Malignant Haematology Flashcards
(85 cards)
1
Q
Mechanisms of low platelets
A
- decreased production (problem with bone marrow) - increased destruction/consumption - over-storage (pooled in spleen rather than circulation)
2
Q
Aetiology of thrombocytopenia
A
- laboratory artefact
- consumptive (sepsis, hypersplenism, DIC, TTP)
- immune (viral inc. HIV, hep B and C, meds, autoimmune, heparin induced)
- underproduction (B12/folate deficiency, alcohol, myelodysplasia/aplastic anaemia, marrow infiltration (leukemia), inherited syndrome, drugs (chemo, anti-epileptics, psych, rheumatological))
- dilutional (massive transfusion, pregnancy)
3
Q
Thrombocytopenia: common things to consider
A
- low platelets as a result of clumping? - check B12 and folate as can cause all types of cytopenias - LFTs, U&Es, clotting (does anything suggest alcohol use, alcohol is directly toxic to bone marrow), (also clotting to rule out DIC) HIV, Hep - can be presenting illness - medications? - are they acutely unwell? (1% of inpatients have low platelets)
4
Q
Thrombocytopenia: serious things to consider
A
- TTP - acute leukemia - DIC - Heparin-induced thrombocytopenia ITP
5
Q
Thrombocytopenia - when to contact haematology
A
- acute and platelets <50X109 without cause - chronic and platelets between 50-100 - bleeding - abnormal blood film - concerned about HIT or TTP
6
Q
Thrombocytopenia - other things to consider in context of low platelets
A
- is there bleeding (may need transfusion) - procedure planned? - pregnancy? very common in pregnancy - remember to do a pregnancy test
7
Q
What would indicate a myeloproliferative neoplasm? (in broad terms)
A
high platelets, high Hb, high white count
8
Q
Thrombocytosis - causes
A
- post-surgery - infection/inflammation (acute or chronic) - bleeding - iron deficiency - malignancy - rebound post-chemotherapy - hyposplenism (rare) - haematological malignancy (rare)
9
Q
First line investigations for thrombocytopenia
A
- inflammatory markers - ferritin - if acute and clear cause repeat once stimulus is over - check blood film if persistent
10
Q
When would you further investigate thrombocytopenia?
A
- persistent - no secondary cause - splenomegaly - unprovoked thrombosis
11
Q
Primary haematological causes of increased platelets
A
- Myeloproliferative neoplasms (ET, PV, PMF, CML) - any malignancy
12
Q
What gene mutation causes essential thrombocythaemia?
A
JAK2, MPL and CALR - remember around 15% are ‘triple negative”
13
Q
What is essential thrombocythaemia?
A
Clonal bone marrow disorder - type of cancer - that normally affects over 50s (rarely children)
14
Q
What investigations would you do for essential thrombocythaemia?
A
- normally picked up incidentally on FBC checking for other reasons - check no other secondary cause - bone marrow biopsy to confirm
15
Q
Management of essential thrombocythaemia
A
- aspirin for all (75mg) - reduces cardiovascular risk (main priority) - review all other cardiovascular risk factors (BP, lipids) - if high risk –> cytoreduction (1st line hydroxycarbamide) Prognosis is good - small risk that it transforms to more aggressive neoplasm (MF/acute leukemia)
16
Q
What makes a patient with essential thrombocythaemia high risk?
A
- over 60 years - platelets over 1500x109/L - previous thrombotic event - other cardiovascular risk factors
17
Q
Basic definition of polycythaemia
A
high haemoglobin and high haematocrit
18
Q
define pseudo/relative polycythaemia
A
caused by a reduction in plasma volume (e.g. dehydration, alcohol, diuretics) NOT increased red cell mass just appears increased
19
Q
What is true/absolute polycythaemia?
A
Red cell mass increased
20
Q
Causes of true polycythaemia
A
Most cases are due secondary to other medical problems: - hypoxia due to resp disease (hypoxic resp failure, OSA, smoking) - cyanotic cardiac disease - abnormal epo production or high altitude (abnormal epo production can be caused by renal carcinomas) - endocrine - testosterone, anabolic steroid, doping)
21
Q
When would you investigate polycythaemia?
A
When HCT is over 0.52 in men and 0.48 in women
22
Q
Primary polycythaemia
A
High red cells Classical picture = no secondary cause identified, epo low, JAK2 mutation identified
23
Q
Pathophysiology of JAK2 V617F mutation
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Mutation results in activation of JAK/STAT signalling pathway –> autonomous erythropoiesis not reliant on erythropoietin growth factor (also often have high PLT and WCC)
24
Q
Primary polycythaemia can present with:
A
- arterial and venous thrombosis - headaches/migraines/blurred vision - aquagenic pruritus - plethora - splenomegaly - haemorrhage - fatigue mainly over 50s
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Management of primary polycythaemia
- aspirin for all - review other cardiovascular risk factors - venesect HCT to \<0.45 (gets rid of excess RBC and decreases amount of iron available for erythropoiesis) - avoid iron supplementation - if high risk then cytoreduct rather than venesect (hydroxycarbamide) - prognosis good as long as blood counts are controlled
26
What is the pathophysiology of myelofibrosis?
- blood picture variable but film changes and splenomegaly - clonal stem cell disease: proliferation of multiple cell lineages and progressive marrow fibrosis - around 85% have mutation in JAK2, CALR, MPL - more aggressive compared with ET & PV
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Clinical picture of myelofibrosis
- weight loss, night sweats, itch and possible massive splenomegaly (that can cause abdo pain and other symptoms) - higher risk of transformation to acute leukemia - patients usually anaemic - can have low or high platelets and low or high WCC depending on stage of disease - leukoerythroblastic bold film with tear drop red cells - myelocytes seen on blood film
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Management of myelofibrosis
- supportive care - epo injections/transfusion for anaemia - ruxolitinib (JAK2 inhibitor) - improves spleen size and quality of life: use if splenomegaly and systemic Sx) - hydroxycarbamide for high platelets/WCC - allogeneic haematopoietic stem cell transplant if fit (bone marrow) particularly if high risk MF
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Name reactive causes of neutrophilia:
- infection/inflammation - malignancy - steroids (not normally \>20) - smoking (results in mixed leukocytosis) - hyposplenism/asplenia - rebound post chemo ALWAYS CHECK FOR SPLENOMEGALY
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First line investigations in neutrophilia
- inflammatory markers - blood film if persistent with no cause - if acute and clear cause then repeat once stimulus is over
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When to investigate neutrophilia further
- persistent - no secondary cause - splenomegaly Contact haematology if persistent with no secondary cause and if basophilia, splenomegaly or abnormal blood film
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possible haematological causes of neutrophilia
* Myeloproliferative neoplasms: PV, PMF, CML, CNL
* ET does not usually cause neutrophilia
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Clinical picture of chronic myeloid leukemia
- results in very high WCC (500-600) - if you see basophilia think CML - often asymptomatic but can have splenomegaly and present with vague generally symptoms - prognosis excellent for most
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What is the genetic abnormality that causes CML
translocation between chromosomes 9 and 22 resulting in Philadelphia chromosome and the BCR-ABL1 fusion gene
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Management of CML
* tyrosine kinase inhibitors
* blocks TK activity by competing with ATP binding site in the fusion gene therefor reducing phosphorylation of downstream pathways
* 1st line: 1st gen TKi - imatinib
* 2nd line: 2nd gen TKi - nilotinib/dasatinib/bosutinib
* 3rd line: 3rd gen TKi - ponatinib
* monitor BCR-ABL1 fusion transcripts and FBC to gauge response
* haematopoietic stem cell transplant if resistant to TKi
36
What is leukemia?
- condition of bone marrow failure secondary to accumulation of malignant blasts - progressive malignant disease of blood-formed organs, characterised by distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow - classified as acute or chronic depending on degree of cell differentiation - myeloid or lymphoid
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Normal physiology of bone marrow:
- 50% fat spaces and 50% cellular activity - pluripotent stem cell --\> lymphoid precursor --\> lymphocyte --\> T-lymphocyte or B-lymphocyte
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What is the pathophysiology of acute leukaemia?
immature cells that become cancerous and proliferate
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What is the pathophysiology of chronic leukaemia?
mature cells that become cancerous and proliferative
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What is myelodysplastic syndrome?
- disease of the elderly - progressive marrow failure due to production of dysplastic blood cells - can be one type of cell or single lineage (e.g. red cells resulting in anaemia) - or could be all cell lineages resulting in pancytopenia - spectrum of diseases ranging from refractory anaemia to refractory anaemia with excess blasts (RAEB) which ultimately leads to leukaemia (AML)
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How do patients with leukaemia present?
Either with S&S of bone marrow failure or S&S of proliferative accumulation of cancerous cells
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S&S of marrow failure
- low red cells (fatigue/dizziness/breathlessness/pallor) - low white cells (fever/mouth ulcers/infection symptoms) - low platelets (bleeding/bruising)
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S&S proliferation
- occurs when counts are high and lots of blast cells circulating in the blood (leukemic picture) - breathlessness and confusion (cells get stuck going through the small vessels) - gum infiltration, skin infiltration, splenomegaly, lymphadenopathy (leukemia cell deposition)
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Investigation findings in MDS
- FBC: macrocytic anaemia and cytopenia - blood film: abnormal neutrophils (one 'lump' to nucleus instead of multi-lobulated) - Bone marrow biopsy showing hypercellular and abnormal maturation
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Investigation findings in acute leukemia
- FBC: cytopenia and high WBC - blood film: blasts and auer rods (typically in AML) - Bone marrow biopsy: hypercellular, 'packed with leukemic blasts' and fat cells replaced with monotonous population of blasts
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Findings in acute promyelocytic leukaemia:
- subtype fo AML - blood film showing extreme numbers of Auer rods - atypical presentation
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Management of MDS
Depends on pt age and where they are on the spectrum - transfusion support to correct abnormal count - growth factors e.g. EPO - disease modifying chemotherapy --\> 'help turn the clock back' on the MDS (not curative/temporary/ used in more intermediate-risk illnesses) - only curative treatment is bone marrow transplant but rarely indicated as MDS population too early
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Management of leukemia
- acutely treated with broad spec antibiotics and urgent transfusion with blood and platelets (due to low counts) - definitively chemotherapy and bone marrow transplantation in high risk patients - targeted therapy for CML: IMATINIB (tyrosine kinase inhibitor)
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Management of promyelocytic leukemia
- subtype of AML (medical emergency) - excessive auer rods on blood film - genetic testing for presence of (t [15:17]) for rapid diagnosis - life threatening coagulopathy that needs to be managed urgently - chemotherapy is 90% curative so important to get patient through life-threatening coagulopathy stage - ATRA alongside chemotherapy (vitamin A derivative that helps blast cells mature --\> helps with coagulopathy)
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Multiple myeloma
- cancer of bone marrow plasma cells
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What is multiple myeloma characterised by?
- monoclonal protein in serum and/or urine (secreted from cancerous plasma cells into the serum) - lytic bone lesions (destroys bone tissue around tumours) --\> can occur in vertebral bodies and long bones - excess plasma cells in the bone marrow
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Describe the appearance of abnormal plasma cells in bone marrow biopsy in multiple myeloma
- large cells with an eccentric nucleus - perinuclear halo - large amount of blue cytoplasm
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Epidemiology of multiple myeloma
- more common in patients over 60 - slightly more common in males than females - more common in patients of afro-caribbean descent
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Aetiology of multiple myeloma
- more common when exposed to radiation, farming, metal, rubbers, chemicals - may have a genetic factor - all patients have a pre-malignant phase known as 'Monoclonal Gammopathy of uncertain significance' but mostly patients present with myeloma
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How does multiple myeloma present?
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Explain renal failure as a presentation of multiple myeloma.
Light chains produced by the plasma cells filter through the glomerulus and into the urine. Tubules are not used to large amounts of protein, reabsorption of light chains is attempted but a lot passes to the loop of Henle. If dehydrated & lots of chains --\> gest jelly or cast formation in ascending loop of Henla and can destroy a nephron. Eventually kidney fails as more and more nephrons are destroyed.
57
How to prevent renal impairment in myeloma patients.
* early diagnosis
* high fluid intake (at least 3 L a day)
* bring down calcium to acceptable levels
* aminoglycosides, NSAIDs and some diuretics should be avoided
* careful monitoring is essential (especially in patients receiving bisphosphonates)
* treat UTIs
58
Explain the bone problems that occur as a result of multiple myeloma.
In multiple myeloma, tumour cells produce osteoclast activating factors. Osteoblasts do not work as hard so discrepancy between bone destruction and bone reformation causing lytic lesions.
Hypercalcaemia due to bone breakdown. Patient can present with:
* confusion
* nausea
* vomiting
* abdo pain
* can contribute to renal impairment
To treat hypercalcaemia --\> IV fluids, steroids, bisphosphonates.
Patients can also present with fractures and spinal cord compression.
59
Describe the prognostic factors of multiple myeloma.
* serum beta-2 microglobulin
* higher levels = poorer prognosis
* cytogenetics
* i.e. genetics of the cancer cells
* LDH
* high LDH associated with poorer prognosis
* age (older = poorer prognosis)
* peripheral blood plasma cells
* cancer cells outside of the bone marrow i.e. in blood - poorer prognosis
* albumen
* lower albumin level associated with poorer prognosis
60
Management for mutiple myeloma.
Supportive treatment (incurable but treatable):
* bisphosphonate for bone disease
* EPO for anaemia
* prophylactic use of antibiotics to reduce infections, especially
* strep pneumoniae
* haemophilus influenzae
* VZV (specifically shingles)
61
Medical history for lymphoma: (patient presenting with lymphadenopathy)
* duration
* is it painful?
* pain not common in lymphoma
* particularly peripheral lymph nodes
* is it changing
* associated B symptoms
* risk factors fot HIV/TB
* could be reactive LN
* acute HIV cause adenopathy
* also immunosuppressed patients have an increased risk of lymphoma: HIV RFs important
* contact with cats?
* cat scratch fever
* adenopathy
* more common in children (quite significantly enlarged nodes)
* Travel history
* think atypical infections
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What to look for in physical examination in with someone presenting with an enlarged lymph node.
* size, shape, surface, mobility, consistency
* if difficult to palpate unlikely to be lymphoma (especially if peripheral lumphadenopathy
* examinate other lumph node areas
* check skin for bruising
* do neuro if any signs/sx e.g. headache
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When to refer a lymphadenopathy to haematology?
* any patient with lymph node \>1cm for more than 6 weeks
* \>1cm is pathological but reactive nodes can be \>1cm, but often resolve as underlying problem resolves
* any patient with generalised lymphadenopathy i.e. two or more non-contiguous areas
* supraclavicular area more worrying than inguinal
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Investigations for lymphoma
Lymphoma can have widespread abdominal involvemnt --\> renal/hepatic obstruction
* FBC
* U&Es
* LFTs
* ESR --\> prognositc marker, particularly in Hodgkin lymphoma
* LDH: non-specific tumour marker for lymphoma (marker of high cell turnover)
* immunoglobulins: can be associated with para-proteins
* full viral screen
* due to increased risk with HIV
* want to know if HEP B +ve due to risk of reactivation once you give them immunosuppression
* CXR: widened mediastinum
* Biopsy is diagnostic (biopsed before referral if nodes look pathological on imaging)
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What kind of biopsy is required to diagnose lymphoma?
CORE BIOPSY
If inconclusive then surgical excision --\> do not waste time with a second core biopsy.
FNA is not adequate.
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Morphology seen in lymphoma
Reed-Sternberg cell (owl-eyes) is diagnostic of Hodgkin lymphoma
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How to image lymphoma:
* CT neck, chest, abdo, pelvis
* PET required for some subtypes of lymphome (glucose uptake is more sensitive than CT)
* MRI brain and spine required for CNS lymphoma
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Ann Arbor Staging System
(effectively look at whether the disease is above/below the diaphragm)
A: absence of B symptoms
B: fever, night sweats, wt loss (e.g. stage 4B is the most advanced type staged)
* stage I: 1 nodal site on 1 side of the diaphragm
* stage II: 2 nodal sites on the same side of the diaphragm
* stage III: disease crosses the diaphragm and remains in nodal sites
* stage IV: extranodal disease
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Management of Lymphoma
* clinical observation for low grade lymphoma
* no improvement of outcome by treating earlier and some may never need treatment
* chemotherapy: mainstay of treatment
* radiotherapy: sometimes treated only by radiotherapy, sometimes as consolidation
* immunotherapy and targeted therapy
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LYMPHOMA EMERGENCIES
Tumour Lysis Syndrome
* can occur when lymphoma responds very quickly to treatment
* within the day of starting steroids/chemo there is massive breakdown of tumour
* puts patients into renal failure and high potassium so large risk of cardiac arrest
* Mx
* hydrate the patient
* allupurinol (reduces production of uric acid in the body)
* raspuricase (enzyme that breaks down uric acid --\> allows for elimination
* close monitoring of patient
* BD bloods and immediate review
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LYMPHOMA EMERGENCIES
Hypercalcaemia
Sx:
* confusion
* dehydration
* abdominal pain
Mx
* hydration
* bisphosphonates
* treat underlying malignancy
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LYMPHOMA EMERGENCIES
Spinal Cord Compression
Urgent MRI essential if suspected & speak to oncology team
CANNOT WAIT UNTIL NEXT DAY
Neuro Sx:
* back pain
* sometimes made worse by lying down or moving
* sharp band around body or which spreads down arms or legs
* sudden weakness in legs
* sensory Sx
* Bladder bowel disturbance (50%)
Pain won't go away with pain killers and prevents sleep
Mx
* MRI whole spine
* steroids (high dose dexamethasone)
* radiotherapy
* surgery (most definitive)
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LYMPHOMA EMERGENCIES
Superior Vena Cava Obstruction
* seen especially in bulky mediastinal lymphomas & some Hodgkin lymphomas
* treat as emergency - ensure that it is recognised
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HAEM MALIGNANCY EMERGENCIES
Neutropenic Sepsis
* mortality 5-20%
* critical to give Abx w/in 60 minutes
* fever to act on:
* one measure over 38.5C
* two measures, an hour apart, of over 38C
* neutropenia that is worrying would be less than 0.5x109/L
* assessment
* BP, ?clammy, UO, ?source
* bloods, esp blood cultures
* CXR often
* Mx
* urgently call for help
* ABx w/in 60 minutes --\> follow local policies
* ITU - early warning
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HAEM MALIGNANCY EMERGENCIES
Hypercalcaemia --\> presentation
* normal: 2.2 to 2.6
* mild: 2.6-3
* moderate: 3-3.4
* severe \>3.4
* usually incidental findin but can present with
* bone pain, fractures, fatigue, muscle weakness, polyuria, kidney stones, nausea, vomiting, constipation, pancreatitis, peptic ulcers, depression, confusion, coma
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Mechanisms for hypercalcaemia in malignancy
1. PTH-related peptide
1. can be produced by tumours
2. lytic bone lesions
3. 1,25 hydroxy vit D
1. increased production by some tumours
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Management of hypercalcaemia
* fluids: isotonic saline
* furosemide only in fluid overloaded pts
* bisphosphonates: pamidronate or zoledronate (main treatment)
* MOA --\> analogue of inorganic pyrophosphate --\> interferes with bone absorption
* onset of action: 1-2/7
* max effect: 2-4/7
* SEs: fever, renal failure
* (calcitonin)
* efficacy: 48h
* rapid reduction
* used only in emergencies
* (steroids)
* sometimes also employed to bring Ca down
79
Mechanism of tumour lysis syndrome
* happens when treatment begins
* as cells break down, release DNA, phosphate, potssium and cytokines --\> syndrome that makes people unwell --\> renal failure due to crystal deposition
* hyperuricaemia
* due to catabolism of purines
* hyperphosphataemia
* phos concentration 4x higher in malignancy cells
* uric acid precipitates in calcium phosphate readily
* uric acid poorly soluble in kidneys
* crystals deposit in renal tubules --\> ARF
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Clinical presentation of tumour lysis syndrome
* electrolyte derangement
* hyperuricaemia
* hyperphosphataemia
* hyperkalaemia
* secondary hypocalcaemia
* acute renal failure
* symptoms
* N+V, diarrhoea, anorexia, lethargy
* cardiac dysrhythmia
* tetany, syncope
* death
81
Haemophagocytic Lympho Histiocytosis --\> haem emergency
* rare
* severe hyperinflammation
* uncontrolled activation of immune system
* cytokines +++, activated lymphocytes & macrophages
* hereditary
* acquired forms
* malignancy
* lymphoma
* leukaemia
* MDS
* rheum conditions
* infections (EBV (SH2D1A mutation associated), CMV, possible SARS-CoV-2
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Presentation of haemophagocytic lympho histiocytosis
Classic triad of:
* persistent, refractory fever
* cytopenia
* organomegaly
* H score
?recent immunosuppression
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Ix and Mx of haemophagocytic lympho histiocytosis
CRP, ferritin, triglycerides, fibrinogen, bone marrow
Mx:
* treat underlying cause
* steroids, etoposide, cyclosporin, IVIG
* (anti IFN gamma antibody: emapalumab)
* not approved by EMA in Europe yet
* call haematology and ask for advice
84
Acute promyelocytic leukaemia
Bruises in leukaemia should ring alarm bells
3 key points in APML:
* easy bruising
* quick FBC and chase results
* be aware
other things to look out for:
* dizziness
* infection
* untreated DIC
* pulmonary/cerebrovascular haemorrhage: 40%
* mortality rate 10-20%
Treated APML has good prognosis.
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