Haematological malignancies Flashcards
Symptoms of bone marrow failure
Anaemia - fatigue, dyspnoea, dizziness
Thrombocytopenia
Neutropenia - recurrent/atypical infections
Constitutional symptoms
Unintentional WL >10% over 6m, drenching night sweats, fever, pruritis
Symptoms of hypercalcaemia
Fatigue, abdo pain N+V, confusion, constipation, headache, polydipsia, polyuria
Mostly a/w myeloma + high grade lymphomas
Symptoms of hyperviscosity
Rare, mostly myeloma - headache, somnolence, visual disturbance, ischaemic events
Outline the steps of the lymphoreticular examination
- Inspection - cachexia, rashes, bleeding
- Lymphadenopathy: cervical, axillary, epitrochlear, inguinal
- Abdo exam
How can you identify splenomegaly on abdomen examination?
- LUQ
- Palpable splenic notch
- Moves infero-medially with inspiration
- Not ballotable
- Cannot get above it
Causes of lymphadenopahty
- Local: bacterial/viral infection, skin conditions like eczema, malignancy (mets or lymphoma)
- General: systemic infections (e.g. TB, HIV, endocarditis), malignancy (lymphoma, lymphoid leukaemias), inflammatory (sarcoid, CT disease), generalised allergic conditions
Red flags for malignancy in a neck lump
- Hard fixed mass
- > 35y
- Mucosal lesion in H+N
- Persistent hoarseness/dysphagia
- Trismus
- Ear pain (Referred from tongue base)
Differentials for a midline neck lump
- LN
- Lipoma: painless smooth
- Dermoid cyst: along lines of embryological fusion, don’t move with tongue protrusion, more in children/YA
- Sebaceous cyst
- Thyroid gland: below thyroid cartilage; thyroid nodules: adenoma/cysts/malignancy
- Thyroglossal cysts: painless/smooth/cystic, rise on tongue protrusion
- Laryngocele: reducible tense mass
- Cystic hygroma: toddlers, trans-illuminates, soft fluctuant mass
- Brachial cyst - doesn’t transillimuninate
Differentials for an anterior triangle neck lump
- LN
- Lipoma, sebaceous cyst
- Salivary gland swelling (doesn’t move on swallow)
- Branchial cyst: from birth, in early adulthood presents as infected neck lump
- Carotid artery aneurysm: pulsatile mass, bruit on auscultation
- Carotid body tumour: transmits pulsation, can be moved sideways but not vertically cos of carotid sheath
- Laryngocele
Differentials for a posterior triangle neck lump
- LN
- Lipoma, sebaceous cyst
- Subclavian artery aneurysm
- Pharyngeal pouch
- Cystic hygroma: often on left, fluctuant, transilluminates
- Branchial cyst
- Tail of parotid mass
When would you refer someone with lymphadenopathy?
- If any red flag symptoms
* If not gone down within 6w
What are the clinical features of lymphadenopathy?
- Benign <1cm, smooth, round, non-tender, mobile
- Reactive smooth, round, tender, mobile
- Haem malignancy localised/generalised, rubbery
- Mets: hard/firm/irregular/tethered
Abnormal lymphocyte counts?
- Lymphocytosis: some viral infections, some bacterial e.g. pertussis, lymphoid neoplasia
- Lymphopenia: viral infection like HIV, CT disease, lymphoma, severe BM failure immunosuppressive drugs
What does the spleen do?
Makes antibodies, processes antigens, phagocytosis (esp encapsulated bacteria), sequesters red cells, removes nuclear remnants (Howell-Jolly bodies), haemopoiesis in early fetus
Mild, moderate and massive splenomegaly?
- Mild: just palpable 1-3cm below costal margin. E.g. haem cancers, portal HTN, EBV, haemolytic anaemia, SLE
- Moderate: between CM+umbilicus, 4-8cm below CM. E.g. haem cancers like CML/lymphoma, amyloidosis
- Massive: crosses umbilicus + midline, >8cm. E.g. CML, myelofibrosis, tropical infections, HIV, hereditary spherocytosis
Indications for bone marrow aspiration
Unexplained cytopenias, suspected BM infiltration (with cancer or storage disorders), suspected infections like Leishmaniasis/TB
What is immunophenotyping (flow cytometry)?
Looks at the protein expressed by cells by labelling cells with an antibody directed against surface proteins and passing them through a flow cytometer
Helps show lineage in leukaemias by seeing if surface proteins are myeloid or lymphoid
Outline the differentiation from a multipotent haematopoietic stem cell
- Common myeloid precursor – megakaryocytic (make thrombocytes), erythrocytes, mast cells, myeloblast (makes basophil, neutrophil, eosinophil, monocytes the latter which make macrophages)
- Common lymphoid precursor – NK cells and small lymphocytes (make T and B lymphocytes)
What is the significance of blast cells in the blood film?
They are precursors of myeloid cell (myeloblasts) or lymphoid cells (lymphoblasts) - bigger, immature nucleus, atypical appearance
Suggests an acute leukaemia or a chronic disorder beginning to become acute e.g. CML blast crisis
What is the difference between leukaemia and lymphoma?
Lots of crossover but leukaemias mostly affect the bone marrow and may have circulating neoplastic cells in the blood, whereas lymphomas mostly affect nodes/organs
What is leukaemia?
Increased WBC
- Myeloid vs lymphoid
- Acute - more immature cells, v proliferative
- Chronic - more differentiated mature cells
Aetiology of leukaemia
- Activation of oncogenes causing prolfieration
- Deletion of TSGs like p53
- Altered apoptosis control
- Epigenetic changes
Due to genetics, chemicals, irradiation and viruses
Describe how acute leukaemias tend to present
- Marrow failure e.g. pallor, cardiac flow murmur, fever, ulcers, sepsis, petechiae, gingival bleeding, fundal haemorrhage
- High WCC: hypoxia, pulmonary infiltrates, retinal vein dilation, papilloedema, confusion
- Tissue infiltration: bone pain, hepatosplenomegaly, lymphadenopathy, gum hypertrophy (AML), violaceous skin deposits (AML), testicular enlargement (ALL), mediastinal masses (ALL)
- Substance release: DIC (AML), hyperuricaemia (acute gout or TLS)
Typical Ix findings in acute leukaemias
Low Hb Raised WCC Low platelets Blood film - blast cells, Auer rods suggests AML BMA - more cells, less erythropoiesis
How are acute leukaemias managed?
- Curative intent: induction of complete remission then a long consolidation phase
- Supportive (cure + palliative): reduce anaemia, prevent bleeding, FFP for clotting abnormalities, leucophoresis to reduce WCC, infection, control hyperuricaemia with hydration + allopurinol
Acute lymphoblastic leukaemia
- Proliferation of lymphoid blasts (B/T cells), commonest cancer in children + young adults
- Sometimes a/w Philadelphia chromosome
- ALL when BM involvement, or localised disease as lymphoblastic leukaemia (but same tumour cells)
- CF: typically rapid deterioration with fever, BM failure, T cell versions can cause mediastinal mass, meningeal signs if CNS involvement, hepato/splenomegaly
- M: 2-3y of chemo, induce remission then maintenance with chemo or allogeneic transplant + intrathecal chemotherapy
- Children have a v good prognosis
Acute myeloid leukaemia (nb no longer adequate label as so many subtypes)
- Proliferation of myeloid blasts (whereas CML is mature cells), Auer rods in film
- Typically affects more elderly people
- CF include gum hypertrophy, splenomegaly and ecchymosis
- M: chemo (intensive if <60 as high chance of remission, often with a monoclonal antibody e.g. gemtuzumab)
- Often offered clinical trials
What affects prognosis in AML?
Improve: t(8;21) and t(15;17), APML subtype
Reduce: age, failure to respond after 2 induction cycles, complex genetics, comorbidities, high WCC on presentation
Chronic myeloid leukaemia
*Presence of Philadelphia chromosome t(9;22) translocation
*Peak 40-60y
*High WCC (esp neuts + basophils) + circulating immature cells
*CF: asymptomatic, or marrow failure, WL, night sweats (hypermetabolic state) + splenomegaly (extra medullary haemopoiesis)
*Slowly progressive - if not cured eventually blast crisis transformation to AML/myelofibrosis
*Blood film shows mix of mature + immature cells - indicates chronic
*Management: imatinib (a TKi that blocks the BCR-ABL fusion protein), allogeneic SCT
Resistant can try a 2nd gen like nilotinib
Chronic lymphocytic leukaemia
- Commonest type of leukaemia mostly occurs in later life
- Clonal expansion of mature lymphocytes, alters T cell immunity so can get autoimmune things like AIHA and ITP
- Often a chance finding on FBC, early diagnosis years survival or if late can be low survival
- CF: usually asymptomatic, may be predisposed to infections like VZV, lymphadenopathy, hepato/splenomegaly causing discomfort, bleeding/petechiae/fatigue, tonsillar enlargement
- Ix: low/normal Hb, high WCC, film shows small/medium lymphocytes or smudge cells {(no immature blasts)
- Median survival 10y
- Management: supportive (e.g. steroids for autoimmune haemolysis, EPO, immunoglobulin replacement, allopurinol), may need chemo if BM failure
- Richters transformation
Hairy cell leukaemia
Clonal proliferation of abnormal B cells in the BM + spleen (usually p/w splenomegaly)
What is lymphoma?
B+T cell neoplasms
They occur at different stages at development so different subtypes, more aggressive if of proliferating cells
What do investigations typically show in lymphoma?
- FBC: anaemia, plt abnormalities
- CXR: mediastinal widening, hilarity LN
- LDH non specific but often rises in haem cancers
What is Hodgkin lymphoma and how does it present?
A distinct tumour of lymphatic system with multinucleated giant cells (Reed-Sternberg cells); there is also a nodular type with a ‘popcorn’ cell (rarer)
Bimodal age dist most common 20s + 60s
Lymphadenopathy (75%) - painless, non-tender, asymmetrical
systemic (25%): weight loss, pruritus, night sweats, fever (Pel-Ebstein)
alcohol pain in HL
normocytic anaemia, eosinophilia
LDH raised
CF: painless rubbery cervical lymphadenopathy often asymmetrical/spreading (75%), mediastinal mass (cough, sob), hepatosplenomegaly, B symptoms (25%-WL, night sweats, fever) pruritus, alcohol-related pain at the LN
Ix often show a normocytic anaemia, eosinophilia and raised LDH
Prognosis based on albumin (lower=worse), WCC, Hb and ESR
Staging of Hodgkin lymphoma
Lugano staging (I + II limited, III + IV advanced), basically same as Ann-Arbor, done via PET scan (no need for BM biopsy as it shows up on scan)
I: one node/group of adjacent nodes
II: two or more groups on same side of diaphragm
III: nodes on both sides, or just above diaphragm with spleen involvement
IV: diffuse involvement of one/more extra-nodal organs or tissue
Management of Hodgkin lymphoma
Aimed towards cure
- Chemotherapy then radiation usually thing for cure
- Try to avoid irradiating chest area but sometimes needed
- Often in stage I or II may do expectant management as no progression for many years, or rituximab to slow progression
- Stage 3+4 also often curable
What is non-Hodgkin lymphoma and how does it present?
A group of lymphoproliferative malignancies with different behaviours, much greater extra-nodal spread than HL, majority B-cell malignancies
CF include painless LN, sx of LN mass, soft tissue masses, sx at BM/spleen/bone/lung/skin/testicular/gastric/CNS
NHL aetiology
- EBV (endemic Burkitt’s lymphoma, transplants, also to a lesser extent a/w HL)
- HIV
- H pylori (gastric MALT)
- HTLV-1 (adult T cell lymphoma/leukaemia)
- HCV (splenic marginal zone lymphoma)
- Inherited syndromes e.g. Wistkott-Aldrich syndrome
- Immunosuppressive drugs
Types of NHL
- High grade: usually aggressive with high mortality early on but good cure rate with intensive treatment . Either B or T cell. E.g. DLBCL, Burkitts
- Low grade: usually incurable but treatable for a long time. Usually B cell. E.g. follicular lymphoma, marginal zone lymphoma, Waldenstrom’s macroglobulinaemia
- Primary extra-nodal NHL: anywhere there there is lymphoid tissue, e.g. in CNS (SOL sx), gastric (a/w H pylori), skin (e.g. Sezary syndrome with erythematous lesions)
Why does lymphoma not involve metastasis?
Talk of progression not mets due to behaviour of disease
May mean transformation to a high grade type or involvement of BM
What is the main MAB used in NHL & why?
Rituximab
Is MAB of CD20, which is expressed on lots of B cells esp in DLBCL
What is myeloma?
Clonal proliferation of BM plasma cells due to a single clone of immunoglobulin that secretes terminally-differentiated B cells
Presentation of myeloma
Typically >60
- Bone disease: lytic lesions in spine/skull/long bones/ribs, vertebral collapse, bone pain
- BM infiltration: anaemia, neutropenia, thrombocytopenia, paraproteinaemia, rarely-hyperviscosity
- Kidney injury (light chains in renal tubules): hypercalcaemia, hyperuricaemia
- Recurrent infection: due to reduced levels of normal immunoglobulins
Investigations in myeloma typically show
- BM suppression on FBC
- High ESR
- FIlm may show rouleaux formation cos of paraprotein
- U+E AKI
- Bone profile - hypercalcaemia
- Serum protein electrophoresis - monoclonal band
- Skeletal survey for lytic lesions (not bone scans as these only show osteoblastic changes which cause sclerotic lesions [which are what most mets cause])
- BM aspirate/trephine: plasma cell infiltration >10% (‘fried egg’ appearance), flow cytometry/protein electrophoresis to establish clonality
Management of myeloma
- Incurable
- Supportive: EPO for anaemia, infections, RT/dexamethasone/bisphosphonates for bone pain
- Palliative chemo may be used e.g. proteasome inhibitors
What is MGUS?
Monoclonal gammopathy of uncertain significance, more common with age
Is when there’s low paraprotein and BM plasma cells are <10% but there is no myeloma-related organ/tissue damage
Risk of progression to myeloma 1% per year so follow up but don;t need treatment
What are myeloproliferative neoplasms?
Clonal stem cell disorders causing uncontrolled proliferation of one or more cell lines in BM, can lead to AML
Basically too many cells cos apoptosis isn’t effective
Essential thrombocythaemia
- Persistently raised platelets due to JAK2 mutation
- Causes thrombosis, haemorrhage, splenomegaly
- Can transform to myelofibrosis, PRV or leukaemia
- Exclude reactive causes
- M: hydroxycarbamide
Polycythaemia vera
- Primary increase in RBC/myeloid/megakaryocytes despite EPO not being made; red cells most affected
- Leads to thrombosis, neuro sequelae, pruritus, plethora, dusky cyanosis, gout, splenomegaly
- Usually in >60y, JAK2 mutation
- Risk of leukaemia + myelofibrosis
- M: venesection (iron def will reduce erythropoiesis), chemo, low dose aspirin, anagrelide (limits megakaryocytic differentiation)
Myelofibrosis
- Clonal disorder of haemopoietic stem cells, abnormal cells make cytokines leading to BM fibrosis
- CF: debilitating, causes lethargy weakness WL splenomegaly, bone pain + gout, extra medullary haemopoeisis, BM failure, tear drop forms of RBCs
- M: supportive e.g. transfusion, cytotoxics like JAK2 inhibitors, splenectomy if massive
What is myelodysplastic syndrome
Heterogenous group of acquired BM disorders due to a defect in stem cells – cells incorrect rather than too many
CF: elderly with pancytopenia (fail in at least one cell line)
~30% transform to AML
M: supportive e.g. EPO, immunosuppression or allogeneic SCT for younger, if evidence of AML chemo
What is BM failure and how does it present?
Pancytopenia + low cellularity of the BM (usually v v low retics), without any malignant cells - may be absent or ineffective production
CF include severe anaemia, thrombocytopenia (e.g. ecchymoses), leukopenia, lymphopenia
What are the types of BM failure?
- Specific lineages like red cell aplasia, agranulocytosis
- Aplastic anaemia - all 3 lineages affected, idiopathic, prob linked to immune. Supportive like plt + red cell transfusions, reduce infection. V severe if untreated, risk of AML, BMT in young pt
- Congenital causes like Diamond-Blackfan syndrome, Fanconi anaemia
- Acquired - COMMONEST REASON
What is acute promyelocytic leukaemia?
APML
A variant of AML with translocation t(15;17)
Causes coagulopathy so risk of presenting with life threatening DIC, but high chance of cure
What is the role of imatinib in CML?
- CML: the Philadelphia chromosome makes a BCR-ABL oncogene (BCR from chromosomal 22 fuses with ABL on chromosome 9) –> abnormal oncogene on Ch 22 –> abnormal tyrosine kinase –> changes in cell adhesion in marrow + increased proliferation
- Imatinib: tyrosine kinase inhibitor specifically for the BCR-ABL protein so mostly jut targets cancer cells
- If have good response just keep taking with a normal lifespan
What is Richters transformation?
When CLL transforms into a high grade lymphoma (usually diffuse large B cell)
Which types of lymphoma are a/w development of autoimmune diseases?
Low grade
Diffuse large B cell lymphoma
Commonest type, high grade
P/w painless LN or intra-abdoimanl disease
Rapidly progressive but good response to RCHOP + radio
Follicular lymphoma
2nd commonest type, low grade, usually adults p/w painless LN
In some it can be relapsing-remitting
About 1/4 transform to DLBCL (worse prognosis) - get increase in B symptoms
M: expectant if well, radiotherapy or chemoimmunotherpay (RCHOP_
What is RCHOP?
Common regime in lymphoma with chemo drugs (CHOP) + rituximab
Burkitts lymphoma
A high grade NHL with v rapid proliferation
Commonest childhood malignancy in developing world - endemic type (always EBV-ass related to malaria), sporadic or AIDs-related
CF: jaw tumour, abdo mass, BM suppression, CNS/kidney/testis involvement
High risk of TLS
Waldenstrom’s macroglobulinaemia?
A low grade NHL that’s a/w IgM paraprotein + BM infiltration
CF: older, LN/anaemia/hyperviscosity syndrome
Explain paraproteins in myeloma
BM has many plasma cells - in myeloma a specific type predominates - the antibody this produces is more prevalent than the others - monoclonal paraprotein
Usually IgG or IgA paraprotein
cf HIV, where all immunoglobulins are raised
What are Bence Jones protein?
Light chains excreted in urine when there is paraproteinaemia
Not checked anymore as just check paraprotein in blood
Causes of acquired bone marrow failure
- Infection: EBV, HIV, HCV, parvovirus
- Drugs: chloramphenicol, co-trimoxazole, sulfasalazine, carbamazepine, phenytoin, NSAIDs, chemo drugs
- Immune-mediated
- Radiation
- Vitamin def: B12, folate, anorexia nervosa
- Infiltration with tumours or storage diseases like Gaucher’s
- Idiopathic
What is the blood count + film like in the different types of leukaemia?
- AML - blasts
- ALL - blasts
- CML - raised granulocytes at different stages of maturation, +/- thrombocytosis (high plt)
- CLL - raised lymphocytes
Essential thrombocytosis
Very high plt usually >450
May also have raised WCC
Aplastic anaemia
Peak age 30y
- normochromic, normocytic anaemia
- leukopenia, with lymphocytes relatively spared
- thrombocytopenia
may be the presenting feature acute lymphoblastic or myeloid leukaemia
a minority of patients later develop paroxysmal nocturnal haemoglobinuria or myelodysplasia
Features of myeloma?
CRAB:
- Calcium high
- Renal insufficiency - abnormal U+E, infection susceptibility as production of normal antibodies is impaired
- Anaemia - BM infiltration
- Bone pain/#/lytic lesions
First line Ix in suspected myeloma?
Serum protein electrophoresis - immunoglobulin produced by dysplastic cells shows up as a monoclonal band
Polycyathaemia vera
Myeloprolifeative. Increase in red cell volume, often a/w high neuts + plts. Mutation in JAK2 in majority. Peak in 50s. CF include hyper viscosity, pruritus, splenomegaly, haemorrhage, plethoric appearance, HTN, low ESR. Test FBC + film, JAK2 mutation, ferritin, U+E, LFT. If JAK2 negative do BMA + trephine + cytogenetics. Management involves aspirin, venesection, hydroxyurea, phosphorus-32 therapy. Comps are thrombotic events, 5-15% progress to myelofibrosis or acute leukaemia
