Haematological Malignancy Flashcards
What is Leukaemia?
Leukaemia is a form of cancer of the cells in the bone marrow.
A genetic mutation in one of the precursor cells in the bone marrow leads to excessive production of a single type of abnormal white blood cell.
What is pancocytopenia?
combination of low red blood cells (anaemia), white blood cells (leukopenia) and platelets (thrombocytopenia)
In what ages do different leukaemias occur?
“ALL CeLLmates have CoMmon AMbitions”
Under 5 and over 45 – acute lymphoblastic leukaemia (ALL)
Over 55 – chronic lymphocytic leukaemia (CeLLmates)
Over 65 – chronic myeloid leukaemia (CoMmon)
Over 75 – acute myeloid leukaemia (AMbitions)
What si the most common malignancy affecting children
Acute lymphoblastic leukaemia (ALL)
Acute lymphoblastic leukaemia (ALL) accounts for 80% of childhood leukaemias
true
What is the aetiology of ALL?
eak incidence is at around 2-5 years of age and boys are affected slightly more commonly than girls
What symptoms do you get in bone marrow failure?
anaemia: lethargy and pallor
neutropaenia: frequent or severe infections
thrombocytopenia: easy bruising, petechiae
What symptoms do you get in ALL?
Pancocytopenia sx
bone pain (secondary to bone marrow infiltration)
splenomegaly, hepatomegaly
fever is present in up to 50% of new cases (representing infection or constitutional symptom)
testicular swelling
What types of ALL do you get?
common ALL (75%), CD10 present, pre-B phenotype
T-cell ALL (20%)
B-cell ALL (5%)
What are some poor prognostic factors of ALL?
age < 2 years or > 10 years WBC > 20 * 109/l at diagnosis T or B cell surface markers non-Caucasian male sex
Chronic lymphocytic leukaemia (CLL) is caused by?
monoclonal proliferation of well-differentiated lymphocytes which are almost always B-cells (99%)
What is the most common form of leukaemia seen in adults?
CLL
How does CLL often present?
often no symptoms: may be picked up by an incidental finding of lymphocytosis
constitutional: anorexia, weight loss
Also, bleeding, infections
lymphadenopathy is more marked in CLL or CML?
lymphadenopathy more marked in CLL than chronic myeloid leukaemia
What is the key investigation for CLL?
immunophenotyping
What will you see on FBC in CLL?
lymphocytosis
anaemia
What will you see on blood film in CLL?
smudge cells (also known as smear cells)
What are the complications of CLL?
anaemia
hypogammaglobulinaemia leading to recurrent infections
warm autoimmune haemolytic anaemia in 10-15% of patients
Richter’s transformation
What is Richter’s Transfromation?
Complication of CLL
Ritcher’s transformation occurs when leukaemia cells enter the lymph node and change into a high-grade, fast-growing non-Hodgkin’s lymphoma.
How does Richter’s transformation present?
Patients often become unwell very suddenly.
lymph node swelling
Constitutional: fever without infection, weight loss, night sweats
nausea, abdominal pain
Which chromosome is associated with chronic myeloid leukaemia?
The Philadelphia chromosome is present in more than 95% of patients with chronic myeloid leukaemia (CML)
What is the Philadelphia Chromosome? What gene does it result in?
It is due to a translocation between the long arm of chromosome 9 and 22 - t(9:22)(q34; q11).
This results in part of the ABL proto-oncogene from chromosome 9 being fused with the BCR gene from chromosome 22.
The resulting BCR-ABL gene codes for a fusion protein which has tyrosine kinase activity in excess of normal
What age group does CML present in?
60-70
How does CML present?
anaemia: lethargy
weight loss and sweating are common
splenomegaly may be marked → abdo discomfort
What would investigations of CML show?
an increase in granulocytes at different stages of maturation +/- thrombocytosis
decreased leukocyte alkaline phosphatase
may undergo blast transformation (AML in 80%, ALL in 20%)
What does BCR ABL do?
tyrosine kinase activity in excess of normal
What is first line for CML? What other options are there?
imatinib is now considered first-line treatment
hydroxyurea
interferon-alpha
allogenic bone marrow transplant
How does Imatinib work?
inhibitor of the tyrosine kinase associated with the BCR-ABL defect
Imanitib has high response rate in which phase of CML?
Chronic
Acute myeloid leukaemia is the more common form of acute leukaemia in adults.
true
AML may occur as a primary disease or following a secondary transformation of a myeloproliferative disorder
true
Feature of AML are largely related to bone marrow failure
true
What symptoms do you get in AML?
anaemia: pallor, lethargy, weakness
neutropenia: whilst white cell counts may be very high, functioning neutrophil levels may be low leading to frequent infections etc
thrombocytopenia: bleeding
splenomegaly
bone pain
What are poor prognostic factors of AML?
> 60 years
20% blasts after first course of chemo
cytogenetics: deletions of chromosome 5 or 7
How is AML classified?
French-American-British (FAB)
OUtline French-American-British (FAB)
MO - undifferentiated M1 - without maturation M2 - with granulocytic maturation M3 - acute promyelocytic M4 - granulocytic and monocytic maturation M5 - monocytic M6 - erythroleukaemia M7 - megakaryoblastic
Acute promyelocytic leukaemia M3 is associated with what?
associated with t(15;17)
fusion of PML and RAR-alpha genes
Acute promyelocytic leukaemia presents younger than other types of AML
true
25 yrs old avg
Acute promyelocytic leukaemia M3 has a bad prognosis
false
good
Acute promyelocytic leukaemia M3 will present with?
DIC or thrombocytopenia often at presentation
Acute promyelocytic leukaemia M3 will show what on myeloperoxidase stain?
Auer Rods
Lymphomas are a group of cancers that affect the lymphocytes inside the lymphatic system.
true
There are two main categories of lymphoma - what are they?
Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. Hodgkin’s lymphoma is a specific disease and non-Hodgkins lymphoma encompasses all the other lymphomas.
Hodgkin’s lymphoma is a malignant proliferation of lymphocytes characterised by the presence of
the Reed-Sternberg cell.
Hodgkin’s lymphoma has a bimodal age distributions being most common in?
the third and seventh decades
Presntation of HL?
lymphadenopathy (75%) - painless, non-tender, asymmetrical
systemic (25%): weight loss, pruritus, night sweats, fever (Pel-Ebstein)
Bloods in HL?
normocytic anaemia, eosinophilia
LDH raised
Alcohol causes pain in HL
TRUE
Symptoms that imply a poor prognosis in HL are called?
‘B’ symptoms
What are ‘B’ symptoms
weight loss > 10% in last 6 months
fever > 38ºC
night sweats
What are the 4 classes of histology in HL?
Nodular sclerosing
Mixed cellularity
Lymphocyte predominant
Lymphocyte depleted
What is the commonest type of HL?
Nodular sclerosing Most common (around 70%)
What is the best prognosis of HL?
Lymphocyte predominant
Describe the frequency, prognosis and cells associated with Nodular Sclerosing HL?
Most common (around 70%)
Good prognosis
Associated with lacunar cells
Nodular Sclerosing HL is most common in women
true
Describe the frequency, prognosis and cells associated with Mixed Cellularity HL?
Around 20% Good prognosis Associated with a large number of Reed-Sternberg cells
Describe the frequency & prognosis of Lymphocyte predominant HL?
Around 5% Best prognosis
Describe the frequency & prognosis of Lymphocyte depleted HL?
Rare Worst prognosis
What system is used to stage HL?
Ann-Arbor
Describe Ann-Arbor staging?
I: single lymph node
II: 2 or more lymph nodes/regions on same side of diaphragm
III: nodes on both sides of diaphragm
IV: spread beyond lymph nodes
Each stage may be subdivided into A or B
A = no systemic symptoms other than pruritus
B = weight loss > 10% in last 6 months, fever > 38c, night sweats (poor prognosis)
Non-Hodgkin’s lymphoma is the 6th most common cause of cancer in the UK.
true
Non-Hodgkin’s lymphoma may affect either ?
B or T-cells
Non-Hodgkin’s lymphoma is much more common than Hodgkin’s lymphoma
true
Non-Hodgkin’s lymphoma typically affects who?
elderly with one-third of cases occurring in those over 75 years of age
men
incidence rate is 28 for men and 20 for females per 100,000 of the population
risk factors for NHL
Elderly
Caucasians
History of viral infection
Family history
Certain chemical agents (pesticides, solvents)
History of chemotherapy or radiotherapy
Immunodeficiency (transplant, HIV, diabetes mellitus)
Autoimmune disease (SLE, Sjogren’s, coeliac disease)
Which virus assoc with NHL
(specifically Epstein-Barr virus)
What is the lymphadenopathy like in NHL?
non-tender, rubbery, asymmetrical
Symptoms of NHL?
Painless lymphadenopathy
Constitutional/B symptoms (fever, weight loss, night sweats, lethargy)
Extranodal Disease - gastric (dyspepsia, dysphagia, weight loss, abdominal pain), bone marrow (pancytopenia, bone pain), lungs, skin, central nervous system (nerve palsies)
How to differentiate from NHL & HL?
biopsy
symptoms can help
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
Signs of NHL?
Signs of weight loss
Lymphadenopathy (typically in the cervical, axillary or inguinal region)
Palpable abdominal mass - hepatomegaly, splenomegaly, lymph nodes
Testicular mass
Fever
Diagnostic investigations in NHL?
Excisional node biopsy is the diagnostic investigation of choice (certain subtypes will have a classical appearance on biopsy such as Burkitt’s lymphoma having a ‘starry sky’ appearance)
Why is a HIV test often performed in NHL?
risk factor for non-Hodgkin’s lymphoma
What bloods are done and what do they show in NHL?
FBC and blood film: patient may have a normocytic anaemia and can help rule out other haematological malignancy such as leukaemia
ESR (useful as a prognostic indicator)
LDH (a marker of cell turnover, useful as a prognostic indicator)
LFT’s if liver metastasis suspected
What other investigations are done in NHL?
CT chest, abdomen and pelvis (to assess staging)
Other investigations can be ordered as the clinical picture indicates (LFT’s if liver metastasis suspected, PET CT or bone marrow biopsy to look for bone involvement, LP if neurological symptoms)
The most common staging system used for non-Hodgkin’s lymphoma is the ?
Ann Arbor system.
Management of NHL?
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.
All patients will receive flu/pneumococcal vaccines
Patients with neutropenia may require antibiotic prophylaxis
Complications of NHL?
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 chemotherap
Prognosis of NHL?
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
What is Burkitt’s Lymphoma?
high-grade B-cell neoplasm
What are the two forms of Burkitt’s?
endemic (African) form: typically involves maxilla or mandible
sporadic form: abdominal (e.g. ileo-caecal) tumours are the most common form. More common in patients with HIV
Burkitt’s lymphoma is associated with which gene translocation?
c-myc gene translocation, usually t(8:14)
Is EBV associated with Burkitt’s?
YES
Epstein-Barr virus (EBV) is strongly implicated in the development of the African form of Burkitt’s lymphoma and to a lesser extent the sporadic form.
What are the Microscopy findings in Burkitt’s?
‘starry sky’ appearance: lymphocyte sheets interspersed with macrophages containing dead apoptotic tumour cells
Management of Burkitt’s?
Management is with chemotherapy.
Chemo can have a rapid response in Burkitt’s. Patients are at ris of what? Complications of this?
‘tumour lysis syndrome’. Rasburicase (a recombinant version of urate oxidase, an enzyme which catalyses the conversion of uric acid to allantoin*) is often given before the chemotherapy to reduce the risk of this occurring.
Complications of tumour lysis syndrome include: hyperkalaemia hyperphosphataemia hypocalcaemia hyperuricaemia acute renal failure
*allantoin is 5-10 times more soluble than uric acid, so renal excretion is more effective
Gastric MALT lymphoma is associated with which infection?
H. pylori infection in 95% of cases
Low grade Gastric MALT lymphoma responds to what?
if low grade then 80% respond to H. pylori eradication
Gastric MALT lymphoma has a good prognosis
true
Gastric MALT lymphoma may also have what?
paraproteinaemia may be present
Describe which infections are associated with which haematological malignancy
Viruses
EBV: Hodgkin’s and Burkitt’s lymphoma, nasopharyngeal carcinoma
HTLV-1: Adult T-cell leukaemia/lymphoma
HIV-1: High-grade B-cell lymphoma
Bacteria
Helicobacter pylori: gastric lymphoma (MALT)
Protozoa
malaria: Burkitt’s lymphoma
What is multiple myeloma?
Myeloma is a cancer of the plasma cells. These are a type of B lymphocyte that produce antibodies. Cancer in a specific type of plasma cell results in large quantities of a single type of antibody being produced.
MM is the second most common haematological malignancy.
true
The median age for MM at presentation is?
70-years-old.
What are the features of MM?
Use the mnemonic CRABBI: hyperCalcaemia Renal impairment Anaemia Bleeding Bone pain/fractures Infection
Why do you get hypercalcaemia in MM?
due primarily to increased osteoclastic bone resorption caused by local cytokines (e.g. IL-1, tumour necrosis factor) released by the myeloma cells
This leads to constipation, nausea, anorexia and confusion
much less common contributing factors: impaired renal function, increased renal tubular calcium reabsorption and elevated PTH-rP levels
Why do you get renal impairment in MM? How does this present?
Monoclonal production of immunoglobulins results in light chain deposition within the renal tubules
This causes renal damage which presents as dehydration and increasing thirst
Why do you get anaemia in MM? How does this present?
Bone marrow crowding suppresses erythropoiesis leading to anaemia
This causes fatigue and pallor
Why do you get bleeding in MM? How does this present?
bone marrow crowding also results in thrombocytopenia which puts patients at increased risk of bleeding and bruising
Why do you get bone problems in MM? How does this present?
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 fragility fractures
Why dyou get more infections in MM?
a reduction in the production of normal immunoglobulins results in increased susceptibility to infection
What will bloods show in MM?
anaemia (FBC) and thrombocytopenia (FBC); raised urea and creatinine (U&E) and raised calcium
What will you see in blood film for MM?
Peripheral blood film: rouleaux formation
What confirms the diagnosis in MM? What will you see?
Bone marrow aspiration and trephine biopsy
number of plasma cells is significantly raised
What feature is pathonogmonic of MM? What tests will show this?
IgA/IgG proteins
In the urine, they are known as Bence Jones proteins
Serum or urine protein electrophoresis
Will you see in XR for MM?
‘rain-drop’ skull. This is numerous randomly placed dark spots seen on X-ray which occur due to bone lysis.
Why would you do an MRI in MM?
used to survey the skeleton for bone lesions
CT if MRI not suitable
Why is it important to diagnose MM?
unlike its pre-malignant counterparts (Monoclonal gammopathy of undetermined significance and Smoldering myeloma), treatment must begin immediately due to the risk of complications occurring as a result on end-organ damage.
Symptomatic multiple myeloma is defined at diagnosis by the presence of the which 3 factors?
Monoclonal plasma cells in the bone marrow >10%
Monoclonal protein within the serum or the urine (as determined by electrophoresis)
Evidence of end-organ damage e.g. hypercalcaemia, elevated creatinine, anaemia or lytic bone lesions/fractures
Is myeloma curable?
no
Myeloma is a chronic relapsing and remitting malignancy
true
Management aims for MM?
control symptoms, reduce complications and prolong survival.
For those who have just been diagnosed with symptomatic multiple myeloma, treatment begins with what therapy?
induction
In MM: For patients who are suitable for autologous stem cell transplantation* induction therapy consists?
Bortezomib + Dexamethasone
In MM: For patients who are UNSUITABLE for autologous stem cell transplantation* induction therapy consists?
Thalidomide + an Alkylating agent + Dexamethasone
Which patients are typically suitable for stem cell transplantation?
younger, healthier patients
In MM After completion of treatment, patients are monitored how?
monitored every 3 months with blood tests and electrophoresis.
In MM Many patients do relapse after initial therapy
true
How to treat relapse in MM?
1st line recommended treatment is Bortezomib monotherapy.
Some patients may also be suitable for a repeat autologous stem cell transplant*, but this is decided on a case-by-case basis.
A large part of multiple myeloma treatment involves managing complications
true
MM - how do you treat Pathological fracture?
Zoledronic acid is given to prevent and manage osteoporosis and fragility fractures as these are a large cause of morbidity and mortality, particularly in the elderly.
MM - how do you manage infection?
patients receive annual influenza vaccinations. They may also receive Immunoglobulin replacement therapy.
MM - how do you manage fatigue?
treat all possible underlying causes. If symptoms persist consider an erythropoietin analogue.
DO MM patients get VTE prophylaxis?
yes
Describe the different types of stem cell transplant
Autologous: Used after high dose chemotherapy which targets stem cells.
It involves the removal of a patient’s own stem cells prior to chemotherapy, which are then replaced after chemotherapy.
Allogenic: stem cells are sourced from HLA matching donors. Currently only used as part of clinical trials when treating multiple myeloma.
The diagnostic criteria for multiple myeloma requires what
one major and one minor criteria OR
three minor criteria
in an individual who has signs or symptoms of multiple myeloma.
Major criteria of MM?
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 of MM? (4 things)
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.
What is MGUS? Why might it be mistaken for MM?
Monoclonal gammopathy of undetermined significance
is where there is an excess of a single type of antibody or antibody components without other features of myeloma or cancer.
This is often an incidental finding in an otherwise healthy person and as the name suggests the significance is unclear. It may progress to myeloma and patients are often followed up routinely to monitor for progression.
benign paraproteinaemia
What % patients with MGUS develop MM?
Around 10% of patients eventually develop myeloma at 10 years, with 50% at 15 years
How does MGUS usually present?
usually asymptomatic
no bone pain or increased risk of infections
around 10-30% of patients have a demyelinating neuropathy
What are the differentiating features (investigations wise) of MGUS over MM?
normal immune function, normal beta-2 microglobulin levels
lower level of paraproteinaemia than myeloma (e.g. < 30g/l IgG, or < 20g/l IgA)/ stable level of paraproteinaemia
no clinical features of myeloma (e.g. lytic lesions on x-rays or renal disease)
What is myelofibrosis? What is the pathophysiology?
Myelofibrosis is where the proliferation of the cell line leads to fibrosis of the bone marrow. The bone marrow is replaced by scar tissue. This is in response to cytokines that are released from the proliferating cells. One particular cytokine is fibroblast growth factor. This fibrosis affects the production of blood cells and can lead to anaemia and low white blood cells (leukopenia).
When the bone marrow is replaced with scar tissue the production of blood cells (haematopoiesis) starts to happen in other areas such as the liver and spleen.
This is known as extramedullary haematopoiesis and can lead to hepatomegaly and splenomegaly. This can lead to portal hypertension. If it occurs around the spine it can lead to spinal cord compression.
How does myelofibrosis present?
elderly person
Symptoms of anaemia e.g. fatigue (the most common presenting symptom)
massive splenomegaly
Constitutional: weight loss, night sweats etc
What will you see on blood film in myelofibrosis?
‘tear-drop’ poikilocytes on blood film
What will you see in bloods of myelofibrosis pts?
high urate and LDH (reflect increased cell turnover)
anaemia
high WBC and platelet count early in the disease
What will you see on bone marrow in myelofibrosis?
unobtainable bone marrow biopsy - ‘dry tap’ therefore trephine biopsy needed
What is Myelodysplastic syndrome?
Myelodysplastic syndrome is caused by the myeloid bone marrow cells not maturing properly and therefore not producing healthy blood cells. There are a number of specific types of myelodysplastic syndrome.
Anaemia
Neutropenia (low neutrophil count)
Thrombocytopenia (low platelets)
can myelodysplastic syndrome result in malignancy
pre-leukaemia, may progress to AML
Features of myelodysplastic syndrome?
more common with age
presents with bone marrow failure (anaemia, neutropaenia, thrombocytopenia)
What is Waldenstrom’s macroglobinaemia?
uncommon condition seen in older men. It is a lymphoplasmacytoid malignancy characterised by the secretion of a monoclonal IgM paraprotein
Symptoms of Waldenstrom’s Macroglobinaemia?
monoclonal IgM paraproteinaemia
systemic upset: weight loss, lethargy
hyperviscosity syndrome e.g. visual disturbance
hepatosplenomegaly
lymphadenopathy
cryoglobulinaemia e.g. Raynaud’s
Why do you get hyperviscosity in Waldenstorm’s
the pentameric configuration of IgM increases serum viscosity
