clinical oncology Flashcards
leukaemia: define leukaemia, explain the difference between lymphoid and myeloid leukaemia, and acute and chronic leukaemia; summarise the clinical, haematological features and genetic features of acute lymphoblastic leukaemia
define leukaemia
bone marrow disease normally causing increased WBC (“white blood”) - hence “cancer of blood”
epidemiology of leukaemia: common and mortality
most common cancers in men/women ages 15-24, main cause of cancer death between 1-34
leukaemia mechanism
mutations in single lymphoid or myeloid stem cell, leading progeny to show abnormalities in proliferation (too rapid), differentiation (don’t reach end cell) or cell survival (too long), leading to steady expansion of leukaemic clone
cells that can be mutated to be involved in leukaemia
pluripotent haematopoietic stem cell (mixed phenotype leukaemia), myeloid stem cell, lymphoid stem cell, pre-B lymphocyte, pre-T lymphocyte
2 hit hypothesis in leukaemia
first mutation gives growth/survival advantage to that line of cells, so expand at expense of normal cells; acquire second mutation to get leukaemia
how is leukaemia different to other cancers: tumours
most cancers exist as solid tumour, with other tumours present in leukaemia patients being uncommon (more often have leukaemic cells replacing normal bone marrow cells and circulating freely in blood stream)
how is leukaemia different to other cancers: cells
haemopoietic and lymphoid cells behave differently from other body cells: normal haemopoietic stem cells can circulate in blood and both stem cells and cells derived from them can enter tissues, and normal lymphoid stem cells recirculate between tissues and blood
how is leukaemia different to other cancers: benign and malignant, and impact on treatment
invasion and metastasis cannot be applied to cells that normally travel around body and enter tissues (must have another way to distinguish benign vs malignant), so treatment must be systemic
what are leukaemias that behave relatively benignly called
chronic
what are leukaemias that behave malignantly called, and outcome if not treated
acute (if not treated, disease is very aggressive and patient dies quite rapidly)
2 classifications of leukaemia
acute vs chronic, lymphoid (B/T cell) vs myeloid (granulocyte, monocyte, erythroid, megakaryocyte)
4 types of leukaemia
acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), chronic myeloid leukaemia (CML)
describe the 2 types of influences which cause a series of mutations in a single stem cell to cause leukaemia (causing characteristics due to proliferation of leukaemic cells and loss of function of normal cells)
some are identifiable oncogenic, while others are random errors that occur throughout life and accumulate in individual cells
3 important leukaemogenic mutations
mutation in known proto-oncogenes, creation of novel gene (e.g. chimaeric or fusion gene when chromosomes translocate), dysregulation of gene when translocation brings it under influence of promoter or enhancer of another gene
what other gene can be affected to contribute to leukaemogenesis
loss of function of tumour-suppressor gene (resulting from deletion or mutation of gene)
what 2 genetic tendencies can increase risk of leukaemia
tendency to increased chromosomal breaks, if cell cannot repair DNA (error persists)
what 4 inherited/other constitutional abnormalities can contribute to leukaemogenesis
Down’s syndrome, chromosomal fragility syndromes, defects in DNA repair, inherited defects of tumour-suppressor genes
4 identifiable causes (not mechanisms) of leukaemogenic mutations
irradiation, anti-cancer drugs, cigarette smoking, chemicals e.g. benzene
why might leukaemia be, in part, an inevitable result of ability of humanity to change through evolution
some mutations appear to be random events rather than caused by exogenous influence, so may result from nature of human genome
2 outcomes of cells continuing to proliferate but being unable to mature in acute myeloid leukaemia (AML)
build up of most immature cells (myeloblasts) in bone marrow with spread into blood; failure of production of normal functioning end cells e.g. neutrophils, monocytes, erythrocytes, platelets, so crowded out (plateles also consumed by intravascular coagulation)
what do mutations in AML usually affect
transcription factors (so transcription of multiple genes is affected)
what does the product of an oncogene prevent (usually acts in dominant manner)
normal function of protein encoded by its normal homologue, disturbing cell behaviour
what to mutations in CML usually affect
gene encoding a protein in signalling pathway between cell surface receptor and nucleus (either membrane receptor or cytoplasmic protein)
CML vs AML: cell kinetics and function
cell kinetics and function not as seriously affected in CML compared to AML
3 features of CML to ensure cell survives longer and leukaemic clone expands progressively
cell becomes independent of external signals, alterations in interaction with stroma, reduced apoptosis
CML vs AML: production of end cells (anaemia occurs due to crowding out of erythrocytes)
in AML there is failure of production of end cells, in CML there is increased production of end cells
ALL vs CLL: maturity of cells
ALL has increase in very immature cells (lymphoblasts) which fail to develop into mature T and B cells; CLL has abnormal mature T and B cells
what 7 things can accumulation of abnormal cells in leukaemia lead to
leucocytosis, bone pain (if leukaemia is acute), hepatomegaly, splenomegaly, lymphadenopathy (if lymphoid), thymic enlargement (if T lymphoid), skin infiltration (leukaemia cutis)
4 metabolic effects of leukaemic cell proliferation
hyperuricaemia -> renal failure; weight loss; low grade fever; sweating
3 effects of crowding out of normal cells in leukaemia
anaemia, neutropenia, thrombocytopenia
acute myeloid leukaemia consequence of thrombocytopenia
bruises and small haemorrhages
why could a sufferer of AML have an intraventricular haemorrhage
associated with disseminated intravascular coagulation, so consumes platelets, causing haemorrhages which can’t be plugged
2 abnormalities in buccal cavity due to AML
haemorrhage, swelling of gums (infiltration of gums by leukaemic cells)
what causes leukaemic cells to infiltrate gums in AML
chemotaxic stimli
what is a feature of CLL due to loss of normal T and B cell function
loss of normal immune function
main age groups affected by ALL, and mechanism for later peak
largely in children (later peak in middle and old age, which is genetically different - same as CML translocation)
what might B-lineage ALL result from
delayed exposure to common pathogen (early exposure to pathogen protects from ALL)
what can affect exposure to common pathogens affecting B-lineage ALL
family size, new towns, socio-economic class, early social interactions, variations between countries
other causes of ALL in young children
irradiation in utero, in utero exposure to certain chemicals; unlikely due to exposure of mutagenic drug (normally AML)
6 clinical features of ALL resulting from accumulation of abnormal cells
bone pain, hepatomegaly, splenomegaly, lymphadenopathy, thymic enlargement, testicular enlargement
4 clinical features of ALL, caused by anaemia, resulting from crowding out normal cells
fatigue, lethargy, pallor, breathlessness
2 clinical features of ALL, caused by neutropenia, resulting from crowding out normal cells
fever, other features of infection
3 clinical features of ALL, caused by thrombocytopenia, resulting from crowding out normal cells
bruising, petechiae, bleeding
5 haematological features of ALL
leucocytosis (due to lymphoblasts in blood), anaemia (normocytic, normochromic), neutropenia, thrombocytopenia, replacement of normal bone marrow cells by lymphoblasts
6 investigations for ALL
blood count and film, liver function, renal function and uric acid, bone marrow aspirate, cytogenetic/molecular analysis, chest x-ray
immunophenotyping ALL to determine lineage (myeloid can have granules so this aids diagnosis)
antibody binding to antigen (CD) to find lineage e.g. B-lineage and maturity of cells
why is cytogenetic/molecular analysis of ALL useful for managing individual patient and for advancing knowledge of leukaemia
gives information about prognosis (ALL is not single disease or even 2 diseases, and has multiple different leukaemogenic mechanisms giving different disease phenotypes), permits discoveries of leukaemogenic mechanisms and specific treatments
good and poor prognosis for ALL found by cytogenetic analysis
hyperdiploidy is a good prognosis, t(4;11) is a poor prognosis
3 leukaemogenic mechanisms of ALL
formation of fusion gene (due to translocation e.g. t(4;11)), dysregulation of proto-oncogene by juxtaposition of it to promoter of another gene (e.g. TCR gene), point mutation in proto-oncogene
cytogenetics of ALL (translocation causing fusion gene), and process by which FISH detect fusion gene
t(12;21)(p12;q22) leading to a ETV6-RUNX1 fusion gene; FISH (flurescence in situ hybridisation) using 2 fluorescent probes (green probe for ETV6 and red probe for RUNX1), so when a fusion gene is formed the two colours fuse to give a yellow fluorescent signal
advantage of FISH over immunophenotyping
can look for fusion gene without cell going into mitosis
3 types of treatment for ALL
supportive, systemic chemotherapy, intrathecal chemotherapy (into CSF and through BBB)
3 types of supportive treatment for ALL
red cells, platelets, antibiotics
EFS vs OS survival
event-free survival vs overall survival
