Haematological Malignancies 2 Flashcards
What is Hodgkin lymphoma
(5)
Clonal B-cell malignant that develops within the lymphatic system
The malignant Reed-Sternberg Cell typically has a bilobed nucleus that gives an “owls eyes” appearance
Diagnosis, excisional lymph node biopsy
Spreads in an orderly fashion to adjacent nodes
Painless lymphadenopathy, constitutional “B” symptoms (fever, night sweat, weight loss), pruritus, hepatosplenomegaly
Write about Reed-Sternberg
Cell may contain more than one nucleus
Presence in peripheral blood indicate advanced stage of disease
What are the three main types of lymphoma
NK cell
B cell
T cell
What cells are involved in leukaemia
Neutrophil
Monocyte
RBC
Megakaryocyte
Write about acute lymphoblastic leukaemia
Usually occurs before 14 years of age
Peak incidence between 2 and 9 years
Less common in adults -> peak at about 50
Low RCC, Hb, Hct, platelet count, low normal or high WBC count
Accumulation of malignant, poorly differentiated lymphoid cells within the Bone marrow, peripheral blood and 20% of the time at extramedullary sites
Chromosomal aberrations are the hallmark of ALL, but are not sufficient to generate leukaemia.
Characteristic translocations
More recently, a variant with a similar gene expression profile to Ph positive ALL but without the BCR-ABL1 rearrangement has been identified (poor prognosis)
Comment on the prevalence of ALL
Usually occurs before 14 years of age
Peak incidence between 2 and 9 years
Less common in adults -> peak at about 50
What are the clinical findings of ALL?
(5)
Low RCC
low Hb
low Hct
low platelet count
low normal or high WBC count
Increased lymphoblast
What exactly happens in ALL
Accumulation of malignant, poorly differentiated lymphoid cells within the Bone marrow, peripheral blood and 20% of the time at extramedullary sites
What causes ALL
Chromosomal aberrations are the hallmark of ALL, but are not sufficient to generate leukaemia.
Characteristic translocations
More recently, a variant with a similar gene expression profile to Ph positive ALL but without the BCR-ABL1 rearrangement has been identified (poor prognosis)
Write about the clinical findings of bone marrow aspirate in ALL
Hypercellularity
High lymphoblasts greater than 20%
Write about acute myeloid leukaemia
Most common type of acute leukaemia in adults
Accounts for 30% of all leukaemia
300-400 cases of AML in Ireland/year
Outcome in patients with AML ranges from death within a few days of beginning treatment to likely cure
The major reason patients are not cured is resistance to treatment, often manifested as relapse from remission, rather than, even in older patients, treatment related mortality, whose incidence is decreasing
Knowledge of the pre-treatment mutation statis of various genes has improved our ability to assign initial treatment and, of particular importance, knowledge of whether patients apparently in remission have measurable residual disease should influence subsequent management
What is the most common type of leukaemia in adults
Acute myeloid leukaemia in adults
Accounts for 30% of all leukaemia in adults
300-400 cases per year
Comment on the severity of AML
One of the harder leukaemias to beat
Outcome in patients with AML ranges from death within a few days of beginning treatment to likely cure
Why is AML so hard to cure
The major reason patients are not cured is resistance to treatment, often manifested as relapse from remission, rather than, even in older patients, treatment related mortality, whose incidence is decreasing
Knowledge of the pre-treatment mutation statis of various genes has improved our ability to assign initial treatment and, of particular importance, knowledge of whether patients apparently in remission have measurable residual disease should influence subsequent management
How is AML classified
M0 -> M7
What is M0 AML
Undifferentiated acute myeloblastic leukaemia
5%
What is M1 AML
Greater number of myeloblasts with less than 10% granulocytic differentiation
What is M2 AML
Myeloblasts in great number with granulocytic differentiation >10%
NSE < 20%
What is M3 AML
Promyelocytes that are hyper granular with many Auer rods on CAE or Wright-stain and variant form cells with reniform nuclei, multilobed or bibbed, primeval cells with multiple Auer rods or relative scarcity of Hypergranular promyelocytes
What is M4 AML
> 20% but <80% NSE-butyrate positivity in Monocytic cells
What is M5 AML
Monocytic cells with >80% NSE positivity
a. Monocytic differentiated
b. Monocytic, differentiated
What is M6 AML
> 30% myeloblasts with more than 50% erythroblasts eliminating the erythrois cells
What is M7 AML
Acute megakaryoblastic leukaemia <5%
Write about CLL
(7)
Most common leukaemia, usually B lineage
Normally B cells produce antibody in CLL they don’t
Often diagnosed on routine check up
BM aspirate not useful in early stages
Rai Binet staging system
Flow cytometry needed for diagnosis
Richters transformation: very rare, very severe, CLL> Prolymphocytic leukaemia
What are the clinical symptoms of CLL
Lymphocytosis B
Smudge/smear cells up
Reticulocyte up
Haemoglobin down
Write about the use of flow cytometry in CLL
Needed for diagnosis
Neoplastic B-cells with co-expression of CD19, CD5, CD23, with weak CD20 and monoclonal surface immunoglobulin expression
What is a telltale feature of CLL
Hairy Cell
What are some laboratory findings of peripheral blood?
(4)
Hairy cells
Pancytopenia
Neutropenia
Flow cytometry
Explain how flow cytometry is used for CLL
(2)
The cells are strongly positive for CD20
In contrast to other B cell disorders they also express CD25, CD103 and CD123
They are CD5 negative
Write about hairy cell trapping
Hairy cells are trapped in the bone marrow and that’s why you get a dry tap
They are also trapped everywhere else, therefore, they don’t show up in the lymph nodes and that’s why the clinical finding of lymphadenopathy is absent
Write about the clinical findings of plasma cell myeloma
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Rouleaux formation
RBCC down
Neoplastic plasma cells
Neoplastic plasma cells in BM aspirate
Bence-Jones in urine electrophoresis
Paraprotein in serum electrophoresis
IG up in serum electrophoresis
Write about the use of flow cytometry in plasma cell myeloma
(3)
Usually lack surface light chain with monotypic cytoplasmic Ig
Express bright CD38, CD138, often CD56+ or CD117+
May have partial CD45, usually negative for CD20, CD19 and CD10
What are MPNs
Myeloproliferative neoplasms
What does Ph negative MPN mean
Philadelphia chromosome negative myeloproliferative neoplasms
What are the four types of philadelphia chromosome negative MPNs
Myelofibrosis
Polycythemia vera
Essential thrombocythemia
Other
What are some clinical findings of CML
(6)
RBCC down
Little to no platelets
WBCC up
Neutrophils myelocytes
PHL Chromosome in BM
Hypercellularity in bone marrow > 90%
Blasts
Write about myelodysplastic Neoplasms
Cytopenias
Dysplasia in one or more of the major myeloid cell lines
Ineffective haematopoiesis
Increased risk of development of acute myeloid leukaemia (AML)
What are the thresholds for crytopenias ?
(4)
The thresholds for crytopenias as recommended in the International Prognostic Scoring System (IPSS) for risk stratification in the MDS are:
- Haemoglobin < 10 g/dL
- Absolute neutrophil count (ANC) < 1.8 x10^9/L
- Platelets < 100 x 10^9/L
What happens in MDS
Bone marrow does not produce enough healthy blood cells
Average age of diagnosis is between 60 and 75 years
Risk factors include smoking and exposure to automobile exhaust
What are the symptoms of MDS
Fever
Fatigue
Weakness
Easy bruising
How is MDS diagnosed
Blood tests
Bone marrow examination
Karyotyping
Comment on the severity of MDS
Death is mostly caused by bleeding and infections
Average survival after diagnosis is 6-12 months
How is MDS treated
Chemotherapy
Stem cell transplantations
What morphological signs are there for MDS
Dysgranulopoiesis
Dyserythropoiesis
Dysmegakaryopoiesis
What is meant by dysgranulopoiesis?
Formation of asynchr
What is meant by dyserythropoiesis
Formation of macrocytic, megaloblastic cells
What is meant by dysmegakaryopoiesis
Formation of Rund, non-lobules megakaryocytes
How does MDS become AML
Normal stem cells undergo aberrant epigenetic programs to become MDS stem cells
MDS stem cells undergo aberrant growth signals and reduced apoptosis to become AML
This results in inhibited differentiation and uncontrolled blast cell proliferation
Thought to be due to epigenetics
How do we diagnose and monitor haematological neoplasms
(5)
FBC and morphology
Flow cytometry
Cytogenetics, FISH, Karyotyping, Array CGH
Molecular sequencing
Molecular methods e.g. RQ-PCR, dPCR, RT-PCR
How do we use PCR to quantify disease burden
(3)
Real time PCR used to quantify amount of disease that is there e.g. cycle numbers in covid
If you have to use cycle numbers then there is a very low disease dose
Real time PCR allows us to find out exactly how
much of a disease they have -> used to monitor disease and the effectiveness of drugs
The higher the disease burden, the more fusion transcripts present so the more template cDNA present and the earlier products appear during PCR cycles e.g PML-RAR, BCR-AbI
Write about next generation sequencing
Making its way to all of the labs
A sequencing method
Allows us to discover mutations
Allows us to see what DNA base pairs are present
What are the four types
Extraction
Library Prep
Sequencing
Analysis
How are malignancies treated
(6)
Chemotherapy - usually combination of drugs is used, 7+3 regimen
Epigenetic therapies - demethylating agents and HDACs
Stem cell transplant (younger patients, allogeneic versus autologous)
Radiotherapy
Immunotherapy - stimulate the patients own immune system to mount a response against the malignant cells
- Monoclonal antibodies - examples include Rituximab
- CAR-T cell therapy
Small molecule inhibtiors e.g. Tyrosine Kinase inhibitors - Imatinib (Gleevec), JAK2 inhibitors, BTK inhibitors
What is chimeric antigen receptor (CAR) T-cell therapy ?
(6)
Used in lymphoid leukaemias and lymphoma patients
Can cure patients
Patients own T cells are taken and genetically engineered to fight their own leukaemia
Patients remain cancer free afterwards
Works well in lymphoid => targets CD19 -> expressed on malignant cells
Phase 1 trials for AML (there isn’t one antigen i.e. CD molecule for myeloid)
What is meant be hide and seek
Leukaemia cells can move to lymph nodes (lymphoma) or hide in the bone marrow
