Haematological Cancers Flashcards
What is myeloma?
A neiplastic disease of the plasma cells (grown up B lymphocytes which have turned into antibody producing cells)
What are the antibodies floating around in myeloma called.
Because it is a cancer of the plasma cells, which produce antibodies you will have lots of antibodies all of the same type, these are called monoclonal but specifically to myeloma they are called paraprotein.
What levels should you measure if someone has myeloma?
It is important to measure paraprotein levels.
What is a lymphoma and what are the two types?
Neoplastic disease of mature lymphocytes in lymphoid tissue, the two types are: hodgkins and non hodgkins lymphoma.
Where are lymphomas normally found?
Anywhere where the lymphoid tissue is found- gut, skin, MALT, lymph nodes.
What is acute leukaemia?
Neoplastic disease of the immature cells (blasts) in the bone marrow, can either be acute myeloid or acute lymphoid.
What is chronic leukaemia?
Neoplastic disease of mature WBC in the bone marrow, again can be myeloid or lymphoid.
What is myeloproliferative disease?
Group of neoplastic disorders which involve bone marrow cells which produce red blood cells, platelets and fibroblasts.
What are the clinical features of Hodgkin’s/ non hodgkins lymphoma?
Face- conjunctival pallor
Retinal haemorrhage
Pallor of mucous membranes
Enlarged lymph nodes
Skin- petichae, ecchymosis, palmar creases pallor
GI- early satiety, hepatosplenomegaly, para aortic, lymphadenopathy
MSK- bone pain
Other- anaemia, pancytopaenia, thrombocytopenia, weight loss, night sweats, malaise, fatigue
What is the staging of hodgkins/ non hodgkins lymphoma?
Stage 1- disease is confined to one lymph node or two contiguous lymph node groups
Stage 2- disease on one side of the diaphragm in two separate lymph node groups
Stage 3- disease on both sides of the diaphragm
Stage 4- extra nodal spread with diffuse or disseminated spread of one or more extralymphatic organs
Modifiers…
a= absence of constitutional symptoms
B= presence of B symptoms (fever, night sweats, weight loss)
C= if disease is extranodal or has spread from lymph nodes to adjacent tissue
X= if the largest deposit is >10cm in diameter or if the mediastinum is wider than 1/3 of the chest diameter on x ray
S= disease spread to spleen
What are the subtypes of Hodgkin’s lymphoma?
. Nodular sclerosing (60%) is the most common subtype
Typically young adults who have early supra-diaphragmatic presentations
Patients have a good prognosis
. Mixed cellularity (30%)
. Lymphocyte predominant (5%) best prognosis
. Lymphocyte depleted (5%) rare subtype with lots of reed Sternberg with only a few lymphocytes
.
What is the usual presentation of hodgkins lymphoma?
Usually painless lymphadenopathy above diaphragm
Can also get systemic symptoms- b symptoms ‘fevers, night sweats, weight loss’ and chronic pruritis
Systemic symptoms have a negative impact on prognosis
What are the most common extra nodal sites to be involved in hodgkins lymphoma?
. Spleen
. Lung
. Liver
. Bone marrow
What are the investigations done for a hodgkins lymphoma?
Careful history and clinical exam
ESR
FBC
LFTs
U&Es
ALP (elevated is non specific but may indicate bone involvement)
LDH (sig elevated is associated with a worse prognosis)
Abnormal liver function should prompt further evaluation with imaging and possible biopsy
Biopsy of an enlarged lymph node is vital for diagnosis, this should be an wide excision biopsy
Imaging should include a CXR and CT or MRI of the chest, abdomen or pelvis
PET imaging can be used to determine the extent of spread and for staging
Bone marrow aspirate and trephine should be considered because of the impact of positive biopsy on further imaging and treatment.
What is the treatment for Hodgkin’s lymphoma?
Stage 1-2a = radiotherapy
Stage 2b-4 = chemo
High dose chemo followed by stem cell teansplantation is the most effective treatment for patients who do not respond to standard chemo
What is the prognosis for hodgkins lymphoma?
90% of patients with small volume, early stage disease are cured with radiotherapy
40-60% with advanced are treated with chemo
What are the poor prognostic factors for Hodgkin’s lymphoma?
. B symptoms . Age >45 . Bulky mediastinal disease . Extranodal involvement . Low haematocrit (the ratio of the volume of red blood cells to blood) . High ESR . High levels of CD30 and soluble IL-2
What viruses are implicated in the pathogenesis of non Hodgkin’s lymphoma?
EBV (burkitts lymphoma)
HTLV-1 (adult T cell leukaemia/ lymphoma)
HHV 8 (kaposis sarcoma)
HCV
How does non hodgkins lymphoma present?
Low grade= painless, slowly progressive peripheral lymphadenopathy which sometimes waxes and wanes.
Spontaneous regression of large lymph nodes can occur which can cause them to be confused with infections
Intermediate/high grade= majority of patients have lymphadenopathy
40% extranodal involvement
B symptoms in about 40% of patients
How do patients with burkitts lymphoma present?
Large abdo mass and symptoms of bowel obstruction
What are the investigations for non hodgkins lymphoma?
Wide excision biopsy for diagnosis FBC ALP LFTs CXR CT of chest and abdomen PET imaging for staging LDH and beta 2 microglobulin HIV serology/HLTV1 serology based on histology
What is the treatment of hodgkins lymphoma?
radiotherapy
chemotherapy
steroids
high dose chemotherapy with a stem cell or bone marrow transplant
People with the rare nodular lymphocyte predominant type of Hodgkin lymphoma (NLPHL) may have a type of biological therapy called rituximab.
You will probably have a short course of chemotherapy if you have limited disease. Your doctor might then recommend radiotherapy to the affected lymph nodes. You might also have radiotherapy to your spleen or other lymph nodes.
You might just have radiotherapy to the affected lymph nodes if you have very early, localised disease and are not able to have chemotherapy for any reason.
Early nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) may not need any treatment. It is a slow growing cancer and your doctor may prefer to wait before giving you any treatment.
Advanced stage generally means that you have stage 2B, 3 or 4 Hodgkin lymphoma.
You are most likely to have chemotherapy with or without steroids. You may also have radiotherapy to particular groups of lymph nodes if they are very swollen (enlarged) or causing symptoms.
You might have high dose chemotherapy with a stem cell or bone marrow transplant, if your lymphoma comes back after treatment (relapses). Or your doctor might suggest treatment with a biological therapy drug called brentuximab.
Or you might have more chemotherapy or radiotherapy, depending on the treatment you have already had.
Sometimes Hodgkin lymphoma does not respond as well to initial treatment as your doctor would hope. You might have more treatment, for example, radiotherapy as well as chemotherapy. Or they may change your chemotherapy drugs, or give you the biological therapy drug brentuximab.
Or your doctor might suggest high dose chemotherapy treatment with a stem cell or bone marrow transplant.
What is rituximab?
Monoclonal antibody that targets the CD20 antigen found on the surface of more than 90% of B cell lymphomas. This is used as a single agent in the treatment of relapses low grade non Hodgkin’s lymphoma and is also used in combo with chemo for follicular, mantle cell and diffuse aggressive NHL
What is myeloma?
Cancer of the plasma cells, plasma cells are a type of B lymphocyte which produce antibodies, therefore cancer in a specific type of plasma cell results in large quantities of a single type of antibody being produced.
What is multiple myeloma?
This is where the myeloma affects multiple areas of the body
What is monoclonal gammopathy of undetermined significance?
This is when there is an excess of a single type of antibody or antibody components without other features of myeloma or cancer, it is often an incidental finding of an otherwise healthy individual, however individuals are often followed up routinely to monitor for progression.
What is the pathophysiology behind myeloma?
Neoplastic disease of plasma cells
Plasma cells are B cells of the immune system which have become activated to produce a certain antibody
They are called B cells because they are found in the bone marrow
Myeloma is a cancer of a specific type of plasma cell where there is a genetic mutation causing it to rapidly and uncontrollably multiply.
Antibodies are also called immunoglobulins
What are the different types of immunoglobulins and why is this significant in myeloma?
A, M, D, E, B, G
When you measure the immunoglobulins in a patient with myeloma, one of the types will be significantly raised, more than 50% of the time this is IgG.
What is a monoclonal paraprotein?
The single type of antibody which is produced by all the identical cancerous plasma cells in myeloma.
What is the bence jones protein?
Found in the urine of patients with myeloma, it is a subunit of the antibodies (light chains)
Why do you get anaemia in myeloma?
The cancerous plasma cells invade the bone marrow, bone marrow infiltration, causes suppression of the the development of other blood cell lines which leads to anaemia (low red cells), thrombocytopenia and neutropenia.
What is myeloma bone disease?
This occurs as a result of increased osteoclast activity and suppressed osteoblast activity
More than 80% of multiple myeloma patients develop bone problems during the course of their disease; 70% of these patients have bone loss in the spine.
Multiple myeloma upsets the osteoclast-osteoblast balance by uncoupling their functions. Myeloma cells produce osteoclast-activating factors, signaling osteoclasts to break down bone uncontrollably. At the same time, they prevent bone repair by inhibiting the formation of osteoblasts.
something to do with cytokines
Where is myeloma bone disease likely to occur?
Skull, spine, long bones, ribs
The abnormal bone metabolism is patchy, some areas of the bone become very thin whereas others remain normal, the patches where the bone is thin are known as osteolytic lesions. The weak parts of the bone lead to pathological fractures
All the osteoclast activity in myeloma bone disease results in calcium being reabsorbed from the bone and therefore leads to hypercalcaemia.
What are plasmacytomas?
These are individual tumours formed by cancerous plasma cells which people with myeloma can develop.
Plasmacytomas can occur in the bones, replacing normal bone tissue or outside bones un the soft tissues of the body.
Why can patients with myeloma develop renal impairment?
High levels pf immunoglobulins can block the flow through tubules
Hypercalcaemia impairs renal function
Treatments- bisphosphonates
Dehydration
Why do patients with myeloma have hyperviscosity?
Plasma viscosity increases when there are more proteins in the blood, in myeloma there are more immunoglobulins (proteins)
What is the problem with increased viscosity?
Easy bruising
Easy bleeding
Reduced/loss of sight due to vascular disease of the eye
Purple discolouration to the extremities (purplish palmar erythema)
Heart failure
What are the important features of myeloma that you should remember?
CRAB HAI C= calcium R= renal failure A= anaemia (normocytic, normochromic) B= bone lesions/pain H= hyper-viscosity A= amyloidosis I= infection
What are the risk factors for myeloma?
Older age Male Black african ethnicity Family history Obesity
What are the investigations needed for a suspected myeloma?
Consider myeloma in anyone over 60 with persistent bone pain, particularly back pain, unexplained fractures. Perform FBC (low WCC) Calcium (raised) ESR (raised) Plasma viscosity (raised)
If any of these are positive or myeloma is still suspected then do an urgent serum protein electrophoresis and a urine bence jones protein test.
Important investigations can be remembered as BLIP
B= bence jones protein (urine electrophoresis)
L= serum light free light chain assay
I= serum immunoglobulins
P= serum protein electrophoresis
Bone marrow biopsy is needed to confirm diagnosis
Imaging is required to assess for bone lesions-
Whole body MRI= top choice
Whole body CT
Skeletal survey (xray images of the full skeleton)
Serum and/or urine electrophoresis will show a paraprotein spike (IgG typically)
What are the xray signs of a myeloma?
Punched out lesions
Lytic lesions
Pepperpot skull (many punched out lesions throughout skull)
What is the treatment of myeloma?
Usually myeloma takes a remitting and relapsing course and treatment aims to improve the quality and quantity of life.
Patient will require induction therapy with non chemotherapeutics (Dexamethasone, thalidomide, bortezombin) or chemotherapeutics (vincristine, doxorubicin, dexamethasone)
Then conditioning regimen with melphalane followed by autologous stem cell transplant is the preferred option
Patients who are unsuitable for transplant will recieve MPT (Melphalane, prednisiolone, thaliomide)
Remember that patients often require venous thromboembolism prophylaxis with aspirin or low molecular whilst on certain chemo as there is a higher risk of them developing a thrombus
How can you treat myeloma bone disease?
Improved using bisphosphonates, these suppress osteoclast activity
Radiotherapy to bone lesions to improve bine pain
Ortho surgery stabilises bone
Cement augmentation (injecting cement into vertebral fractures or lesions)
What are the complications of myeloma?
Infection Pain Renal failure Anaemia Hypercalcaemia Peripheral neuropathy Spinal cord compression Hyperviscosity
What is meant by myeloproliferative disorders?
Conditiobs which occur due to an uncontrolled proliferation of a single type of stem cell. They are considered a type of bone cancer The 3 main ones to remember are: 1) polycythaemia vera 2) primary myelofibrosis 3) essential thrombocythaemia
What proliferating cell line in primary myelofibrosis? What is myelofibrosis?
Haematopoietic stem cell
Myelofibrosis is where the haematopoietic stem cells in the bone marrow gets replaced by scar tissue.
The haematopoetic stem cells instead migrate to the liver/ spleen/lungs
What is the proliferating cell line is polycythaemia vera?
Erythroid cells
What is the proliferating cell line in essential thrombocythaemia?
Megakaryocyte
What genes are the mutations associated with myeloproliferative disorders found in?
JAK2
MPL
CALR
What is myelofibrosis?
This is where the proliferation of cell lines in myeloproliferative disease leads to bone marrow fibrosis
The bone marrow is replaced with scar tissue in response to cytokines released by the proliferating cells
One particular cytokine is fibroblast growth factor
The fibrosis affects production of blood cells and can lead to anaemia and leukopenia
What are myeloproliferate disorders?
Rare disorders of the bone marrow that cause an uncontrollable production of a specific type of bloode cell, usually occurs in over 60s and may be asymptomatic.
What is the name when too many red blood cells are produced?
Polycythaemia ruba vera
What is the mutation usually associated with polycythaemia ruba vera?
JAK2 mutation
What are the clinical features of polycthaemia ruba vera?
symptoms Hyper viscosity (headaches/vision changes) Abdominal pain recurrent infections (low WCC)
Signs Increased blood pressure Plethoric complexion Central cyanosis Splenomegaly Ascites, varcies Bleeding and petechiae
How do you treat polycythaemia ruba vera?
Aspirin
JAK2 inhibitors
Hybroxycarbamide (chemo drug)
venesection
What investigations are used for detecting polycythaemia ruba vera and what would they show?
FBC- raised haematocrit and sometimes raised neutrophils and platelets
Blood film
Genetic testing for JAK2 mutation
Serum EPO (low)
Renal and LFTs
US of the abdomen to confirm hepatosplenomegaly
Bone marrow biopsy
What are patients with polycythaemia ruba vera more likely to get in the future?
Myelofibrosis
AML
What are the secondary causes of high red blood cell?
chronic hypoxia Obstructive sleep apnoea Smoking High altitudes Renal dysfunction
What is essential thrombocythaemia?
Rare type of blood cancer causing excess platelets
What are the symptoms of essential thrombocythaemia?
Symptoms
- thrombosis (arterial/venous)
- headache
- bleeding (GI/intracranial)
- dizziness/syncope (secondary to hyper viscosity)
What are the Ix used in essential thrombocythaemia?
. Bone marrow biopsy
. US to confirm hepatosplenomegaly
. FBC- shows high platelet count
What is the treatment of essential thrombocythaemia?
Aspirin if platelets are below 1000x10^9
If platelets are over 1000 then hydroxycarbamide is given
Risk factors for clotting should also be minimised like smoking and lack of exercise
What can essential thrombocythaemia lead to?
AML and myelofibrosis.
What are the secondary causes of increased platelets?
Bleeding Iron deficiency Splenectomy Inflammation/infection Post surgery
What is myelofibrosis?
The replacement of normal bone marrow with collagen, which is due to the release of platelet derived growth factor causing fibrosis and bone marrow failure.
What are the symptoms/signs of essential thrombocythaemia?
B symptoms- fever, weight loss, night sweats, anorexia
Decreased RBC results in anaemia symptoms (SOB, fatigue, pallor)
Decreased WCC results in severe infection
Decreased platelets results in easy bruising and petechiae
Others= splenomegaly, abdominal pain
What investigations would you do for myelofibrosis and what would they show…
FBC- reduced RBC, reduced WCC, reduced platelets
LDH and Urate (would be high due to an increased cell turnover)
Blood sample would show teardrop shaped poikilinocytes
JAK2
Trephine bone marrow biopsy- increased cellularity, fibrosis
How do you treat myelofibrosis?
Blood transfusions
Chemo
Select few have a bone marrow transplant/splenectomy
What are the risk factors for lymphoma?
Increase age Being caucasian Hx of EBV/HIV Immunodeficiency Hx of chemo/RT FHX Autoimmune Smoking
How is lymphoma staged?
It is based on the Ann arbor staging system
Stage 1= single LN involvement
Stage 2= 2 or more regions are involved but on the same side of the diaphragm
Stage 3= when 2 or more regions are involved on different sides of the diaphragm
Stage 4= when extra nodal sites are involved
Who does hodgkins lymphoma normally affect?
More likely to occur in males
Has a peak incidence in 15-34 and then again after 55
How do patients with lymphoma present?
Painless asymettrical spreading lymphadenopathy, usually in the cervical region which develops gradually over time
The nodes may wax and wane and are thought to become painful with the consumption of alcohol
If the patient has a mediastinal mass then the patient can present with superior vena cava obstruction or bronchial obstruction, cough or haemoptysis.
Other features= Cyclical fever (Pel ebstein fever), pruritus, unexplained weight loss, malaise and night sweats
What would you find on examination in patients with lymphoma?
Hepatosplenomegaly
Enlarged lymph nodes (lymphadenopathy)
What investigations should be done for someone you are suspecting to have lymphoma?
FBC (reduced RBC would exclude leukaemia), bone profile, LDH and ESR (if raised they have a poor prognosis)
Test for HIV, Hep B/C, EBV
Lymph node excisional biopsy to give histology and immunophenotyping
Imaging should be done for staging
BM biopsy can be done if there is an uncertain diagnosis, B symptoms,or inconclusive imaging
Before treatment as well, should have ECG and baseline LFTS
What is pathognomicn for hodgkin lymphoma?
Reed steinberg (large multinucleated cells)
What is the treatment for hodgkin lymphoma?
Depend on the stage, prognostic markers and patient factors
Hodgkin lymphoma is usually treated with a combination of…
Chemotherapy
Radiotherapy
Relapses are treated with salvage chemotherapy, radiotherapy and / or autologous haematopoietic stem cell transplants
Autologous stem cell transplant
Supportive
Irridiated blood products
What is the treatment of non hodgkin lymphoma?
Non hodgkin lymphoma can either be high grade and rapidly progressive or low grade, high grade is curable whereas low grade is not, this is because high grade are rapidly proliferating and therefore they are susceptible to cancer treatments.
What are the causes of lymphadenopathy?
Vascular
Infective causes= infectious mononucleosis, TB, HIV, CMV
Trauma
Autoimmune- SLE, RA, sarcoidosis
Leukaemia, lymphoma
What are the classical findings on biopsy of AML?
Auer rods in blast cells
What would you see on blood film in a patient with ALL?
Blast cells
Why do you get a relative deficiency of functional antibodies in myeloma, and what is this called?
Because there is an abnormal clonal proliferation of post germinal B cells
The cells secrete monoclonal antibodies (most commonly Ig subtype) and antibody fragments into the serum and urine
It is called relative hypogammaglobulinaemia
What investigations would you do for myeloma?
Bloods:
FBC would show anaemia
U and Es would show renal impairement (raised serum creatinine)
Hypercalcaemia is a common feature
Serum free light chain assay
Serum immunoglobuins
Serum protein electrophoresis
Urine protein: Creatinine and urine albumin:Creatinine is done (ratio will be high as excess protein being secreted)
Skeletal survery- xray is typically done however CT and MRI is more sensitive
Serum/urine protein electrophoresis is done
Tissue diagnosis is typically done by bone marrow aspirate and biopsy (myeloma is confirmed if there is >10% of plasma cells in the bone marrow)
What are the investigations to inform the prognosis of myeloma?
CRP (higher level, the worse prognosis)
LDH (higer level, the worse prognosis)
Beta-2 microglobulin (very high over a very low level indicates a poor prognosis)
FISH and cytogenetic analysis (may also help with finding treatment)
High serum creatinine and low albumin are also poor prognosis markers
When would you offer a haematopoietic stem cell transplant and what does it involve?
This is a treatment option with young patients who have minimal comorbidities
It involves induction therapy with non chemotherapeutics eg- bortezomib, thalidomide, dexamethasone or chemotherapeutic (vincristine, doxorubicin, dexamethasone)
Conditioning regimen (with melphalan) followed by Autologous transplants is the preferred option
How do you treat myeloma patients who are unsuitable for stem cell transplant?
The standard of care is with MPT
Melphalan plus prednisolone plus thalidomide
What supportive management is needed for myeloma?
Analgesia, bisphosphonates, surgical, phsyiotherapy for bone disease
EPO (+/- transfusion) for anaemia
Influenzae and pneumococcal vaccination for infection
What are the associations of non hodgkins lymphoma?
Commonly associated with viral infection and immunodeficiency
H pylori with gastric MALT
EBV with burkitts lymphoma and AIDS related CNS lymphoma
Human T cell lymphovirus with type 1 T cell lymphoma
Hep C with diffuse large B cell lymphoma
Autoimmune- sjorgens syndrome and coeliac diseases
What is the main blood result to remember in non hodgkins lymphoma?
Elevated LDH- this is a poor prognostic factor as it reflects greater red cell turnover
What would you see on a blood film of someone with non hodgkins lymphoma?
Nucleated red cells and left shift, (the presence of early white blood cell precursors
Blood film may also reveal circulating lymphoma cells (abnormal lymphocytes)
What is the prognosis for someone with lymphoma?
5 year survival is 30% for Low grade and 50% for high grade
How can you diagnose myelofibrosis (myeloproliferative disorder which is characterised by bone marrow fibrosis)
On blood film you would expect to see poikilocytes (tear shaped rbc), because of the bone marrow fibrosis it is difficult to aspirate the bone marrow, resulting in a dry tap.
What is the treatment of myelofibrosis?
Stem cell transplantation or modulatory drugs (thalidomide)
What are the factors predicting a poor prognosis in myeloma?
Multiple osteolytic lesions
beta-2-microglobulin raised (a protein found on surface of cells, WCC has them)
Low haemoglobin
Low albumin
What is polycythaemia?
What is the difference between relative and absolute polycythaemia?
Raised haematocrit and RCC and haemoglobin concentration
Relative polycythaemia= there is a falsely raised haemoglobin concentration due to a low plasma volume
Absolute= the plasma volume is normal
What is the difference between primary and secondary absolute poolycythaemia?
Primary= excess erythrocytosis independent of EPO Secondary= the excess red cell production is driven by EPO (chronic hypoxia like COPD, high altitude), or inappropriate sceretion of EPO in renal neoplasms (paraneoplastic).
What are the features of polycythaemia ruba vera?
Ruddy complexion Hyperviscosity symptoms- chest pain, myalgia, weakness, headache, blurred vision, loss of concentration Low EPO JAK-2 mutation Raised haematocrit Splenomegaly Ruddy complexion
What are the signs of essential thrombocythaemia?
Splenomegaly
Erythomelalgia (red/blue discolouration of the extremities accompanied by burning pain)
Livedo reticularis (net like purple rash)
