Cancer Care - Blood Cancers

Question 1

Leukaemia

Pathophysiology
Clinical Features
Differential Diagnosis of Petechiae
Investigations

Answer 1

1. ) Pathophysiology - cancer of stem cells in the bone marrow causing unregulated proliferation of a single type of WBC meaning they no longer differentiate
   - excessive production of a single type of cell can lead to suppression of the other cell lines –> bone marrow failure (BMF) –> anaemia, thrombocytopenia, leukopenia
   - 4 main types: acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL)
   - risk factors: smoking, Down syndrome (ALL/AML) aggressive radiotherapy (secondary cancer),
2. ) Clinical Features - non-specific presentation
   - sx of BMF: ↓Hb (fatigue, lethargy, pallor), ↓plts (bleeding, bruising, petechiae), ↓WBCs (infections)
   - lymphadenopathy: can cause pain in the lymph nodes
   - hepatosplenomegaly: can cause abdominal fullness
   - bone pain: expansion of the bone marrow
   - constitutional symptoms: unintentional weight loss, drenching night sweats, fevers, pruritis
3. ) Differential Diagnosis of Petechiae - bleeding under the skin causing a non-blanching rash
   - leukaemia, meningococcal septicaemia
   - vasculitis, Henoch-Schonlein Purpura (HSP)
   - Idiopathic Thrombocytopenia Purpura (ITP)
   - non-accident injury (esp kids and vulnerable adults)

4.) Management
- can be treated with ALLOGENIC bone marrow transplant

Question 2

Investigations in Leukaemia

Blood Tests
Bone Marrow Biopsy
Staging Tests
Additional Tests

Answer 2

1. ) Blood Tests
   - FBC: can see leucocytosis +/- lymphocytosis, however, may also see neutropenia and signs of BMF if severe: anaemia, thrombocytopenia (can see ↑plts in CML), leukopenia
   - other blood tests: CRP, U+Es, LFTs, haematinics, Ca2+, reticulocyte count, LDH, urate
   - haemolysis investigation: blood film, reticulocytes, LDH, haptoglobin, direct coombs test (autoimmune)

2,) Peripheral Blood Film/Smear
- AML: (myelo-)blast cells which may contain Auer rods
- CML: blasts cells (appear in later disease)
- ALL: lymphoblast cells
- CLL: smear cells (smudged fragile lymphocytes)

3. ) Bone Marrow Biopsy - definitive for diagnosis
   - aspiration (liquid) or trephine (solid core)
   - looking for an increase in blast cells
   - flow cytometry: immunophenotyping looking for surface markers associated with certain cells, it uses bone marrow aspirate (peripheral blood used in CLL)
4. ) Staging Tests
   - CT-CAP
   - PET-CT
   - MRI
5. ) Additional Tests
   - lymph node biopsy: lymph node involvement
   - CXR: infection or mediastinal lymphadenopathy
   - LP: if there is CNS involvement

Question 3

Acute Lymphoblastic Leukaemia (ALL)

Pathophysiology
Clinical Features
Poor Prognostic Factors

Answer 3

1. ) Pathophysiology - malignant change in one of the lymphocyte precursor cells causing acute proliferation of a single type of lymphocyte, usually B-lymphocytes
   - most common cancer in children (peaks at 2-4years) and accounts for 80% of childhood leukaemia
   - it can also affect adults over 45 (associated with the Philadelphia chromosome (t(9:22) translocation)
   - often also associated with Downs syndrome
2. ) Clinical Features
   - sx of anaemia, thrombocytopenia and leukopenia
   - failure to thrive in children
   - organomegaly, lymphadenopathy more common
   - bone pain (secondary to bone marrow infiltration)
   - fever is present in up to 50% of new cases due to an infection or as a constitutional symptom
   - testicular swelling in children
   - blood film shows blast cells
3. ) Poor Prognostic Factors
   - diagnostic age: <2 or >10 years, non-Caucasian, M>F
   - WBC count at diagnosis: >20
   - T or B cell surface markers

Question 4

Other Forms of Leukaemia

Acute Myeloid Leukaemia (AML)
Chronic Myeloid Leukaemia (CML)
Chronic Lymphocytic Leukaemia (CLL)

Answer 4

1. ) Acute Myeloid Leukaemia (AML) - presents in middle-aged adults onwards
   - there are many different types of AML all with slightly different cytogenetic differences and presentation
   - may occur as a primary disease or as a secondary transformation of a myeloproliferative disorder e.g. polycythaemia ruby vera or myelofibrosis
   - bloods: often presents with bone marrow failure
   - blood film: high proportion of (myelo-)blast cells which may contain Auer rods in the cytoplasm
   - definitive Mx: allogenic stem cell transplant
2. ) Chronic Myeloid Leukaemia (CML) - strong linked w/ cytogenic translocation t(9:22) (Philadelphia) –> BCR-ABL causing excessive activity of tyrosine kinase
   - bloods: WCC is highest (>100 is diagnostic), bands are present, thrombocythemia can also be present
   - chronic phase: can last 5yrs, often when patients are diagnosed incidentally w/ ↑WCC (60-70yrs). Can also cause massive splenomegaly
   - accelerated phase: blast cells 10-20% of cells in bone marrow, patients become more symptomatic
   - blast phase: >30% blasts, severe sx, often fatal
   - CML is considered potentially curable, tyrosine-kinase inhibitors (Imatinib) allow for long periods of remission and normal life expectancy
   - allogenic bone marrow transplant can also be used
3. ) Chronic Lymphocytic Leukaemia (CLL) - the chronic proliferation of well-differentiated B lymphocytes
   - most common leukaemia in adults (often >55s)
   - often asymptomatic: typically diagnosed from an incidental finding of isolated lymphocytosis
   - bloods film: smudge cells (fragile lymphocytes that are smudged by physically making a smear)
   - flow cytometry is also used in the diagnosis
   - Rai staging: 1 = lymphadenopathy, 2 = organomegaly, 3 = anaemia, 4 = thrombocytopenia
   - can cause immune dysregulation leading to warm autoimmune haemolytic anaemia and ITP
   - Richter’s transformation: can transform into a high-grade lymphoma, become unwell very suddenly

Question 5

Hodgkin’s Lymphoma (HL)

Pathophysiology
Clinical Features
Investigations
Management

Answer 5

1. ) Pathophysiology - malignant proliferation of lymphocytes inside the lymphatic system, often presenting as painless lymphadenopathy
   - 20% of all lymphomas, bimodal age distribution with peaks around aged 20 and 75 years
   - risk factors: HIV, EBV, family history, autoimmune conditions e.g. RA and sarcoidosis
2. ) Clinical Features
   - painless lymphadenopathy: non-tender, rubbery, asymmetrical, locations: neck, axilla, groin, abdomen
   - alcohol-induced painful lymph nodes only in HL
   - constitutional (‘B’) symptoms appear earlier in HL: fever >38, night sweats, weight loss (>10% in 6mths), fatigue, pruritus
   - mediastinal involvement (more common in HL):
   cough, SOB, chest pain
3. ) Investigations
   - excisional lymph node biopsy (gold): Reed-Sternberg cells (large multinucleate cells w/ eosinophilic nucleoli)
   - bloods: ↑LDH, normocytic anaemia, eosinophilia
   - CTneck+CAP/MRI/PET scans can be used for diagnosing and staging lymphoma and other tumours
   - Ann Arbor Staging: 1: 1 lymph node, 2: 2+ nodes on the same side of diaphragm, 3: nodes on both sides of the diaphragm, 4: involves non-lymphatic organs
4. ) Management
   - curative chemotherapy and radiotherapy is usually successful but there’s risk of relapse and other things:
   - chemo (ABVD): risk of leukaemia and infertility
   - radiotherapy: risk of secondary cancer, damage to surrounding tissues, hypothyroidism
   - should receive irradiated blood products
   - high curative rates with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)
   - poor prognostic features: >45 at diagnosis, male gender, presence of B-symptoms, lymphocyte-depleted HL,
   ↑WCC, ↓Hb, ↑ESR or low albumin

Question 6

Non-Hodgkin’s Lymphoma

Pathophysiology
Risk Factors
Clinical Features
Management

Answer 6

1. ) Pathophysiology - every other type of lymphoma that is not HL, is more common than HL and a third of all cases occur in those over 75s, notable types are:
   - Burkitt lymphoma: associated w/ HIV, EBV, malaria
   - MALT: mucosa-associated lymphoid tissue, usually around the stomach, associated w/ H. pylori infection
   - Diffuse large B cell lymphoma: rapidly growing painless mass in patients over 65 years
2. ) Risk Factors
   - ↑age, Caucasian, family history
   - hx of viral infections: EBV (main), HIV, Hep B or C
   - H. pylori (MALT lymphoma)
   - immunodeficiency: hx of chemo/radiotherapy, transplant, HIV, diabetes mellitus
   - exposure to chemical agents: pesticides, solvents
3. ) Clinical Features - same as HL but:
   - systemic (‘B’) symptoms appear later
   - no alcohol-induced painful lymph nodes
   - no Reed-Sternberg cells on lymph node biopsy
   - extra-nodal disease is much more common: affects gastric, bone marrow, lungs, skin, CNS
4. ) Management
   - watch and wait approach for asymptomatic low grade lymphomas e.g. follicular lymphoma
   - immuno-chemotherapy (R-CHOP): used for high grade lymphomas e.g. diffuse large B cell lymphoma
   - R-CHOP: rituximab (CD20i), cyclophosphamide, doxorubicin, vincristine, prednisolone
   - radiotherapy can also be used
   - autologous stem cell transplantation
   - prognosis: low-grade has a better prognosis but a high grade has a higher cure rate

Question 7

Multiple Myeloma (MM)

Pathophysiology
Clinical Features
Investigations
Management

Answer 7

1. ) Pathophysiology - the malignant proliferation of a specific type of plasma cell due to mutations as B-lymphocytes differentiate into mature plasma cells
   - monoclonal paraprotein: large quantities of a single type of antibody are produced (often IgG)
   - risk factors: ↑age, male, African ethnicity, FH, obesity
2. ) Clinical Features - CRAB, see next card
   - suspect myeloma in anyone over 60 with persistent bone pain (esp back pain), or unexplained fractures
3. ) Initial Investigations
   - 1°bloods (myeloma screen): FBC (signs of BMF), U+Es ( (AKI), LFTs (total protein), bone profile (↑Ca2+), ↑plasma viscosity, ↑ESR
   - if bloods show either ↑Ca2+, ↑plasma viscosity (OR ↑ESR), or ↓WBC, arrange for electrophoresis and serum free light chain assay (looks at kappa:lambda)
   - 2°serum/urine protein electrophoresis: raised serum paraprotein (monoclonal Igs), Bence Jones proteins appear in urine

4.) Definitive Investigations
- bone marrow aspiration and trephine biopsy (confirms diagnosis): significantly raised plasma cells
- imaging to assess bone lesion: 1°whole-body MRI
2°whole-body CT, 3°skeletal survey
- X-Ray: “Raindrop skull” caused by many punched out (lytic) lesions throughout the skull
- diagnostic criteria for symptomatic myeloma:
- bone marrow biopsy >10% monoclonal plasma cells
- ↑serum paraprotein or Bence-Jones protein in urine
- evidence of end organ damage (CRAB): hypercalcaemia, elevated creatinine, anaemia or lytic bone lesions

5. ) Management - relapsing-remitting course, no cure, Tx aims to improve quality and quantity of life
   - 1°chemotherapy with Bortezomib, Thalidomide, and dexamethasone, require VTE prophylaxis (↑clot risk)
   - stem cell transplantation in suitable patients
   - bone disease improved with bisphosphonates
   - radiotherapy for bone lesions can improve bone pain
   - surgery can stabilise bones or treat fractures

Question 8

Clinical Features/Presentation of Multiple Myeloma
CRAB-H

Calcium
Renal
Anaemia, Bleeding, Infection 
Bones
Hyperviscosity

Answer 8

1. ) Calcium - hypercalcaemia due to increased bone resorption (↑osteoclast activity, ↓osteoblast activity)
   - sx: constipation, nausea, anorexia and confusion
2. ) Renal Impairment - high levels of immunoglobulins can cause light chain deposition within the renal tubules which can block the flow through the tubules
   - hypercalcaemia can also impairs renal function, and bisphosphonates used to treat hypercalcemia can also be harmful to the kidneys
   - often presents as dehydration and polydipsia
3. ) Anaemia, Bleeding, Infection - cancerous plasma cells invade the bone marrow –> bone marrow failure
   - causes suppression of other blood cell lines:
   - anaemia, thrombocytopenia, leukopenia
4. ) Bone Disease - ↑osteoclast activity and ↓osteoblast activity due to cytokine release from plasma cells
   - common locations: skull, spine, long bones, ribs
   - osteolytic lesions: patches of thin bone (osteoporosis) can lead to pathological fractures
   - may also present as pain (especially in the back)
   - ↑bone resorption causes the hypercalcemia
   - plasmacytomas: individual tumours made up of the cancerous plasma cells which replace normal bone tissue or can occur in soft tissues of the body
5. ) Hyperviscosity - due to increased amounts of protein (immunoglobulin) in the blood, this can lead to:
   - stroke/clots, easy bruising and bleeding, purple discolouration to the extremities, HF, vascular disease in the eye

Question 9

Monoclonal Gammopathy of Undetermined Significance (MGUS)

What is it?
Smouldering Myeloma
Clinical Features
Differentiating Features from Myeloma

Answer 9

1. ) What is it? - excess of a single type of antibody or component w/o other features of myeloma or cancer
   - also known as benign paraproteinaemia
   - often an incidental finding in a healthy person
   - it may progress to myeloma and patients are often followed up routinely to monitor for progression
2. ) Smouldering Myeloma - progression of MGUS w/ higher levels of antibodies or antibody components
   - it is premalignant and more likely to progress to myeloma than MGUS
   - Waldenstrom’s macroglobulinemia: is a type of smouldering myeloma with excessive IgM specifically which is the largest immunoglobulin so ↑ stroke risk
3. ) Clinical Features
   - asymptomatic: no bone pain or ↑risk of infection
   - 10-30% have a demyelinating neuropathy
4. ) Differentiating Features from Myeloma
   - normal immune function
   - normal beta-2 microglobulin levels
   - a stable level of paraproteinaemia (lower levels)
   - no clinical features of myeloma

Question 10

Myeloproliferative Disorders

Pathophysiology
Myelofibrosis
Clinical Features

Answer 10

1. ) Pathophysiology - type of bone marrow cancers due to overproliferation of a single type of stem cell:
   - primary myelofibrosis: haematopoietic stem cells
   - polycythaemia vera: erythroid cells
   - essential thrombocythemia: megakaryocytes
   - can all progress and transform into AML (leukaemia)
   - associated with mutations in JAK2, MPL, CALR
2. ) Myelofibrosis - fibrosis of the bone marrow in response to cytokine release by proliferating cells
   - one particular cytokine is fibroblast growth factor
   - can occur in all types of myeloproliferative disorders
   - bone marrow is replaced with scar tissue which affects haematopoiesis which then leads to:
   - extramedullary haematopoiesis in liver and spleen causing hepato/splenomegaly. This can lead to portal hypertension or spinal cord compression
3. ) Clinical Features
   - can initially be asymptomatic
   - constitutional sx: fatigue, weight loss, night sweats, fever
   - BMF: anaemia, thrombocytopenia, leukopenia
   - thrombosis: polycythaemia and thrombocythemia
   - extramedullary haematopoiesis: splenomegaly (abdo pain), portal HTN (abdo pain, ascites, varices)
   - polycythaemia vera: conjunctival plethora, “ruddy” complexion (reddish tone), splenomegaly, pruritis (esp after hot baths)

Question 11

Management of Myeloproliferative Disorders

Investigations
Management of Primary Myelofibrosis
Management of Polycythaemia Vera
Management of Essential Thrombocythaemia

Answer 11

1. ) Investigations
   - polycythaemia vera: ↑Hb (>185 in men, >165 women)
   - essential thrombocythemia: ↑plts (>600)
   - myelofibrosis: anaemia, ↑/↓ WCC, ↑/↓plts, ↑LDH and ↑urate due to increased cell turnover
   - blood film in myelofibrosis: teardrop-shaped RBCs, varying sizes of red blood cells (poikilocytosis) and immature red and white cells (blasts)
   - bone marrow biopsy (diagnostic for myelofibrosis): “dry-tap” on aspiration (scar tissue) so trephine needed
   - genetic testing: JAK2, MPL and CALR genes
2. ) Management of Primary Myelofibrosis
   - mild disease: monitored and not actively treated
   - allogeneic stem cell transplantation is potentially curative but carries risks
   - chemotherapy can help control the disease, improve symptoms and slow progression but is not curative
   - Mx of the anaemia, splenomegaly and portal HTN
3. ) Management of Polycythaemia Vera
   - diagnosed by confirming JAK2 mutation
   - 1°venesection: keeps Hb in the normal range
   - aspirin: reduce the risk of developing blood clots
   - chemotherapy (e.g. hydroxyurea) can be used to control the disease, however, this can increase the risk of developing leukaemia
   - can progress into myelofibrosis or AML
4. ) Management of Essential Thrombocythemia
   - aspirin: reduce the risk of developing blood clots
   - hydroxycarbamide (hydroxyurea) can be used to ↓ platelet count
   - chemotherapy can be used to control the disease