Haematological Malignancy

Question 1

What are the blood cancers?

Answer 1

-Leukaemia
=Precursor red blood cells. Acute myeloid, acute lymphoblastic, chronic myeloid, chronic lymphocytic (both marrow and lymph nodes)
=Bone marrow
=Marrow failure +/- cellular proliferation. Anaemia (tiredness, pallor), leukopenia (fever and infection), thrombocytopenia (bleeding, bruising) so FBC (pancytopenia, blasts on film)
=Bone marrow biopsy

-Lymphoproliferative Disorders (lymphoma)
=Lymphocytes
=Lymph glands
=Mass effect, metabolic effect: lymphadenopathy (neck/ axilla/ groin/ internal mass effect so obstruction), (B symptoms: nights sweats, fevers, weight loss)
=Node biopsy (excision/ core), HIV screen, staging CT scan (grading high/ low determines speed)
=Hodgkin’s (young), non-Hodgkin’s (older)

-Myeloma
=Plasma cell
=Marrow
=Protein excess, bone lysis, marrow failure (CRAB)
=Myeloma screen (urinary Bence Jones protein, serum free light chains, protein electrophoresis) + bone marrow (aspirate and trephine) biopsy, skeletal survey (CT/MRI/PET/X-Ray)

-Myeloproliferative Neoplasms

• some lymph nodes in leukaemia, some marrow in lymphoma
• myeloid (neutrophil) and lymphoid (T-cells, B-cells= plasma cell in bone marrow and memory)

Question 2

Malignancy definitions

Answer 2

-Leukaemia: Cancer of blood precursors in marrow. Malignant cells are myeloid (AML,CML) or lymphoid (ALL, CLL)
-Lymphoma: A cancer of lymphocytes. Typically in lymph nodes, but also extra-nodal (spleen, liver, bone marrow, etc).
-Myeloma: Cancer of plasma cells in marrow. Secretes clonal antibody: paraprotein
-Myeloproliferative Neoplasms Malignant diseases causing cellular proliferation (ET,PV) and/or fibrosis (PMF). Includes CML
-Lymphoproliferative Disorders Diseases where malignant lymphoid cells accumulate e.g. lymphoma, CLL and similar problems

Question 3

Plasma vs serum

Answer 3

-Plasma: Blood minus cells, but with clotting proteins present. Centrifuge anticoagulated blood and extract the clear fraction. Used for coagulation tests.

Serum – Plasma minus clotting proteins. Centrifuge clotted blood and remove clear fraction. Used for most biochemical tests and non-coagulant proteins e.g. albumin.

Question 4

Myeloma screen

Answer 4

-Serum free light chains (Or urinary Bence Jones Protein) and serum paraprotein
-Normal results= not detected
-Abnormal= paraprotein/ abnormal light chain ratio/ BJP detected

-Imaging
=Skeletal survey
=Newer imaging- CT and MRI

-Bone marrow definitive

Question 5

What is multiple myeloma?

Answer 5

Multiple myeloma is a cancer of plasma cells in the bone marrow. The malignant cells secrete large amounts of paraproteins into the blood which lead to various clinical complications.

Question 6

Paraproteins and detecting them

Answer 6

-Paraproteins: Monoclonal immunoglobulin (Ig) or light chains secreted by malignant plasma cells. Myeloma is one of several causes of paraproteinemia
-Protein electrophoresis of serum separates blood proteins based on size and electrical charge (diagram).Abnormal light chains can also be detected in serum(free light chains), or urine(Bence-Jones protein)

Question 7

Clinical features of myeloma

Answer 7

-Elderly
-Lethargy, bony pain, polyuria/dipsia, increasing confusion
-Anaemia, hypercalcaemia and renal failure
-Lytic lesions on x-rays, paraprotein in blood

-CRAB
=Calcium (high) as lytic lesions
=Renal Failure (cast nephropathy/ light chain deposition)
=Anaemia (bone marrow failure, normocytic
=Bone (loss, pain, pathological fracture, cord compression) and bleeding (risk of bleeding and bruising)

Question 8

Investigating myeloma

Answer 8

-Blood tests
=FBC/film can show anaemia. U&Es may show kidney injury and Corrected Ca2+ and ALP maybe high. ESR often very high.
-Paraprotein tests
=Serum protein electrophoresis (for the paraprotein) + urinary Bence-Jones. Serum ‘free light chains’ (antibody fragments) also elevated
-Radiology
=Traditionally a skeletal survey (X-ray of most bones) for lytic lesions e.g. ‘pepper pot skull.’ Increasingly, CT/MRI is 1st line where available
-Bone marrow aspirate and trephine
=This is the definitive test to demonstrate the cancer; clonal plasma cells are increased.

Question 9

Treatment of myeloma

Answer 9

Myeloma is incurable but treatable. Treatment involves combinations of steroids, chemotherapy, novel targeted agents alongside bisphosphonates. Refer to a haematologist

Question 10

Types of myeloproliferative neoplasms

Answer 10

-Red cell= polycythaemia vera= thrombosis
-Platelets- essential thrombocythemia= thrombosis
-Fibroblasts= myelofibrosis= marrow failure, splenomegaly

Question 11

What is leukaemia?

Answer 11

-A cancer of blood cells in marrow. Blasts crowd out normal haematopoiesis and cause marrow failure. They circulate in blood and cause enlarged liver, spleen and lymph nodes
-The malignant cells are either myeloid (acute myeloid leukaemia, chronic myeloid leukaemia) or lymphoid (acute lymphoblastic leukaemia, chronic lymphocytic leukaemia)

=Leukaemia cell: acquired genetic mutations and hallmarks of cancer (self-sufficiency of growth signals, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential)
=Accumulation of these cells in the bone marrow
=Failure of haematopoiesis
=Malignant cells evident in peripheral blood

Question 12

Features of bone marrow failure

Answer 12

-Anaemia (normocytic)
=Pallor, fatigue, dyspnoea

-Leukopenia
=Usual infections but unusually severe/ recurrent

-Thrombocytopenia
=Mucocutaneous bleeding; epistaxis, bruising, menorrhagia

Question 13

Acute vs chronic leukaemia

Answer 13

-Acute
=Marrow: proliferation of blasts
=Days to weeks
=Clinical features: marrow failure, blasts in blood, +/- liver, spleen, lymph node enlarged

-Chronic
=Proliferation of myeloid cells (CML), proliferation of lymphocytes (CLL)
=Months- years
=Leucocytosis, +/- liver, spleen, lymph node enlarged (marrow failure occurs late in disease)

Question 14

Describe acute myeloid leukaemia (AML)

Answer 14

-Epidemiology:
=Most common acute leukaemia in adults. Two-thirds of cases occur in people >60

-Cell of origin
=Primitive myeloid cells ‘blasts’

-A typical patient
=Middle age to elderly
=Short history
=Bone marrow failure
=Anaemia (pallor, lethargy, weakness), neutropenia, bleeding, splenomegaly, bone pain
=Infiltrates in liver, spleen and other tissues
=WCC high or low depending on circulating blasts
=Coagulation disorders - DIC

If patients are fit enough they undergo treatment with intensive chemotherapy. This has many side effects (cytopenias, nausea, alopecia etc) but is usually aimed at curing the disease. Otherwise care is supportive, particularly in the frail or elderly – transfusions, antibiotics and some low-intensity chemotherapy to promote quality of life and prolong survival modestly

Question 15

Describe Acute lymphoblastic leukaemia (ALL)

Answer 15

-Epidemiology:
=The most common childhood malignancy (80%)
=Adult ALL incidence increases with age

-Cell of origin
=Primitive lymphoid cells ‘blasts’.

-A typical patient
=Child, The peak incidence is at around 2-5 years of age and boys are affected slightly more commonly than girls
=Short history
=Bone marrow failure: lethargy, pallor, neutropenia, easily bruising, petechiae, bone pain, spleno and hepatomegaly, fever, testicular swelling
=Infiltrates in lymph nodes, bones, liver and spleen, CNS
=WCC high or low depending on circulating blasts

-Blood films may identify Auer rods (AML) or other diagnostic features, but final diagnosis and World Health Organisation (WHO) classification depends on analysis of bone marrow to look for immunological, molecular and genetic signatures.

Question 16

Describe chronic myeloid leukaemia (CML)

Answer 16

Cancers of marrow where lymphocytes (CLL) or granulocytes (CML) spill into blood and infiltrate the liver, spleen (and lymph nodes in CLL). Marrow failure can occur late in disease

-Epidemiology:
=Most frequently between ages of 40 and 60.
=Philadelphia chromosome 5%

-Cell of origin:
=Pluripotent stem cells (usually myeloid lineage) acquire t(9;22)

-A typical patient
=Late middle age
=Abdominal discomfort and splenomegaly
=Very high white count – mostly neutrophils and neutrophil precursors. These will increase the blood viscosity and can lead to “hyperviscosity” (mucosal bleeding, shortness of breath, visual changes and new neurology)
=Lethargy, weight loss, sweating, abdo discomfort

-Excellent response to treatment with imatinib (inhibitor of tyrosine kinase), hydroxyurea, interferon alpha, allogenic bone marrow transplant

Question 17

Describe chronic lymphocytic leukaemia

Answer 17

-Epidemiology: Most common leukaemia in Western world. A disease of the elderly (mean 72 years) monoclonal proliferation of well-differentiated lymphocytes which are almost always B-cells (99%). It is the most common form of leukaemia seen in adults.

-Cell of origin: Mature B lymphocytes

-A typical patient
=Asymptomatic - incidental lymphocytosis
=Anorexia, weight loss, bleeding, infections, lymphadenopathy more marked than myeloid
=Very slow progression
=Associated immune problems – ITP, autoimmune haemolysis
=No treatment required for several years

-I: FBC lymphocytosis, anaemia, thrombocytopenia. Blood film (smudge film), immunophenotyping

-Treatment
=For most people, a watch and wait policy – only treat when the disease is symptomatic.
=Treatment traditionally involves combination chemotherapy but newer therapies are targeting B-cell signalling.

Lymphocytosis, lymphadenopathy, hepatosplenomegaly, bone marrow failure

Question 18

Investigating leukaemia

Answer 18

-FBC: abnormal as bone marrow normal
-Acute leukaemias show pancytopenia +/- circulating blasts
-Chronic leukaemia show lymphocytosis (CLL) or neutrophils and myeloid precursors (CML)
-A blood film looks for circulating malignant cells

-Bone marrow aspirate and trephine
=of bone) are tested for: morphology (cell appearance), immuno phenotype (cell surface markers), cytogenetics (chromosomal analysis)and molecular studies (genetic changes)

Question 19

What are myeloproliferative neoplasms?

Answer 19

These disorders are characterised by a clonal proliferation of malignant bone marrow cells (Essential Thrombocythaemia, ET, and Polycythaemia Vera, PV) or fibrosis/scarring of the marrow (Primary Marrow Fibrosis, PMF). Chronic Myeloid Leukaemia is also in this group but is discussed under ‘Chronic Leukaemia.’

Question 20

Mechanism of myeloproliferative neoplasms

Answer 20

-One of the most important drivermutations is the V617F point mutation in the JAK2tyrosine kinase gene. This mutation is found in >95% of PV,and c. 50% of PMF and ET. Other driver mutations also exist
-PV and ET sometimesprogress to myelofibrosis. They can alsodevelop into AML with poor prognosis

Question 21

Clinical features of myeloproliferative neoplasms

Answer 21

-Polycythaemia vera… disorder of proliferation
=The increased RBC count leads to hyperviscosity and its associated symptoms
=The main patient risk is of thrombosis (arterial and venous) because of the hyperviscosity

-Essential thrombocythemia disorder of proliferation
=Asymptomatic thrombocytosis with no reactive cause
=Main risk is thrombosis including in veins and arterial microcirculation (ischaemia, gangrene)and larger arteries
=Rarely there can also be haemorrhagic complications due to platelet dysfunction

-Primary myelofibrosis– disorder of marrow fibrosis in response to clonal myeloproliferation
=The scarring of the bone marrow leads to bone marrow failure. Interestingly, bone marrow aspiration often leads to a “dry tap” because scarred marrow cannot be aspirated.
=The condition presents insidiously with fatigue and weight loss. Splenomegaly is present in all cases since haematopoiesis starts taking place in tissues outside the marrow like the spleen

Question 22

Overview of Hodgkin’s lymphoma

Answer 22

-Epidemiology:
=Peaks in young adults (15-35 years) and more elderly (over 50 years)
=More common in me

• Cell of origin
  =Germinal-centre B cells

-Pathological hallmark in classical HL
=Reed-Sternberg cells (multinucleate, EBV important)
=Hodgkin cell (mononuclear)

-A typical patient
=Young man
=Asymmetrical and painless superficial lymphadenopathy, usually cervical
=Constitutional symptoms: weight loss, pruritus, night sweats, fever
=Mediastinal mass, incidental or cough
=Alcohol induced nodal pain!
=RF: HIV, EBV

-I: normocytic anaemia, eosinophilia, raised LDH, lymph node biopsy

-Treatment
=Early stage: chemotherapy +/-radiotherapy
=Advanced stage: Chemotherapy +radiotherapy in bulky disease. Novel agents are being developed

Question 23

Overview of Non-Hodgkin’s lymphoma

Answer 23

-Epidemiology:
=The most common haematological malignancy
=Median age 55 - 60 years

-Cell of origin
=B-lymphocyte in 70 to 90% of cases
=T- lymphocytes / NK cells for rest

-Clinical classification
=Low-grade e.g. follicular lymphoma
=High grade e.g. diffuse large B-cel

-A typical patient
=Late middle age
=Aggressive course (high grade) and indolent course (low grade)
=Lymphadenopathy (painless) and constitutional symptoms
=Extra-nodal involvement more common than in Hodgkin’s
=Extranodal Disease - gastric (dyspepsia, dysphagia, weight loss, abdominal pain), bone marrow (pancytopenia, bone pain), lungs, skin, central nervous system (nerve palsies)
=RF: elderly, Caucasian, EBV, FHx, chemicals like pesticides, Hx chemo or radio, immunodeficiency (transplant, HIV, DM), autoimmune (SLE, Sjorgen’s, coeliac)

I: 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)
CT chest, abdomen and pelvis (to assess staging)
HIV test (often performed as this is a risk factor for non-Hodgkin’s lymphoma)
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)
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)

-Treatment
=Depends on subtype of NHL, Rituximab

Question 24

Hodgkin’s vs non-Hodgkin’s lymphoma

Answer 24

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

Complications: 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

Question 25

What is lymphoma?

Answer 25

A cancer of lymphocytes in lymph nodes and extra-nodal areas (spleen, liver, bone marrow, etc). If lymphoma is in the bone marrow you may find lymphoma cells in the blood.

Question 26

How is lymphoma classified?

Answer 26

-Hodgkin’s
-Non-Hodgkin’s
=Low grade: follicular lymphoma. Indolent: grow over months-years. May not require treatment until symptoms develop. Treat to induce remission but not cure
=High grade: diffuse large B cell lymphoma (DLBCL). Aggressive, life threatening and need urgent treatment but more often curable

Question 27

Clinical presentation of lymphoma

Answer 27

-Painless lymphadenopathy (>1 to 2 cm)
=External nodes : cervical, epitrochlear, axillary and inguinal. Enlargement of “Internal” nodes like mediastinal and retroperitoneal chains lead to compressive problems e.g. dysphagia, hydroureter, superior vena cava obstruction, stridor.

-Organomegaly: hepatomegaly / splenomegaly (lymphoid tissue)

-Constitutional “B” symptoms – especially high grade disease
=Fever, Night sweats (drenching), Weight loss >10% in 6 months, Pruritus

-Marrow failure if diffuse marrow involvement

Question 28

Investigating lymphoma

Answer 28

-FBC/ film
=FBC abnormal if marrow involved. Serum LDH is a useful prognostic marker.

-Imaging
=CT scans important in staging disease. PET scanning now central in Hodgkin’s disease.

-Bone marrow
=Bone marrow aspirate and trephine valuable in assessment of disease extent

-Node biopsy
=The definitive test to examine the cancer. A whole lymph node biopsy is the gold standard since this preserves architecture. Fine needle aspirate is NOT sufficient. The biopsy is assessed for morphology (with different stains) and immunophenotype

Question 29

Lymphoma staging

Answer 29

-Stage 1: singe lymph node area
-Stage 2: 2 or more lymph node areas on same side of diaphragm
-Stage 3: node involvement above and below diaphragm
-Stage 4: involvement outside node areas e.g. liver or bone marrow

Question 30

What is neutropenic fever?

Answer 30

Anyone who has had systemic cytotoxic therapy within the last c. 6weeks should be considered neutropenic until proven otherwise.
=Any sign of clinical infection = treat aggressively
=High mortality rate
=May not show other signs of ‘sepsis’ such as shock, rigors

Question 31

History of neutropenic fever

Answer 31

-Timing of fever – how it started etc, association with procedures, line use etc
-Associated features of sepsis – rigors, chills, sweats, urine output etc
-Localising symptoms
=Chest
=Urinary
=Skin
=CNS
=Gastrointestinal
-Clues as to causative organisms
=Prior organisms grown, treatments associated with e.g. fungal or viral disease

Question 32

Examination of neutropenic fever

Answer 32

-ABCDE approach (of course)
-Assess severity of sepsis (shock, organ failure)
-Looking for signs of source
=Chest, heart, abdomen, skin, CNS
=Don’t forget perineum, feet, indwelling lines, mouth

Question 33

Investigation of neutropenic fever

Answer 33

-FBC – are they neutropenic?
-Biochemistry – assess organ function
-Lactate and CRP – assess severity

-SEPTIC SCREEN
=Blood cultures including line AND peripheral samples
=Urine culture
=Chest XR (especially if chest symptoms)
=Mouth/throat/viral swabs
=etc

Question 34

Management of neutropenic fever

Answer 34

-Fluids
-Oxygen if hypoxic
-Antibiotics – e.g. piperacillin/tazobactam + gentamicin
=Treat the things that kill quickly
=Gram positives – staphylococcus, streptococcus
=Gram negatives – E.coli, Pseudomonas spp, etc
=Knowing the source may change empirical antibiotic choice (e.g. atypical chest cover) and culture/sensitivities will help us narrow antibiotic choice later

-Reculture and reassess – have new clues developed?
-Empirical change to antibiotics e.g. meropenem and vancomycin (broader coverage)
-If still no response at c. 96h – look for fungal disease – CT chest/abdomen for invasive disease in lung, liver, spleen. Consider empiric antifungals e.g. liposomal amphotericin B (Ambisome). This is toxic and causes drug reactions but may be necessary

Question 35

Prevention of neutropenic fever

Answer 35

-Hand /personal hygiene
-Neutropenic diet (similar to recommendations in pregnancy)
-Single rooms / reverse barrier nursing
-Antiseptic mouthwash
-G-CSF injections (granulocyte colony stimulating factor) – boosts neutrophil production
-Prophylactic antibiotics – see next question

Question 36

Prophylactic antibiotics for neutropenic fever in blood cancers

Answer 36

-Bacterial prophylaxis – evidence for ciprofloxacin/ofloxacin in acute leukaemia to prevent gram negative sepsis
-Pneumocystis prophylaxis – cotrimoxazole esp lymphoma, where heavy steroid use
-Viral prophylaxis - Aciclovir – for herpes zoster (shingles), valganciclovir for CMV (after allogeneic stem cell transplant)
-Fungal prophylaxis - Fluconazole (prevent candida) used in Hodgkin’s Lymphoma, liposomal amphotericin B – used in acute lymphoblastic leukaemia regimens