Protein Electrophoresis

c.       Immunofixation

d.      X-rays

e.      All on the above

e

How is the prognosis determined for a patient with multiple myeloma?

a.      Stage of disease

b.      Age of patient

c.       Kidney function

d.      Cytogenetic markers

e.      All of the above

e

Yasuo Yamagata, 63 years old, experienced severe back pain for several weeks before visiting his family physician. He also complained of fatigue and looked pale. Blood analysis revealed a red blood cell count of 3.2 × 106/μl (normal 4.2–5.0 × 106/μl), a white blood cell count of 2800/μl (normal 5000/μl), neutropenia (low levels of neutrophils in the blood), a sedimentation rate of 30 mm/h (normal

b

Which two linages do B-cell tumours arise from?

B-1, B-2

What proof do B-cell tumours have to their derivation from the same ancestral gene?

as an identical immunoglobulin-gene rearrangement

Despite individual B-cell tumours being homogenous what do B-cell tumours have that reflects multiplicity of rearrangements found in the normal B cells of a healthy person?

different rearrangements

Where do tumour characteristics come from?

retain characteristics of the cell type from which they arose

Where do tumours derived from mature B cells grow?

follicles of lymph nodes

Where do plasma cell tumours grow?

bone marrow

What are plasma-cell tumours called?

myelomas

What are tumors derived from mature naive B cells grow in the follicles of lymph nodes called?

follicular centre cell lymphoma

What was one of the first tumours to be successfully treated by radiotherapy?

Hodgkin’s

Why do Hodgkins tumours no longer have antigen receptors?

somatic mutation

What morphology do Hodgkins tumours have?

Reed-Sternberg cells

What are the two forms of Hodgkins?

In some people the disease is dominated by the proliferation of nonmalignant T cells that respond to the tumor cells, whereas others have Reed–Sternberg cells as well as more normal-looking malignant B cells.

Where did the very first sequences of heavy and light chains were obtained from?

multiple myeloma

What tumours have rearranged **B-cell receptor** genes and resemble naive **B cells**?

Mantle cell lymphoma

What lymphoma arises from transformation of B-cells in germinal centre?

Hodgkin’s

Which lymphoma do not express immunoglobulin?

Hodgkin’s

Which tumours resemble lymphoid progenitor cells and would not have a non-germline **B-cell receptor** gene?

ALL

What tumours resemble activated or memory **B cells** with non-germline immunoglobulin genes and surface expression of the receptor and signaling complex?

CLL

What tumours resemble germinal center **B cells** with non-germline immunoglobulin genes and surface expression of the receptor and signaling complex?

Burkitts lymphoma

Why do B-cells immunoglobulin light chains would be in their **germline configuration** whereas their heavy-chain genes would be rearranged?

lack a functional B-cell receptor

Where are ALL and Pre-B cell leukaemia tumours found?

Bone marrow and blood

Where are CLL, mantle cell lymphoma, follicular center cell lymphoma, Hodgkin’s and Waldenstrom’s macroglobunemia tumours located?

Periphery

Where are multiple myeloma tumours located?

bone marrow

What leukaemia has various isotypes and originates in plasma cells?

Multiple myeloma

Which tumour is found in IgM-secreting B cells?

Waldenstrom’s macroglobunemia

Which tumour arises from mature memory B cells?

follicular centre cell lymphoma

Which tumour originates from Pre-B cells?

Pre-B cell leukaemia

What is the status of Ig V genes in MM?

Mutated, no variability within clone

What is the status of Ig V genes in Waldenstrom’s macroglobunemia?

Mutated, no variability within clone

What is the status of Ig V genes in Hodgkin’s?

Mutated +/- intraclonal variability

What is the status of Ig V genes in follicular centre cell lymphoma and Burkitts?

Mutated intraclonal variability

What is the status of Ig V genes in CLL?

Usually unmutated

What is the status of Ig V genes in mantle cell?

Unmutated

What is the status of Ig V genes in Pre-B cell?

Unmutated

What is the status of Ig V genes in ALL?

Unmutated

Gammopathy

a disorder characterised by abnormality of gamma globulins

Hypergammaglobulinaemias

the overproduction of more than one class of immunoglobulins by plasma cells

Monoclonal gammopathy arises from?

single clone of plasma cells producing high levels of a single class and type of antibody (monoclonal protein/M protein/paraprotein)

Monoclonal gammopathy examples?

MM, Waldenstrom primary macroglobulinaemia

What do XS light chains κ (kappa) free light chains secreted as?

monomers

What do XS light chains λ (lambda) free light chains secreted as?

dimers or polymers

Where do XS lights chains enter?

kidney

How do XS light chains enter the kidney through the glomerulus and PCT?

due to low molecular weight

Where are XS free light chains reabsorbed and degraded into smaller peptides?

PCT

What is the normal amount of light chains dialy reaching distal tubule and in urine?

1-10 mg

When are much higher levels of light chains is seen in the urine detected?

Monoclonal gammopathies

Why are much higher levels of light chains is seen in the urine detected in monoclonal gammopathies?

capacity of PCT are overwhelmed

What allows plasma cells to overcome growth restraints?

chromosome abnormalities

Why alongside the extensive growth replication is a discrete band by electrophoriesis seen?

the cell secretes its programmed immunogloubulin isotype (class) in such large amounts

What is secreted by growth of abnormal plasma clones?

monoclonal antibody, paraprotein or M protein

How is monoclonal gammopathy defined by?

monoclonal immunoglobulin in the serum and/or urine

Examples of monoclonal gammopathy

—Monoclonal gammopathy of undetermined significance (MGUS)



—Myeloma/Multiple Myeloma



—Waldenstrom primary macroglobulinaemia



—Light-chain disease



—Heavy-chain disease

Why do patients with MGUS not have symptoms?

due to the monoclonal gammopathy

What monoclonal band is seen in MGUS?

less than 30g/L

What is the % of plasma cells in BM?

Less than 10%

How does the incidence of MGUS change with age?

Increases from 1% in 50y to 10% in 80y

Who has the highest incidence of MGUS?

African-Caribbean patients

How many patients with MGUS transform into MM?

1%

How often should patients with MGUS be seen and monitored?

Annually

What are the characteristics of MM?

Malignant monoclonal proliferation of bone marrow marrow plasma cells, and accumulation of plasma cells in the bone marrow



Lytic bone lesions

How is MM detected?

Monoclonal immunoglobulin in serum and/or urine

Why does MM have symptoms?

Due to

Malignant monoclonal proliferation of bone marrow marrow plasma cells, and accumulation of plasma cells in the bone marrow

Lytic bone lesions

Monoclonal immunoglobulin in serum and/or urine

Clinical features of MM

* bone pain,
* anaemia,
* infections (defects in humoral not cell immunity),
* renal failure,
* proteinuria in 50% of patients excreting abnormal amounts of Bence Jones proteins (light chains), 
* hyperviscosity syndrome

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Which monoclonal gammopathy has lytic bone lesions?

MM

Lab features of MM

* —electrophoresis of serum or urine shows a monoclonal protein in 90% of patients,
* increased serum calcium,
* low haemoglobin,
* raised mean cell volume (MCV) and
* increased erythrocyte sedimentation rate

Overall incidence of MM

Incidence is \~5-7 per 100,000; very rare

Paraprotein

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this is the type of antibody that is characteristic of and produced by the malignant cells in multiple myeloma. Because this paraprotein is produced by a clone of cells it has a single light chain type, kappa or lambda.

What is the possible mechanism of MM?

IL-6

What happens to untreated patients with MM?

Rapidly progressive and usually die in a year

MM Ig

—IgG (60%)



—IgA (>20%)



—IgD 1%



—IgE very rare



—IgM extremely rare

10% are κ or λ light chain only     

non-producing myeloma

are myeloma subtype with more than 10% of monoclonal plasma cells in the bone marrow

What is the most common Ig secreted by MM?

IgG then IgA

What myeloma does not secrete Ig?

non-secreting

What myeloma cannot produce Ig/Ig fragments?

non-producing

When does proteinuria occur?

if levels of free light chains are too high

What forms discrete bands on electrophoresis?

light chains

What property of light chains leads to the formation of discrete bands on electrophoresis?

monoclonal

What determines whether κ or λ?

immunofixation

Why is renal function deteriorates the presenting symptom?

The renal tubules suffer increasing damage

What is found in patients with renal failure in MM?

Bence jones proteins

What do all secretory myelomas produce?

XS free light chains

What do light chain myelomas often have?

immune paresis

What is immune paresis?

suppression of normal immunoglobulin production by a malignant plasma clone

What may be the only sign of a small serum free light chain or an IgD monoclone ?

Low immunoglobulin levels

What is the reason for doing immunofixation on samples with low immunoglobulin even if no abnormal electrophoretic band seen in serum electrophoresis?

Low immunoglobulin levels may be the only sign of a small serum free light chain or an IgD monoclone

What is heavy-chain disease?

Characterized by monoclonal proteins composed of the heavy chain part of the immunoglobulin molecule

What is γ heavy chain disease?

Franklin disease

What is the commonest type of heavy chain gammopathy, and often seen in men of Mediterranean descent?

α heavy chain disease

What heavy-chain disease is rare?

M heavy chain