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Lymphoid Haematological malignancy Flashcards

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1
Q

What is one of the main difference between lymphomas and leukemia?

A

Lymphoma tends to arise in the nodal tissue and peripheries
Leukemia arises in the bone marrow and spills out into the peripheral blood

There is significant overlap between the diseases

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2
Q

What are the three types of lymphoproliferative disorders?

A

Leukemia
Lymphoma
Multiple myeloma (derived from terminally diferentiated B cell - plasma cell)

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3
Q

Des scribe the basic anatomy / structure of a lymph node? where do B and T cells develop in the node?

A

Afferent and efferent lymph limbs
Also have arterial and venous limb for blood supply
From the periphery inwards, there is the capsule, then the surrounding marginal sinus, the the follicles, then the para cortical zone, then the medulla sinus flowing into teh efferent limb

Primary follicles develop into secondary folicles which contain germinal centers

B cell mature in the germinal follicles
T cells mature in the paracortical area

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4
Q

Where does B cell maturation happen?

A

Germinal follicles of the peripheral LNs

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5
Q

Where does T cell maturation primarily occur?

A

Thymus, then further maturation in the peripheries (LN and other organs)

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6
Q

Lymphoma RF?

A

Immune suppression
- medications (MTX, AZA etc)
- Organ or bone marrow transplant
- HIV infection

Exposure to toxins:
- primor chemo
- agent orange herbicide
- Nuclear radiation

Infection
- H pylori, HCV, HIV, HTLV

Autoimmune conditions

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7
Q

How is lymphoma most broadly classified?

A

Hodkins and non-hodkins lymphoma

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8
Q

How is non hodkins lymphoma most broadly subdivided?

A

T cell NHL
B cell NHL

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9
Q

What is the most common form of lymphoma? what is the second and third most common? (options: T cell, B cell, Hodgkins)

A
  • B cell NHL are most common, approx 80%
  • HL is second most common
  • T cell NHL is third most common (much more common in asians)
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10
Q

How is B cell NHL most broadly subdivided? Why is it useful to categorize in this way?

A

Very aggressive, Aggressive, and Indolent

For example:
- Burkits NHL is very aggressive
- DLBC NHL is aggressive
- Follicular NHL is indolent

Useful because agressive ones require Rx, indolent one may be able to be observed

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11
Q

What is the most common B cell NHL?

A

DLBC NHL is most common, then follicular NHL

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12
Q

Which form of lymphoma is curable, and which is not?

A

Contrary to what you might expect, indolent lymphomas are not curable, aggressive lyumphomas often are
- Indolent: follicular, CLL, MZL
- aggressive: DLBC NHL
- very aggressive: Burkits NHL

Hodkins lymphoma is often curable

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13
Q

How does lyumphoma present?

A

Can present with symptoms:
- Weight loss
- fever
- drenching night sweats
- noticed a lump in axilla or neck etc

Can present as incidental examination finding by doctor (ie noticed a lump in neck)

Can be incidental finding on imaging or bloods

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14
Q

Which form of Lymphoma is H pylori related to?

A

MALT lymphoma of the stomach
- MALT = mucosa-assisted lymphoid tissue

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15
Q

Which part of the gut does mantle cell lymphoma have a predilection for?

A

Colon

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16
Q

In which part of the gut can folicular B cell NHL arrise?

A

Duodenum

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17
Q

Which form of lymphoma particularly can affect the skin? and what are some examples?

A

T cell lymphomas

Examples:
- Mycoses fungoides - a form of primary cutaneous T cell NHL
- Anaplasic Large cell lymphoma

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18
Q

How is lymphoma diagnosed? What type of Bx is preferred?

A

Biopsy (tissue, hone marrow, blood, other)
Clinical features

Core or excicional Bx is preferred, dont get FNA

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19
Q

How is Bx tissue used to establish Dx of lymphoma? (ie what are the broad aspects of Bx processing / analysis)

A

Morphology (histology)
Immunohistochemistry / flow cytometry
Genetic profile
- FISH, PCR, cytogenetics

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20
Q

What cell surface markers are almost always expressed on Hodkins lympohoma (can also be expressed on other types)?

A

CD30, CD15

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21
Q

What is Ki-67 in lymphoma?

A

The Ki-67 is teh proliferation index, gives a measure of how fast the lymphoma is replicating

ie buirkits has a Ki-67 of almost 100% (very fast replicating)

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22
Q

How is Bx immunohistochedmistry used in establishing Dx of lymphoma?

A

Immunohistochemistry
- used to determine subtype of lymphoma ie B cell T cell, hodkins
- Used to determine proliferation index Ki-67
- used to determine cell of origin in DLBC NHL (determines subtype of DLBL NHL)
- to identify prognostic markers such as myc, blc2…

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23
Q

How is lymphoma staged? explain the different stages?

A

Staged with the ann arbor staging system
from stage 1 - 4

Stage 1 - localized disease. single LN or organ affected

Stage 2 - 2 or more LN regions on teh same side of teh diaphragm

stage 3 - two or more LN regions above and below the diaphragm

stage 4 - Widespread disease (extranodal tissue) affecting multiple organs with or without LN involvement

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24
Q

What are some examples of low grade/ indolent lymphoma? (give 4 most common ones)

A
  • Follicular (most common by far)
  • Marginal zone Lymphoma
  • CLL/SLL
  • Lymphoplasmocytic lymphoma (waldenstroms macroglobulinaemia)
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25
Who gets follicular NHL? (demographic features)
Older adults (median 60yrs) Less common in asia and developing countries
26
Can follicular b cell NHL progress / transform? what does it transform into
Yes Transformation to higher grade DLBC lymphoma
27
What are 2 characteristic cell surface markers of follicular B cell NHL? What is the characteristic translocation leading to up regulation of one of these surface markers?
CD10, BCL2 t(14:18)m leads to up regulation of BCL2 which is an antiapototic protein (pro survival)
28
How is follicular B cell NHL treated?
Usually watch and wait approach, prognosis is good (approx 20 years), however may need to treat advanced disease / symptomatic disease Stage I/II disease: - Targeted local radio + R-CVP (rituximab, cyclophosphamide, vincristine, prednisolone) - Observation Stage III / IV disease: - Asymptomatic or low tumour burden can be observed - Symptomatic / high tumor burden is treated with immuno-chemotherapy +/- maintainance
29
What are some common immuno-chemotherapy regimes used for treatment fo follicular B cell NHL?
Immunotherapy agent combined with chemotherapy "backbone" regime Immunotherapy agent: - Rituxumab OR obinutuizumab (CD20) Chemo regime: - CVP (cyclophosphamide, vincristine, prednisone) - CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) - Bendamustine
30
What are the three types of MZL?
extra nodal marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT) Nodal MZL (rare) Splenic MZL
31
What is MZL commonly associated with?
Chronic inflamatory diseases (autoimmune or chronic infections) such as: - H pylori infection in stomatch - Sjogrens syndrome - Hashimotos thyroiditis
32
Gastric MALT is sometimes associated with specific translocation. What is this translocation and why is it relevant?
t(11:18) BIRC3/MALT1 translocation - confers worse prognosis (more difficult to treat)
33
What type of paraprotein is usually associated with lymphoplasmocytic lymphoma? what is the epponomous name for this?
usually IgM paraprotein (Waldenstroms macroglobulinaemia) - can also have IgG/IgA parprotein
34
What precursor condition can develop into LPL?
IgM MGUS can develop into LPL (approx 10%)
35
Can pts with LPL transformation of IgM MGUS ever get MM?
No, MGUS that has transformed into LPL will not develop into MM
36
What are 2 mutation associated with LPL?
MYD88 (very specific for LPL, >90% LPL will have this) CXCR4 mutation confers worse prognosis (approx 30% have it)
37
What are some symptoms fo very high levels of IgM paraprotein in LPL?
this is known as hyperviscopsity syndrome Sx include visual blurring, headache, retinal changes this is an indication to treat
38
How is LPL treated?
Often no treatement required (very indolent progression) If treatment required: - Rituxumab-chemo regimes - BTKi (zanubrutinib) for relapsed disease or pts unfit forR-chemo)
39
What is a side effect of initial treatment of LPL with rituxumab to be aware of?
Rituxumab can cause an initial increase in IgM, so need to be cautious if pre-existing high levels of IgM
40
How is LPL treatment monitored?
Serial IgM measurements
41
Where does Mantle cell Lymphoma sit in relation to agressive / very agressive lymphomas and indolent lymphomas?
Mantle cell lymphoma is not indolent and it is not aggressive / very aggressive It is considered an intermediate lymphoma
42
What is the characteristic translocation of mantle cell lymphoma? What is the result of this translocation?
t(11:14), in >95% Resulting in over-expression of cyclin D1
43
How is mantle cell lymphoma treated?
There are some situation in which observation can be initially used, however low threshold to move to treatment (relative to indolent NHLs for example) Treatrement for <65yrs: - Intensive immunochemotherapy (cytarabine containing regimes) - Upfront autologous SCT following immunochemotherapy (doesnt cure, just increase survival) - ritux maintainance Treatment for >65yrs: - Less intense immunochemotherapy (R-Bendamustine, R-BAC) - Ritux maintainance
44
Who gets DLBC lymphoma?
Median age 60-70s Higher incidence in developing countries
45
Is there any role for observation in DLBC lymphoma?
No, it is an aggressive lymphoma that will always progress if not treated
46
How is DLBC NHL classified into risk groups?
International prognostic index (IPI) is used to classify into low risk, low intermediate, intermediate high, high risk groups - IPI 0 - 1 is low risk - IPI 2 is low intermidate - IPIN 3 is intermidate high - IPI 4 -5 is high
47
What are some poor prognostic factors in DLBC NHL?
Clinical prognostic factors - High IPI - Advanced stage - Bulky tumor (>7.5cm) Tumor prognostic factors: - Molecular subtype (germinal centre DLBC NHL, or activated B cell subtypes) - Dual expression of MYC and BCL2
48
What proteins are expressed in double and triple hit DLBC NHL?
Double hit - BCL2, MYC Triple hit - BCL2, MYC, BCL6 These are both known as high grade DLBL NHL
49
Explain the concept of cell of origin in DLBC lymphoma?
DLBC NLH can arise from B cells at different stages of development. for example it can arrive from a germinal B cell (called Germinal center B cell DLBC Lymphoma) or can arse from an activated B cell (called activated B Cell lymphoma) the cell of origin is determined by immunohistochem looking at cell surface markers
50
What is the mainstay of treatment for DLBC lymphoma?
R-CHOP (rituixumab, cyclophosphamide, doxorubicin, vincristine, prednisone) More intensive chemo regimes are used in high grade DLBC lymphoma
51
What is the treatment for hypersensitivity syndrome?
Plasmaphoresis to filter out the paraproteins
52
What is the malignant cell in HL called?
Reid sternburg cell (owl eye cells)
53
Why is interpretation of tissue Bx in HL fraught?
Because the reid sturnburg cell is often in the minority with numerous reactive normal cells present. Therefore can get sampling error
54
What are the common cell markers on reed sternburg cells?
CD 15, CD30
55
Who gets HL?
Bimodal age distribution - 30s and older adults 2:1 male predominance
56
How does HL classically present?
Non tender rubbery lymphadenopathy most often in cervical LN, but also axilia, and mediastinum Alcohol intolerance (pain when drink alcohol) Constitutional Sx commonly associated
57
What are the classifications of HL and how are pts classified into these groups?
Early stage, favourable Earlky stage unfavourable Advannce Classified using combination of ann arbor staging (early or advanced stage), and risk factors (favourable, unfavourable)
58
How is HL treated?
Trteated with chemoitherapy regimes Treatment depends on the stage ABVD (adramycin AKA doxorubacin, bleomycin, vioncristine, dacarbazine) - Used in early stage disease, or advanced stage disease in the more elderly pts Escalated BEACOPP (bleomycin, etoposide, Adramycin AKA DOXOrubicin, CYCLOPHOSPHamide, vinCRISTine, procarbazine, prednisolone) - more intense regime used in advanced stage in young pts - better cure rate but more side effects such as INFERTILITY
59
ABVD and BEACOPP include Bleomycin. What is a main side effect of bleomycin?
Lung toxicity
60
What is a main side effect / toxicity of doxorubicin?
Cardiovascular toxicity
61
What are some common blood film findings in CLL?
Many small mature lymphocytes in peripheral blood. Smudge cell on film
62
Who gets CLL?
Disease of the elderly (70-80yrs)
63
How do pts commonly present with CLL?
Most often an incidental findings on bloods (very high WCC) - 60% asymptomatic at Dx If symptomatic, common symptoms include lymphadenopathy, fatigue, autoimmune cytopenia's (AIHA, ITP)
64
What is the precursor lesion to CLL?
Monoclonal B lymphocytosis - monoclonal population of B lymphocytes <5000 cells/microL (<5 x 109/L) in peripheral blood for ≥3 months, without other features of a B cell lymphoproliferative disorder Approx 1% MBL progress to CLL per year
65
What is the nodal counterpart of CLL?
small lymphocytic lymphoma
66
Poor prognostic markers in CLL?
High LDH High Beta 2 microglobulin Chromosomal abnormalities TP53 inactivated and unmutated IgVh - CLL cells that have not entered the germinal center and havent undergone hypermutation of their IgVh have a poorer prognosis than those that have This is similar to the cell of origin concept of DLBC NHL (ie prognosis of the disease depends on at which point it develops in the normal cells process of maturation)
67
Describe the disease course and progressive sequelae of CLL?
Usually a slow progressive disease of the elderly - slow rising lymphocytosis - increasing lymphadenopathy and splenomagly - progressive BM failure - Progressive immunparesis and B cell immune suppression - Autoimmune complications such as AIHA, ITP - secondary skin cancers
68
When should CLL be treated?
When it becomes symptomatic - usually due to worsening anaemia or thrombocytopenia - AIHA or ITP - Symptomatic extra nodal involvment - Constitutional Sx Treatment may be indicated with progressive lymphocytosis, or lymphocyte doubling time of <6 months
69
How is CLL treated?
All pts: - Ibrutinib/zanubrutinib (BTKi) + venetoclax (BCL2 inhibitor) + Obinutuzumab is first line treatment for all age groups Chemo used to be first line until Sept 2023
70
What is multiple myeloma?
It is a malignancy of plasma B cells which accumulate and destroy bone and bone marrow
71
Why is infection risk increased in multiple myeloma if it is a disease of too much immunoglobulin poroduction?
Normal B cell populations produce polyclonal immunoglobulin which provided broad protection against infections Multiple myeloma malignant plasma cells lead to monoclonal immunoglobulin production (paraprotein), or elevated serum free light chains which leads to a reduction in polyclonal immunoglobulins and therefore increased risk of infection
72
What feature on an electrophretogram is concerning for MM?
an M spike - caused by M protein (AKA paraproteins) The M spike given the Electrophoretogram and double spike appearance, whereas the normal appearance is that of a single initial spike (due to albumin in the blood) followed by lots of smaller spikes that represent the various other poly clonal immunoglobulins and proteins in the blood
73
What is the difference between light chains and para proteins in MM?
paraptoteins is another name for the abnormal monoclonal immunoglobulin that is produced by some myelomas However some myeloms just produce light chains (either kappa, or lambda light chains) rather than a whole immunoglobulin molecule (which is comprised of 2x heavy chains, and 2x light chains)
74
Approximately what percentage of MM is free light chain only? (ie not paraproteins)
15%
75
What are the CRAB features of MM?
hyperCalcaemia Renal failure Anaemia Boney leision / osteoporosis Boney lesions, anaermia, hypogammaglobulinaemia / iunfection, and hypercalcaemia are caused by too many plasma cells renal failure, hypoerviscosity and neuropathy are caused by too much protein or light chains
76
Myeloma exists on a spectrum of disease. What are the other diseases on this spectrum? (there are three in total)
MGUS Asymptomatic myeloma (used to be called smoldering myeloma Symptomatic myeloma (used to be called multiple myeloma)
77
What is the definition of MGUS?
M protein <30g/L, clonal plasma cells in BM <10%, nil myeloma defining events
78
What is the definition of asymptomatic myeloma? (used to be called smoldering myeloma)
M protein >30g/L in blood or >500mg/24hrs in urine Clonal plsama cell 10-60% in BM Nil myeloma defining events
79
hat is the definition of symptomatic myeloma? (used to be called multiple myeloma)
- Clonal plasma cells >10% in BM AND a myeloma defining event >/=1 CRAB feature >/= 1 biomarker of malignancy - Clonal plasma cells >60% in BM - Serum FLC ratio >100 - > 1 focal MRI leision >5mm
80
How does myeloma typically present?
Bone pain Low BMD / OP with paraprotein Pathological fractures Anaemia with high total protein Acute renal failure and anaemia with high total protein Back pain and anaemia (bone pain) Hyperviscosity syndrome
81
How can renal function be affected in myeloma?
Myeloma cast nephropathy Light chain deposition disease AL amyloidosis Aquired fanconi syndrome Hypercalcaemia, hyperuricaemia
82
Features of MM on blood film?
Rouleaux cells Occasional circulating plasma cell
83
Bone marrow findings in MM?
Plasma cells, often with atypical features
84
Broadly speaking, how is symptomatic myeloma treated?
Treatment regime depends on whether the pt is SCT eligible (ie <60 and fit) Transplant eligible patients - induction - Transplant - Maintenance - Treatment of relapsed disease Transplant ineligible patients: - Induction - Maintenance - treatment of relapsed disease
85
What regime is used for induction in both SCT eligible and ineligible pts with symptomatic myeloma? What regime is used for maintainance therapy in symptomatic myeloma?
Induction Bortezomib (proteasome inh) + lenolidomide + dexamethazone Maintenance - SCT eligible - Lenolidomide ongoing - SCT ineligible - lenolidomide + dexamethazone
86
What are some aspects of supportive care in MM?
Treatment of Osteoporosis / bony lesions - Bisphosphonates Treatment of hypogamaglobulinaemia - IVIg Treatment of anaemia - PRBC tranfusions PRN Management of steroid side effects Management of Bortexomib side effects - Neurpathy - VZV prophylaxis
87
How are Chimeric Antigen receptor T cell made (CAR T cells)?
T cells are collected from teh pt via venepuncture A modified virus is used to transfer DNA into the pts T cells so they will produce the desired chimeric antigen receptor - the CAR has 2 ends: a binding site specific to the tumour cell, and a signalling end that activateds the T cell to kill the tumour cell Once the desired CAR T cell is made it is grown in the lab (millions of copies) The expanded population of CAT T cells is infused into the pt
88
What are some toxicities of CAR T cells?
- Cytokine release syndrome (CRS) - Immune effector cell associated neurotoxicity syndrome (ICANS) - Infection - T cell suppression from leukodepletion prior to CAR T cell infusion - B cell aplasia (hypogammaglobulinaemia) - Haemophagocytic lymphohistiocytosis/ macrophage activation syndrome (HLH/ MAS
89
Does CRS or ICANS occurs first?
CRS is the initial side effect, then ICANS happens
90
What are some symptoms / features of CRS? How is it graded based on symptoms / signs?
CRS is a systemic inflammatory condition due to mass release of cytokines following CAR T cell infusion It is graded 1 - 4 based on presence or absence of fever, hypotension and hypoxia - Grade 1: fever - Grade 2: fever + hyupotension (not on supports) + hypoxia (LFNP) - Grade 3: fever + hypotension (ionotropes but not vassopressin) + hypoxia (HFNP, non re breather) - Grade 4 - - Grade 3: fever + hypotension (Multiple ionotropes) + hypoxia (NIV, intubation)
91
Treatment of CRS?
Stepwise increased in Tocilizumab +/- dexamethasone based on grade Supportive care (ie ICU) if required
92
What are some symptoms / features of ICANS? How is it graded based on symptoms / signs?
It is graded 1 - 4 based on conscious state, seizures, motor findings, Elevated ICP/cerebral oedema
93
How is ICANS managed?
Managed based on grade 1-4 - Grade 1: dex 10mg stat - Grade 2: Dex 10mg QID, consider methyl pred if nil improvment, consider anikinra - Grade 3: high dose methyl pred, consider anikinra, control seizures - Grade 4: ICU

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