Haematology Flashcards
what is myeloma?
- a malignant (cancer) disease of differentiated bone marrow plasma cells, accounting for 1% of plasma cells
- clonal expansion of abnormal, proliferating plasma cells producing a monoclonal paraprotein
- accumulation of malignant plasma cells in the bone marrow leads to progressive bone marrow failure
what is the monoclonal paraprotein that is produced in myeloma?
mainly IgG (55%) or IgA (20%) and rarely IgM and IgD
- produced by clonal expansion of abnormal, proliferating plasma cells
- malignant plasma cells just produce an excess of one type of immunoglobulin (monoclonal paraprotein)
- may be associated with excretion of light chains in urine (Bence Jones protein), kappa or lambda
what are differences in production of paraprotein/light chain production in myeloma?
- production of paraprotein may be associated with excretion of light chains in urine (Bence Jones protein), kappa or lambda
- in 20% there is no paraproteinaemia, only light chains in urine
- non secretory myeloma in <5%: no paraprotein or light chains
what is the epidemiology of myeloma?
- disease of the elderly
- median age at presentation is over 60yrs
- rare under 40yrs
- annual incidence is 4 per 100000
- commoner in males and black Africans
- less common in asians
what are clinical features of myeloma?
- bone destruction often causing long bone fractures or vertebral collapse, osteolytic lesions, pathological fractures, spinal cord compression and hypercalcaemia and back pain
- soft tissue plasmacytomas
- bone marrow infiltration with plasma cells -> anaemia, neutropenia, thrombocytopenia, paraprotein production which may lead to hyperviscosity, infections and bleeding
- kidney injury
how can myeloma cause kidney injury?
- deposition of light chains in the renal tubules
- hypercalcaemia
- hyperuricaemia
- use of NSAIDs
- deposition of AL amyloid (rare)
what types of cytogenetic abnormalities have been found in myeloma?
associated with poor survival
- chromosome 13
- hypodiploidy (<45 chromosomes)
- t(4;14), t(14;16) and p53 (17p) deletions
associated with better prognosis
- t(11:14)
- hyperdiploidy (>50 chromosomes)
what is the WHO (2008) classification of plasma cell neoplasms?
- monoclonal gammopathy of undetermined significance
- plasma cell myeloma
- solitary plasmacytoma of bone
- extraosseous plasmacytoma
- monoclonal immunoglobin deposition diseases
- heavy chain diseases
what are types of heavy chain diseases?
Gamma heavy chain disease
Mu heavy chain disease
Alpha heavy chain disease
what are features of bone disease caused by myeloma?
- dysregulation of bone remodelling -> lytic lesions in spine, skull, long bones, ribs
- increased osteoclastic activity with no increased osteoblast formation of bone
- adhesion of stromal cells to myeloma cells
what does adhesion of stromal cells to myeloma cells stimulate?
production of RANKL, IL-6 and VEGF
- RANKL stimulates osteoclast formation and the lytic lesions
- myeloma cells produce dickkopf-1 (DKK1) which inhibits osteoblast activity and production of new bone
what is DKK1? what is its action in myeloma?
dickkopf-1
- produced by myeloma cells
- inhibits osteoblast activity and production of new bone
- binds to Wnt co-receptor, lipoprotein receptor-related protein 5 (LRP5), inhibiting Wnt signalling and osteoblast differentiation
what are life-threatening complications of myeloma? how are they treated?
- renal impairment (due to hypercalcaemia) -> urgent attention and long-term dialysis
- hypercalcaemia treated by rehydration and bisphosphonates e.g. pamidronate
- spinal cord compression treated by dexamethosome and radiotherapy
- hyperviscosity due to paraprotein treated by plasmapheresis
what are general investigations of myeloma and what may be found?
- FBC (Hb, WCC and platelet count are normal/low; shows anaemia, thrombocytopenia and leucopenia)
- ESR (often high)
- blood film (may be roleaux formation due to paraprotein and circulating plasma cells)
- U+E (evidence of kidney infection)
- serum biochemistry (calcium normal or raised; serum alkaline phosphatase usually normal)
- serum beta2-microglobulin and albumin used in prognosis
what are immunoglobin investigations of myeloma?
- total protein normal or raised
- serum protein electrophoresis and immunofixation shows monoclonal band and immune paresis
- serum free light chain assay (abnormal ratio and increased total amount of light chains)
- 24hr urine electrophoresis and immunofixation for light chain excretion
what are radiological investigations of myeloma?
skeletal survey
- lytic lesions, esp. in skull
- CT, MRI and PET used in plasmacytomas
- MRI spine useful if back pain
when can symptomatic myeloma (SMM) be diagnosed?
if either of the following are present:
- significant paraproteinaemia
- increased bone marrow plasma cells (>10%)
with evidence of end organ failure i.e. hypercalcaemia, renal impairment, anaemia, lytic bone lesions (CRAB)
what is AMM? how is it diagnosed?
asymptomatic myeloma
- 10% of cases
- significant paraprotein (IgG or IgA >30g/dL or urinary light chain excretion >1g/day) and/or marrow plasmacytosis but no end organ damage
- time to progression ~2-3yrs
- risk is highest for IgA isotype and light chains in urine
what is MGUS? how is it diagnosed?
monoclonal gammopathy of unknown significance
- isolated finding of a monoclonal paraprotein in serum that doesn’t fulfil diagnostic criteria for SMM or AMM
- raised level of paraprotein (usually IgA) found in blood, without other features of myeloma
- usually in elderly
- 20-30% develop muliple myeloma over 25yrs
- low risk: IgG subtype, paraprotein <15g/dL and normal serum free light chain ratio
what is plasmacytoma? how is it diagnosed?
- isolated tumour of neoplastic plasma cells
- no evidence of multiple myeloma
- may be solitary plasmacytoma outside the marrow cavity typically in upper aerodigestive tract
what are features of supportive therapy for myeloma?
- anaemia corrected by blood transfusion and/or erythropoietin
- hypercalcaemia, kidney injury and hyperviscosity treated
- infection treated with antibiotics
- yearly flu vaccinations
- bone pain helped by radiotherapy and systemic chemotherapy or high-dose dextamethasone, and analgesia
- hyperviscosity treated by plasmapheresis together with systemic therapy
- avoid NSAIDs due to risk of renal impairment
- bisphosponates to reduce progression of bone disease; they inhibit osteoclastic activity
- pathological fractures prevented by orthopaedic surgery with pinning of lytic bone lesions at critical sites seen on skeletal surgery
what are examples of specific therapy for myeloma?
- thalidomide
- chemotherapy
- stem cell transport
- high-dose melphalan autograft
- allogeneic transplant
- melphalan and prednisolone
- bortezomib
- bisphosphonates e.g. Zolendronate
- lenalidomide
- rehydrate and ensure 3L/day to prevent further renal damage
how does myeloma lead to immunoparesis?
monoclonal paraprotein production -> other immunoglobin levels are low, leading to increased susceptibility to infections
what does OLD CRAB mean, in relation to myeloma?
clinical presentation of myeloma
• old age
• calcium elevated
• renal failure - nephrotic syndrome, due to raised immunoglobulins which are proteins which precipitate (especially immunoglobulin light chains) and deposit in organs especially the kidneys - results in thirst due to lack of water retention due to failure
• anaemia - neutropenia or thrombocytopenia resulting in infection, bleeding and fatigue and pallor
• bone lytic lesions - back pain
what is seen in blood tests in myeloma?
- normocytic normochromic anaemia
- raised ESR
- rouleaux formation on blood film
how is U+E used to diagnose myeloma?
- high calcium
- high alkaline phosphatase
- Bence-jones protein in urine
what is seen in plain X-ray in myeloma?
• lytic ‘punched-out’ lesions: - pepper-pot skull - vertebral collapse • fractures • osteoporosis
what types of chemotherapy are used to treat myeloma?
CTD: Cyclophosphamide, Thalidomide and Dexamethsasone; max 8 cycles, for less fit people
VAD: Vincristine, Adriamycine and Dexamethasone in fitter people; max 6 cycles
what are lymphomas?
- lymphomas are disorders caused by malignant proliferations of B and T lymphocytes
- these accumulate in the lymph nodes causing lymphadenopathy, may also be found in the peripheral blood or infiltrate organs
- predominantly in lymph nodes but also blood, bone marrow, liver, spleen, anywhere
what can lymphomas be histologically divided into?
Hodgkins and Non-Hodgkins lymphoma
what characterises Hodgkins lymphoma?
have characteristic cells with mirror-image nuclei called Reed-Sternberg cells
what characterises non-Hodgkins lymphoma?
- do not have characteristic cells
- low grade e.g. Follicular Lymphoma
- high grade e.g. Diffuse Large B Cell Lymphoma
- very high grade e.g. Burkitt’s Lymphoma
what is the causes of lymphomas?
primary immunodeficiency:
- ataxia telangiectasia
- Wiscott-Aldrich syndrome
- common variable immunodeficiency
secondary immunodeficiency:
- HIV
- transplant recipients
infection:
- Epstein-Barr Virus (EBV)
- Human T-lymphotropic virus
- Helicobacter pylori
autoimmune disorders e.g. SLE
what is the epidemiology of Hodgkins lymphoma?
- male predominance
- majority of cases occur in teenagers e.g. 13-19 and elderly e.g. over 65
- 2 peaks of incidence; teenagers and elderly
- Epstein-Barr Virus (EBV) has a suggested role in pathogenesis
what can Hodgkins lymphoma be further divided into?
- classical Hodgkins lymphoma (cHL)
- nodular lymphocyte predominant Hodgkins lymphoma (NLPHL)
what is classical Hodgkins lymphoma characterised by?
- Reed-Sternberg cell with mirror image nuclei
- 90-95% of cases
what is nodular lymphocyte predominant Hodgkins lymphoma characterised by?
the Reed-Sternberg variant, the popcorn cell
what are risk factors for Hodgkins lymphoma?
- affected sibling
- Epstein-Barr virus (glandular fever) - ‘hide’ in white blood cells and can result in malignancy
- SLE
- obese
- post-transplantation
what is clinical presentation of Hodgkins lymphoma?
- most commonly there is painless cervical lymphadenopathy, described on examination as ‘rubbery’
- a smaller proportion of patients (often young women) present with disease localised to the mediastinum with cough due to mediastinal lymphadenopathy
- generalised disease including hepatosplenomegaly and constitutional B symptoms (weight loss, fever, night sweats)
- other constitutional symptoms e.g. pruritus, fatigue, anorexia and alcohol-induced pain at the site of the enlarged lymph nodes also occur
what are some constitutional B symptoms in Hodgkins lymphoma?
weight loss, fever, night sweats
what is the emergency presentation of Hodgkins lymphoma?
- infection
- superior vena cava obstruction with increased jugular venous pressure (JVP)
- sensation of fullness in the head
- dyspnoea
- blackouts
- facial oedema
how is Hodgkins lymphoma diagnosed?
- CT/MRI of chest, abdomen and pelvis for staging (Ann Arbor); may show intrathoracic, abdominal and pelvic nodes
- lymph node excision or bone marrow biopsy; shows mirror-image nuclei Reed-Sternberg cells or popcorn cells
- liver biochemistry may be abnormal, with or without liver involvement
- bloods film and bone marrow:
• high ESR or Low Hb - indicate worse prognosis
• high serum lactate dehydrogenase - immunophenotyping
- cytogenetics
- PET scan
- molecular techniques (PCR)
what is used to stage Hodgkins lymphoma?
Ann Arbor classification
- 4 stages
- each stage is either A, B, X or E
what is stage I Hodgkins lymphoma?
involvement of a single lymph node region or a single extralymphatic organ or site
what is stage II Hodgkins lymphoma?
involvement of two or more lymph node regions on the same side of the diaphragm, or localized involvement of an extralymphatic organ or site and of one or more lymph node regions on the same side of the diaphragm
what is stage III Hodgkins lymphoma?
involvement of lymph node regions on both sides of the diaphragm, which may also be accompanied by involvement of the spleen (IIIS) or by localized involvement of an extralymphatic organ (IIIE) or site or both (IIISE)
what is stage IV Hodgkins lymphoma?
diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement
what does A, B, X and E mean in the Ann Arbor classification of Hodgkins lymphoma?
- A: no systemic symptoms other than pruritus (severe itching of skin)
- B: presence of B symptoms such as fever, weight loss and night sweats
- X: bulky disease
- E: involvement of a single extranodal site that is contiguous or proximal to the known nodal site
what is the treatment of Hodgkins lymphoma?
combination chemotherapy - ABVD: • A - Adriamycin • B - Bleomycin • V - Vinblastine • D - Dacarbazine
how is ABVD combination chemotherapy used to treat Hodgkins lymphoma?
stages I-A to II-A (with less than 3 areas involved and no bulk):
• short course of ABVD followed by involved field irradiation
stages II-A to IV-B (with more than 3 areas involved):
• longer course of ABVD
• cyclical combination chemotherapy (8 cycles of AVBD) with irradiation at sites of bulk disease
• PET/CT used to detect disease activity after treatment and to distinguish between active tumour (PET-positive) and necrosis or fibrosis (PET-negative) in residual masses
- irradiation, with its attendant complications, can be omitted in PET-negative masses after chemotherapy
what are complications of treatment of Hodgkin’s lymphoma?
radiotherapy:
- may increase risk of second malignancies - solid tumours especially in the lung, breast, melanoma, stomach, sarcoma and thyroid
- increase risk of ischaemic heart disease, hypothyroidism and lung fibrosis due to radiation field
chemotherapy:
- myelosuppression, nausea, alopecia (hair loss) and infection
- infertility
what is the epidemiology of non-Hodgkin’s lymphoma?
- includes all lymphomas without Reed-Sternberg cells
- around 80% is of B-cell origin, diffuse large B-cell lymphoma (DLBCL) is commonest
- around 20% is of T-cell origin
- generally more varied in terms of presentation, sub-types, treatments and outcomes
- presentation rare before 40yrs
- not all centre on nodes
- there is a strong link with Epstein-Barr virus and Burkitts lymphoma
what are risk factors for non-Hodgkin’s lymphoma?
- nodal disease (75%) e.g. superficial lymphadenopathy
- extranodal disease (25%): skin (esp. T cell lymphomas and oropharynx, gut, small bowel, bone, CNS and lungs)
- systemic B symptoms
- pancytopenia
what is non-Hodgkin’s lymphoma classified into?
low/indolent grade and high grade
what are features and an example of low/indolent non-Hodgkin’s lymphoma?
example is Follicular Lymphoma
- slow growing
- usually advanced at presentation
- incurable
- median survival 9-11 years
what are features and an example of high grade non-Hodgkin’s lymphoma?
example is Diffuse Large B-cell Lymphoma
- usually has nodal presentation
- 1/3 cases have extranodal involvement
how is non-Hodgkin’s lymphoma diagnosed?
- raised lactate dehydrogenase reflects worse prognosis since its a sign of increased cell turnover and thus cell proliferation
- blood count: may show anaemia, ESR may be raised, elevated WCC or thrombocytopenia suggests marrow involvement
- liver biochemistry abnormal if liver involved
- serum lactate dehydrogenase and beta2-microglobulin are prognostic indicators
- CXR, CT, PET and gallium scans helpful in staging
- lymph node excision or bone marrow biopsy; will not see mirror-image nuclei Reed-Sternberg cells or popcorn cells
- marrow aspiration and trephine biopsy confirms marrow involvement
- CT/MRI of chest, abdomen and pelvis for staging (Ann Arbor)
- immunophenotyping
- cytogenetics
what is treatment of non-Hodgkin’s lymphoma?
R-CHOP regimen: • R - Rituximab (monoclonal antibody - minimal side effects) • C - Cyclophosphamide • H - Hydroxy-daunorubicin • O - Vincristine (Oncovin brand name) • P - Prednisolone
with field irradiation for those with bulky disease
60-70% of those with early-stage disease are cured with this regimen
what is Rituximab?
- monoclonal antibody
- targets CD20 expressed on cell surface B cells
- chimeric mouse/human protein
- minimal side effects
how is low grade non-Hodgkin’s lymphoma treated?
- none may be required
* radiotherapy may be curative in localised disease
what is treatment for high grade non-Hodgkin’s lymphoma?
early:
- 3 months R-CHOP regimen with radiotherapy
late:
- 6 months R-CHOP regimen with radiotherapy
what is Burkitt’s lymphoma? what is the treatment?
- endemic, sporadic and AIDS related types
- occurs mainly in African children
- associated with EBV infection
- usually B cells with jaw lymphadenopathy in children, usually with gastrointestinal involvement
- treatment with cyclical combination chemotherapy
what are the four main subtypes of leukaemia?
- acute lymphoblastic leukaemia (ALL)
- acute myeloid leukaemia (AML)
- chronic myeloid leukaemia (CML)
- chronic lymphocytic leukaemia (CLL)
what is leukaemia?
- malignant neoplasms of haemopoietic stem cells (can be precursors of RBCs, platelets or white cells) in the bone marrow that are non functional
- proliferate rapidly
- characterised by diffuse replacement of bone marrow by neoplastic cells
- leukaemic cells usually spill over into the blood, where they may be seen in large numbers
- may also infiltrate the liver, spleen, lymph nodes and other tissues
what is the basic pathophysiology of leukaemia?
- firstly, the leukaemia cells are dividing rapidly but serve no function and are wasting energy making useless cells and there is less energy available to make useful functional cells
- secondly, due to rapid replication these cells take up a lot of space within the bone marrow meaning there is little space and food for other cells to grow
• the bone marrow is unable to make as many normal functioning cells resulting in non-functional cells in the blood and symptoms of leukaemia
• eventually when there is no longer space in the bone marrow, leukaemia cells will be present in the blood too
what is the epidemiology of acute lymphoblastic leukaemia?
- most common between 2 and 4 years of age
- the commonest cancer in childhood
- thought to develop from a combination of genetic susceptibility and an environmental trigger
- ionising radiation e.g. x-rays during pregnancy and Down’s syndrome (trisomy 21) are important associations
- CNS involvement is common
what is acute lymphoblastic leukaemia? what happens in it?
- malignancy of immature lymphoid cells (give rise to T cells and B cells)
- affects B or T lymphocyte cell lines, arrests the maturation and promotes uncontrolled proliferation of immature blast cells (immature precursor of
myeloid cells (myeloblasts) or lymphoid cells (lymphoblast)) - majority of cases derive from B-cell precursors
- there is increased proliferation of immature lymphoblast cells (B or T cell precursors) in the bone marrow:
• if all B cells = children
• if all T cells = adults
what are clinical presentations of acute lymphoblastic leukaemia?
- marrow failure
- organ infiltration
- bone marrow infiltration resulting in bone pain and anaemia, bleeding and infection
- liver/spleen infiltration resulting in hepatosplenomegaly
- node infiltration resulting in lymphadenopathy
- CNS infiltration resulting headache and cranial nerve palsies
- mediastinum infiltration resulting in mediastinal masses with superior vena cava obstruction
what are features of marrow failure in acute lymphoblastic leukaemia?
anaemia - low Hb:
- resulting in breathlessness, fatigue, angina and claudication
- there is pallor and cardiac flow murmur
infection - low WCC:
- resulting in infections
- there is fever and mouth ulcers
bleeding - low platelets:
- resulting in bleeding and bruising
how is acute lymphoblastic leukaemia diagnosed?
- FBC and blood film:
• WCC is usually high
• blast cells on film and in bone marrow - CXR and CT scan to look for mediastinal and abdominal lymphadenopathy
- lumbar puncture to look for CNS involvement
what is the treatment of acute lymphoblastic leukaemia?
- blood and platelet transfusions
- neutropenia may lead to deadly infections; treat with prophylactic antivirals, antibacterials and antifungals
- allopurinol (prevents tumour lysis syndrome)
- IV fluids - insert Hickman line (permanent cannula into main vessel, tunnelled under sub-cutaneous fat so harder for infection to arise) so can easily take blood for testing and administer drugs and fluids
- remission induction with combination chemotherapy including vincristine, dexamethasone, asparaginase and daunorubicin
- involves CNS, so prophylaxis of intrathecal drugs, methotrexate or cytosine arabinoside and occasionally cranial irradiation is used
- marrow transplantation
what is acute myeloid leukaemia?
the neoplastic proliferation of blast cells derived from marrow myeloid (gives rise to basophils, neutrophils and eosinophils) elements
what is the epidemiology of acute myeloid leukaemia?
- progresses rapidly with death in 2 months if untreated
- affects mostly children
- the commonest acute leukaemia of adults
- associated with radiation and syndromes such as Down’s (trisomy 21)
- complete remission is usually achieved in about 80% of patients under 60 years with no comorbidity, in whom treatment is offered with curative intent
what is clinical presentation of acute myeloid leukaemia?
- marrow failure
- hepatomegaly and splenomegaly occur due to infiltration
- gum hypertrophy
- DIC occurs in a subtype of AML where there is release of thromboplastin
how is acute myeloid leukaemia diagnosed?
- WCC is often raised, but can be normal or even low
- may be few blast cells in the peripheral blood so diagnosis depends on bone marrow biopsy
- differentiation from acute lymphocytic leukaemia is based on microscopy, immunophenotyping and
molecular methods
what are complications of acute myeloid leukaemia?
- infection is a major issue; be alert to septicaemia
- causes common organisms to present oddly, with few antibodies being made
what is treatment of acute myeloid leukaemia?
- blood and platelet transfusions
- neutropenia may lead to deadly infections; treat with prophylactic antivirals, antibacterial and antifungals
- allopurinol (prevents tumour lysis syndrome)
- IV fluids - insert Hickman line (permanent cannula into main vessel, tunnelled under sub-cutaneous fat so harder for infection to arise) so can easily take blood for testing and administer drugs and fluids
- chemotherapy
- marrow transplantation
what is the epidemiology of chronic myeloid leukaemia?
- most exclusively a disease of adults
- uncontrolled clonal proliferation of myeloid cells
- occurs most often between 40-60 yrs
- slight male predominance
- rare in childhood
- insidious onset
- more than 80% have the Philadelphia chromosome which forms a fusion gene BCR/ABL on chromosome 22, which has tyrosine kinase activity: stimulates cell division
what is the clinical presentation of chronic myeloid leukaemia?
- chronic phase lasts 3-4 years, followed by blast transformation with development of acute leukaemia and rapid death
- may also transform into myelofibrosis, with death from bone marrow failure
- symptomatic anaemia e.g. shortness of breath
- abdominal discomfort due to splenomegaly
- weight loss
- tiredness
- pallor
- fever and sweats in the absence of infection
- may be features of gout due to purine breakdown
- may be bleeding due to platelet dysfunction
- 40-60yrs
- metabolic features
what is the action of the Philadelphia chromosome in leukaemia?
- esp. CML
- abnormality in chromosome 22
- defective and unusually short due to reciprocal translocation of genetic material between chromosome 9 and 22
- contains fusion gene called BCR-ABL1
- codes for a hybrid 210-kDa fusion protein: a tyrosine kinase signalling protein that is always on, causing the cell to divide uncontrollably by interrupting stability of the genome and impairing signalling pathways
how is chronic myeloid leukaemia diagnosed?
blood count:
• very high WCC, often > 100 × 109/L; with whole spectrum of myeloid cells i.e. increased neutrophils, myelocytes, basophils and eosinophils
• low Hb (normochromic and normocytic anaemia)
• platelets are low, normal or raised
bone marrow aspirate:
- hypercellular (increased myeloid progenitors)
what is the treatment of chronic myeloid leukaemia?
- oral Imatinib (Glivec); specific BCR/ABL1 tyrosine kinase inhibitor; produces a complete haematological response in over 95% of patients
- Nilotinib, Dasatinib, Ponatinib (tyrosine kinase inhibitors)
- stem cell transplant
what is the epidemiology of chronic lymphocytic leukaemia? what is it?
- the most common leukaemia
- often incidental finding on FBC
- occurs predominantly in later life
- it is the uncontrolled proliferation and accumulation of mature B cells that have escaped programmed cell death and undergone cell-cycle arrest
- mutations, trisomies and deletions influence risk
- pneumonia may be a triggering event
what is the most common leukaemia?
chronic lymphocytic leukaemia
what is the clinical presentation of chronic lymphocytic leukaemia?
- often no symptoms, presenting as a surprise on a routine FBC (done pre-op)
- may be anaemic (due to haemolysis or marrow infiltration) or infection prone
- if severe then weight loss, sweats and anorexia
- hepatosplenomegaly
- enlarged, rubbery, non-tender nodes
- indolent corse
how is chronic lymphocytic leukaemia diagnosed with blood count and blood film?
blood count
• normal or low Hb
• raised WCC with lymphocytosis (> 5 × 109/L)
• may be anaemia and thrombocytopenia
blood film
• smudge cells may be seen in vitro; these are small lymphocytes of mature appearance with are an artefactual finding due to cell rupture while the film is being made
bone marrow
• reflects peripheral blood usually heavily infiltrated with lymphocytes
immunophenotyping and cytogenetics
what are the complications of chronic lymphocytic leukaemia?
- autoimmune haemolysis
- increased infection risk due hypogammaglobulinaemia (low IgG); bacterial and viral especially herpes zoster
- marrow failure
what is the progression of chronic lymphocytic leukaemia?
- many stay stable for years and may even regress
- death is often due to complication of infection
- may transform into aggressive lymphoma = Richter’s syndrome
- the median survival from diagnosis is very variable and correlates closely with disease stage at diagnosis and cytogenetic findings, e.g. patients with either 11q or 17p deletions (the sites of two tumour suppressor genes) are at high risk of not responding to initial treatment and rapid progression. In other patients there is near-normal life expectancy.
what is the treatment of chronic lymphocytic leukaemia?
- blood transfusions
- combination therapy with fludarabine, cyclophosphamide and rituximab is standard first line therapy
- chlorambucil usually reduces lymphocytosis, lymphadenopathy and splenomegaly in older patients
- alemtuxumab used in patients where there is disease progression after treatment with Fludarabine
- human IV immunoglobulins
- chemotherapy or radiotherapy
- monoclonal antibodies (e.g. anti-CD20: rituximab)
- try stem cell/bone marrow transplant
what is the rule of 3s of prognosis for chronic lymphocytic leukaemia?
- 1/3 will never progress
- 1/3 progress slowly
- 1/3 progress actively
what are late effects of lymphoma?
- infertility
- anthracyclines; cardiomyopathy
- bleomycin; lung damage
- vinca alkaloids; peripheral neuropathy
- second cancers
- psychological cancers
what is treatment of indolent non-Hodgkin’s lymphoma?
- alkylating agents
- combination chemotherapy
- purine analogues
- monoclonal antibodies
- radio-immunoconjugates
- new oral targeted agents
- radiotherapy
- bone marrow transplant
- do nothing
what haemopoietic cells does each type of leukaemia affect?
acute myeloid leukaemia = myeloblast
chronic myeloid leukaemia = basophil, neutrophil, eosinophil
acute lymphoblastic leukaemia = lymphoblast
chronic lymphocytic leukaemia = B lymphocyte
what can a multipotential haematopoietic stem cell differentiate into?
- common myeloid progenitor
- common lymphoid progenitor
what can a common myeloid progenitor differentiate into?
- megakaryocyte
- erythrocyte
- mast cell
- myeloblast
what can a megakaryocyte differentiate into?
platelets
what can myeloblasts differentiate into?
- basophil
- neutrophil
- eosinophil
- monocyte
what can a monocyte differentiate into?
macrophage (in tissues)
what can common lymphoid progenitors differentiate into?
- natural killer cell (large granular lymphocyte)
- small lymphocyte
what can small lymphocytes differentiate into?
- T lymphocyte
- B lymphocyte
what can B lymphocytes differentiate into?
plasma cells
what increases risk of acute myeloid leukaemia?
- preceeding haematological disorders
- prior chemotherapy
- exposure to ionising radiation
what is supportive care for acute myeloid leukaemia?
- HML
- blood product support
- prompt treatment of infectiosn
- recognition of atypical/unusual infections
what abnormalities are present in a good risk category for acute myeloid leukaemia?
t(8;21), t(15;17), inv(16)
- t(15;17) = acute promyelocytic leukaemia
what abnormalities are present in intermediate risk category for acute myeloid leukaemia?
normal, +8, +21, +22, del(7q), del(9q), abnormal 11q23, all other structural or numerical changes
what abnormalities are present in poor risk category for acute myeloid leukaemia?
-5, -7, del(5q), abnormal 3q, complex cytogenetics
what are features of acute promyelocytic leukaemia?
- 5-8% of AML in adults
- t(15;17) – PML/RARA gene
- blocks differentiation of promyelocyte to mature granulocyte
- haematological emergency – DIC
- 90% remission rate
- targeted treatment = ATRA
what are the outcomes of acute lymphoblastic leukaemia?
- children majority cured
- TYA (16-25yrs) most cured with Paediatric style treatment
- adults up to ½ cured
- depends critically on age and cytogenetics
what is the clinical staging of CLL?
Binet Stage
Stage A: lymphocytosis (<3 nodal areas): survival 10-15yrs
Stage B: nodes (3+ nodal areas): survival 5-7yrs
Stage C: anaemia and/or thrombocytopenia: survival 2-3yrs
what is autologous stem cell transplantation? what are advantages/disadvantages?
own
- enables escalation of chemo with stem cell rescue
- relatively straightforward
- mortality 2%
what is allogenic stem cell transplantation? what are advantages/disadvantages?
- much more toxic
- mortality 15-30%
- stem cells attack residual tumour (GVL)
- stem cells also attack recipient (GVHD)
- used in acute and chronic leukaemias
what is the definition of anaemia?
present when there is a decrease of haemoglobin in the blood below the reference level for the age and sex of the individual
what is the lifespan of erythrocytes?
120 days
what can cause anaemia?
- may be due either to a low red cell mass (RCM) or increased plasma volume (e.g. in pregnancy where there is small increase in red cell mass as well as high
plasma volume so concentration is decreased thus look anaemic) - may be due to reduced production from bone marrow or increased loss of RBC’s i.e. by the spleen, liver, bone marrow and blood loss and has many causes
what can cause reduced production from bone marrow or increased loss of RBCs?
- the test to determine if bone marrow production is the issue is to look at the reticulocyte count which is a count of immature RBC’s in the bone marrow
- if production is the issue then the reticulocyte count will be low
- if removal is the issue then the reticulocyte count will be high
what causes a falsely high haemoglobin? where can this be seen?
reduction in plasma volume
- seen in dehydration
what is MCV? how is it calculated?
- a measure of the average volume of a red blood corpuscle (or red blood cell)
- the measure is attained by multiplying a volume of blood by the proportion of blood that is cellular (the hematocrit), and dividing that product by the number of erythrocytes (red blood cells) in that volume
what are indices in anaemia?
- low MCV <80fL
- high MCV >96fL
- normal MCV
what are causes of microcytic anaemia?
- iron deficiency
- Thalassaemia
- anaemia of chronic disease
- sideroblastic anaemia
what can the appearance of bone marrow be with macrocytic erythrocytes?
- megaloblastic
- normoblastic
what can be diagnosed with macrocytic erythrocytes with megaloblastic appearance of bone marrow?
vitamin B12 or folate deficiency
what can be diagnosed with macrocytic erythrocytes, with normoblastic appearance of bone marrow?
- alcohol
- increased reticulocytes (e.g. haemolysis or haemorrhage)
- liver disease
- hypothyroidism
- drug therapy e.g. azathioprine
what are causes of normocytic anaemia?
- acute blood loss
- anaemia of chronic disease
- CKD
- combined deficiency, e.g. iron and folate
- autoimmune rheumatic disease
- marrow infiltration/fibrosis
- endocrine disease
- haemolytic anaemias
what are consequences of anaemia?
- reduced O2 transport
- tissue hypoxia
- compensatory changes
what are compensatory changes that occur due to anaemia?
- increased tissue perfusion
- increased O2 transfer to tissues
- increased RBC production
what are pathological consequences of anaemia?
- myocardial fatty change
- fatty change in liver
- aggravates angina and claudication
- skin and nail atrophic changes
- CNS cell death (cortex and basal ganglia)
what are non-specific symptoms of anaemia?
- fatigue, headaches and faintness
- dyspnoea and breathlessness
- angina if there is pre-existing coronary disease
- anorexia
- intermittent claudication
- palpitations
what are signs of anaemia?
- may be absent even in severe anaemia - this is because a very slowly falling level of Hb allows for haemodynamic compensation and enhancement of oxygen-carrying capacity of the blood
- pallor - skin and mucous membranes are pale
- tachycardia
- systolic flow murmur
- cardiac failure
what is the most common cause worldwide of microcytic anaemia?
iron deficiency anaemia
what is the average daily intake of iron? how much is absorbed?
average daily intake of iron is 15-20mg, although normally only 10% is absorbed in the duodenum
how is iron absorbed?
- actively transported into the duodenal intestinal epithelial cells by the intestinal haem transporter (HCP1) which is highly expressed in the duodenum
- some is incorporated into ferritin (protein-iron complex) that acts as an intracellular store for iron
what happens to absorbed iron that does not bind to ferritin?
released into the blood where it is able to circulate around the body bound to the plasma protein transferrin
what is the role of transferrin in iron transport?
- is a plasma protein which binds to absorbed iron that doesn’t bind to ferritin
- allows iron to circulate around the body in the blood
- transports iron in the blood plasma to the bone marrow to be incorporated into new erythrocytes
- synthesised in the liver
- normally about 1/3 saturated with iron
what happens to the majority of iron?
incorporated into haemoglobin in developing erythroid precursors and mature red cells
what happens to iron that is not incorporated into haemoglobin? where is it stored?
the rest is stored in reticuloendothelial cells, hepatocytes and skeletal muscle cells either as ferritin (majority; more easily mobilised than haemosiderin for Hb formation, found in small amounts in plasma and in
most cells especially liver, spleen and bone marrow) or haemosiderin in hepatocytes, skeletal muscle and reticuloendothelial macrophages
what is the epidemiology of iron deficiency anaemia?
- most common cause of anaemia worldwide
- seen in 14% of menstruating women
- develops when there is inadequate iron for haemoglobin synthesis
what are the causes of iron deficiency anaemia?
- blood loss
- poor intake; rare in developed countries
- increased demands e.g. in growth and pregnancy
- malabsorption/decreased absorption, e.g. small bowel disease or post-gastrectomy
what can cause blood loss that leads to iron deficiency anaemia?
- menorrhagia (severe menstruation with heavy blood loss)
- pregnancy and breast feeding
- GI bleeding
- hookworm - the leading cause of iron deficiency worldwide resulting in intestinal blood loss and iron deficiency
what are risk factors for iron deficiency anaemia?
- undeveloped countries
- high vegetable diet
- premature infants
- introduction of mixed feeding delayed, since breast milk contains low iron
what is the pathophysiology of iron deficiency anaemia?
less iron is available for haemoglobin synthesis; this is crucial for haemoglobin production, thus reduction in iron will result in a decrease in haemoglobin and smaller RBC’s resulting in microcytic anaemia
what is the clinical presentation of iron deficiency anaemia?
- fatigue, headaches and faintness
- dyspnoea and breathlessness
- angina if there is pre-existing coronary disease
- anorexia
- intermittent claudication
- palpitations
- may be absent even in severe anaemia
- pallor
- tachycardia
- systolic flow murmur
- cardiac failure
- brittle nails and hair
- spoon-shaped nails: koilonychia
- atrophy of the papillae of the tongue: atrophic glossitis
- angular stomatitis/cheilosis: ulceration of the corners of the mouth
what are differential diagnoses of iron deficiency anaemia?
- thalassaemia
- sideroblastic anaemia
- anaemia of chronic disease
what is used to diagnose iron deficiency anaemia?
- blood count and film
- serum ferritin
- serum iron
- serum soluble transferrin receptors
- further investigations into cause of blood loss e.g. GI tract examination
- low reticulocyte count
- bone marrow examination is generally unnecessary
what is seen on a blood count and film in iron deficiency anaemia?
- RBCs are microcytic (MCV <80fL) and hypochromic (MCH <27pg) (pale)
- there is poikilocytosis (variation in RBC shape) and anisocytosis (variation in RBC size)
what is seen on serum ferritin in iron deficiency anaemia?
- the level of serum ferritin reflects the amount of stored iron
- in simple iron deficiency this is low - confirms diagnosis
- however may be normal in malignancy or infection (since it rises in these events i.e. inflammation)
what is seen on serum iron in iron deficiency anaemia?
- serum iron is low
- total iron-binding capacity (TIBC) rises compared to normal, iron deficiency is present with the transferrin saturation (serum iron divided by TBIC) falls below 19%
what is treatment of iron deficiency anaemia?
- find and treat underlying cause
- oral iron e.g. ferrous sulphate or ferrous gluconate
- parenteral iron e.g IV iron or deep intramuscular iron in extreme cases e.g. severe malabsorption or when patients are intolerant
what are examples of oral and parenteral iron given to treat iron deficiency anaemia?
- oral iron e.g. ferrous sulphate or ferrous gluconate
- parenteral iron e.g. IV iron or deep intramuscular iron
what are side effects of oral iron? what can be done about this?
- nausea, abdominal discomfort, diarrhoea/constipation, black stools
- can give ferrous gluconate if side effects are bad
what is anaemia in chronic disease? what are the red cells like?
- anaemia that is secondary to a chronic disease; if the body is sick then the bone marrow will be too, resulting in anaemia
- occurs in patients with chronic inflammatory disease (e.g. Crohn’s and RA), chronic infections (e.g. TB), malignancy and CKD
- RBC’s are often normocytic but they can be microcytic, especially in rheumatoid arthritis and Crohn’s disease, or can be normochromic
what is the epidemiology of anaemia of chronic disease?
- the second most common anaemia
- the commonest anaemia in hospital patients
- occurs in individuals with chronic infections such as:
• tuberculosis
• Crohn’s
• rheumatoid arthritis
• SLE
• malignant disease
what are risk factors for anaemia of chronic disease?
have a chronic disease, e.g. • tuberculosis • Crohn’s • rheumatoid arthritis • SLE • malignant disease
what is the pathophysiology of anaemia of chronic disease?
- there is decreased release of iron from the bone marrow to developing erythroblasts (early RBC, before reticulocyte)
- an inadequate erythropoietin response (cytokine which increases RBC production) to anaemia
- high levels of hepcidin expression (binds to export transport protein, ferroportin, in the iron-absorbing cells in the duodenum, causing its degradation, with consequent reduction in trasnport of iron from duodenal cells into the plasma)
- decreased RBC survival
what is the clinical presentation of anaemia of chronic disease?
- fatigue, headaches and faintness
- dyspnoea and breathlessness
- angina if there is pre-existing coronary disease
- anorexia
- intermittent claudication
- palpitations
how is anaemia of chronic disease diagnosed?
- serum iron and total iron-binding capacity (TIBC) are low
- serum ferritin is normal or raised due to the inflammatory process
- serum soluble transferrin receptor level is normal
- blood count and film:
• RBC’s are normocytic or microcytic and hypochromic as in rheumatoid arthritis and Crohn’s
what is seen on blood count and film in anaemia of chronic disease?
RBC’s are normocytic or microcytic and hypochromic as in rheumatoid arthritis and Crohn’s
what is treatment of anaemia of chronic disease?
- treat underlying chronic cause
- erythropoietin is effective in raising the haemoglobin level and is used in anaemia of renal disease and inflammatory disease e.g. rheumatoid arthritis and inflammatory bowel disease
• side effects; flu-like symptoms, hypertension, mild rise in the platelet count and thromboembolism
what are side effects of erythropoietin used in anaemia of chronic disease?
flu-like symptoms, hypertension, mild rise in the platelet count and thromboembolism
what is the clinical presentation of normocytic anaemia?
- fatigue, headaches and faintness
- dyspnoea and breathlessness
- angina if there is pre-existing coronary disease
- anorexia
- intermittent claudication
- palpitations
how is normocytic anaemia diagnosed?
- normal B12 and folate
- raised reticulocytes
- Hb down
- blood count and film: RBCs are normocytic
what is the treatment of normocytic anaemia?
- treat underlying cause
- improve diet with plenty of vitamins
- erythropoietin injections
what are megaloblasts?
- erythroblasts with delayed nuclear maturation because of delayed DNA synthesis
- they are large (i.e. high MCV) and have no nuclei
- may also affect the white cells (causing hypersegmented neutrophil nuclei with six lobes, and sometimes leucopenia) and platelets (causing thrombocytopenia)
what is pernicious anaemia?
- B12 deficiency
- type of megaloblastic anaemia
- pernicious anaemia is an autoimmune disorder where the parietal cells of the stomach are attacked resulting in atrophic gastritis and the loss of intrinsic factor production and thus vitamin B12 malabsorption
where is vitamin B12 found?
meat, fish and dairy products but not plants
how long do body stores of vitamin B12 last?
4 years
how is vitamin B12 absorbed?
- B12 is absorbed by binding to intrinsic factor produced by the parietal cells of the stomach then being absorbed in the terminal ileum of the small intestines by carrier protein transcobalamin II
- B12 is liberated from protein complexes in food by gastric acid and pepsin
- binds to vitamin B12-binding protein (R binder) derived from saliva
what is vitamin B12 used for in the body?
- B12 is essential for thymidine and thus DNA synthesis
- thus in B12 deficiency there is an impairment of DNA synthesis resulting in delayed nuclear maturation resulting in large RBCs as well as decreased RBC production in the bone marrow
- this DNA impairment will affect all cells, but bone marrow is most affected since its the most active in terms of cell division
what are some causes of vitamin B12 deficiency? what is the most common cause?
- dietary (vegans)
- malabsorption (lack of intrinsic factor or terminal ileum removed/ileal resection)
- pernicious anaemia (most common cause)
what is the epidemiology of pernicious anaemia?
- the disease is common in the elderly (over 60)
- seen in all races but more common in fair-haired, blue eyed individuals and those who have blood group A
- more common in females than males
- there is also an association with other autoimmune disease e.g. thyroid disease, Addison’s disease and vitiligo
- many cases are undiagnosed
what are risk factors for pernicious anaemia?
- elderly
- female
- fair-haired, blue eyes
- blood group A
- thyroid and Addison’s disease
what is the pathophysiology of pernicious anaemia?
- parietal cell antibodies are present in the serum in 90% of patients with pernicious anaemia, and also in 10% of normal individuals
- intrinsic factor antibodies, although found in only 50% of patients with pernicious anaemia, are specific for diagnosis
- atrophic gastritis (plasma and lymphoid cell infiltration in the fundus)
- the parietal and chief cells are replaced by mucin-secreting cells
- there is achlorhydria (reduced HCL acid production) and the absent secretion of intrinsic factor
what is achlorhydria?
reduced HCL acid production
what is clinical presentation of pernicious anaemia?
- onset is insidious with progressively increasing symptoms of anaemia e.g. fatigue, headache, pallor, dyspnoea, anorexia, tachycardia and palpitations
- may have a lemon-yellow skin colour due to the combination of pallor and mild jaundice caused by excess breakdown of haemoglobin (due to fact that body will try to remove defective large RBCs)
- red sore tongue (glossitis) and angular stomatitis/cheilosis (ulceration of the corners of the mouth) may be present
- neurological features can occur with very low levels of serum B12 and include a polyneuropathy caused by symmetrical damage to the peripheral nerves and posterior and lateral columns of the spinal cord (subacute combined degeneration of the cord).
- the latter presents with progressive weakness, ataxia and eventually paraplegia if untreated.
- dementia and visual disturbances due to optic atrophy may also occur.
- there is a higher incidence of gastric carcinoma with pernicious anaemia than in the general population.
why may patients with pernicious anaemia have a lemon-yellow skin colour?
due to the combination of pallor and mild jaundice caused by excess breakdown of haemoglobin (due to fact that body will try to remove defective large RBCs)
what are neurological features seen with pernicious anaemia?
- only occur with very low levels of B12
- symmetrical paresthesia (burning or prickling pain, tingling) in fingers and toes
- early loss of vibration sense and proprioception
- progressive weakness and ataxia
- paraplegia may result
- dementia, psychiatric problems, hallucinations, delusions and optic atrophy may occur from vitamin B12 deficiency
what are differential diagnoses of pernicious anaemia?
- must differentiate from the other cause of megaloblastic anaemia - folate deficiency
- differentiate from other causes of B12 deficiency
- any disease in the terminal ileum or bacterial overgrowth in the small bowel can result in B12 deficiency
- gastrectomy
how is pernicious anaemia diagnosed?
- blood count and film
- serum bilirubin may be raised as a result of ineffective erythropoiesis resulting in increased RBC breakdown
- serum B12 is low, frequently <50ng/L
- red cell folate may be reduced because vitamin B12 is needed to convert serum folate to the active intracellular form
- Hb is low
- reticulocyte count is low
- intrinsic factor antibodies are diagnostic but lower sensitivity i.e. not present in all patients
- small bowel barium follow-through and distal duodenal biopsies may be needed
- bone marrow examination shows hypercellular bone marrow with megaloblastic changes
what is seen on a blood count and film in pernicious anaemia?
- typical of megaloblastic anaemia
- RBCs are macrocytic (MCV often >110fL)
- peripheral film shows oval macrocytes (large RBC’s) with hypersegmented neutrophil polymorphs with six or more lobes in the nucleus
- in severe cases, leucopenia and thrombocytopenia
what is the treatment of pernicious anaemia?
- if not pernicious anaemia then treat cause
- if a low B12 is due to malabsorption then injections are required
- if cause is dietary then give oral B12 2mg per day
- replenish B12 stores by giving IM hydroxocobalamin
where is folate found?
green vegetables e.g. spinach and broccoli, nuts, yeast and offal e.g. liver and kidney
in which patients may folate deficiency develop rapidly?
both poor intake and excess utilisation of folate e.g. in ICU
what is folate absorbed by?
duodenum/proximal jejunum (upper small intestine)
what is folate used for by the body?
- folate is essential for DNA synthesis
- thus in folate deficiency there is an impairment of DNA synthesis resulting in delayed nuclear maturation and in large RBCs as well as decreased RBC production in the bone marrow
- this DNA impairment will affect all cells, but bone marrow is most affected since it’s the most active in terms of cell division
- folate is also essential for fetal development; deficiency can result in neural tube defects
what are causes of folate deficiency?`
- main cause is poor intake e.g. poverty, alcoholics and elderly
- increased demand/utilisation e.g. pregnancy or increased cell turnover i.e. haemolysis, malignancy, inflammatory disease and renal dialysis
- malabsorption e.g. coeliac disease or Crohn’s disease
- antifolate drugs e.g. methotrexate and trimethoprim
