pathology course haematology 2

Pathology Course Haematology 2

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What will be discussed

Tuesday: Anaemia, coagulation, thrombosis

Thursday: Haematological malignancies Paraproteinaemias Myelodysplastic / myeloproliferative disorders

General tips for written exams

Don’t focus too much on Eponymous syndromes Nitty gritty facts e.g. chromosomal translocations

Do WebCT questionsSome questions will be hard / strangeUnderstanding is key

Acute Leukaemia

Acute Leukaemia

Neoplastic process of bone marrow and blood‘Acute’ therefore rapidly progressive and

fatalImmature blasts > 20% BM cells

Signs/symptoms: BM failure: anaemia, thrombocytopenia, neutropenia Organ infiltration: hepato/spleno-megaly,

lymphadenopathy, bone pain, gum hypertrophy

Aetiology

Ionising radiation – radiotherapyCytotoxic drugs – chemotherapyBenzenePre-leukaemic disorders e.g. MDS/MPDDown’s

Significnatly increased risk of AML/ALL Also, Down’s neonates often develop transient

abnormal myelopoeisis Resembles AML Resolves spontaneously after a few weeks

Acute Lymphoblastic Leukaemia

Childhood (ALL)Symptoms as previously mentioned

Lymphadenopathy +++ CNS involvement +++ Testicular enlargment Thymic enlargement

High WCC (accumulation of lymphoblasts)Ph+ve t(9;22) – poor prognosis

ALL: Treatment

Chemotherapy: (memory aid: I Can Cure Mankind) Remission Induction Consolidation CNS treatment Maintenance

Supportive Blood products, fluids, electrolyes

Acute Myeloid Leukaemia

Adulthood (risk increases with age) and under 2’s

Signs/symptoms as before Lymphadenopathy less common

Subtypes M3: Acute promyelocytic leukaemia DIC M5: Skin/gum infiltration +

hypokalaemia

AML: Lab

High WCCAuer rods and granulesMyeloperoxidase and Sudan black +ve

AML: Treatment

Chemotherapy Similar principles to ALL but… No CNS prophylaxis or maintenance needed

ATRA for M3Consider allo-SCT in young

Chronic Myeloid Leukaemia

Chronic Myeloid Leukaemia

A myeloproliferative diseaseOften diagnosed on routine bloodsNow very successfully treated in the majority

CML: Presentation

40-60 years peak (middle-aged)May be asymptomaticAnaemiaWeight loss, low grade fever, night sweatsMassive splenomegaly (down to RIF)Gout (raised urate – hypermetabolism)

CML: Lab

Huge WCC > 100 (neutrophilia)Hypercellular BM with spectrum of mature

and immature cells in the blood Malignant cells proliferate excessively but retain

ability to differentiate into mature cellsPh+ve in 80%; t(9;22)PCR for BCR-ABL

Monitor disease and therapeutic response

CML: Phases & Treatment

Chronic Phase< 5% blasts in BM/bloodWBC slowly increasesOver 3-4 years

Rx = Imatinib BCR-ABL tyrosine kinase inhibitor

CML: Phases & Treatment

Accelerated phase > 10% blasts in BM/bloodIncreasing manifestations e.g. splenomegalyUp to a yearLess responsive to therapy

CML: Phases & Treatment

Blast phase> 20% blasts in BM/bloodResembles an acute leukaemiaCourse = monthsTreatment similar to AML

Chronic Lymphocytic Leukaemia

Chronic Lymphocytic Leukaemia

A lymphoproliferative disease Others include ALL, MM and Waldenstrom’s

Also often an incidental finding on routine bloods

Disease of the elderly

CLL & SLL

Chronic lymphocytic leukaemia and small lymphocytic lymphoma

Same underlying disease, different presentation

CLL is primarily located in BMSLL is primarily located in lymph nodes

CLL: Presentation

> 40 years, elderlyMay be asymptomaticSymmetrical painless lymphadenopathyAnaemia, thrombocytopenia, neutropeniaWt loss, low grade fever, night sweatsHepato/Spleno-megaly (less prominent)Ass w/ autoimmunity

AIHA (Coomb’s +ve) + ITP = Evan’s syndrome

CLL: Lab

High WCC with lymphocytosis > 5 (high % lymphocytes)

Low serum Ig‘Smear cells’Prognostic factors

LDH raised = bad Hypermutated Ig gene = good

CLL: Stages & Treatment

Binet Staging A, B & C

Stage A < 3 groups of enlarged LN No treatment required

Stage B & C > 3 groups of LN, patient becomes more symptomatic Rx: 1st line is chlorambucil

CML CLL

Middle-aged

Massive splenomegaly

Neutrophilia

Ph+ve, BCR-ABL fusion gene

Imatinib Rx

Older

AID

Lymphocytosis

Smear cells

Chlorambucil Rx

CML vs CLL

Lymphoma

Lymphoma

Neoplastic tumour of lymphoid tissue Lymph nodes Spleen, MALT Rarely anywhere –

skin, testes, breast

1. Hodgkin’s – 20%2. Non- Hodgkin’s –

80%

Hodgkin’s lymphoma

M>FBimodal incidenceEBV associatedSpreads to adjacent lymph nodes – often

involves single LN groupAssymetrical painless lymphadenopathyConstitutional symptoms (Pel-Ebstein fever in

a minority)Pain after alcohol in affected nodes

Presentation CXR

nk

NormalMediastinal mass: Cough & resp infections SVC syndrome Dysphagia

Hodgkin’s: lab

CD15 & CD30Reed-Sternberg cell: binucleate / multinucleate

cell on background of lymphocytes

Subtypes Nodular sclerosing – most common

Staging

Stage I: 1 lymph node regionStage II: 2+ LN region; same side of diaphragmStage III: 2+ LN regions; opposite sides of

diaphragmStage IV: Extranodal sites, e.g. liver/BM

A: No constitutional symptomsB: Constitutional symptoms

Treatment

Combination chemotherapy ABVD – adriamycin, bleomycin, vinblastine,

dacarbazine 2-4 cycles in I/II, 6-8 cycles in III/IV

Radiotherapy Sometimes used alongside chemo against bulky areas

Intensive chemo + autologous SCT Relapsed patients

ESR used for progress and monitoring

Non-Hodgkin’s Lymphoma

• All lymphomas other than Hodgkin’s• Approximately 40 different subtypes

Mature/ImmatureHistology

High grade Very aggressive – Burkitt’s Aggressive – Diffuse Large B-Cell, Mantle Cell

Low grade Indolent – Follicular, Marginal Zone, Small Lymphocytic

Lineage B-Cell: All of the above T-Cell

Non-Hodgkin’s Lymphoma

Presentation varies significantly from subtype to subtype Painless lymphadenopathy Often involves multiple sites Constitutional symptoms No pain after alcohol

Staging as per Hodgkin’s

Burkitt’s Lymphoma

Very aggressiveThree variants

Endemic – most common malignancy in equatorial Africa; EBV associated; jaw involvement and abdominal masses

Sporadic – found outside of Africa, EBV associated, less commonly affects jaw

Immunodeficiency – HIV/Post-Tx patients; not EBV associated

Histology ‘Starry-sky’ appearance

t(8;14) translocation; c-myc oncogene overexpressionTreatment – chemotherapy (rituximab)

Diffuse Large B-Cell Lymphoma (DLBCL)

Middle-aged and elderlyAggressive• Richter’s transformation: leukaemias

DLBCLHistology

Sheets of large lymphoid cellsTreatment

Rituximab-CHOP

Mantle Cell Lymphoma

Middle-agedAggressive

Disseminated at presentation Median survival 3-5 years

Histology ‘Angular nuclei’

t(11;14) translocationDysregulation of cyclin D1Tx similar to DLBCL

Follicular Lymphoma

ElderlyIndolent

Median life expectancy 12-15 years Mostly incurable

Histology ‘Follicular pattern’, ‘Nodular appearance’

t(14;18) translocationTreatment

Watch and wait Rituximab-CVP

MALT lymphomas

Mucosal Associated Lymphoid Tissue Marginal Zone NHL

Middle agedChronic antigen stimulation

H. Pylori gastric MALT lymphoma Sjogren’s syndrome parotid lymphoma

Treatment Remove antigenic stimulus e.g. H pylori triple therapy Chemotherapy

T-Cell Lymphomas

Adult T-Cell leukaemia/lymphoma HTLV-1 infection

Enteropathy associated T-cell lymphoma Long standing coeliac disease

Cutaneous T-cell lymphoma

Anaplastic large cell lymphoma Children and young adults Aggressive Large ‘epitheloid’ lymphocytes

Peripheral T-Cell Lymphoma Middle aged and elderly Aggressive Large T cells

Question Time!

A. CMLB. AMLC. ALLD. NormalE. CLLF. Mantle Cell LymphomaG. Hodgkin’sH. Follicular Lymphoma

A routine medical of a 33 year old footballer reveals: Hb 9.9, WCC 130. Blood film shows spectrum of myeloid precusors including a few blast cells. He admits to having frequent night sweats and blurred vision. Cytogenetic analysis shows Ph chromosome t(9;22)

Question Time!

A. CMLB. AMLC. ALLD. NormalE. CLLF. Mantle Cell LymphomaG. Hodgkin’sH. Follicular Lymphoma

A routine medical of a 33 year old footballer reveals: Hb 9.9, WCC 130. Blood film shows spectrum of myeloid precusors including a few blast cells. He admits to having frequent night sweats and blurred vision. Cytogenetic analysis shows Ph chromosome t(9;22)

Question Time!

A. CMLB. AMLC. ALLD. NormalE. CLLF. Mantle Cell LymphomaG. Hodgkin’sH. Follicular Lymphoma

A 5 year old girl presents with failure to thrive, recurrent fever and bruising. Immunophenotyping reveals the presence of CD10.

Question Time!

A. CMLB. AMLC. ALLD. NormalE. CLLF. Mantle Cell LymphomaG. Hodgkin’sH. Follicular Lymphoma

A 5 year old girl presents with failure to thrive, recurrent fever and bruising. Immunophenotyping reveals the presence of CD10.

Question Time!

A. CMLB. AMLC. ALLD. NormalE. CLLF. Mantle Cell LymphomaG. Hodgkin’sH. Follicular Lymphoma

A 64 year old woman receiving long-term chemotherapy for lymphoma presents with worsening bone pain, recurrent fever and night sweats. Blood film shows blast cells and Aeur rods.

Question Time!

A. CMLB. AMLC. ALLD. NormalE. CLLF. Mantle Cell LymphomaG. Hodgkin’sH. Follicular Lymphoma

A 64 year old woman receiving long-term chemotherapy for lymphoma presents with worsening bone pain, recurrent fever and night sweats. Blood film shows blast cells and Aeur rods.

Question Time!

A. CMLB. AMLC. ALLD. NormalE. CLLF. Mantle Cell LymphomaG. Hodgkin’sH. Follicular Lymphoma

An 85 year old lady with a painless swelling in her neck. After undergoing several investigation, she is told that there is cancer present but it is very slow growing. She is advised that she will be followed up regularly but no intervention is necessary at present.

Question Time!

A. CMLB. AMLC. ALLD. NormalE. CLLF. Mantle Cell LymphomaG. Hodgkin’sH. Follicular Lymphoma

An 85 year old lady with a painless swelling in her neck. After undergoing several investigation, she is told that there is cancer present but it is very slow growing. She is advised that she will be followed up regularly but no intervention is necessary at present.

Multiple Myeloma

Multiple Myeloma

Neoplasia of plasma cells of BMProduction of monocloncal Ig (IgG most

common) = paraproteinaemia

Middle aged – elderlyIncreased incidence in Afro-Caribbeans

Multiple Myeloma: Presentation

Multiple Myeloma: Presentation

Calcium high Thirst, abdo pain, constipation, stones, confusion

Renal failure Light chain obstruction of tubules Chains in urine = Bence Jones protein

Anaemia Infiltrate of plasma cells in BM Tiredness (also easy bleeding and infection)

Bone pain Osteoperosis, osteolytic lesions, wedge compression fractures

Multiple Myeloma: Lab

Dense narrow band on serum electrophoresisRouleax on blood filmESR very highBence Jones protein in urine> 10% plasma cells in BM

Multiple Myeloma: Treatment

Supportive for CRAB symptoms Bisphosphonates EPO

Chemotherapy Melphalan

Proteosome inhibitor: Bortezomib is 2nd line

Lenalidomide 3rd line

MGUS & Smouldering Myeloma

Monoclonal gammaglobinopathy of unknown significance

<10% plasma cells in BM (>10 % = MM)Incidental findingProgresses to MM at rate of 1-2%/year

Smouldering Myeloma>10% plasma cells in BM but no CRAB

Waldenstrom’s Macroglobinaemia

Older menLymphoplasmacytoid cells in BMIgM paraproteinaemiaUnlike myeloma, similar to NHL –

lymphadenopathy, wt loss, fatigueHyperviscosity syndrome – blurred vision,

headachesPlasmapheresis for hyperviscosity

MDS, MPD & ‘The Rest’

Myelodysplastic Syndromes

Group of progressive disorders where clonal proliferation of abnormally maturing stem cells occurs Cytopenias Hypercellular BM Dysplasia: Defective RBCs, WBCs, platelets e.g.

ringed sideroblasts Leukaemia transformation risk (AML)

ElderlySymptoms and signs relate to each cytopeniaBy definition, pts have < 20% blasts

>20% blasts = acute leukaemia

MDS: Treatment

Supportive – transfusions, EPOBiological ModifiersChemotherapy: hydroxyureaAllogenic SCT

PrognosisDepends on International Prognostic Scoring SystemMortality rule of 1/3: infection, bleeding, acute

leukaemia

Aplastic Anaemia

Inability of BM to produce adequate blood cells AA typically refers to anaemia i.e. just RBCs, but these

pts have a pancytopeniaSymptoms and signs relate to each cytopenia

Patients typically present with bleeding problemsAA closely linked to

Leukaemia Paroxysmal nocturnal haemoglobinuria

Aplastic Anaemia

Classification

Primary Idiopathic (70%) Inherited (10%) – see next slide

Secondary (10-20%) Radiation, drugs, viruses, immune

Inherited AA / BM Failure Syndromes

Fanconi Anaemia AR Presents at 5-10 years Skeletal abnormalities, short stature, renal

malformations, microopthalmia, skin pigmentation AML risk

Schwachman-Diamond Syndrome AR Skeletal abnormalities, short stature, endocrine

panreactic dysfynction, hepatic impairment AML risk

Inherited AA / BM Failure Syndromes

Dyskeratososis Congenita X linked Triad: skin pigmentation, nail dystrophy, leukoplakia

Diamond-Blackfan Syndrome Pure red cell aplasia; normal WCC and platelets Presents at 1 yr Dysmorphology

Myeloproliferative disorders

Group of conditions characterised by clonal proliferation of one or more haemopoietic component

1. Polycythaemia vera – RBCs2. Essential thrombocythaemia – platelets3. Idoiopathic myelofibrosis – WBCs Associated with JAK2 mutations (PRV)

Polycythaemia

Absolute polycthaemia Red cell mass raised Primary

PRV, familial Secondary

Disease states (renal Ca, hypoxia - COPD), high altitude raised EPO

Relative (pseudo) polycythaemia Red cell mass normal – plasma volume reduced Dehydration, burns, vomiting, diarrhoea Cigarette smoking, alcohol, HTN, obesity

Polycythaemia rubra vera (PRV)

MPD where erythroid precursors dominate BM JAK2 point mutations

Symptoms/signs Hyper-viscosity/volaemia/metabolism plethoric (red

nose), gout, splenomegaly Histamine release aquagenice pruritus (e.g. hot shower)

and peptic ulcersLab

Raised Hb, HCT Low serum EPO (cf secondary polycythaemia) Platelets, WCC may also be raised

Tx: venesection, hydroxycarbamide, aspirin

Idiopathic myelofibrosis

MPD where abnormal stem cells fibrosis of BM JAK2 mutation in 50%

Symptoms/signs Related to cytopenias Hepatomegaly, massive splenomegaly Weight loss, fever

Lab findings Tear drop poikilocytes, leucoerythroblasts Abnormally shaped RBCs, nucleated RBCs, immature myeloid cells BM: fibrosis, dry tap appearance

Treatment Supportive with blood products, splenectomy Cytoreductive therapy if platelet count is high: hydroxycarbamide

Essential thrombocythaemia

MPD where megakaryocytes dominate BMSymptoms/signs

Thrombosis (stroke and MI) and haemorrhage Erythromelalgia – extremities become blocked

painfully inflamed and hyperemicLab

Platelet count >600 x 109

Large platelets and megakaryocyte fragments BM – increased megakaryocytes

Tx: aspirin, angrelide, hydroxycarbamide

Question Time!

A. CMLB. DehydrationC. Essential ThrombocytopeniaD. Hodgkin’sE. MGUSF. Multiple MyelomaG. MyelofibrosisH. Non-hodgkin’s I. Osteoperosis J. PRV K. Secondary polycythaemia L. Waldenstrom’s macroglobinaemia

A 74 year old man is being investigated following a crush fracture of his T8 verterbra. He is found to have a monoclonal band on serum electrophoresis and free light chains in his urine.

Question Time!

A. CMLB. DehydrationC. Essential ThrombocytopeniaD. Hodgkin’sE. MGUSF. Multiple MyelomaG. MyelofibrosisH. Non-hodgkin’s I. Osteoperosis J. PRV K. Secondary polycythaemia L. Waldenstrom’s macroglobinaemia

A 74 year old man is being investigated following a crush fracture of his T8 verterbra. He is found to have a monoclonal band on serum electrophoresis and free light chains in his urine.

Question Time!

A. CMLB. DehydrationC. Essential ThrombocytopeniaD. Hodgkin’sE. MGUSF. Multiple MyelomaG. MyelofibrosisH. Non-hodgkin’s I. Osteoperosis J. PRV K. Secondary polycythaemia L. Waldenstrom’s macroglobinaemia

A 74 year old woman presents to her GP complaining of headaches and itchiness that is much worse after a warm bath. OE she has a normal CV and respiratory system. While palpating the abdomen, the doctor feels a vague fullness in the left upper quadrant. A full blood count shows Hb 22.1g/dl

Question Time!

A. CMLB. DehydrationC. Essential ThrombocytopeniaD. Hodgkin’sE. MGUSF. Multiple MyelomaG. MyelofibrosisH. Non-hodgkin’s I. Osteoperosis J. PRV K. Secondary polycythaemia L. Waldenstrom’s macroglobinaemia

A 74 year old woman presents to her GP complaining of headaches and itchiness that is much worse after a warm bath. OE she has a normal CV and respiratory system. While palpating the abdomen, the doctor feels a vague fullness in the left upper quadrant. A full blood count shows Hb 22.1g/dl

Question Time!

A. CMLB. DehydrationC. Essential ThrombocytopeniaD. Hodgkin’sE. MGUSF. Multiple MyelomaG. MyelofibrosisH. Non-hodgkin’s I. Osteoperosis J. PRV K. Secondary polycythaemia L. Waldenstrom’s macroglobinaemia

A 25 year old man presents to his GP complaining of a mass in his neck. The mass is generally painless, although it occasionally aches after alcohol. He admits to losing a significant amount of weight over the last month and also complains of excessive sweating and general itching. A biopsy of the mass reveals the presence of Reed-Sternberg cells.

Question Time!

A. CMLB. DehydrationC. Essential ThrombocytopeniaD. Hodgkin’sE. MGUSF. Multiple MyelomaG. MyelofibrosisH. Non-hodgkin’s I. Osteoperosis J. PRV K. Secondary polycythaemia L. Waldenstrom’s macroglobinaemia

A 25 year old man presents to his GP complaining of a mass in his neck. The mass is generally painless, although it occasionally aches after alcohol. He admits to losing a significant amount of weight over the last month and also complains of excessive sweating and general itching. A biopsy of the mass reveals the presence of Reed-Sternberg cells.

Question Time!

A. CMLB. DehydrationC. Essential ThrombocytopeniaD. Hodgkin’sE. MGUSF. Multiple MyelomaG. MyelofibrosisH. Non-hodgkin’s I. Osteoperosis J. PRV K. Secondary polycythaemia L. Waldenstrom’s macroglobinaemia

A 65 year old man on long term oxygen therapy for COPD is found to have a Hb of 18.4 g/dL

Question Time!

A. CMLB. DehydrationC. Essential ThrombocytopeniaD. Hodgkin’sE. MGUSF. Multiple MyelomaG. MyelofibrosisH. Non-hodgkin’s I. Osteoperosis J. PRV K. Secondary polycythaemia L. Waldenstrom’s macroglobinaemia

A 65 year old man on long term oxygen therapy for COPD is found to have a Hb of 18.4 g/dL

Question Time!

A. CMLB. DehydrationC. Essential ThrombocytopeniaD. Hodgkin’sE. MGUSF. Multiple MyelomaG. MyelofibrosisH. Non-hodgkin’s I. Osteoperosis J. PRV K. Secondary polycythaemia L. Waldenstrom’s macroglobinaemia

An 83 year old man is referred for bone marrow aspiration after presenting with heaptomegaly and splenomegaly. No marrow could be aspirated on the first attempt. Trephine biopsy is successfully performed and histology reveals hypercellular marrow containing many abnormal megakaryocytes.

Question Time!

A. CMLB. DehydrationC. Essential ThrombocytopeniaD. Hodgkin’sE. MGUSF. Multiple MyelomaG. MyelofibrosisH. Non-hodgkin’s I. Osteoperosis J. PRV K. Secondary polycythaemia L. Waldenstrom’s macroglobinaemia

An 83 year old man is referred for bone marrow aspiration after presenting with hepatomegaly and splenomegaly. No marrow could be aspirated on the first attempt. Trephine biopsy is successfully performed and histology reveals hypercellular marrow containing many abnormal megakaryocytes.

The END!

Go through the Blood Transfusion lecture

Understanding is key

Any questions email:anika.kaura09@imperial.ac.uksarneet.singh09@imperial.ac.uk