Haematology 3 Flashcards
1
Q
Features of spinal cord compression?
A
back pain
the earliest and most common symptom
may be worse on lying down and coughing
lower limb weakness
sensory changes: sensory loss and numbness
neurological signs depend on the level of the lesion. Lesions above L1 usually result in upper motor neuron signs in the legs and a sensory level. Lesions below L1 usually cause lower motor neuron signs in the legs and perianal numbness. Tendon reflexes tend to be increased below the level of the lesion and absent at the level of the lesion
2
Q
Investigations for spinal cord compression?
A
Urgent MRI
3
Q
Management of spinal cord compression?
A
high-dose oral dexamethasone
urgent oncological assessment for consideration of radiotherapy or surgery
4
Q
Where is vitamin B12 absorbed?
A
It is absorbed after binding to intrinsic factor (secreted from parietal cells in the stomach) and is actively absorbed in the terminal ileum. A small amount of vitamin B12 is passively absorbed without being bound to intrinsic factor.
5
Q
What is haemophilia?
A
Haemophilia is an X-linked recessive disorder of coagulation. Up to 30% of patients have no family history of the condition. Haemophilia A is due to a deficiency of factor VIII whilst in haemophilia B (Christmas disease) there is a lack of factor IX
Features
haemoarthroses
haematomas
prolonged bleeding after surgery or trauma
Blood tests
prolonged APTT
bleeding time, thrombin time, prothrombin time normal
6
Q
What electroylte disturbance is cisplatin most associated with?
A
Hypomagnesaemia
7
Q
What are the different forms of allergy testing?
A
8
Q
What are the histological classification of Hodgkin’s lymphoma?
A
Hodgkin’s lymphoma is a malignant proliferation of lymphocytes characterised by the presence of the Reed-Sternberg cell.
9
Q
What symptoms are associarted with poor prognosis in Hodgkin’s lymphoma?
A
‘B’ symptoms also imply a poor prognosis
weight loss > 10% in last 6 months
fever > 38ºC
night sweats
Other factors associated with a poor prognosis identified in a 1998 NEJM paper included:
age > 45 years
stage IV disease
haemoglobin < 10.5 g/dl
lymphocyte count < 600/µl or < 8%
male
albumin < 40 g/l
white blood count > 15,000/µl
10
Q
What is multiple myeloma?
A
Multiple myeloma (MM) is a haematological malignancy characterised by plasma cell proliferation. It arises due to genetic mutations which occur as B-lymphocytes differentiate into mature plasma cells.
11
Q
Features of multiple myeloma?
A
**CRABBI **
Calcium - hypercalcaemia
Renal dysfunction
Anaemia
Bleeding
Bone pain
Infection
Other features include
amyloidosis e.g. macroglossia
carpal tunnel syndrome
neuropathy
hyperviscosity
12
Q
causes of hypercalcaemia in multiple myeloma?
A
primary factor: due primarily to increased osteoclastic bone resorption caused by local cytokines (e.g. IL-1, tumour necrosis factor) released by the myeloma cells
much less common contributing factors: impaired renal function, increased renal tubular calcium reabsorption and elevated PTH-rP levels
this leads to constipation, nausea, anorexia and confusion
13
Q
What causes renal dysfunction in multiple myeloma?
A
monoclonal production of immunoglobulins results in light chain deposition within the renal tubules
this causes renal damage which presents as dehydration and increasing thirst
other causes of renal impairment in myeloma include amyloidosis, nephrocalcinosis, nephrolithiasis
14
Q
Causes of anaemia and bleeding in multiple myeloma?
A
Anaemia
bone marrow crowding suppresses erythropoiesis leading to anaemia
this causes fatigue and pallor
Bleeding
bone marrow crowding also results in thrombocytopenia which puts patients at increased risk of bleeding and bruising
15
Q
Causes of bone pain in multiple myeloma?
A
bone marrow infiltration by plasma cells and cytokine-mediated osteoclast overactivity creates lytic bone lesions
this may present as pain (especially in the back) and increases the risk of pathological fractures
16
Q
Causes of increased risk of infection in multiple myeloma?
A
a reduction in the production of normal immunoglobulins results in increased susceptibility to infection
17
Q
Investigations for multiple myeloma?
A
full blood count: anaemia
peripheral blood film: rouleaux formation
urea and electrolytes: renal failure
bone profile: hypercalcaemia
Protein electrophoresis
raised concentrations of monoclonal IgA/IgG proteins will be present in the serum
in the urine, they are known as Bence Jones proteins
Bone marrow aspiration
confirms the diagnosis if the number of plasma cells is significantly raised
Imaging
historically a skeletal survey has been done to look for bone lesions
however, whole-body MRI is increasingly used and is now recommended in the 2016 NICE guidelines
X-rays: ‘rain-drop skull’ (likened to the pattern rain forms after hitting a surface and splashing, where it leaves a random pattern of dark spots). Note that a very similar, but subtly different finding is found in primary hyperparathyroidism - ‘pepperpot skull’
18
Q
Diagnostic criteria in multiple myeloma?
A
The diagnostic criteria for multiple myeloma requires one major and one minor criteria or three minor criteria in an individual who has signs or symptoms of multiple myeloma.
Major criteria
Plasmacytoma (as demonstrated on evaluation of biopsy specimen)
30% plasma cells in a bone marrow sample
Elevated levels of M protein in the blood or urine
Minor criteria
10% to 30% plasma cells in a bone marrow sample.
Minor elevations in the level of M protein in the blood or urine.
Osteolytic lesions (as demonstrated on imaging studies).
Low levels of antibodies (not produced by the cancer cells) in the blood.
19
Q
MGUS vs smouldering multiple myeloma vs multiple myeloma?
A
Monoclonal Gammopathy of Uncertain Significance (MGUS):
▪︎M protein <30 g/l
▪︎BM plasma cells <10%
▪︎No CRAB features
Smoldering Multiple Myeloma:
▪︎M protein > 30 g/l
▪︎BM plasma cells 10-60%
▪︎No CRAB features
▪︎Rx: Observe + monitor
Multiple myeloma:
▪︎M protein >30g/l
▪︎BM plasma cells >10%
▪︎CRAB features
20
Q
What is anastrozole ?
A
aromatase inhibitor
Anastrozole and letrozole are aromatase inhibitors that reduces peripheral oestrogen synthesis. This is important as aromatisation accounts for the majority of oestrogen production in postmenopausal women and therefore anastrozole is used for ER +ve breast cancer in this group.
21
Q
What cytotoxic agents can cause peripheral neuropathy?
A
Vincristine/vinblastine
Cisplatin
22
Q
What is Leucocyte alkaline phosphatase raised in?
A
myelofibrosis
leukaemoid reactions
polycythaemia rubra vera
infections
steroids, Cushing’s syndrome
pregnancy, oral contraceptive pill
23
Q
What is Leucocyte alkaline phosphatase low in?
A
chronic myeloid leukaemia
pernicious anaemia
paroxysmal nocturnal haemoglobinuria
infectious mononucleosis
24
Q
Pulmonary causes of eosinophillia?
Other causes
Drugs/derm
A
asthma
allergic bronchopulmonary aspergillosis
Churg-Strauss syndrome
Loffler’s syndrome
tropical pulmonary eosinophilia
eosinophilic pneumonia
hypereosinophilic syndrome
Other causes
drugs: sulfasalazine, nitrofurantoin
psoriasis/eczema
eosinophilic leukaemia (very rare)
25
Infective causes of Eosinophilia?
schistosomiasis
nematodes: Toxocara, Ascaris, Strongyloides
cestodes: Echinococcus
26
Pathophysiology of Hereditary angioedema?
The primary pathophysiological defect is in the complement cascade and deficiencies in factors C4 and C1-esterase inhibitor are seen in type I. In type II HAE C1-esterase inhibitor levels are normal but the enzyme is dysfunctional and activity is low. An acquired form of HAE is described in which all complement levels are low. In type III HAE the clinical features of angioedema are present but immunological testing reveals normal levels and activity of complement factors. Ultimately, failure of C1-esterase inhibitor leads to upregulation of the rest of the complement system and membrane attack complex, but also it leads to activation of the signalling protein kallikrein which acts directly on the vascular wall to increase permeability, and it cleaves high molecular weight kininogen to release bradykinin, again a potent peripheral vasodilator giving rise to the symptoms of HAE.
## Footnote
HAE should be recognised as a separate entity from anaphylaxis since the clinical signs are different, as is the pathophysiology of the condition and its treatment. Anaphylaxis is an IgE mediated immune phenomenon related to a specific allergen causing massive mast cell degranulation and histamine release. HAE is driven by complement dysregulation and consequent release of the inflammatory cytokines bradykinin and kallikrein.
**Since the driving mechanism is not histamine in HAE, steroids and antihistamines are of no value.**
27
Causes of Warm vs Cold autoimmune haemolytic anaemia?
Causes of warm AIHA
idiopathic
autoimmune disease: e.g. systemic lupus erythematosus*
neoplasia
lymphoma
chronic lymphocytic leukaemia
drugs: e.g. methyldopa
Causes of cold AIHA
neoplasia: e.g. lymphoma
infections: e.g. mycoplasma, EBV
28
What are the three types of cryoglobulinaemia?
Three types
type I (25%):
monoclonal - IgG or IgM
associations: multiple myeloma, Waldenstrom macroglobulinaemia
type II (25%)
mixed monoclonal and polyclonal: usually with rheumatoid factor
associations: hepatitis C, rheumatoid arthritis, Sjogren's, lymphoma
type III (50%)
polyclonal: usually with rheumatoid factor
associations: rheumatoid arthritis, Sjogren's
## Footnote
Immunoglobulins which undergo reversible precipitation at 4 deg C, dissolve when warmed to 37 deg C. One-third of cases are idiopathic
29
What are the possible features of Cryoglobulinaemia?
Raynaud's only seen in type I
cutaneous
vascular purpura
distal ulceration
ulceration
arthralgia
renal involvement
diffuse glomerulonephritis
30
Investigations and management of cryoglobulinaemia?
Investigations
low complement (esp. C4)
high ESR
Management
treatment of underlying condition e.g. hepatitis C
immunosuppression
plasmapheresis
31
What is the best screening tool for hereditary angioedema?
Serum C4
32
What is likely to be seen on blood gas in Acquired methaemoglobinaemia ?
Normal pO2 but decreased oxygen saturation is characteristic of methaemoglobinaemia
In methaemoglobinaemia, the haemoglobin has been oxidised from Fe2+ to Fe3+. There is tissue hypoxia as Fe3+ cannot bind oxygen. Hence saturations are low. The ability for oxygen to dissolve in the plasma is unaffected so remains normal.
33
Features of SVC obsruction?
dyspnoea is the most common symptom
swelling of the face, neck and arms - conjunctival and periorbital oedema may be seen
headache: often worse in the mornings
visual disturbance
pulseless jugular venous distension
34
Causes of SVC obsrtuction?
common malignancies: small cell lung cancer, lymphoma
other malignancies: metastatic seminoma, Kaposi's sarcoma, breast cancer
aortic aneurysm
mediastinal fibrosis
goitre
SVC thrombosis
35
Management of SVC obstruction?
Management is dependant on the individual patient and malignancy and advice should be taken from the oncology team. Options include:
endovascular stenting is often the treatment of choice to provide symptom relief
certain malignancies such as lymphoma, small cell lung cancer may benefit from radical chemotherapy or chemo-radiotherapy rather than stenting
the evidence base supporting the use of glucocorticoids is weak but they are often given
36
Isolated thrombocytopenia in an otherwise well patient?
immune thrombocytopaenic purpura (ITP) - often presenting as isolated thrombocytopaenia in an otherwise well patient.
37
1st line management for ITP?
oral pred
38
Why is Haptoglobin low in haemolysis?
Haptoglobin levels are reduced in intravascular haemolysis because they bind to free haemoglobin released from lysed erythrocytes. The complexes are then removed from the plasma by the hepatic reticulo-endothelial cells. Haptoglobin levels decrease if the rate of haemolysis is greater than the rate of haptoglobin production.
39
Management of Antiphospholipid syndrome in pregnancy?
low-dose aspirin should be commenced once the pregnancy is confirmed on urine testing
low molecular weight heparin once a fetal heart is seen on ultrasound. This is usually discontinued at 34 weeks gestation
these interventions increase the live birth rate seven-fold
40
complications of antiphospholipid syndrome in pregnancy?
recurrent miscarriage
IUGR
pre-eclampsia
placental abruption
pre-term delivery
venous thromboembolism
41
What is Myelofibrosis ?
a myeloproliferative disorder
thought to be caused by hyperplasia of abnormal megakaryocytes
the resultant release of platelet derived growth factor is thought to stimulate fibroblasts
haematopoiesis develops in the liver and spleen
42
What are the features of Myelofibrosis?
e.g. elderly person with symptoms of anaemia e.g. fatigue (the most common presenting symptom)
massive splenomegaly
hypermetabolic symptoms: weight loss, night sweats etc
43
What are the laboratory findings in Myelofibrosis?
anaemia
high WBC and platelet count early in the disease
'tear-drop' poikilocytes on blood film
unobtainable bone marrow biopsy - 'dry tap' therefore trephine biopsy needed
high urate and LDH (reflect increased cell turnover)
44
What in the t(9:22) translocation associated with?
t(9;22) - Philadelphia chromosome
present in > 95% of patients with CML
this results in part of the Abelson proto-oncogene being moved to the BCR gene on chromosome 22
the resulting BCR-ABL gene codes for a fusion protein which has tyrosine kinase activity in excess of normal
poor prognostic indicator in ALL
45
What is the t(15;17) translocation associated with?
t(15;17)
seen in acute promyelocytic leukaemia (M3)
fusion of PML and RAR-alpha genes
46
What is the t(8;14) translocation associated with?
seen in Burkitt's lymphoma
MYC oncogene is translocated to an immunoglobulin gene
## Footnote
Burkitt’s : B (looks like 8) (t(8;14))
47
t(11;14) transloaction associated with ....?
t(11;14)
Mantle cell lymphoma
deregulation of the cyclin D1 (BCL-1) gene
## Footnote
-T(11;14) – 11antle ce11 LØma
48
What is the t(14;18) transloaction associated with?
t(14;18)
follicular lymphoma
increased BCL-2 transcription
## Footnote
Follicular (F) : Fourteen (t(14;18))
49
HUS VS TTP?
Both TTP and HUS as common symptoms of MAT,
MAT: M=Microangiopathi hemolytic anemia, A=Acute kidney injury T= Thrombocytopenia
Now, When there is MAT + Fever + Neurological signs = TTP
and MAT + bloody diarrhea = HUS
50
Key differences between myeloma and waldenstrom's macroglobulinema?
* Hyperviscosity symptoms are more common in Waldenstrom's than Myeloma
* Hepatosplenomegaly and Lymphadenopathy are more common in Waldenstrom's (very rare in Myeloma)
* Waldenstrom's secretes an IgM paraprotein whereas Myeloma is associated with IgG (55%), IgA, or light chain paraprotein
* Both involve the bone marrow, but only myeloma causes bone pain / pathological fractures / hypercalcemia
51
When should lead poisoning be considered?
Along with acute intermittent porphyria, lead poisoning should be considered in questions giving a combination of abdominal pain and neurological signs. Lead poisoning results in defective ferrochelatase and ALA dehydratase function.
52
Features of lead poisoning?
abdominal pain
peripheral neuropathy (mainly motor)
neuropsychiatric features
fatigue
constipation
blue lines on gum margin (only 20% of adult patients, very rare in children)
53
Investigations for lead poisoning?
Blood lead levels
Microcytic anaemia
Blood film shows red cell abnormalities including basophilic stippling and clover-leaf morphology
## Footnote
raised serum and urine levels of delta aminolaevulinic acid may be seen making it sometimes difficult to differentiate from acute intermittent porphyria
urinary coproporphyrin is also increased (urinary porphobilinogen and uroporphyrin levels are normal to slightly increased)
in children, lead can accumulate in the metaphysis of the bones although x-rays are not part of the standard work-up
54
Management of Lead Poisoning?
dimercaptosuccinic acid (DMSA)
D-penicillamine
EDTA
dimercaprol
55
when doe neutropenic sepsis usually occur?
It most commonly occurs 7-14 days after chemotherapy
56
what is Neutropenic sepsis defined as?
It may be defined as a neutrophil count of < 0.5 * 109 in a patient who is having anticancer treatment and has one of the following:
a temperature higher than 38ºC or
other signs or symptoms consistent with clinically significant sepsis
57
Most common cause of neutropenic sepsis?
coagulase-negative, Gram-positive bacteria are the most common cause, particularly Staphylococcus epidermidis
this is probably due to the use of indwelling lines in patients with cancer
58
Prophylaxis in neutopenic sepsis?
if it is anticipated that patients are likely to have a neutrophil count of < 0.5 * 109 as a consequence of their treatment they should be offered a fluoroquinolone
59
Management of neutropenic sepsis?
antibiotics must be started immediately, do not wait for the WBC
NICE recommends starting empirical antibiotic therapy with piperacillin with tazobactam (Tazocin) immediately
many units add vancomycin if the patient has central venous access but NICE do not support this approach
following this initial treatment patients are usually assessed by a specialist and risk-stratified to see if they may be able to have outpatient treatment
if patients are still febrile and unwell after 48 hours an alternative antibiotic such as meropenem is often prescribed +/- vancomycin
if patients are not responding after 4-6 days the Christie guidelines suggest ordering investigations for fungal infections (e.g. HRCT), rather than just starting therapy antifungal therapy blindly
there may be a role for G-CSF in selected patients
60
What can be used in sickle cell disease to redice the incidence of acute cute crisis?
Sickle cell patients should be started on long term hydroxycarbamide to reduce the incidence of complications and acute crises
61
What is thrombocytosis?
Thrombocytosis is an abnormally high platelet count, usually > 400 * 109/l.
62
Causes of thrombocytosis?
reactive: platelets are an acute phase reactant - platelet count can increase in response to stress such as a severe infection, surgery. Iron deficiency anaemia can also cause a reactive thrombocytosis
malignancy
essential thrombocytosis (see below), or as part of another myeloproliferative disorder such as chronic myeloid leukaemia or polycythaemia rubra vera
hyposplenism
63
What is essential thrombocytosis?
Features and mutation seen?
Essential thrombocytosis is one of the myeloproliferative disorders which overlaps with chronic myeloid leukaemia, polycythaemia rubra vera and myelofibrosis. Megakaryocyte proliferation results in an overproduction of platelets.
Features
platelet count > 600 * 109/l
both thrombosis (venous or arterial) and haemorrhage can be seen
a characteristic symptom is a burning sensation in the hands
a JAK2 mutation is found in around 50% of patients
64
Management of essential thrombocytosis?
hydroxyurea (hydroxycarbamide) is widely used to reduce the platelet count
interferon-α is also used in younger patients
low-dose aspirin may be used to reduce the thrombotic risk
65
what is the most common inherited thrombophilia?
Factor V Leiden (activated protein C resistance) is the most common inherited thrombophilia, being present in around 5% of the UK population.
It is due to a gain of function mutation in the Factor V Leiden protein. The result of the mis-sense mutation is that activated factor V (a clotting factor) is inactivated 10 times more slowly by activated protein C than normal. This explains the alternative name for factor V Leiden of activated protein C resistance,
66
what are the diffent types of allergy testing?
67
when to offer plt transfsion in patients who have active bleeding?
Offer platelet transfusions to patients with a platelet count of <30 x 10 9 with clinically significant bleeding (World Health organisation bleeding grade 2- e.g. haematemesis, melaena, prolonged epistaxis)
Platelet thresholds for transfusion are higher (maximum < 100 x 10 9) for patients with severe bleeding (World Health organisation bleeding grades 3&4), or bleeding at critical sites, such as the CNS.
It should be noted that platelet transfusions have the highest risk of bacterial contamination compared to other types of blood product
68
when to offer plt transfusion pre invasive procedure?
Platelet transfusion for thrombocytopenia before surgery/ an invasive procedure. Aim for plt levels of:
> 50×109/L for most patients
50-75×109/L if high risk of bleeding
>100×109/L if surgery at critical site
69
when to offer plt transfusion if no active bleeding or planned inasive procedure?
A threshold of 10 x 109 except where platelet transfusion is contradindicated or there are alternative treatments for their condition
For example, do not perform platelet transfusion for any of the following conditions:
Chronic bone marrow failure
Autoimmune thrombocytopenia
Heparin-induced thrombocytopenia, or
Thrombotic thrombocytopenic purpura.
70
ALL good prognostic features?
French-American-British (FAB) L1 type
common ALL
pre-B phenotype
low initial WBC
del(9p)
71
ALL bad prognostic features?
FAB L3 type
T or B cell surface markers
Philadelphia translocation, t(9;22)
age < 2 years or > 10 years
male sex
CNS involvement
high initial WBC (e.g. > 100 * 109/l)
non-Caucasian
72
what is seen on blood film in hyposplenism?
Hyposplenism e.g. post-splenectomy, coeliac disease (occurs in around 30% of coeliac patients)
target cells
Howell-Jolly bodies
Pappenheimer bodies
siderotic granules
acanthocytes
73
what is seen on blood film in IDA?
Iron-deficiency anaemia
target cells
'pencil' poikilocytes
if combined with B12/folate deficiency a 'dimorphic' film occurs with mixed microcytic and macrocytic cells
74
what is seen on blood film in myelofibrosis?
'tear-drop' poikilocytes
75
what is seen on blood film in intravascular haeolysis?
schistocytes
76
MDS vs PMF?
Myelodysplastic syndromes (MDS) and primary myelofibrosis (PMF) are both disorders of the bone marrow, but they have distinct characteristics and manifestations.
MDS is a group of disorders characterised by ineffective haematopoiesis leading to cytopenias, often presenting with anaemia. The blood film may show dysplastic changes and there may be blasts present, but usually less than 20% in the peripheral blood or bone marrow. There is a risk of progression to acute myeloid leukaemia.
On the other hand, PMF is a chronic myeloproliferative neoplasm characterized by progressive fibrosis of the bone marrow that disrupts normal haematopoiesis. This leads to extramedullary haematopoiesis resulting in hepatosplenomegaly. Patients often present with fatigue, weight loss and splenomegaly; lab findings include anemia, leukocytosis or leukopenia, thrombocytosis or thrombocytopenia. The blood film shows teardrop poikilocytes, nucleated red cells and immature white cells (leukoerythroblastosis).
77
What is Leukaemoid reaction?
The leukaemoid reaction describes the presence of immature cells such as myeloblasts, promyelocytes and nucleated red cells in the peripheral blood. This may be due to infiltration of the bone marrow causing the immature cells to be 'pushed out' or sudden demand for new cells
78
What causes a Leukaemoid reaction?
severe infection
severe haemolysis
massive haemorrhage
metastatic cancer with bone marrow infiltration
79
How to differenciate between a Leukaemoid reaction and CML?
Leukaemoid reaction
high leucocyte alkaline phosphatase score
toxic granulation (Dohle bodies) in the white cells
'left shift' of neutrophils i.e. three or fewer segments of the nucleus
Chronic myeloid leukaemia
low leucocyte alkaline phosphatase score
80
What causes high leukocyte alkaline phosphatase ?
leukemoid reaction.
essential thrombocytosis.
myelofibrosis.
polycythemia vera
infections
81
What tumour marker is seen in ovarian cancer
CA125
82
What tumour marker is seen in pancreatic cancer?
CA19-3
83
What tumour marker is seen in breast cancer?
CA15-3
84
What tumour marker is part of prostate cancer?
PSA
85
What cancers are associated with AFP?
Hepatocellular carcinoma, teratoma
86
What tumour marker is colorectal cancer associated with ?
CEA?
87
What cancers are associated with S-100?
Melanoma, schwannomas
88
What cancers are associated with the tumour marker of Bombesin?
Small cell lung carcinoma, gastric cancer, neuroblastoma
89
What age group does non-hodgkin's lymphoma affect?
While different subtypes can affect different ages, it typically affects the elderly with one-third of cases occurring in those over 75 years of age
90
How does non-hodkins lymphoma present with?
Painless lymphadenopathy (non-tender, rubbery, asymmetrical)
B-symptoms
Extranodal Disease - gastric (dyspepsia, dysphagia, weight loss, abdominal pain), bone marrow (pancytopenia, bone pain), lungs, skin, central nervous system (nerve palsies)
Signs
Signs of weight loss
Lymphadenopathy (typically in the cervical, axillary or inguinal region)
Palpable abdominal mass - hepatomegaly, splenomegaly, lymph nodes
Testicular mass
Fever
91
what elements can point towards Hodgkin's vs non-Hodgkins lymhoma?
While differentiating Hodgkin's lymphoma from non-Hodgkin's lymphoma is done by biopsy certain elements of the clinical presentation can help point towards one rather than the other.
Lymphadenopathy in Hodgkin's lymphoma can experience alcohol-induced pain in the node
'B' symptoms typically occur earlier in Hodgkin's lymphoma and later in non-Hodgkin's lymphoma
Extra-nodal disease is much more common in non-Hodgkin's lymphoma than in Hodgkin's lymphoma
92
Investigations for non-hodgkins lymphoma?
Excisional nodal biopsy
CT TAP
HIV
FBC and Blood film
ESR (usefull as a poor prognostic indicator)
LDH (a marker of cell turnover, useful as a prognostic indicator)
93
Staging on non-hodgkins lymhoma?
Lugano staging
Stage I: Involvement of a single lymph node region (I) or a single extralymphatic organ or site (IE).
Stage II: Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm (IIE).
Stage III: Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an extralymphatic organ or site (IIIE), involvement of the spleen (IIIS), or both (IIIE+S).
Stage IV: Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement.
## Footnote
In addition to these stages, the classification includes the following:
A/B Symptom Designation: The absence of significant symptoms is designated as 'A', while the presence of fever, night sweats, or weight loss is designated as 'B'.
E: The presence of extranodal disease is denoted by the letter 'E'.
S: Involvement of the spleen is denoted by the letter 'S'.
X: Bulky disease (large tumor mass) is denoted by the letter 'X'.
94
Management of Non-hodgkins lymphoma?
Management is dependent on the specific sub-type of non-Hodgkin's lymphoma and will typically take the form of watchful waiting, chemotherapy or radiotherapy.
Rituximab is used in combination with conventional chemotherapy regimes (e.g. CHOP) for a variety of types of NHL
95
What should patientas be screened for before recieving Rituximab?
All patients should be screened for hepatitis B (HBV) before treatment with rituximab as it can cause reactivation of HBV in patients with prior exposure
## Footnote
Check hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc)
96
Complications of non-hodgkins lymphoma?
Bone marrow infiltration causing anaemia, neutropenia or thrombocytopenia
Superior vena cava obstruction
Metastasis
Spinal cord compression
Complications related to treatment e.g. Side effects of chemotherapy
97
Prognosis in non-hodgkins lymphoma?
Prognosis
Low-grade non-Hodgkin's lymphoma has a better prognosis
High-grade non-Hodgkin's lymphoma has a worse prognosis but a higher cure rate
98
How does acute promyelocytic leukaemia usually present?
Features
presents younger than other types of AML (average = 25 years old)
DIC or thrombocytopenia often at presentation
good prognosis
99
what genetics are associated with acute promyelocytic leukaemia?
APML is associated with the t(15;17) translocation which causes fusion of the PML and RAR-alpha genes.
100
how is acute promyelocytic leukaemia treated?
APML is treated with all-trans retinoic acid (ATRA) to force immature granulocytes into maturation to resolve a blast crisis prior to more definitive chemotherapy.
101
what is TTP caused by?
in TTP there is a deficiency of ADAMTS13 (a metalloprotease enzyme) which breakdowns ('cleaves') large multimers of von Willebrand's factor
102
management of sickle cell crisis?
analgesia e.g. opiates
rehydrate
oxygen
consider antibiotics if evidence of infection
blood transfusion
exchange transfusion: e.g. if neurological complications
103
Long term management of sickcell disease?
hydroxyurea
increases the HbF levels and is used in the prophylactic management of sickle cell anaemia to prevent painful episodes
sickle cell patients should receive the pneumococcal polysaccharide vaccine every 5 years
104
what is sickle cell anaemia?
Sickle-cell anaemia is an autosomal recessive condition that results for synthesis of an abnormal haemoglobin chain termed HbS. It is more common in people of African descent as the heterozygous condition offers some protection against malaria.
## Footnote
Around 10% of UK Afro-Caribbean's are carriers of HbS (i.e. heterozygous). Such people are only symptomatic if severely hypoxic.
105
Pathophysiology of sickle cell anaemia?
haemoglobin
normal haemoglobin: HbAA
sickle cell trait: HbAS
homozygous sickle cell disease: HbSS. Some patients inherit one HbS and another abnormal haemoglobin (HbC) resulting in a milder form of sickle cell disease (HbSC)
polar amino acid glutamate is substituted by non-polar valine in each of the two beta chains (codon 6). This decreases the water solubility of deoxy-Hb
in the deoxygenated state the HbS molecules polymerise and cause RBCs to sickle
HbAS patients sickle at p02 2.5 - 4 kPa
HbSS patients at p02 5 - 6 kPa
sickle cells are fragile and haemolyse; they block small blood vessels and cause infarction
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Diagnosis of sickle cell?
definitive diagnosis of sickle cell disease is by haemoglobin electrophoresis
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What is paroxysmal nocurnal haemoglobinurina?
Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired disorder leading to haemolysis (mainly intravascular) of haematological cells. It is thought to be caused by increased sensitivity of cell membranes to complement due to a lack of glycoprotein glycosyl-phosphatidylinositol (GPI). Patients are more prone to venous thrombosis
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Pathophysiology of paraoxysmal nocturnal haemoglobinuria?
Glycoprotein glycosyl-phosphatidylinositol (GPI) can be thought of as an anchor which attaches surface proteins to the cell membrane
complement-regulating surface proteins, e.g. decay-accelerating factor (DAF), are not properly bound to the cell membrane due a lack of GPI
thrombosis is thought to be caused by a lack of CD59 on platelet membranes predisposing to platelet aggregation
109
features of Paroxysma noctural haemoglobinuria?
haemolytic anaemia
red blood cells, white blood cells, platelets or stem cells may be affected therefore pancytopaenia may be present
haemoglobinuria: classically dark-coloured urine in the morning (although has been shown to occur throughout the day)
thrombosis e.g. Budd-Chiari syndrome
aplastic anaemia may develop in some patients
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Diagnosis of paroxysmal nocturnal haemoglobinuria?
flow cytometry of blood to detect low levels of CD59 and CD55 has now replaced Ham's test as the gold standard investigation in PNH
Ham's test: acid-induced haemolysis (normal red cells would not)
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Management of paroxysmal noctural haemoglobinuria?
blood product replacement
anticoagulation
eculizumab, a monoclonal antibody directed against terminal protein C5, is currently being trialled and is showing promise in reducing intravascular haemolysis
stem cell transplantation
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What is Li-Fraumeni syndrome?
a rare autosomal dominant disorder characterised by the early onset of a variety of cancers such as sarcoma, breast cancer and leukaemias. It is caused by mutation in the p53 gene.
## Footnote
Diagnosed when:
*Individual develops sarcoma under 45 years
*First degree relative diagnosed with any cancer below age 45 years and another family member develops malignancy under 45 years or sarcoma at any age
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What is Lynch syndrome?
Autosomal dominant
Develop colonic cancer and endometrial cancer at young age
80% of affected individuals will get colonic and/ or endometrial cancer
High risk individuals may be identified using the Amsterdam criteria
## Footnote
Amsterdam criteria
Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two.
Two successive affected generations.
One or more colon cancers diagnosed under age 50 years.
Familial adenomatous polyposis (FAP) has been excluded.
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What is Gardners syndrome?
Autosomal dominant familial colorectal polyposis
Multiple colonic polyps
Extra colonic diseases include: skull osteoma, thyroid cancer and epidermoid cysts
Desmoid tumours are seen in 15%
Mutation of APC gene located on chromosome 5
Due to colonic polyps most patients will undergo colectomy to reduce risk of colorectal cancer
Now considered a variant of familial adenomatous polyposis coli
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Causes of Polycythaemia?
Relative causes
dehydration
stress: Gaisbock syndrome
Primary
polycythaemia rubra vera
Secondary causes
COPD
altitude
obstructive sleep apnoea
excessive erythropoietin: cerebellar haemangioma, hypernephroma, hepatoma, uterine fibroids*
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how to differentiate between true (primary or secondary) polycythaemia and relative polycythaemia?
red cell mass studies are sometimes used. In true polycythaemia the total red cell mass in males > 35 ml/kg and in women > 32 ml/kg
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indications for treatment in CML?
progressive marrow failure: the development or worsening of anaemia and/or thrombocytopenia
massive (>10 cm) or progressive lymphadenopathy
massive (>6 cm) or progressive splenomegaly
progressive lymphocytosis: > 50% increase over 2 months or lymphocyte doubling time < 6 months
systemic symptoms: weight loss > 10% in previous 6 months, fever >38ºC for > 2 weeks, extreme fatigue, night sweats
autoimmune cytopaenias e.g. ITP
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Management of CML?
patients who have no indications for treatment are monitored with regular blood counts
fludarabine, cyclophosphamide and rituximab (FCR) has now emerged as the initial treatment of choice for the majority of patients
ibrutinib may be used in patients who have failed a previous therapy
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what is cyclophosphamide?
Cyclophosphamide is an alkylating agent used in the management of cancer and autoimmune conditions. It works by causing cross-linking of DNA
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Adverse effects of cyclophosphamide?
Adverse effects
haemorrhagic cystitis: incidence reduced by the use of hydration and mesna
myelosuppression
transitional cell carcinoma
Mesna
2-**me**rcaptoethane **s**ulfonate **Na**
a metabolite of cyclophosphamide called acrolein is toxic to urothelium
mesna binds to and inactivates acrolein helping to prevent haemorrhagic cystitis
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what chromosome is present in CML?
The Philadelphia chromosome is present in more than 95% of patients with chronic myeloid leukaemia (CML).
It is due to a translocation between the long arm of chromosome 9 and 22 - t(9:22)(q34; q11).
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Presentation of CML?
Presentation (60-70 years)
anaemia: lethargy
weight loss and sweating are common
splenomegaly may be marked → abdo discomfort
an increase in granulocytes at different stages of maturation +/- thrombocytosis
decreased leukocyte alkaline phosphatase
may undergo blast transformation (AML in 80%, ALL in 20%)
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What age group in CML common in?
60-70 years
124
Management of CML?
imatinib is now considered first-line treatment
inhibitor of the tyrosine kinase associated with the BCR-ABL defect
very high response rate in chronic phase CML
hydroxyurea
interferon-alpha
allogenic bone marrow transplant
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Mechanism of action of imantinib?
inhibitor of the tyrosine kinase associated with the BCR-ABL defect
126
mechanism of action of methotrexate?
Inhibits dihydrofolate reductase and thymidylate synthesis
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what is chronic granulomatous disease?
Neutrophil disorder
Lack of NADPH oxidase reduces ability of phagocytes to produce reactive oxygen species
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what does chronic granulomatous disease cause?
recurrent pneumonias and abscesses, particularly due to catalase-positive bacteria (e.g. Staphylococcus aureus and fungi (e.g. Aspergillus)
Negative nitroblue-tetrazolium test
Abnormal dihydrorhodamine flow cytometry test
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What is Chediak-Higashi syndrome?
Neutrophil disorder
Microtubule polymerization defect which leads to a decrease in phagocytosis
Affected children have 'partial albinism' and peripheral neuropathy. Recurrent bacterial infections are seen
Giant granules in neutrophils and platelets
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what is leukocyte adhesion deficiency?
Neutrophil disorder
Defect of LFA-1 integrin (CD18) protein on neutrophils
Recurrent bacterial infections.
Delay in umbilical cord sloughing may be seen
Absence of neutrophils/pus at sites of infection
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What is common variable immunodeficiency?
B-cell disorder?
Low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM and IgA. Recurrent chest infections. May also predispose to autoimmune disorders and lymphona
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What is Bruton's (x-linked) congenital agammaglobulinaemia?
B-cell disorder
Defect in Bruton's tyrosine kinase (BTK) gene that leads to a severe block in B cell development
X-linked recessive. Recurrent bacterial infections are seen
Absence of B-cells with reduced immunoglogulins of all classes
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What is selective immunoglobulin A deficiency?
B cell disorder
Maturation defect in B cells
Most common primary antibody deficiency. Recurrent sinus and respiratory infections
Associated with coeliac disease and may cause false negative coeliac antibody screen
Severe reactions to blood transfusions may occur (anti-IgA antibodies → analphylaxis)
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What is DiGeorge syndrome?
T cell disorder
Underlying defect - 22q11.2 deletion, failure to develop 3rd and 4th pharyngeal pouches
Common features include congenital heart disease (e.g. tetralogy of Fallot), learning difficulties, hypocalcaemia, recurrent viral/fungal diseases, cleft palate
135
Combined B and T cell disorders?
136
how to differentitate between multiple myeloma and waldenstrom's macroglobulinaemia?
Waldenstrom's macroglobulinaemia - Organomegaly with no bone lesions
Multiple myeloma - Bone lesions with no organomegaly
137
what conditions require CMV negative blood and irradiated blood?
138
what is seen in beta-thalassaemia trait?
mild hypochromic, microcytic anaemia - microcytosis is characteristically disproportionate to the anaemia
HbA2 raised (> 3.5%)
139
features of wiskott-aldrich syndrome?
recurrent bacterial infections (e.g. Chest)
eczema
thrombocytopaenia
low IgM levels
140
complications of CLL
Complications
anaemia
hypogammaglobulinaemia leading to recurrent infections
warm autoimmune haemolytic anaemia in 10-15% of patients
transformation to high-grade lymphoma (Richter's transformation)
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What is Richter's transformation?
Ritcher's transformation occurs when leukaemia cells enter the lymph node and change into a high-grade, fast-growing non-Hodgkin's lymphoma. Patients often become unwell very suddenly.
Ritcher's transformation is indicated by one of the following symptoms:
lymph node swelling
fever without infection
weight loss
night sweats
nausea
abdominal pain
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APML?
You are not normally expected to be able to differentiate the different subtypes of acute myeloid leukaemia (AML) for the MRCP. An exception to this is acute promyelocytic leukaemia (APML, the M3 subtype of AML). The importance of identifying APML lies in both the presentation (classically disseminated intravascular coagulation) and management
APML is associated with the t(15;17) translocation which causes fusion of the PML and RAR-alpha genes.
Features
presents younger than other types of AML (average = 25 years old)
DIC or thrombocytopenia often at presentation
good prognosis
APML is treated with all-trans retinoic acid (ATRA) to force immature granulocytes into maturation to resolve a blast crisis prior to more definitive chemotherapy.
