Week 5 Flashcards
What is leukemia
white blood
orginate in BM
can infiltrate lymphoid tissues
-replacement of bone marrow or lymph nodes with proliferating WBC
-can be chronic, acute, myeloid or lymphoid
What is lymphoma
-neoplasm of lymphoid tissue originating in reticuloendothelial and lymphatic systems - malignant
-can circulate in peripheral cells
Where do leukocyte neoplasms come from
-most are acquired genetic diseases
-systemic not localized single cell goes into the blood stream and travel anywhere
-mutations that occur during DNA replication or altered expression of genes
-origin of leukemia is related to mutation or altered expression of genes that escape correction process
What are some HOST factors that increase the chances of developing neoplasms
risk factors
Congenital Chromosomal Abnormalities -Downs, Turners, Klinefelters a 10-20x increase with Downs in acute leukemia extra gene interfere with gene processes
Chronic Marrow Dysfunction = becomes acute leukemia
Immunodeficiency - inherited form becomes lymphoid leukemia, defected DNA processes
Previous treatment like chemo- induces DNA damage that can later lead to neoplasms
What are some ENVIRONMENTAL factors that increase the chances of developing leukocyte neoplasms
Ionizing radiation - xray, gamma rays can cause DNA breaks also UV light
Chemicals and drugs - mutagens that cause increased rate of mutation like benzene, alkylating agents - mustard gas, oxidative products, dioxin , nitrous acid
Viruses- Epstein Barr = Burkitt Non Hodgkin lymphoma
HTLV-1 = adult T cell leukemia/lymphoma
-virus coded proteins prevent apoptosis
What genetic factors can cause leukemia
-chromosomal translocations in hematopoietic cells can cause Acute leukemia
t(9,22) for CML
t(8, 14) in Burkitt lymphoma
Proto- oncogene vs oncogene
Proto-oncogene normal = protein in normal cell regulation; cell division and maturation
Oncogene -mutated form
Most chromosomal translocations in leukemias involve oncogenes
-dominate disorder only one copy is needed
Mutations that activate proto-oncogene can be qualitative or quantitative
What are the different changes in chromosome structure that can occur to cause mutations
deletions = loss of genes
Translations = fusion of genes = fusion protein that can encourage cell division or prevent apoptosis
What are tumor suppressor genes
Normal genes that code for inhibitory proteins which help to resist malignant transformation - prevent cancer
-different oncogenes because they slow down cell division and promote apoptosis
-
if both alleles (need two to be deactivated) are lost or inactivated (mutations) = malignancy in comparison to protooncogene which is activated and then causes malignancy
-if one is turned off then the other allele can take over
What is the multi hit theory of malignancy
What happens when you have genetic mutations under normal vs malignant conditions
Errors occur regularly in DNA replication and normally the cell would stop dividing and go into apoptosis
In malignant conditions there will be disruptions and abnormal cells will be able to divide and a CLONE of leukemic cell would result.
Increased proliferation and arrested differentiation
Examples of Altered Gene Expression
-arrested differentiation
Acute Promyelocytic Leukemia
translocation
t(15:17) fusion gene causes arrested differentiation and the cell will not mature past the preomyelocyte stage
lymphocyte neoplasms
-excessive DNA repression will stop lymphs at germinal stage
What is the result of gene mutations
Loss of inhibitor proteins = uncontrolled proliferation - mutation in tumor suppression gene
Abnormal proteins produced (activation of protooncogenes )= stimulated proliferation and arrested differentiation
Leukemic cells are different from normal cells because
Functionally abnormal
Structurally abnormal
Maturation arrested before cell is fully mature
Unregulated Proliferation
What are the two objectives when treating leukemic cells
and what are the categories of treatment
-remove leukemic cells through cytoreduction
-provide supportive care
categories of treatment
Chemotherapy
Radiation therapy
Supportive therapy
Targeted therapy
Stem cell transplantation
What is chemotherapy ** listen
-made with anti tumor properties
-mode of action - interferes with cell cycle in BOTH normal and cancer cells
-affects mainly rapidly dividing cells
such those in the mucocsa, BM – especially malignant clones ** and GI mucosa – makes patients very sick**
-limits dosage and determines max dose
What would you expect the results of chemotherapy to be
- marrow hypoplasia
-destruction of leukemic cells
-affects normal cells too reduction of WBC, RBC, and PLT
-neutrophil and plt are routinely monitored because they are the first to be affected when someone is on chemo
-helps to improve quality of life but it can increase risk of infection by inducing neutropenia
-CSFs or cytokines will stimulate RBC formation in BM
-EPO for anemia
-can do transfusion for RBC and PLT if hgb is needed
-Abtics and Anti fungals can be given at the same time
How does radiation therapy work
- kills cells by producing unstable ions which damage DNA causing instant or delayed death
-toxic effects of treatment can occurring during or after
-most affected are hematopoietic system, the gastrointestinal tract, and the skin
-toxic effects are reversible and stop when the treatment stops
What does targeted treatment do
-targets tumor cells and doesnt touch the normal ones
-type of specific therapy getting away from chemo or radiation
examples:
-uses monoclonal AB specific for CD AG
-CML – tyrosine kinase inhibitors block the fusion protein that causes uncontrolled proliferation
What type of donors can be used for stem cell transplantation
What are the sources of stem cells for transplant
Types of donors
Identical twin (syngeneic transplant)- desirable
Genetically different (allogeneic transplant)
Patient’s own marrow (autologous transplant)
Sources for hematopoietic stem cells
Bone Marrow
Peripheral blood
Umbilical cord blood
STC trans very expensive and youll be in the hospital for a long time
-Stem cells will go to pt BM engraft, multiply and repopulate can be allogenic (from a donor) or autologous (from yourself)
prognostic score is between 3 – 4.5 so patients with a prognostic score of 3 or higher may be considered for HSC transplantation
What complications can arise from HSC transplant
Allogenic - GVHD
-when donor T cells react against tissues of recipient
-acute (in post transplant time see with rash or diarrhea ) or chronic ( 100 days after transplant- skin lesions, Hep)
-higher fatality
Autologous you own cells transplanted but risk:
-disease can come back
How is treatment monitored
-through blood work during treatment to assess transfusion requirements and BM response
can look at
RBC, PLTs, BM aspirate , cytogenic study
CBC, manual diff - % blasts, retic count- done daily , blasts should reduce
What is complete remission
-goal in pt with acute leukemia
defined as
-absence of signs of leukemia
-absence of disease
-BM and blood cells count return to normal
no evidence but not cure
cure is remission for over 4 years and no return of disease and no therapy
Cures are realistic for Hodgkin Lymph, CML, Hairy cell leukemia, ALL
What are the traditional classifications of leukemia
-based on maturity and clinical presentation
Acute = immature malignant cells found forming quickly in disease
Chronic - mostly mature forms of cells in disease that progresses slowly
What are general classifications of leukemia
important for diagnosis, therapy and prognosis
Myeloid v.s. Lymphoid which line is malignancy in
Leukemia (proliferating WBC precursors) v.s. Lymphoma -solid tumor of lymphoid tissue
Mature v.s. Immature with arrested development
Proliferative (in one or more cell line) v.s. Dysplastic (cytopenia in cell line)
Leukemia – diffuse
Lymphoma – solid tumor
What are the four major classifications
Myelodysplastic:
Defective maturation
Peripheral blood cytopenias
Myeloproliferative:
Increased numbers of immature myeloid-derived cells
Chronic Leukemias
Acute Leukemia – Myeloid or Lymphoid
Mature Lymphoid Neoplasms- solid tumor in lymph node
What is FAB
-distinguishes between Myeloid and Lymphoid Leukemias, Chronic and Acute Leukemias
-based on Morphological characteristics, Cytochemical stains
can also be used for the classification of
-BM counts can be used
-flow uses CD markers
-Cytochemical uses granule contents seen
What can give a more precise classification of leukocyte neoplasms
Recurring chromosomal translocations
Genetic lesions
What does WHO emphasize
molecular and cytogenetic changes
classification of myloid malignancies with AMLs
B-ALL is subdivided into 7 types
T cell lymph are not divided subclinically
What is a myelodysplastic syndrome
-acquired clonal hematological disorders
-progressive cytopenia’s in the peripheral blood with defects in erythroid, myeloid or megakaryocytic maturation
PB cytopenia despite hypercellular BM
Dyspoiesis in cell lines
-BM isnt making enough healthy cells
-age of most that get it 70
-develops after chemo or radiation
-mutated stem cell that proliferates into clone of abnormal cell
-need Bone marrow, PB, cytogenetics, molecular diagnostics & flow cytometry for diagnosis
-mimics MEGA and IDA
What is refractory anemia or preleukemia
another name for myelodysplastic syndrome
-because pt have feature of megaloblastic anemia or iron deficiency anemia but didnt repost to treatment of iron, folic acid, B12
How does MDS occur
-GEMM myeloid progenitor is mutated
-affecting erythroid, myeloid or megakaryocytic cell lines
-lymphoid not likely affected
-mutated stem cell produces a pathologic clone that expands at the expense of other cells = dysplastic hematopoiesis
-can disrupt apoptosis causing premature death
-apoptosis regulated cell population by decreasing cell survival
MDS vs. Leukemia
Chromosome abnormalities in MDS are usually chromosomal deletions as opposed to translocations like in Acute leukemia
distinguish based on morphology, % blasts, cytogenetic abnormalities
What is dyspoiesis
occurs in MDS
-when blood cells become abnormal in appearance and function
-pancytopenia in PB with <20% in BM
-preleukemia turns into leukemia
-MDS has 20% more blasts in BM
MDS does transform into leukemia so monitoring BM is important
Morphologic Evidence of Dyserythropoiesis
In Peripheral blood:
Oval macrocytes even with normal B12
Hypochromic microcytes even with normal iron
Dimorphic RBC population
Basophilic stippling, HJB,
Morphologic Evidence of Dyserythropoiesis
In Bone Marrow
RBC precursors with:
More than one nucleus - lobes or buds
Abnormal nuclear shapes
Uneven cytoplasmic staining - Bso stippling, or uneven staining
Ringed sideroblasts
precursors also showing nuclear bridging
What will neutrophils look like in Dysmyelopoiesis
nuclear or cytoplasmic dysplasia
cytoplasm is unevenly stained or is basophilic
-hypo/hyper granulation
Nucleus
hypo or hyper segmentation
Pseudo- Pelger Huet
-Asynchrony in maturation where the chromatin is clumped but the shape is immature (hyposegmented)
Dysmegakaryocytopoiesis in MDS - Morphology
Thrombocytopenia (60%)
Giant platelets
Hypogranulation
Micromegakaryocytes in PB seen with budding of the cytoplasm
What abnormal function can arise from abnormal maturation of cells
- granulocytes can have decreased adhesion, deficient phagocytosis, decreased chemotaxis, or impaired microbicidal capacity
RBCs can have shortened lifespans, precursors can have a decreased response to EPO causing anemia
-pts can have increased bleeding despite adequate number of platelets
type and degree of dysfunction depend on the mutation present in the hematopoietic stem cell.
What other conditions can cause dysplasia
dysplasia is not enough to diagnose MDS
Vitamin B12or folate deficiency (pancytopenia and dysplasia)
-heavy metals (Copper deficiency may cause reversible myelodysplasia)
-Fanconi anemia and congenital dyserythropoietic anemia
-Parvovirus B19 and some chemotherapeutic agents
-Paroxysmal nocturnal hemoglobinuria
-Human immunodeficiency virus (HIV)
Myelodysplastic Syndrome (MDS) Classification:
FAB and WHO
FAB – based on morphology
% blasts in BM
amount of dysplasia
Which cells lines show pancytopenia
Refractory
RARS, RAEB, CMML, RAED-t
WHO – based on :
Molecular
Cytogenetic
Chromosome abnormalities
Best to differentiate from acute leukemias
Immunological (CD markers)
What is Refractory Anemia (RARS)
low grade MDS with anemia and BM erythrodysplasia
-low amount of blasts
-can have megaloblastic changes with oval macros, multi nucs, fragmentation, or cytoplasmic budding
-has 15% ringed sideroblasts where iron laden mitochondria are around 1/3 of the nucleus
What is Chronic Myelomonocytic Leukemia CMML
-persistent monocytosis of more than 1.0× 10^9/L
-too many monos and immature monos
-less blasts and promonocytes
-dysplasia in 1 or more myeloid cell lines
-pts will have increased leukocytes with absolute monocytosis
-splenomegaly
colonial diseases
hematological conditions that are derived from a single cell
