Haematology

Question 1

Hodgkin’s lymphoma:

• Definition
• Types
• Causes (3)
• Risk factors (3)
• Symptoms (6)
• Signs (2)
• Investigations (1)
• Management

Answer 1

Lymphoma:

• Definition: malignancy of lymphocytes in the lymphatic system divided into Hodgkin’s (less common than NHL but better prognosis) and non hodgkins. Peaks around 20-25 years and 80 years
• Types:
  4 subtypes - nodular sclerosis, mixed cellularity, lymphocyte rich, depleted
• Causes: infection, genetic factors, environmental
• Risk factors: epstein barr virus, HIV (attacks T cells so body can’t fight infection or stop cancer development), fam history, autoimmune conditions (hodgkins), immunosuppression/organ transplant, fam history
• Symptoms: gradual lymphadenopathy, B systemic symptoms (weight loss, night sweats, fever), lethargy, anorexia, lymph node pain after drinking in hodgkins, itching, cough, sob
• Signs: non tender lymphadenopathy (non tender, firm, rubbery) (cancerous cells proliferating inside nodes), mediastinal lymphadenopathy with cough/wheeze/SVC obstruction, hepatosplenomegaly
• Investigations: lymph node biopsy for definitive diagnosis (if hodgkins Reed Sternberg cells which are cancerous b lymphocytes with 2 nuclei)
• Management:
  Hodgkin’s: chemo + radio - ABVD - doxorubicin, bleomycin, vinblastine, dacarbazine
  If blood transfusion required needs to be irradiated blood to reduce risk graft vs host disease
  Depends on staging + prognostic markers (age, esr, presence of bulky mediastinal disease)
  Then lifelong follow up

Question 2

Acute lymphoblastic leukaemia:
- Definition
- Pathophysiology
- Risk factors (1)
- Symptoms (6)
- Signs (3)
- DD (3)
- Investigations (5)
- Management - pre therapy, stages
- Complications (4)
- Prognosis

Answer 2

Acute lymphoblastic leukaemia:

• Definition: malig disorder of the lymphoid stem cells in the bm. Most common paed cancer in 2-5yrs
• Pathophysiology: mutation of lymphoid precursor cells (which become wbcs) create an uncontrolled capacity for self renewal and developmental arrest so in bm leads to proliferation hence excessive production of immature wbc blast cells leading to drop in functional rbcs, wbcs + platelets
• Risk factors: downs, kleinfelters, radiation exposure
• Symptoms: lethargy/pale/sob/dizzy (anaemia due to bm failure), easy bruising/bleeding (thrombocytopenia due to bm failure), fevers/infections (leukopenia due to bm failure), bone pain (increased pressure in hyperplastic bm), weight loss, headache/seizures (CNS involvement or cytokine release or leucostasis (inc plasma viscosity due to high wcc), fever, testicular enlargement (tissue infiltration), failure to thrive
• Signs: pale, excessive bruising, lymphadenopathy, hepatosplenomegaly (due to infiltration by cancer cells)
• DD: non accidental injury, immune deficiency, reactive lymphadenopathy
• Investigations: bloods (fbc within 48 hours (pancytopenia OR anaemia + thrombocytopenia + lymphocytosis (due to blast cells in circulation), ldh, U+es, lfts, clotting screen), blood film (blast cells), cxr (mediastinal mass?), bm biopsy (aspirate/trephine) to confirm diagnosis, LP
• Management: resus + hyperhydration if high wcc to stop hyperviscosity, steroids if mediastinal mass, abx if infection, UKALL 2011 protocol which is intravasc chemo/orally/intrathecally)/ blood products / prophylactic anti fungals. Maintenance treatment 2 years for F and 3 years M. Regular follow up for 5 years then yearly

Also radio, bm transplant, surgery

• Complications: tumour lysis syndrome, infertility, stunts growth, AVN, peripheral neuropathy, mucositis, neutropenic sepsis
• Extra facts: 90% survival. Prognosis determined by:
  Age 1-10 yrs better
  WCC>50 at presentation poor
  Female better prognosis
  CNS involvement poor
  Hyperdiploid blast cells is good

Question 3

Acute myeloid leukaemia:
- Definition
- Pathophysiology
- Risk factors (3)
- DD (4)
- Symptoms (5)
- Signs (4)
- Investigations (4)
- Management
- Complications (6)
- Extra facts

Answer 3

Acute myeloid leukaemia:

• Definition: genetic mutations in myeloid sc, normally from middle age onwards
• Pathophysiology: myeloid scs (usually becomes mature rbcs/wbcs/platelets) get uncontrollable capacity for self renewal and development arrest creating immature blasts. Now there is less room for healthy cells causing infection, anaemia, bleeding due to bm failure. These blasts can also infiltrate other tissues. There’s also systemic effects where cytokines released by these cells increasing plasma viscosity (due to high WCC)
• Risk factors: Down’s, Li Fraumeni syndrome, affected sibling, can be due to a transformation from a myeloproliferative disorder such as myelofibrosis
• DD: ALL, iron def anaemia, immune thrombocytopenic purpura ITP, immunodeficiency
• Symptoms: pale / lethargic / sob (anaemia), fever / recurrent infections (neutropenia), petechiae (thrombocytopenia) , bone pain / testicular enlargement / hepatosplenomegaly (tissue / bm infiltration), fever / malaise / headache (cytokine release/leucostasis)
• Signs: pale (anaemia), bruising (thrombocytopenia), hepatosplenomegaly, lymphadenopathy
• Investigations: bloods (fbc (pancytopenia), blood film (blasts WITH AUER RODS), cxr, bm aspirate + trephine definitive diagnosis (under light microscopy shows myeloblasts with Auer rod inclusions)
• Management:
  Initial: supportive (treat for infections/coagulopahty), hydroxycarbamide if leukostasis, treat TLS
  Chemo - 2 cycles. 1 to induce remission + 2 reduce risk relapse. Can also give haematopoietic sc transplant, bm transplant if not working
• Complications: tumour lysis syndrome, neutropenic sepsis, myelosuppression, N+V, mucositis, hair loss, reduced fertility (cyclophosphamide), cardiotoxicity (doxorubicin), tumour lysis syndrome
• Extra facts:
  66% 5 year survival.
  Poor prognostic factors: age >60, poor performance status, comorbs, previous dysplasia, previous chemo/radio exposure
  Spreads to CNS, skin, gums

Acute vs chronic leukaemia: acute is impaired cell differentiation so get lots of malignant precursor cells where chronic is excess prolif of mature cells but cell diff unaffected

Question 4

Different types of bruises

Answer 4

• Petechiae are less than 3 and caused by burst capillaries
• Purpura are 3 – 10mm
• Ecchymosis is larger than 1cm

Question 5

Differentials for non- blanching rash

Answer 5

Leukaemia
Meningococcal septicaemia
Vasculitis
Henoch-Schönlein purpura (HSP)
Immune thrombocytopenic purpura (ITP)
Thrombotic thrombocytopenic purpura (TTP)
Non-accidental injury

Question 6

Chronic lymphocytic leukaemia:

• Definition
• Pathophysiology
• Symptoms
• Signs
• Investigations
• Staging
• Management - definitive + supportive
• Complications
• Prognosis

Answer 6

Chronic lymphocytic leukaemia:

• Definition: slow proliferation of a single well differentiated lymphocyte (usually b). Usually affects male >60yrs.
• Pathophysiology: CLL cells accumulate because they survive for long time rather than accelerated rate of dividing
• Symptoms: assymp, non tender symmetrical lymphadenopathy, hepatosplenomeg, bm failure signs - infections, anaemia, bleeding, b symptoms,
• Investigations: bloods (fbc (lymphocytosis), blood film (smear/smudge cells (ruptured wbcs which are aged/fragile due to lack cytoskeleton protein), Immunophenotype of the cells is CD5 and CD23 positive, FMC negative, CD22 and surface immunoglobulin weak, staging via binets system based on lymphoid tissue enlargement, hb, platelets
• Management: depends on stage/activity of disease. Watchful monitoring if assymp with binets stage A/B, then active treatment if bm failure, symptomatic splenomeg/lymphad, progressive lymphocytosis.
  Treatment depends on performance status, comorbs. Includes chemo (fludarabine, cyclophosphamide, rituximab), sc transplant if failed other forms treatment
  Supportive care: vaccines, abx, Iv IG
• Complications: warm autoimmune haemolytic anaemia (needs rituximab), Richter’s transformation refers to the rare transformation of CLL into high-grade B-cell lymphoma (rapidly enlarged lymph nodes)
• Prognosis: 1/3 don’t progress, 1/3 progress slowly, 1/3 progressive actively
  Factors affecting: stage, atypical lymphocyte morphology, lymphocyte doubling time <12 months, male

Staging:
Binets:
A - <2 lymphoid sites
B - >3 lymphoid sites
C - anaemia and/or thrombocytopenia

Question 7

Chronic myeloid leukaemia:

• Definition
• Risk factor
• Genetics
• Phases and symptoms
• Signs
• Investigations
• Management
• Prognosis

Answer 7

Chronic myeloid leukaemia:

• Definition: common in 40-50yrs
• Risk factor: high dose ionising radiation
• Genetics: assoc with the Philadelphia chromosome (22) where reciprocal translocation of genetic material of 9 +22 which now codes for abnormal tyrosine kinase enzyme (BCR-ABL1 gene) driving prolif abnormal granulocytes
• Phases + symptoms: 3 phases
  1. Chronic phase: assymp, incidental finding of raised wcc, lasts several years
  2. Accelerated phase: abnormal blast cells take up 10-20% of bm/blood cells. Pt develops anaemia, thrombocytopenia, immunodeficiency
  3. Blast phase:>20% blast cells in blood, severe symptoms, pancytopenia, weight loss, tired, fever, sweat

Hyperleukocytosis symptoms: visual, confusion, deaf, priapism

• Signs: MASSIVE splenomeg, bleeding, gout
• Investigations: bloods (fbc (leucocytosis, neutrophils, monocytes, basophils, eosinophili, anaemia), blood film (mature myeloid cells and multiple basophils), bm aspirate +/- treophine (hypercellular with myeloid hyperplasia), bcr-abl/phili chromo is diagnostic marker via cytogenic tests
• Management: tyrosine kinase inhibitors imatinib (nausea, thrombocytopenia, neutropenia, fluid retention), hydroxycarbamide normalises blood count, sc transplant if don’t respond
• Prognosis: 5-6 years survival

Question 8

Myeloma:

• Definition
• Types: multiple, smouldering, MGUS
• Risk factors
• Symptoms
• Associated conditions
• Investigations
• Management
• Prognosis
• Extra facts - benign polyclonal hypergammaglobulinaemia

Answer 8

Myeloma:

• Definition: cancer of a single type of plasma cell in bm with a genetic mutation causing uncontrollable proliferation (plasma cells are b lymphocytes that make ab) resulting in the production of an abnormal ab - paraprotein (M protein) or part of an ab (often light chain). Abnormal high levels of M protein = paraproteinaemia
• Types:

1. Multiple: affects multiple bm areas in body. Organ damage present
2. Monoclonal gammopathy of undetermined significance MGUS involves abnormal plasma cell response to an antigen causing plasma cell clone secreting an ab which has potential of progressing to myeloma
3. Smouldering: an intermediate stage between myeloma and MGUS where there are more abnormal plasma cells in bm which are in more advanced premalig stage

• Risk factors: older age, male, black ethic, fam hx, obesity
• Symptoms: CRAB - Calcium elevate (bone pain/abdo pain, cons tip, confusion, polyuria), renal impairment, anaemia, bone pain/lesions/ Pathological fractures, fever/recurrent infections, fatigue, weight loss
• Associated/presenting conditions:

1. Anaemia normocytic/chromic: bm infiltration of plasma cells results in suppression of other blood cells + renal disease may contribute via less EPO
2. Renal disease: due to paraproteins deposited in kidneys, hypercalc affects function, dehydration, glomerulonephritis, meds
3. Hyper viscosity syndrome: due to more paraproteins in blood. Can cause: bleeding, retinal haemorrhages, stroke, heart failure so need plasma exchange - headache blurred vision, sob, mucosal bleeding
4. Bone disease: inc clast activity + suppressed blasts due to cytokines released from abnormal plasma cells. Common sites are skull, spine, long bones, ribs. Abnormal bone metabolism is patchy so thin areas = osteolytic lesions which can lead to pathological fractures. Also causes hypercalc. Can also get plasmacytomas which are tumours found in bone

• Investigations:

Diagnosis involves identifying monoclonal ab, bm analysis and assessing organ damage (bloods/imagine)

bloods (fbc (anaem/leukopenia), bone profile, ca, esr (inc), plasma viscosity, u+es, inc creatinine (bc renal impairment)

Serum protein electrophoresis (detects paraproteinaemia (inc ab from same plasma cell) then immunofixation tells us what type of ab is inc (normally IgG/A or the accompanying light chain,

However above assumes all myelomas secrete intact ab but 20% only secrete light chains so …

Serum free light chain assay (detects abundant light chains made by plasma cells),

Urine protein electrophoresis (detects bence jones protein),

bm aspirate and trephine with cytogenetics, full body xray (punched out lesions, diffuse osteopenia, fractures, raindrop skull where lytic lesions in skull), MRI/low dose CT full body

• Management:

No cure, want to induce remission and maintain disease free survival for long

Induction therapy - chemo combination (proteasome inhib bortezomib, thalidomide, dexmethasone), if fit then high dose chemo + sc transplant (autologous where pts own sc, allogenic), bone disease - bisphosphonates, radiotherapy, ortho surgery, cement augmentation

• Prognosis: tool is serum beta 2 microglobulin + albumin which predicts median survival stage 1-3, high plasma cell counts, high levels monoclonal ab in blood/urine, complications
• Extra facts: - benign polyclonal hypergammaglobulinaemia
  Overproduction of more than 1 class of Igs by plasma cells. Doesn’t progress to myeloma. Commonly assoc with liver disease, acute/chronic inflamm and autoimmune disorders. Check bloods (fbc, crp, esr, lfts, liver screen, Igs, IgG subtypes, cytokine profile), blood film. Treat underlyig disease, corticosteroids/plasmapheresis for hyperviscosity, rituximab

Question 9

Non hodgkins lymphoma:

• Definition
• Types
• Staging
• Risk factors (3)
• Symptoms (6)
• Signs (2)
• DD (2)
• Investigations (5)
• Management
• Complications (5)
• Extra facts: staging

Answer 9

Lymphoma:

• Definition: malignancy of lymphocytes in the lymphatic system divided into Hodgkin’s (better prognosis) and non hodgkins
• Types:

1. DLBCL diffuse large b cell lymphoma - most common NHL where rapidly enlarging mass neck/abdo/mediastinum. If limited stage I/II then R-CHOP
2. Follicular - more gradual painless, due to translocation of 14/18 chromosome. If stage I/II local radio/watch wait, if above relapse freq but immunotherapy with rituximab if assmp or R-CHOP if symptomatic
3. Burkitts - high grade rapidly prolif esp in jaw/neck, bowel obstruction, in children esp due to EBV/immunodef. Immunochemotherapy or if low risk methotrexate

• Risk factors: epstein barr virus, HIV (attacks T cells so body can’t fight infection or stop cancer development), fam history, h pylori (non hodg), exposure to pesticides/trichloroethylene (non-hodg), immunosuppression/organ transplant, fam history
• Symptoms: lymphadenopathy, B systemic symptoms (weight loss, night sweats, fever, lethargy, anorexia), itching, cough, sob, abdo pain or may present as an oncological emergency
• Signs: non tender lymphadenopathy (non tender, firm, rubbery) (cancerous cells proliferating inside nodes), mediastinal lymphadenopathy with cough/wheeze/SVC obstruction
• DD: reactive lymphadenopathy (recent infection or lymphadenitis where tender/fluctuant), leukaemia
• **Investigations: bloods (FBC rules out infection, U+Es including LDH inc to rule out tumour lysis syndrome before treatment begins, lft, esr, bone profile), USS, CXR, CT full body neck chest abdo pelvis, PET CT (staging + treatment response), lymph node biopsy for definitive diagnosis
• Management:
  R-CHOP chemo regimen = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone
  Watchful waiting, chemo, radio, monoclonal ab, hsct
  Then lifelong follow up
• Complications: tumour lysis syndrome, SVCO, cord compression, hypercalc, neutropenia, chemo issues
• Extra facts: Lugano classification
  Stage 1: disease in single group nodes or single organ
  2: in 2 or more groups of nodes or organs on same side of diaphgram (above or below)
  3: on both sides diaphragm
  4: diffuse involvement
  + B if B symptoms, A if absence symptoms

Ann Arobor staging is old version