Lymphoma & Myeloma Flashcards
What is the product of antigen-independent B-cell differentiation?
what surface markers does it have?
naïve B-cell which is capable of responding to antigen
it expresses:
complete surface IgM and IgD
pan B-cell markers - CD 19, 20, 22, 40, 79a
complement receptors
CD23 and some express CD5
What type of antibody gene do naïve B-cells have?
they have a rearranged but unmutated Ig gene
each B cell is committed to a single light chain (kappa or lambda)
In which locations does B cell development occur?
B cell activation occurs in the secondary lymphoid organs, such as the spleen and lymph nodes
After B cells mature in the bone marrow, they migrate through the blood to the SLOs
By which 2 ways can mature antigen-naïve B cells be activated?
they can be activated by antigens directly
(they apoptose or differentiate into short-lived plasma cells with production of IgM antibody of the primary immune response)
or with the input of T cells
What is a germinal centre?
What type of cells are present here and where do they originate from?
naïve B-cells develop into proliferating IgM expressing B-cell blasts
these have encountered antigen in the paracortex or T-cell zone
they migrate into the centre of the primary follicle to form a germinal centre
the germinal centre is formed from 3-10 naïve B-cells and eventually contains 10,000 - 15,000 B-cells
What are the 4 steps involved in naïve B-cells becoming plasma or memory B cells?
- proliferation
- immunoglobulin somatic hypermutation and class switch
- selection
- differentiation
What happens to the naive B cell following antigen stimulation?
What is the rate of the cell cycle like in the product?
B cells differentiate into centroblasts
these accumulate in the dark zone of the germinal centre
they are highly proliferative with a cell cycle that is completed within 6 - 12 hours
What genes are downregulated within centroblasts?
What is the result of this?
anti-apoptotic genes are downregulated
e.g. BCL-2
pro-apoptotic molecules are present
e.g. CD95
this means only cells which generate highly specific receptors to the antigen in the germinal centre will survive
What is the purpose of somatic hypermutation of centroblasts?
Where does this occur?
somatic hypermutation of the Ig V-region genes of centroblasts occurs within the germinal centre
this increases intraclonal diversity
what do centroblasts mature into?
Where are they found and which process occurs here?
centroblasts mature to non-proliferating centrocytes
these are found in the light zone of the GC
heavy-chain class switch occurs here to alter the Ig constant regions to IgG, IgA or IgE
What happens after heavy chain class switching depending on the centrocytes Ig gene mutation?
if a centrocyte’s Ig gene mutation results in a lower affinity antibody for the antigen, it undergoes apoptosis
if the gene mutation results in increased affinity, the antibody can bind to the antigen
(up until now, this has been trapped by complement receptors on follicular dendritic cells)
What happens once the centrocyte antibody has bound to the antigen?
the centrocytes process the antigen and presents it to T-cells
T-cells express the CD40 ligand
this binds to the B-cell CD40 and rescues it from apoptosis
what is required for differentiation post-GC?
inactivation of BCL6
What step in terminal differentiation is involved in the pathogenesis of Burkitt lymphoma?
downregulation of the myc gene
What is the main mechanism which inactivates BCL6?
the CD40 - CD40 ligand interaction stimulates centrocyte expression of IRF4
IRF4 represses BCL6
BCL6 has an inhibitory effect on BLIMP1, so this is upregulated when BCL6 is downregulated
WHat is the consequence of upregulation of BLIMP1?
BLIMP1 represses PAX5, enabling plasma cell differentiation
it also upregulates XBP1, which helps to regulate plasma cells in their secretory phenotype
What are the different molecules involved in plasma cell development?
- interferon regulatory factor 4 (IRF4)
- B-lymphocyte induced maturation protein 1 (BLIMP1)
- X-box binding protein 1 (XBP1)
- paired box protein 5 (PAX5)
- MYC - a regulatory gene which codes for a transcription factor
What are immunoglobulins?
When are they produced?
They are glycoprotein molecules
they are produced by plasma cells in response to an immunogen
What is the composition of immunoglobulins like?
they are composed of 2 heavy chains and 2 light chains
they are held together by covalent disulphide bonds
each chain has one variable and one constant region
How are immunoglobulins classified?
according to the amino acid sequences in the constant region of the:
heavy chains:
- IgG, IgM, IgA, IgD, IgE
light chains:
- kappa or lambda
What is protein electrophoresis?
What 5 major fractions are normally identfied?
the laboratory technique whereby serum is placed in a gel and exposed to an electric current
5 major fractions normally identified:
- serum albumin
- alpha-1 globulins
- alpha-2 globulins
- beta globulins
- gamma globulins
When is immunofixation performed?
What can it detect?
it is performed when “M-spike” is seen on electrophoresis
it enables the detection and identification of monoclonal immunoglobulins
What is the process involved in immunofixation?
serum or urine is placed on a gel and electric current is applied to separate the proteins
anti-immunoglobulin antisera is added to each migration lane
if the immunoglobulin is present, a complex precipitates
What is myeloma?
What is it preceeded by?
an incurable malignant disorder or clonal plasma cells
it is preceeded by asymptomatic MGUS in all patients
What is MGUS?
monoclonal gammopathy of undetermined significance
it is a condition in which an abnormal protein (a monoclonal protein) is present in the blood
What is the median age at presentation of myeloma?
Which groups have a higher incidence?
median age at presentation is 70 years
higher incidence in Afro-Carribean ethnic groups
Where does myeloma lie on a spectrum of plasma cell dyscrasias?
What are these called?
myeloma is one of a spectrum of plasma cell dyscrasias called paraproteinaemias
this is the presence of excessive amounts of myeloma protein or monoclonal gamma globulin in the blood
What is the diagnostic criteria used for myeloma?
IMWG diagnostic criteria
clonal bone marrow plasma cells >/= 10% or biopsy-proved bony / extramedullary plasmacytoma
and any one or more of:
CRAB features
MDEs
What are the CRAB features in myeloma?
C - hypercalcaemia:
- > 2.75 mmol / L
R - renal insufficiency:
- creatine clearance < 40 ml / min or serum creatinine > 177 micromol / L
A - anaemia:
- Hb < 100 g / L
B - bone lesions:
- one or more osteolytic lesions on skeletal radiography, CT or PET/CT
What is meant by MDEs in myeloma?
What are the 3 MDEs?
myeloma defining events
- >/= 60% clonal plasma cells on bone marrow biopsy
- SFLC ratio > 100mg / L provided the absolute level of involved LC is > 100 mg / L
- > 1 focal lesion on MRI measuring > 5mm
What % of myeloma patients have renal insufficiency at diagnosis?
How many will develop this and need treatment?
20-25% have renal insufficiency at diagnosis
50% will have renal insufficiency at some point during their disease course
2-12% will require RRT
What are the 9 external factors that can influence renal insufficiency?
- renal vein thrombosis
- bisphosphonates
- hypercalcaemia
- ACE inhibitors
- dehydration
- NSAIDs
- CT contrast
- hyperviscosity
- type 1 cryoglobulinaemia
What are the clinical features of renal insufficiency as part of myeloma?
- confusion
- poor appetite
- thirst
- chest infections
- breathlessness
- polyuria or oliguria / anuria
- peripheral oedema
- constipation
- pathological fractures
- nausea
- bone pains
What are the 3 main blood tests performed when investigating myeloma and why?
full blood count - Hb, WBC, platelets & blood film:
- looking for anaemia? active infection?
- degree of bone marrow infiltration
- rouleaux
U&Es - urea, creatinine, sodium, potassium:
- looks for renal failure & dehydration
calcium:
- is it elevated?
What is meant by rouleaux?
stacks or aggregations of red blood cells
they form due to the unique discoid shape of the RBC
What other blood tests may be performed when looking for myeloma and why?
c-reactive protein:
- if clinical suspicion of active infection
immunoglobulin levels:
- look for one elevated immunoglobulin subtype with low levels of the others
protein electrophoresis:
- is paraprotein present?
light-chain analysis:
- if no paraprotein is detected but there is clinical suspicion of myeloma
What imaging investigations are performed in myeloma?
- skeletal survey
- whole body CT or MRI
- PET scan (not all myelomas are PET positive)
What is a medical emergency relating to myeloma?
acute kidney injury with suspected myeloma is a medical emergency
What are the stages involved in myeloma management?
How long should it take to complete these stages?
- blood film
- electrophoresis
- immunofixation
- bone marrow biopsy with flow cytometry
should all be expedited within 24 hours
treatment with steroids in the meantime
What is the treatment for myeloma?
steroids are given during as an early intervention
hydration, avoid nephrotoxics and appropriate chemotherapy (attenuated dosing)
What is the IMWG diagnostic criteria for MGUS?
- serum M-protein < 30 g / L
- < 10% clonal plasma cells in the bone marrow
- absence of end-organ damage (CRAB)
What % of people have MGUS?
Is it more common in men or women?
- 3.2% of people > 50 years
- 5.3% of people > 70 years
- 8.9% of people > 80 years
- more common in males than females
What are the risks of progression of MGUS?
What can it progress to?
approx 1 % per year will progress
majority will progress to myeloma
others may progress to:
- Waldenstrom’s macroglobulinaemia
- primary AL amyloidosis
- lymphoproliferative disorders
What increases the risk of progression of MGUS?
- high vs. low M-protein (15 g/L)
- IgA / IgM vs. IgG PP
- abnormal SFLC ratio vs. normal
What may urinary PCR show in MGUS?
nephrotic range proteinuria
apple-green birefringence of congo red stained preparates under polarised light is indicative for the presence of amyloid fibrils
What is meant by AL amyloidosis?
amyloid light chain (AL) amyloidosis
light chain fragments misfold and self-aggregate to form beta-pleated fibrils then deposit in organs
What organs tend to be involved in AL amyloidosis?
1.5% of native kidney biopsies
cardiac and liver involvement in 30%
peripheral neuropathy in 10%
ESFR in 40%
What type of urinary symptoms are present in AL amyloidosis?
nephrotic-range proteinuria
this is mainly albumin
there is a small monoclonal light chain component so classical myeloma symptoms are usually not present
what are the clinical features of AL amyloidosis?
- macroglossia
- confusion
- poor appetite
- thirst
- palpitations
- breathlessness
- peripheral neuropathy
- oliguria / anuria
- peripheral oedema
- constipation
- ascites
- nausea
- PND or orthopnoea
What are lymphomas caused by?
How are they classfied?
lymphomas are caused by malignant proliferations of lymphocytes
they are classified according to the presence or absence of Redd-Sternberg cells
What other organs may be involved in lymphomas?
lymph nodes are predominantly affected in advanced stages
there may be bone marrow and other organ involvement (e.g. gut, skin, CNS)
What type of lymphoma is present if Reed Sternberg cells are present?
Hodgkin lymphoma
What are the symptoms of Hodgkin lymphoma?
What ages tend to be affected and what is the cure rate like?
- lymphadenopathy
- night sweats
- weight loss
- fatigue
- bone marrow involvement is uncommon
it has a bimodal age distribution (20-29 and 60-70)
excellent cure rates (>90%)
What type of lymphoma is present if there are no Reed-Sternberg cells?
either T cell lymphoma or Non-Hodgkin lymphoma
this can be aggressive or indolent
What are examples of aggressive non-hodgkin lymphoma?
What are the symptoms?
Is it curable?
e.g. DLBCL, Burkitt lymphoma
- rapid onset lymphadenopathy
- night sweats
- weight loss
it is curable
What are examples of indolent non-hodgkin lymphoma?
What are typical symptoms?
Is it curable?
e.g. follicular lymphoma, marginal zone lymphoma
- insidious onset lymphadenopathy
- systemically well
it is usually not curable
When someone presents with a lump, what questions are important to ask?
nature of the lump:
- size
- rate of change
- tenderness and skin changes
- history of trauma
additional lumps / lesions elsewhere
- history of weight loss / night sweats
- history of breathlessness / cough / haemoptysis
- past medical history - previous malignancies
- social history - smoking
- family history - bone marrow disorders or malignancies
What would a clinical examination for a neck lump focus on?
nature of the lump:
- size
- location
- skin changes & contour
- is it fixed to underlying structures
- evidence of additional neck masses
- presence of palpable lymphadenopathy
- presence of hepatosplenomegaly
- presence of breast lumps
- chest examination - insection, auscultation and percussion
what are malignant and non-malignant causes of a neck mass?
malignant:
- lymphoma
- chronic lymphocytic leukaemia
- metastatic cancer of the lung / breast / cervix
non-malignant:
- infective (bacterial, viral, mycobacterial)
- inflammatory (sarcoidosis)
- lipoma
- fibroma
- haemangioma
What blood tests should be performed in a neck lump?
- full blood count
- U&Es
- LFTs
- Ca2+
- lactate dehydrogenase (LDH)
- immunoglobulins and protein electrophoresis
What imaging should be performed in a neck lump?
- chest x-ray
- ultrasound scan of the neck lump
- fine needle aspirate and/or core needle biopsy
What is shown here?
follicular lymphoma
What other investigations should be performed on a neck lump?
- CT neck, chest, abdomen, pelvis +/- PET scan
- bone marrow biopsy depending on the results of other investigations
What is follicular lymphoma?
What is it characterised by?
a neoplastic disorder of lymphoid tissue
it is a type of non-Hodgkin lymphoma characterised by slowly enlarging lymph nodes
What % of non-Hodgkin lymphomas are follicular lymphoma?
Which groups are more at risk?
it accounts for around 15% of all non-Hodgkin lymphoma diagnoses
incidence rises with age
it is equally present in males and females
What type of chromosomal translocation is present in most cases of follicular lymphoma?
t(14;18)
this brings the BCL2 protooncogene under the influence of the immunoglobulin heavy-chain gene
this leads to over-expression of the BCL2 protein
this confers a survival advantage to the neoplastic lymphoid cells by inhibiting apoptosis
What is the median and five-year survival in follicular lymphoma?
median survival is 8 - 10 years
five year overall survival is 72 - 77%
what is FLIPI and how is it used to work out prognosis of follicular lymphoma?
follicular lymphoma international prognostic index
- age >/= 60 years
- Ann Arbor stage III or IV
- LDH above the limit of normal at diagnosis
- Hb < 120 g / L
- presence of more than four nodal sites of disease
if a patient has 4 or more prognostic factors, 10-year survival rate is 36% compared with 71% for those with 1 or none
When a patient presents with breathlessness, what questions should be asked?
nature of breathlessness:
- rate and duration of onset
- variability with activities
- exacerbating and relieving factors
additional symptoms:
- cough
- sputum production
- ankle swelling
- orthopnoea
- weight loss & night sweats
past medical history:
- childhood illnesses
social history:
- smoking, occupational and animal exposure
family history:
- of respiratory and cardiac problems
What will a clinical examination of someone with breathlessness focus on?
- chest and cardiovascular examination
- lymphadenopathy
What blood tests should be performed in a case of breathlessness?
- full blood count
- U&Es
- LFTs
- lactate dehydrogenase (LDH)
- ACE level
- ESR
(chest X ray also performed)
What other investigations may be performed in breathlessness?
What is the worst outcome?
PET-CT scan is done
this may reveal an abnormal lymph node as a result of Hodgkin lymphoma
What is hodgkin lymphoma characterised by?
the presence of Hodgkin Reed-Sternberg (HRS) cells
within a cellular infiltrate of non-malignant inflammatory cells
e.g. eosinophils
How do HRS cells evade apoptosis?
they fail to express surface immunoglobulin and evade apoptosis through several mechanisms
e.g. activation of NFkB, incorporation of EBV and latent membrane proteins (LMP1 and LMP2)
How is Hodgkin lymphoma managed?
chemotherapy and radiotherapy
the doses / number of courses depends on the stage
What is the prognosis of Hodgkin lymphoma like?
What are some of the long term effects of therapy?
a high proportion are cured with an 86% 5-year survival
long term effects of therapy:
- increased mortality still seen at >20 years post therapy
- pulmonary toxicity
- cardiovascular disease
- secondary malignancies
What are the general differences between acute and chronic leukaemias?
acute:
- rapid onset
- dramatic presentation - severe sepsis & bleeding
- life-threatening without urgent treatment
chronic:
- insidious onset
- can be incidental finding in otherwise asymptomatic patients
- doesn’t always require treatment - “active monitoring”
What are the main differences between myeloid and lymphoid leukaemias?
myeloid:
- cells which develop into neutrophils, eosinophils, monocytes & basophils
lymphoid:
- cells which develop into lymphocytes
what is chronic lymphocytic leukaemia (CLL)?
a malignant disorder of mature B-cells
it is the most common type of leukaemia in the UK
What is the presentation of chronic lymphocytic leukaemia (CLL) like?
presentation ranges from:
incidental finding of lymphocytosis to
widespread lymphadenopathy, splenomegaly, bone marrow failure & systemic symptoms
What system is used to stage chronic lymphocytic leukaemia (CLL)?
Binet system
this ranges from A to C
What are the criteria and median survival of stage A CLL?
criteria:
- Hb > 100 g / L
- platelets > 100 x 109 / L
- <3 areas of lymphadenopathy
median survival:
- > 10 years
What are the criteria and median survival of stage B CLL?
criteria:
- Hb > 100g / L
- platelets > 100 x 109 / L
- 3 or more areas of lymphadenopathy
median survival:
- 8 years
What are the criteria and median survival for stage C CLL?
criteria:
- Hb < 100 g/L
- platelets < 100 x 109 / L
- any number of areas of lymphadenopathy
median survival:
- 6.5 years
What is shown here?
a bone marrow biopsy showing extensive infiltration with CLL
What is the treatment for CLL?
it needs active treatment
this is usually chemo-immunotherapy with Bendamustine and Rituximab
What is meant by Richter’s transformation?
a rare complication of CLL (<10% of cases)
it is a transformation of CLL into a fast-growing diffuse large B cell lymphoma (DLBCL)
this is a variety of non-Hodgkin lymphoma
What is the prognosis like in DLBCL?
poor prognosis
median survival is < 9 months even with intensive chemotherapy
What are other possible complications of CLL?
- recurrent infections secondary to reduced immunoglobulin production
- autoimmune phenomenon
- ITP
- haemolytic anaemia
- pure red cell aplasia
- autoimmune neutropenia
In what different types of ways do plasma cell disorders present?
plasma cell disorders such as MGUS, myeloma and amyloidosis present in a variety of non-specific ways
- incidental finding (MGUS)
- symptoms secondary to hypercalcaemia, anaemia & renal failure
- bone pains
- organ infiltration (amyloidosis)
What is meant by lymphadenopathy having a wide differential?
you must take into account:
- distribution
- timing of onset
- systemic symptoms (or lack of)
- bloods (can be normal, particularly in lymphomas)
What is important to bear in mind when it comes to progression and prognosis of CLL?
most patients remain asymptomatic for months to years
additional disease genetic features can influence prognosis
(e.g. 17p deletion)
What must be monitored in CLL?
a sudden deterioration in symptoms +/- rapidly enlarging lymph node group raises the possibility of transformation to a high-grade lymphoma
