Introduction to Haematological Malignancies Flashcards
What is a malignancy?
- presence of cancerous cells or tumors that have the potential to spread to other parts of the body.
What causes Haemopoiesis
Rapidly dividing cells more prone to cytogenetic abnormalities (mutations) during division.
Ionising radiation
Chemicals/drugs
Genetics
Viruses
Consequences of acquired mutations
- Abnormal Maturations
- Uncontrolled proliferation and abnormal maturation
- Uncontrolled proliferation: Increased cellular division and reduced cell death
Consequences of uncontrolled proliferation
- Malignant cells crowd out the bone marrow
- Normal cells cant compete for space of nutrients
- Reduction in production of normal cells
- Malignant cells spill out into the peripheral circulation but they are functionally incompetent.
Common features of Anemia
Lethargy
Pallor
Common features of Leucopenia
Infections
Common features of thrombocytopenia
- Easy bruising
- Bleeding
Secondary symptoms of hematological malignancies
Splenomegaly
Bone pain (myeloma)
Weight loss
Extramedullary haemopoiesis
Night sweats
What kind of proliferation causes acute leukemia?
Haemopoietic stem cell with abnormal clones causes proliferation with minimal or no differentiation.
What kind of proliferation causes Myelodysplastic Syndromes?
Haemopoietic stem cell with abnormal clones causes proliferation with abnormal differentiation
What kind of proliferation causes Myeloproliferative Disorder?
Haemopoietic stem cell with abnormal clones causes proliferation with differentiation
Myeloproliferative Neoplasms
Caused by clonal proliferation of haemopoietic cells leading to excess production of one or more cell lines.
Examples of Myleoproliferative Neoplasms (MPs)
Polycythaemia vera (PV)
Essential thrombocythemia (ET)
Primary myelofibrosis
What can MPs turn into
these disroders are closely related to each other sharing clinical/ morphological/ ,olecular features
can transform into each other - e,g JAK2 mutations or can transform into acute myeloid leukemia
Myelodysplasia / Myelodysplastic Syndrome (MDS)
Clonal disorder of haemopoetic stem cells characterised by production of abnormal cells (dysplasia)
Low incidence ( 2-12 cases per 100000) each year
patients are usually > 60 years old at diagnosis
Numerous subtypes
Myelodysplasia / Myelodysplastic Syndrome (MDS) - clinical pathogenesis
Bone marrow is hypercellular
- blood shows pancytopenia due to disturbed maturation and inability to replace the cells
- Retarded maturation and cell death in bone marrow causes ineffective cell production
What is panytopenia
reduction in the number of all three major types of blood cells (RBC, WBC, Platelets)
Myelodysplasia / Myelodysplastic Syndrome (MDS) - Diagnosis
Via microscopy and mrophology
Leukemia
characterised by the abnormal proliferation of haemopoeitic cells that progressively infiltrate the bone marrow and lymphatic tissues compromising the production of normal blood cells.
accounts for 4% of deaths from malignant disease
Initial classification of leukaemia - Difference between myeloid and lymphoid
Myeloid: originates in the myeloid cells (precursors to main blood cells) except lymphocytes
Lymphoid : originates in the lymphoid cells, which are precursors to lymphocytes. Affects lymphoblast’s and lymphocytes
Initial classification of leukaemia - Chronic or acute
Chronic Leukaemia - progress slowly over time (months to years) with the cells produced by the bone marrow being partially mature with improper function causing the accumulation of dysfunctional cells in the blood stream.
Acute Leukemia - rapid progression ( weeks to months) with immature abnormal cells (blasts) multiplying quickly and crowding out healthy cells in the bone marrow causing a rapid onset of symptoms.
acute leukaemia: AML
acute myeloid leukemia (AML).
More common in adults w- peak incidence at 60+ years
Causes majority of adult leukemia
Acute Leukaemia - ALL
More common in children
Peak incidence of 3 years of age for B-ALL
15-20 years of age for T-ALL
Chronic Leukemia - CML
Chronic Myeloid Leukaemia
Peak incidence of 50-60 years of age
Chronic phase -> accelerated phase -> Blast crisis
Chronic Leukaemia -> CLL
chronic lymphocytic leukemia (CLL)
- peak incidence in over 50s
about 25% of leukaemias
Types of lymphoid malignancies
Lekuaemia: Originates in the bone marrow in singular cells
Lymphoma: originates in the lymph nodes causing a solid network of cells?
What is multiple myeloma
type of cancer that originates from plasma cells,
How does classifying malignancies help the patients?
- Identifying most at risk patients
- Identifying patients who need to be treated sooner
- I dentifying the most effective treatments
How does classifying malignancies help research?
- Aids understanding of underlying mechanisms: targets for new therapies
- Helps researchers communicate effectively with each other
Classification of Leukaemia - French American British (FAB) system advantages and limitations
Advantages: Quick, Cheap, Helps to identify medical emergencies
Disadvantages: Limited prognostic information, no predictive information
WHO Classification of Haematological Malignancies advantages
-Includes subcategories that have predictable clinical outcomes.
-Includes immunophenotyping, cytogenetic and molecular characteristics.
-Accurate and precise with clearly defined criteria makes classification less subjective.
-Allows international collaboration on research
-Subtypes of AML respond differently to standard treatment: Cytogenetics and molecular abnormalities help identify subgroups with good or bad prognosis
-Treatment may now be tailored to genetic abnormality e.g. the use of all‐trans retinoic acid in acute promyelocytic leukaemia with t(15;17)
Lab Diagnosis of Leukaemia - Immunotyping
Performed using flow cytometry as immature cells are difficult to differentiate morphologically
Detects different cell markers that cells express at different stages of maturation
- Confirms which cell type has been affected and at what stage of maturation the affected clone has been trapped
Samples taken for immunotyping
Peripheral Blood
Bone Marrow Aspirate
Immunohistochemistry types
Indirect/direct
immunofluorescence
Immunohistochemistry samples
Bone marrow trephine
Lymph nodes biopsies
Types of Cytogenetics (with increasing resolutions)
Karyotyping
FISH
Genomic Microarray
NGS
Karyotyping: Euploidy chromosome error
Normal chromosome complement
Diploid in autosomal cells (2n)
46 chromosomes
aneuploidy
More or less of a chromosome than normal.
Monosomy (2n-1)
Trisomy (2n+1)
Polyploidy
Multiple sets of chromosomes
Triploidy (3n-69 chromosomes)
Tetraploidy (4n – 92 chromosomes
Karyotyping: chromsomal structural abnormalities
-Additions
- Insertions
- Duplications
- Deletions
- Translocations
- Inversions
FISH
- Identifies specific sequences using a probe (complementary piece of DNA strand attached to a flourescent marker)
- Doesn’t need live cells or cell culture
- Quick turn around time (less than 24 hrs)
- Can only detect specific mutations
Genomic Microarray
Tests for copy number variation (deletions and duplications) across the genome.
Genomic Microarray Advantages and Limitations
Advantages: High resolution, no cell culturing, global.
Limitations: Cant detect balanced structural abnormalities or repetitive DNA sequences.
Considerations: Incidental findings
NGS advantages
High specificity and sensitivity
