12 - Haematological 1 Flashcards
How do haematological malignancies arise?
- Too much proliferation
- Cells don’t differentiate
- Cells do not apoptose
What is the main cause of morbidity and mortality in haematological malignancy?
Immunosupression due to both disease and treatment
What is myeloma?
> Malignant disorder of plasma cells (mature B lymphocytes)
- Second most common haematological malignancy
- Excess secretion of a monoclonal antibody
What is the definition of the following:
- Multiple myeloma
- Monoclonal gammopathy of undetermined significance (MGUS)
- Smouldering myeloma
Multiple myeloma: myeloma affects multiple areas of the body
Monoclonal gammopathy of undetermined significance (MGUS): excess of a single type of antibody or antibody components without other features of myeloma or cancer. May progress to myeloma so routine monitoring
Smouldering myeloma: progression of MGUS with higher levels of antibodies. It is premalignant and more likely to progress to myeloma than MGUS. Waldenstrom’s macroglobulinemia is a type of smouldering myeloma where there is excessive IgM specifically.
What is the structure of an antibody?
Made by B cells/plasma cells
Light chains: kappa or lambda
Heavy chains: IgG, IgA, IgE, IgD, IgM
What is the pathophysiology of multiple myeloma?
- Mutation in one of the plasma cells so divides uncontrollably and produces monoclonal antibodies
- Imunoglobulins in a patient with myeloma one of the types of immunoglobulin (A, G, M, D or E) will be significantly abundant. Usually IgG. They are called monoclonal paraprotein.
- “Bence Jones protein” found in urine in myeloma as they are subunits of the light chains
- Step one is development of MGUS, then step two is progression from MGUS to smouldering myeloma then to MM
What is the issue with MM?
- Infiltration of bone marrow by B cells causing bone marrow suppression
- Excess monoclonal antibodies/light chain secretion
What are the 5 key features/clinical presentations of MM?
CRABBI
- C – Calcium (elevated)
- R – Renal failure
- A – Anaemia (normocytic, normochromic) from replacement of bone marrow
- B – Bone lesions/pain
- B - Bleeding
- I - Infection
What are some myeloma defining events?
Myeloma can present with hyper viscosity symptoms, especially if Walden’s myeloma. What are some of the symptoms of this?
What is the cause of hypercalcaemia and bone pain in multiple myeloma?
Myeloma Bone Disease
- Increased osteoclast activity and suppressed osteoblast activity due to cytokines released from plasma cells and stromal cells in contact witht the plasma cells
- Abnormal bone metabolism is patchy, meaning that in some areas the bone becomes very thin whereas others remain relatively normal. Leads to weak points that can cause pathological fractures
- All the osteoclast activity causes a lot of calcium to be reabsorbed from the bone into the blood
What sites does myeloma bone disease tend to occur?
- Skull
- Spine
- Long bones
- Ribs
What are plasmacytomas?
Individual tumours made up of the cancerous plasma cells
Can occur in the bones, replacing normal bone tissue OR in soft tissue
Why does renal disease occur in myeloma?
- High levels of immunoglobulins can block flow through tubules
- Hypercalcaemia impairs renal function
- Dehydration
- Medications used to treat conditions such as bisphosphonates can be harmful to the kidneys
What may bone marrow suppression due to replacement of bone marrow by plasma cells cause in MM?
- Anaemia
- Recurrent or persistent bacterial infection: immune dysfunction and hypogammaglobulinaemia due to suppression of normal plasma cell function
Why is there hyper viscosity of blood in MM and what are the complications this can cause?
Large amounts of immunoglobulins (proteins) in the blood causing the plasma viscosity to be significantly higher
- Easy bruising
- Easy bleeding
- Reduced or loss of sight due to vascular disease in the eye
- Purple discolouration to the extremities
- Heart failure
How may MM present symptom wise? (apart from CRAB symptoms)
- Hyperviscosity syndrome: easy bruising/bleeding, blurred vision, headaches, dyspnea
- Spinal cord compression symptoms
- Peripheral neuropathy/radiculopathy
- Splenomegaly/hepatomegaly
- Fever
- Lymphadenopathy
What are some risk factors for myeloma?
USUALLY PRESENTS AGED 70
- Older age
- Male
- Black African ethnicity
- Family history
- Obesity
What is the criteria for screening for MM?
Anyone over 60 with bone pain (particularly back) or pathological fractures
Consider in:
- Unexplained bone pain (and pathological fractures)
- Fatigue
- Symptoms of hypercalcaemia: bone pain, abdo pain, constipation, confusion, polyuria
- Weight loss
- Symptoms of cord compression: back pain, new leg weakness, bladder/bowel dysfunction
- Symptoms of hyperviscosity: headache, blurred vision, shortness of breath, mucosal bleeding
- Recurrent infections
What investigations are done as part of screening for myeloma?
- FBC (low WCC in myeloma)
- Calcium (raised in myeloma)
- ESR (raised in myeloma)
- Plasma viscosity (raised in myeloma)
If any of these are positive or myeloma is still suspected do an urgent serum protein electrophoresis, a urine Bence-Jones protein test, serum free light chains
How do the following tests help to screen for MM?
- Serum protein electrophoresis
- Urine Bence-Jones protein
- Serum free light chains
Protein electrophoresis
Separates proteins into different bands using an electric current. The distance individual proteins travel is dependent on their shape, size and electrical charge
Immunofixation then fixes protein in place using antbodies
Urine Electrophoresis and Serum Free Light Chains
Protein electrophoresis assumes that all myelomas secrete an intact antibody. In fact, around 20% of myelomas only secrete light chains
SFLCs looks at amount of light chain unbound to heavy chains within blood. Light chains are secreted in healthy individuals as plasma cells produce more light chains than heavy chains. Therefore, it is the ratio between the light chains kappa and lambda, which is the most important factor. An elevated ratio is suggestive of myeloma and needs further work-up.
What is the diagnostic test for myeloma?
Bone Marrow Aspiration and Trephine Biopsy
Number of plasma cells in sample will be significantly raised
What is a prognostic marker for MM?
B2M
What other investigations need to be done once myeloma is diagnosed with biopsy?
Need these investigations for diagnostic criteria
Assess for bone lesions: PET-CT (skeletal survey will not pick up lytic lesions)
Assess for organ damage: FBC, U+Es, Bone profile
Staging: beta-2 microglobulin, albumin
What X-ray features are there for bone lesions of multiple myeloma?
- Punched out lesions
- Lytic lesions
- “Raindrop/salt and pepper skull”
What investigations are done to aid with working out the prognosis of MM?
- CRP (higher, worse the prognosis)
- LDH (higher, worse the prognosis)
- Beta-2 microglobulin (very high, poor prognosis)
- FISH and cytogenetic analysis
High serum creatinine and low albumin are also poor prognostic markers
How is myeloma staged and how does this affect the prognosis?
Incurable disease with relapses and remission
International Staging System (ISS) for myeloma divides patients into three groups (I, II, III) based on serum beta-2 microglobulin and albumin levels, which predicts the median survival.
- Stage I: median survival 62 months
- Stage II: median survival 44 months
- Stage III: median survival of 29 months
How is myeloma managed?
Induce disease remission and then maintain disease free survival for as long as possible with ongoing monitoring for disease relapse
- Induction therapy: first line with a mix of chemo and other drugs
- Autologous Stem Cell Transplant
- Maintenance: maintain remission, given post-induction or post-transplant. Choices include bortezomib or lenalidomide
- Relapse or refractory disease: almost all patients will relapse, even if they respond to treatment. Therapy indicated if a clinical relapse or rapid rise in paraproteins
- Treat complications
What is an example of induction therapy in MM?
- Suitable for autologous stem cell transplantation: Bortezomib + Dexamethasone
- Unsuitable for autologous stem cell transplantation: Thalidomide + an Alkylating agent + Dexamethasone
- Give VTE prophylaxis (aspirin or LMWH) with chemo, especially thalidomide
How can myeloma bone disease be managed?
- Bisphosphonates: suppress osteoclast activity.
- Radiotherapy: to bone lesions can improve bone pain.
- Orthopaedic surgery: to stabilise bones or treat fractures
- Cement augmentation: into vertebral fractures or lesions
What are some complications of multiple myeloma and how may they be managed?
- Myeloma bone disease: previous slide
- Hypercalcaemia
- Cord compression
- Renal impairment
- Anaemia: give EPO
- Pain: treat with analgesia (using the WHO analgesic ladder)
- Infection: annual influenza vaccines and Immunoglobulin replacement
- VTE prophylaxis
- Fatigue
What is the difference between and autologous and allogenic stem cell transplant?
Autologous: 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
What is the diagnostic criteria for MM?
International Myeloma Working Group (IMWG) classification
What is smouldering/asymptomatic myeloma?
No myeloma defining events or amyloidosis
What is MGUS?
Monoclonal Gammopathy of Undetermined Significance
MGUS progresses to smouldering myeloma to MM. When do you start treating myeloma?
Only one of CRAB criteria needed plus 10% clonal population
What are the different classifications of lymphoma?
What is Hodgkin’s lymphoma and how common is this?
Malignant proliferation of B lymphocytes characterised by the presence of the Reed-Sternberg cell
1 in 5 lymphomas are Hodgkin’s
What are the risk factors for Hodgkin’s lymphoma and what age do they tend to occur at?
Bimodal - 20s/30s and 60s/70s
- Male
- HIV
- Epstein-Barr Virus
- Autoimmune conditions such as RA and sarcoidosis
- Family history
- Smoking
- Immunosuppression
How does Hodgkin’s lymphoma present?
- Lymphadenopathy (75%) - painless, non-tender, asymmetrical, rubbery. Usually cervical or supraclavicular
- B Symptoms: weight loss, night sweats, fever
- Alcohol pain in lymph nodes
If you suspect a patient has lymphoma, what examination do you need to do?
- Lymph node exam for lymphadenopathy
- Abdo exam for hepatomegaly and lymphadenopathy
What are the different types of Hodgkin’s lymphoma?
- Nodular sclerosis: Most common subtype, 70% of cHL
- Mixed cellularity: 20% of cHL.
- Lymphocyte-rich: 5% of cHL. Best prognosis
- Lymphocyte-depleted: Rare, worst prognosis
What is the referral criteria for a two week wait for potential Hodgkin’s lymphoma?
UNEXPLAINED LYMPHADENOPATHY +/- ONE OF:
- Alcohol-induced lymph node pain
- Fever
- Lymphadenopathy
- Night sweats
- Pruritus
- Shortness of breath
- Weight loss
What is the difference with referral for Hodgkin’s lymphoma in children?
Very urgent 48 hour referral instead of 2 weeks
What investigation is done to diagnose Hodgkin’s lymphoma?
Excisional lymph node biopsy and immunophenotyping of HRS cells
Will show multinucleate Reed-Sternberg cells
What further investigations are done to stage Hodgkin’s lymphoma?
- PET/CT: preferred choice
- LDH: often raised but not specific
- FBC
- UE
- LFT
- Bone profile
- LDH
- Uric acid
- ESR
- HIV, Hep B and Hep C
- HTLV-1
What investigations are done prior to treatment for Hodgkin’s lymphoma?
- LP and CSF analysis: those with suspected CNS disease
- Echocardiogram: Assess cardiac function, particularly if considering doxorubicin chemotherapy
- Pulmonary function tests: particularly if considering bleomycin chemotherapy
How is Hodgkin’s lymphoma commonly staged?
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)
What is another way of staging Hodgkin’s lymphoma?
Lugano
What are some prognostic markers for HL?
Age, ESR, number of regions involved and presence of bulky mediastinal disease
B symptoms are poor prognosis
What is the mainstay of management in Hodgkin’s lymphoma?
Chemotherapy with Radiotherapy adjunct
May have supportive blood transfusions but need irradiated blood and platelets!
How are the following stages of Hodgkin’s lymphoma managed?
- Early
- Advanced
- Relapse
Early (Stage I/II)
ABVD chemotherapy for 3 or 4 cycles. May have radiotherapy adjunct
Advanced (III/IV)
ABVD or BEACOPP or Stanford V with radiotherapy adjunct
Relapse
Salvage chemotherapy, radiotherapy and autologous haematopoietic cell transplantation
What is the ABVD chemotherapy regime for Hodgkin’s lymphoma?
- Doxorubicin (A).
- Bleomycin (B)
- Vinblastine (V):
- Dacarbazine (D): Converted to MTIC an alkylating agent
What is the prognosis with Hodgkin’s lymphoma?
Reasonably good
- Limited disease:, 90% survive 5 years.
- Advanced disease: 75-90% survive 5 years
What is Non-Hodgkin’s lymphoma and how common is it?
More than 60 subtypes and they can be B-cell or NK/T-cell in origin
More common than Hodgkin lymphoma, accounting for around 80-85% of lymphomas
6th most common cancer
What are some risk factors for Non-Hodgkin’s lymphoma?
- Older age
- Epstein-Barr Virus
- H. pylori (MALT lymphoma)
- Hepatitis B or C infection
- Caucasian
- FHx
- Exposure to pesticides and solvents
- Certain chemical agents (pesticides, solvents)
- History of chemotherapy or radiotherapy
- Immunodeficiency (transplant, HIV, diabetes mellitus)
- Autoimmune disease (SLE, Sjogren’s, coeliac disease)
What types of NHL are caused by the following:
- EBV
- H.Pylori
- Hep C
- Human T cell lymphotropic virus type 1
- EBV: Burkitt’s lymphoma and AIDS-related CNS lymphoma.
- H pylori: gastric MALT
- Hep C virus with diffuse large B-cell lymphoma and splenic marginal zone lymphoma.
- Human T cell lymphotropic virus type 1 with T-cell lymphoma.
What types of NHL are caused by the following:
- EBV
- H.Pylori
- Hep C
- Human T cell lymphotropic virus type 1
- EBV: Burkitt’s lymphoma and AIDS-related CNS lymphoma.
- H pylori: gastric MALT
- Hep C: diffuse large B-cell lymphoma
- HTCLVT1: T-cell lymphoma
How may NHL present?
Very similar to HL
- Painless lymphadenopathy: Non-tender, rubbery, asymmetrical. Most common
- 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 much weight loss is significant to be classed as a B symptom?
Unexplained, > 10% in the last 6 months
It is hard to differentiate between NHL and HL without a biopsy. What are some features in the presentation that may help you differentiate between the two?
- Lymphadenopathy in Hodgkin’s can experience alcohol-induced pain
- ‘B’ symptoms typically occur earlier in Hodgkin’s
- Extra-nodal disease more common in non-Hodgkin’s lymphoma
What is a poor prognostic sign in lymphomas?
B symptoms
What are some criteria that would warrant a referral for a 2 week wait for suspected NHL?
UNEXPLAINED LYMPHADENOPATHY +/-
- Fever
- Night sweats
- Pruritus
- Weight loss
- Splenomegaly
- SOB
What investigations are done for NHL?
- Excisional node biopsy
- CT chest, abdo, pelvis
- HIV test (as this is a risk factor for non-Hodgkin’s lymphoma)
- FBC and blood film (may have normocytic anaemia,can help rule out other haematological malignancy such as leukaemia)
- ESR (prognostic indicator)
- LDH (prognostic indicator)
- LFT’s if liver metastasis suspected
- LP if neurological symptoms
What histology does Burkitt lymphoma have?
Starry sky appearance
How is NHL staged?
Ann Arbor or Lunago
Split into Type A or B
How is NHL managed?
Dependent on the specific sub-type
- All patients will receive flu/pneumococcal vaccines
- Patients with neutropenia may require antibiotic prophylaxis
What are the complications of B cell lymphoma?
What are some targets used for targeted therapy of lymphoma?
What is the typical chemotherapy regime in NHL?
R-CHOP
- Rituximab: A monoclonal antibody with activity against CD20
- Cyclophosphamide
- Doxorubicin
- Vincristine
- Prednisolone
What is the most common form of NHL?
Diffuse large B cell lymphoma
More common in men, young people, black ethnicity
How does Diffuse large B cell lymphoma present?
- Rapidly enlarging mass, commonly in the neck, abdomen or mediastinum
- May have ‘B’ symptoms are seen in around a third of patients.
- Extranodal disease is common and can arise essentially anywhere but is most commonly seen in the GI tract.
- Disease in the mediastinum may lead to SVCO
- May have spinal cord compression
How is Diffuse Large B cell lymphoma?
Always assess for CNS involvement
- Limited stage disease: Chemoimmunotherapy in the form of R-CHOP. May have radiotherapy too
- Advanced stage disease: R-CHOP or other regimens
Autologous haematopoietic cell transplantation is used at times
What is the second most common form of NHL and how does it present?
Follicular lymphoma
Gradual lymphadenopathy that waxes and wanes. May have B symptoms
How is follicular lymphoma managed?
- Radiotherapy
- Watch and wait
- Immunotherapy with Rituximab if asymptomatic
- Chemoradiotherapy if symptomatic
What is the most common lymphoma in children and the different types of it?
Burkitt Lymphoma
It is high grade and rapidly proliferating
What mutation causes Burkitt’s lymphoma?
Burkitt Lymphoma
It is high grade and rapidly proliferating
How may Burkitt’s lymphoma present?
Endemic: rapidly enlarging tumour in the jaw of a child. It can also present with enlarged lymph nodes in the neck and abdominal masses.
Sporadic: abdominal symptoms, with the ileoceacal valve often affected. It may present with bowel obstruction
Fever, weight loss and night sweats may all be present
How may Burkitt’s lymphoma present?
Endemic: rapidly enlarging tumour in the jaw of a child. It can also present with enlarged lymph nodes in the neck and abdominal masses.
Sporadic: abdominal symptoms, with the ileoceacal valve often affected. It may present with bowel obstruction
Fever, weight loss and night sweats may all be present
What is the biggest complication with treatment of Burkitt’s lymphoma?
Tumour Lysis syndrome
Give prophylaxis
How is Gastric MALT lymphoma treated?
H Pylori eradication
How can lymphomas be classified? (know some examples of each)
Low and High grade
How is stage 2A Follicular lymphoma treated?
Watch and wait if radiotherapy not suitable
If there is pancytopenia in lymphoma what does this mean?
BONE MARROW INFILTRATION!
Before any biopsy or procedure in haematological malignancy what do you need to consider?
Clotting profile
May be throbocytopenic and this needs to be resolved to prevent excessive bleeding. May need blood transfusions
Before any biopsy or procedure in haematological malignancy what do you need to consider?
Clotting profile
May be throbocytopenic and this needs to be resolved to prevent excessive bleeding. May need blood transfusions
What is Rituximab?
What is a complication of MM?
Amyloidosis due to deposition of light chains
What might cause a polyclonal rise in immunglobulins?
- Liver disease
- Autoimmune disease
- Infection
Also remember raised light chains can be due to increased production or decreased excretion, if light chain ratio normal then likely just renal failure and polyclonal
What is a cryoglobulin?
Abnormal immunoglobulin
Why may there be splenomegaly in MM?
Proliferation of b-cells
Why is bone scan not good for MM?
Will only pick up blastic lesions
What type of amyloid is in MM?
AL amyloidosis
Amyloid is a beta pleated sheet secreted by plasma cells
What is Waldenstrom’s macroglobulinaemia?
Low grade lymphoma in older men
Monoclonal IgM paraprotein
Signs of hyperviscosity
What test can you do in the GP routinely to help find asymptomatic myeloma (MGUS)
- PCR and ACR
What is the main cause of death in MM?
- Renal impairment
- Infection
What is the purpose of an autologous stem cell transplant in MM?
Chemo is the treatment, stem cell transplant is to just replenish the bone marrow so don’t get infections
What are the symptoms of hypercalcaemia?
- Constipation
- Polyuria
- Increased thirst
- Lethargy
- Abdominal pain
- Nausea and vomiting
