Haemato-oncology‎ > ‎

Myeloproliferative neoplasms

WHO Classification

1.      CML – BCR-ABL

2.      Chronic neutrophilic leukaemia

3.      Chronic eosinophilic leukaemia

4.      Chronic idiopathic myelofibrosis

5.      PV

6.      ET

7.      Myeloproliferative disorders unclassified

 

 

Polycythaemia

Classification

§        Raised Hb / Red cell mass

§        Should be measured in relation to surface area rather than ml/kg

§        Because of avascularity of adipose tissue in obese patients

§        Not raised = apparent polycythaemia

§        Raised = true polycythaemia

§        Primary polycthaemia = PV or congenital polycythaemia

§        Secondary polycythaemia

§        Eg. Increased epo

§        Idiopathic erythrocytosis

§        Exclusion criteria met but not positive criteria

 

Polycythaemia vera

§        2-3/ 100 000

§        Median age of onset is 55-60 years

§        M:F: 1:1

 

§        Expansion of total red cell mass +/- increased platelets, neutrophils

 

§        Pathophysiology

§        Red cells, platelets, neutrophils and a variable number of BB lymphocytes all from the malignant clone

§        Erythropoiesis independent of epo and epo levels are low

§        Thrombocytosis / Raised HCT and viscosity lead to thrombotic complications but platelets also clonal and often have abnormal function leading to bleeding.

§        2 phases:

§        Initial proliferative phase

§        Increased red cell mass

§        ‘spent’ post-polycythaemic phase

§        Cytopenias, fibrosis, extramedullary haemopoiesis and hypersplenism

 

Clinical features

Thrombotic complications (20-40% of deaths)

§        Presenting feature in 25%

§        Arterial (2/3)

§        Increased if pre-existing vascular disease / risk factors

§        Venous (1/3)

§        Mesenteric, splenic, hepatoportal thromboses are not uncommon presentations

§        Microvascular (eg. Erythromelalgia)

§        Sluggish cerebral blood flow (headaches, drowsiness, insomnia, amnesia, tinnitus, vertigo, chorea, visual disturbances)

 

Haemorrhagic complications (5-10% deaths)

 

Skin

§   Pruritius (25%)

§        Characteristically aquagenic - usually relieved by controlling PCV

§        Exacerbated by hyperhistaminaemia and iron deficiency

§        Plethora, dilated conjunctival vessels, brown discolouration of skin

§        Sweets syndrome (erythematous popular rash with fever – associated with a variety of haematological malignancies and rhematological conditions)

 

Splenomegaly (30-50%)

§        May be associated with increased risk of progression to MF

 

Hypertension

 

Hyperuricaemia in 5%

 

Myelofibrosis / Post Polycythaemic Myeloid Metaplasia (PPMM)

§        <5% reticulin fibrosis at diagnosis – 50% at 20 years

§        Extramedullary haemopoiesis – hepatosplenomegaly

§        Median survival 3 years

§        25-50% transform to AML

 

Leukaemic transformation (AML)

§        Rare in patients treated only with venesection (1-3%)

§        Risk increases with radioactive phosphorus, chlorambucil, irradiation (time to progression with these treatments is 5-8 years)

§        Treated with standard induction but responds poorly

 

Investigations

§        HCT >0.52 males, >0.48 females for >2 months should have a red cell mass

§        HCT >0.6 males, >0.56 females can be assumed to have an absolute erythrocytosis

 

Jak-2 mutations – probably first line investigation now

§        V617F mutation (2005 NEJM – Swiss group)

§        95% in PV

§        50% in  IMF and ET

§        20% in atypical CML and MPDu

§        2-3% in HES, CMML and SM

 

§        If negative:

§        Exon 12 mutations 3% in PV (Green et al., 2007 – NEJM - Cambridge)

§        Recent case series in BJH – 114 patients meeting Polycythaemia Vera Study Group Criteria

§        110 had V617F mutations

§        3 had exon 12 mutations

§        1 case had V617F detectable in the erythroid independent colonies which had been at too low a level to be detected by allele specific PCR

§        However probably possible to have PV without currently identified mutations in JAK2

 

§        Jak kinases are composed of 4 domains

1.     N-terminal FERM domain

§        Interacts with cytokine receptors

2.      SH2 domain

3.    Pseudokinase (JH2) domain

§        Involved in inhibition of kinase activity

§        Location of V617F mutation

§        Gain of function

§        Mutant Jak-2 binds to cytoplasmic domain of intracellular and cell surface epo receptor , which promotes ligand independent signalling

4.    C-terminal kinase (JH1) domain

 

Modified diagnostic criteria

§        Jak 2 – positive; both criteria need to be present

§        HCT >0.52 men, >0.48 women or raised red cell mass (>25% predicted)

§        Mutation in Jak 2

§        Jak 2 – negative; A1 + A2 + A3 + either 1 other A or 2 B’s

§        A1: HCT >0.6 men, >0.56 women or raised red cell mass

§        A2: Absence of Jak 2 mutation

§        A3: No cause of secondary erythrocytosis

§        A4: palpable splenomegaly

§        A5: acquired genetic abnormality (excluding Bcr-Abl)

§        B1: thrombocytosis > 450

§        B2: neutrophilia >10 in non-smokers (>12.5 in smokers)

§        B3: radiological evidence of splenomegaly

§        B4: endogenous erythroid colonies or low epo

 

§        Stage 1

§        History and examination

§        Including pulse oximetry

§        Misleading in

§        CO poisoning

§        High affinity Hb/ low 2,3-biphosphoglycerate levels

§        Sleep apnoea

§        Sa02 <92% indicates a causal relationship with an absolute erythrocytosis

§        FBC and film

§        Neutrophilia in 1/3

§        In smokers should consider ULN 12.5

§        Thrombocytosis in ½

§        Jak 2 mutation

§        Ferritin and B12

§        Low ferritin more common in PV than secondary causes

§        Elevated B12 due to trancobalamin release from increased granulocytic mass

§        Renal, bone and liver function

 

§        Stage 2 – if Jak 2 negative and no obvious secondary cause

§        Red cell mass

§        Arterial oxygen saturation

§        Abdominal USS

§        Excludes underlying renal/ hepatic pathology

§        Splenomegaly

§        Epo

§        Usually low in PV, even following venesection

§        Bone marrow

§        Baseline to assess disease progression

§        Chromosoamal abnormalility establishes clonality

§        Karyotype

§        Culture studies of erythroid burst-forming units (BFU-e)

§        Endogenous erythroid colonies

§        Not standardised and expensive

 

§        Stage 3 – erythrocytosis but do not fulfil criteria

§        Arterial oxygen dissociation curve

§        Sleep study

§        Lung function studies

§        Gene mutations (VHL, EPOR)

 

§        Morphology

§        Polycythaemic stage

§        Blood film

§        Packed film

§        Thrombocytosis (50%), neutrophilia

§        Basophilia

§        Iron deficiency

§        Monocytes are not increased

§        Hypercellular bone marrow – panmyelosis

§        Erythroid hyperplasia

§        Granulocytic and megakaryocytic (large with increased lobulation but increased micromegakaryocytes may be seen on trephine)

§        Increased reticulin

§        Hepatosplenomegaly, if present due to congestion

§        Post-polycythaemic / fibrotic stage

§        Red cell mass normalises, then decreases

§        Progressive fibrosis and leucoerythroblastic film

§        Reticulin and collagen fibrosis

§        Hepatosplenomagely, if present cue to extramedullary haemopoiesis

§        Cytogenetics

§        Only in10-20%

§        +8, +9, del(20q), del(13q) and del(1p)

 

Treatment

Venesection

§        Target haematocrit <0.45 for PV

§        Target haematocrit <0.54 if secondary polycythaemia

§        Often result in iron deficiency and thrombocytosis

§        Polycythaemia vera study group (PVSG)  have found that initial aggressive phlebotomywithout myelosuppression may be associated with increased risk of thrombosis especially in the elderly

§        Should consider adding hydroxyurea if over 60 or thrombotic risk factors

§        HCT should be controlled for 3 months before elective surgery

 

Aspirin

§        ECLAP study established benefit – 60% reduction (7.9% to 3.2% at 3 years) in thrombotic events with no increase in major bleeding

§        Consider clopidogrel if intolerant

§        CURE study showed benefit of aspirin and clopidogrel to reduce cardiovascular events but at the expense of more bleeding, therefore role unclear in MPD

 

Cytoreductive therapy

§        Recommended for

§        Thrombocytosispoor tolerance of venesection

§        Symptomatic splenomegaly (except anagrelide)

§        B symtpoms

§        Hydroxyurea

§        1st line >40 years

§        Non-alkylator

§        Reduces haematocrit and platelets

§        Side effects = GI disturbance, leg ulcers, photosensitivity

§        Potentially leukaemogenic but not found to be in ECLAP study

§        Interferon alpha (SC 3-5,000,0000 U x3/week)

§        1st line < 40 years

§        Suppresses proliferation of pluripotent and lineage committed haematopoietic progenitors

§        Reduces platelets and haematocrit

§        Formidable side effects (anorexia, nausea, flu like, depression)

§        Useful in young patients reluctant to take cytotoxic agents, in pregnancy and in intractable pruritis

§        Anagrelide

§        Inhibits megakaryocyte differentiation

§        Can be combined with hydroxyurea to allow lower doses of both

§        10% completely refractory

§        Side effects =  headaches, palpitations, fluid retention

§        PT1 trial in ET showed worse than aspirin and HU – increased thrombosis and progression to MF

§        Busulphan

§        Alkylating agent

§        Convenient as can be administered intermittently

§        Better than radioactive phosphorus

§        Should be reserved for the elderly

§        Probably increases risk of leukaemia

§        Chlorambucil

§        High rate of acute leukaemia NOT recommended

§        Pipobroman

§        Used extensively in Europe – little evidence of increased AML

§        Radioactive phosphorus

§        Good disease control

§        Intermittent treatment and therefore less follow up

§        Clearly increases leukaemic transformation

 

Address other risk factors

§        Smoking, BP etc

§        No role for thombophilia screening

 

Pruritus

§        AntihistaminesCimetidine

§        PUVAIron replacement

§        IFN alpha

 

Prognosis

§        Untreated median survival 18 months

§        Treated – survival 10-18 years for patients age <40

 

Pregnancy

§        High risk of complication if

§        Previous venous/ arterial thrombosis

§        Previous haemorrhage attributed to PV

§        Previous pregnancy complication that mey be attributable to PV

§        3 or more first trimester or 1 or more 3rd trimester  pregnancy losses, birthweight <5th centile for gestation

§        IUD or still birth (no other obvious cause and placental dysfunction and growth restricted fetus)

§        Ante or post partum haemorrhage requiring transfusion

§        Severe pre-eclampsia (requiring delivery <37 weeks)

§        Plt >1000

 

§        Treatment

§        Venesect to within normal range for pregnancy <36%

§        Aspirin is safe (CLASP study)

§        Consider LMWH if high risk and for all in puerperium

§        Previous venous thrombosis of fetal mortality

§        40mg enoxaparin od, increased to bd at 16-20 weeks, reduced to od 3 days post partum for 6 weeks

§        Previous arterial thrombosis

§        40mg bd throughout pregnancy

§        If evidence of recurrence, consider increasing after 14 weeks

§        Treat iron deficiency

§        IFN if cytoreduction needed (not safe for breast feeding)

§        Regular growth scans including Doppler for placenctal insufficiency

§        HU and anagrelide should be withdrawn 3-6 months before conception

 

 

Primary polycythaemia

§   Primary and familial congenital polycythaemia

§        Rare

§        Erythropoiesis intrinsically overactive

§        AD

§        Isolated erythropoiesis

§        Not associated with evolution to leukaemia or MF

§        Mutations in the gene encoding the epo receptor have been described

§        Increased sensitivity to epo

 

Secondary polycythaemia

Hypoxia

§        Chronic lung disease

§        Associated with cor pulmonale and poor prognosis

§        Referred to respiratory for consideration of LTOT

§        Suggest venesect if symptomatic and haematocrit > 0.56, target of 0.50-0.52

§        Limited evidence of beneficial effect of ACE-I or angiotensin receptor antagonists

§        High altitude

§        Some decompensate and develop chronic mountain sickness (Monge’s disease) – PCV > 0.75

§        ACE-I may reduce haematocrit and proteinuria

§        Congenital cyanotic heart disease

§        PCV > 0.65

§        Surgical correction if possible

§        Like chronic lung disease, increase in oxygen carrying capacity but also increased viscosity. Unlike lung disease patients are young and can tolerate higher PCVs

§        Decision to venesect should be based on symptoms

 

High affinity Hb

§        Release less oxygen for a given oxygen partial pressure

§        Result in tissue hypoxia

§        Epo-driven polycythaemia with a resultant normalization in epo

§        Left shift in the oxygen dissociation curve

§        Diagnosis by DNA or mass spectrometry

§        Dominantly inherited

§        Most due to mutations in B-globin gene

§        Most asymptomatic

§        Plethoric

§        Excessive muscle fatigue after exercise

§        No increase in cardiovascular morbidity or mortality

§        No adverse effect in pregnancy

§        Indications for venesection

§        Symptoms likely caused by HCT eg. Dizzy, dyspnoes

§        1 or more thrombotic episodes

§        Asymptomatic but complications in family members

§        Target <0.6

§        Red cell metabolic defects

§        Low 2,3-BPG

§        Low P50

§        AR

 

Methaemoglobinaemia

§        Increased affinity for Hb

§        Left shifted oxygen dissociation

§        Can result from exposure to strong oxidants

§        Dapsone, paraquat benzocaine

§        Can be life threatening

§        Rarely sufficiently long-lived to give rise to polycythaemia

§        Can be inherited – secondary erythrocytosis as per high affinity Hbs

 

Heavy smoking

§        Mild polycythaemia in the absence of hypoxic lung disease

§        Raised carboxy-Hb

§        CO levels - <2% in non-smokers, 3-20% in smokers

 

Sleep apnoea

§        Epworth score >10/24

§        BMI >30

 

Absence of hypoxia

Inherited – Chuvash polycythaemia (AR)

§        Russian mid-Volga river region, but also some in Asia and with West European ancestry

§        Mutation in the von-Hippel Lindau gene (increased epo but no mutations of epo receptor)

 

Abnormal epo secretion

§        Renal tumours

§        PCKDRenal cysts / Hydronephrosis / Renal artery stenosis

§        Post renal transplant

§        10-15% develop erythrocytosis 8-24 months after transplant

§        Avoid dehydration

§        Treat with ACE-I or angiotensin II inhibitor

§        Venesect to a HCT <0.45

§        Hepatocellular carcinoma

§        Cerebellar tumours

§        Fibroids

 

Endocrine disorders

§        Overproduction of androgens which increase epo levels

 

Idiopathic erythrocytosis

§        Raised red cell mass, but don’t fill criteria for PV and no other cause can be found

§        Venesect to <0.45 if HCT >0.54

§        Venesect to <0.45 if HCT <0.54 and increased risk of thrombosis

§        Cytoreductive therapy contraindicated

 

Apparent polycythaemia

§        Raised haematocrit but normal red cell mass

§        Smoking, hypertension, obesity, alcohol and diuretics

§        Consider venesection

§        Recent thrombosis or additional RFs for thrombosis

§        HCT >0.54

§        Aim <0.45

 

Relative erythrocytosis

§        RCM in normal ranges, but plasma volume low

§        True pathological states of dehydration

 


Essential thrombocythaemia

§        Epidemiology

§        1.5-2/ 100 000

§        Median age is 50-55

§        Second peak at 30 years, where women are more commonly affected

§        Clinical Features

§        50% are asymptomatic

§        Thromobotic complications (15-20% at presentation)

§        Risk factors

§        Age > 60 years

§        Previous thrombosis

§        Plt > 1000

§        Hyperlipidaemia

§        Hypertension

§        Smoking

§        Haemorrhagic complications

§        Platelet function abnormalities don’t correlate with bleeding risk

§        More common if plt > 1000

§        May be related to acquired vWD (reduced HMW multimers)

§        Splenomegaly and hyposplenism

§        20-50% at presentation

§        Progressive enlargement raises possibility of MF

§        Occasionally splenic atrophy due to infarcts

§        Transformation to PV or MF

§        MF (<10%) >PV (1-2%)

§        May represent correction of iron deficiency

§        Leukaemic transformation

§        Increased risk with cytogenetic abnormalities or alkylating agents

 

Investigation

§        Plt  >600 for at least 2 months

§        No cause for reactive thrombocytosis with normal ESR/ CRP

§        No evidence of PV / CML / MF / MDS

§        No evidence of iron deficiency

§        Morphology

§        Platelet anisocytosis (some giant and hypogranular)

§        Platelet aggregates, occasionally bare megkaryocyte nuclei

§        Mild elevation in wcc

§        Occasionally signs of hyposplenism due to splenic infarction

§        Bone marrow

§        Proliferation of large to giant megakaryocytes

§        Loose clusters

§        Megas have abundant  mature cytoplasm, deeply and hyperlobulated nuclei

§        The bizarre, highly atypical features of MF are not a feature

§        Fibrosis if present, suggests MF

§        Cytogenetics

§        50% JAK 2 positive

§        Found only in 5-10%

§        +8, +9, del(13q22)

Treatment

§        High risk

§        Age > 60

§        Plt > 1500

§        Prior history of thrombosis

§        Thrombotic risk factors eg. Diabetes, hypertension

§        Target of treatment – platelet count <400 (unless requiring high doses in which case <600 is acceptable)

§        Hydroxyurea and aspirin (age >40)

§        Starting dose 15-20 mg/kg/day

§        If plt count very high consider delaying aspirin if risk of acquired vWD

§        PT-1 trial (Harrision et al NEJM 2006)

§        Hydroxyurea and aspirin versus anagrelide and aspirin

§        Anagrelide arm was associated with more arterial events, major haemorrhage and myelofibrotic transformation, but less venous thrombosis

§        Interferon alpha - as for PV (possibly first line if age <40)

§        Anegralide

§        Need to check ECG / Echo prior to commencing treatment

§        Busulphan, radioactive phosphorus, alkylating agents

§        Splenectomy, results in a dramatic increase in platelets

§        Intermediate risk

§        40-60 years and no risk factors

§        Not clear whether it is beneficial to lower platelet count

§        Most treat with aspirin alone

§        Low risk

§        < 40 years and no risk factors

§        Aspirin or alternative anti-platelet

Prognosis

§        In high risk patients, HU reduces risk of thrombosis from 10.7 to 1.6 per 100 patient years

 

Pregnancy

§        Fertility is probably reduced

§        First trimester miscarriage in 30%

§        Placental microinfarcts and insufficiency

§        Reported increased incidence of APLa may contribute

§        Live birth in 60%

§        Most recommend aspirin

§        If high risk, interferon +/- LMWH prophylaxis

§        Platelet count may rise dramatically post partum

§        Can be controlled with HU or anagrelide, but this excludes breast feeding

 



Chronic megakaryocytic leukaemia (Idiopathic myelofibrosis)

§        Pathophysiology

§        Clonal proliferation of multiple cell lineages with progressive marrow fibrosis

§        Fibrosis is secondary to cytokine release from abnormal clonal cells which stimulate fibroblast proliferation and fibrosis

§        Epidemiology

§        0.5-1.5/ 100 000

§        Median age 50-60

§        M=F

§        Clinical features

§        Up to 1/3 discovered incidentally

§        Splenomegaly

§        Almost all at presentation

§        May have splenic discomfort and splenic infarcts

§        Massive splenomegaly may result in portal hypertension

§        Extramedullary haemopoiesis

§        Most commonly spleen and liver

§        Rarely other sites, eg. CNS, lymph nodes

§        Systemic symptoms

§        B- symptoms

§        Associated with worse prognosis

§        Anaemia

§        Reduced erythropoiesis

§        Hypersplenism

§        Bleeding

§        Iron/ folate deficiency

§        Aquired HbH is a rare complication

§        Platelet abnormalities

§        Often raised at presentation but progressively fall

§        Dysmegakaryopoiesis adds to haemorrhagic risk

§        White cells

§        Leucocytosis is common followed by leucopenia

§        Transformation to AML in 5-10% and is rapidly fatal

 

Investigation

§        A1 + A2 + B1 + 1 other B or A1 + A2 + 4B’s (if not B1)

§        A1 = diffuse marrow fibrosis

§        A2 = No Philadelphia chromosome

§        B1 = splenomegaly

§        B2 = anisopoikilocytosis with tear drop poikilocytes

§        B3 = circulating immature myeloid cells

§        B4 = circulating erythroblasts

§        B5 = clustered and anomalous megakarycocytes

§        B6 = myeloid metaplasia

 

§        Bone marrow

§        Silver – reticulin fibres

§        Collagen fibres – trichrome stain

§        Grade I – IV

§        <10% - osteosclerois

§        Pre-fibrotic stage

§        20-30% detected at this stage

§        Diffusely hypercellular

§        Diagnosis largely based on megakaryocyte abnormalities in the trephine (very variable megakaryocytes ranging from small hypolobated forms to hyperchromatic hyperlobated cells, which may be clustered)

§        Fibrotic stage

§        Becomes hypocellular replaced with connective tissue or flat

§        Dilated sinuses and inttrasinusoidal haemopoiesis

 

§        Cytogenetics

§        No specific defect

§        Occur in about 60%

§        Del(13q), del(20q), partial trisomy 1q, +8, +9

 

Treatment

§        Curative treatment is SCT

§        Most treatment is supportive

§        > 45 years, long-term survival 10-20%

§        Danazol and epo for anaemia, but most become transfusion dependant

§        HU may be useful for thrombocytosis, B-symptoms, organomegaly

§        Splenomegaly

§        Pain

§        B-symptoms

§        Portal hypertension

§        Transfusion dependant anaemia

§        Problems

§        Bleeding, infection, thrombosis

§        Rebound thrombocytosis

§        Progressive hepatomegaly

§        Splenic irradiation

§        Thalidomide

§        Increases thrombotic risk

§        Poorly tolerated at standard dose

§        May be used at lower dose combined with steroids

§        Bisphosphonates

§        Bone pain

§        JAK2 inhibitors

§        CEP70 tried at MD Anderson with little activity

§        INCYTE more promising – reduced splenomegaly, fatigue and pruritus

 

Prognosis

§        Median survival is 3-5 years

§        Adverse prognostic features

§        Elevation in the circulating CD34 count / marked granulocytic immaturity

§        Age >70

§        Hb <10

§        Plt <100

§        Abnormal karyotype

 


Mastocytosis

Pathophysiology

§        C kit point mutation (D816V) = tyrosine kinase receptor for stem cell factor

§        Ligand independent phosphorylation of  c-kit and clonal expansion of mast cells

 

Classification

§        Cutaneous mastocytosis

§        Urticaria pigmentosa

§        Mastocytoma of the skin

§        Systemic mastocytosis

§        Indolent

§        Aggressive

§        SM with associated haematological non-mast cell disorder

§        Mast cell leukaemia

§        Mast cell sarcoma

 

Clinical Features

§        Cutaneous

§        Urticaria pigmentosa, pruritus, flushing

§        Darier’s sign

§        Systemic (due to mast cell mediator release)

§        Fever, fatigue and weight loss

§        Angiodema, anaphylaxis

§        Abdo pain, diarrhoea, nausea and vomiting, gastritis and peptic ulceration, malabsorption

§        Osteoporosis

§        Cytopenia secondary to bone marrow involvement

§        Organ infiltration and failure in aggressive disease

 

Investigations

§        Diagnostic criteria (1 major and 1 minor or 3 minor)

§        Major

§        Multifocal dense infiltrates of mast cells in bone marrow or other extracutaneous tissues

§        Minor

§        > 25% of mast cells are atypical or spindle shaped

§        D816V mutation

§        Mast cells expressing CD25 or CD2

§        Tryptase > 20ng/mL

§        Mast cells easier to identify with toluidine blue stain

§        USS abdomen

§        Bone densitometry

§        OGD (Gastric ulcers secondary to histamine induced acid release)

 

Treatment

§        Avoid factors that trigger mediator release

§        Eg general anaesthesia, contrast, insect stings, morphine

§        Treatment of acute mediator release

§        Epipen

§        Treatment of chronic mediator release

§        H1 and H2 blockers

§        Topical corticosteroids, sodium chromoglycate

§        PUVA

§        PPI

§        Bisphosphonates and calcium supplements

§        IFN-alpha +/- steroids

§        Reduction of mast cell burden

§        Novel agents/ tyrosine kinase inhibitors

§        Imatinib inhibits wild type kit but not theD816V mutation

 

Prognosis

§        Paediatric – 50% resolve

 

Clonal hypereosinophilic syndromes

§        Eosinophilia

§        0.5-1.5 = mild

§        1.5-5 = moderate

§        >5 = severe

 

Pathophysiology

§        Reactive

§        Reflects release of IL3, IL5 and GM-CSF

§        Infections

§        Parasitic – tissue invasive parasitosis

§        Stool, duodenal aspirates and sputum

§        Neoplasia

§        HD, NHL, ALL

§        Vasculitides

§        PAN, Churg-Strauss

§        Connective tissue disorders

§        RA, SLE

§        Allergic and inflammatory disorders

§        Asthma, ABPA (aspergillus fumigatus), eczema, IBD

§        Drug reaction

§        Hypersensitivity

§        Immunodeficiencies

§        Wiskott-aldrich

 

§        Idiopathic - Hypereosinophilic syndrome

§        Unexplained eosinophilia (>1.5)for more than 6 months with end-organ damage, but no increase in blasts and no evidence of clonality

§        M>>F

§        <50% 10 year survival

 

§        Clonal

§        Chronic eosinophilic leukaemia

§        Eosinophils >1.5 with evidence of clonality or increased blasts (but <20%) in blood or bone marrow

§        Eg. FIP1L1 PDGFR-alpha fusion generates an active TK

§        Responds to imatinib

§        M>F

§        Atypical CML (PDGFR-beta)

§        Also responds to gleevec

§        8p11 myeloproliferative syndrome (FGFR1)

§        Eosinophilia and T-cell lymphoblastic lymphoma

§        May respond to PKC-412

§        CML

§        AML Eo

§        ALL

 

Clinical Features

§        Tissue damage secondary to eosinophil degranulation and mediator release

§        Eg. Eosinophil cationic protein, major basic protein

§        Constitutional symptoms

§        Pruritius, angiodema, diarrhoea cough

§        Cardiac damage is main cause of mortality

§        Endomyocardial fibrosis, pericarditis, myocarditis, intramural thrombus formation and dilated cardiomyopathy

§        Troponin level correlates with presence of cardiomyopathy

§        Neurological

§        Mononeuritis multiplex, paraparesis, encephalopathy, dementia

§        Pulmonary damage

§        Infiltrates, fibrosis, pleural disease

§        GI damage

§        Diarrhoea, gastritis, colitis, hepatitis, Budd-chiari

 

Investigations

§        Diagnostic criteria

§        Exclude reactive eosinophilia

§        Exclude underlying neoplasm with reactive eosinophilia

§        Exclude neoplasm where eosinophils are part of the neoplastic clone

§        Exclude abberant T-cell population with abnormal cytokine release

§        If all of the above and no clonality = HES

§        If all of the above, and clonality or blasts <2% in PB or 5-19% in BM = CEL

 

§        Echocardiogram annually as major cause of morbidity

 

 

Morphology

§        Usually mature eosinophilia

§        Sparse granulation

§        Cytoplasmic vacuolation

§        Hyper, hyposegmentation

§        Not specific for clonal disease             

§        Bone marrow

§        Charcot-leyden crystals

§        Fibrosis secondary to eosinophil degranulation

§        Cytogenetics

 

Cytogenetics

§        TCR rearrangements

§        FIP1L1-PDGFRa

§        Bcr-Abl

§        PDGFRb - D816V (and tryptase)

§        FGFR1

§        +8 or i(17q) or 8p11 abnormalities

 

Treatment

§        Imatinib if PDGFRa/b rearrangements

§        HES

§        Prednisolone

§        70% response rate

§        Relapses off therapy are usual

§        HU, IFN-alpha

§        Alemtuzumab has shown promising results

§        Cladrabine, Cyclosporine

 

Prognosis

§        Adverse risk factors

§        Lack of response to steroids

§        Markedly elevated eosinophil count

§        Normal IgE levels

§        Splenomegaly

§        Dysplastic features

§        Male sex

§        Blasts

§        Probably markers of clonal disease

 


Chronic neutrophilic leukaemia

§        Sustained neutrophilia with hypercellular bone marrow and hepatosplenomegaly

§        Diagnosis of exclusion

§        <100 cases reported

§        Diagnostic criteria

§        PB Leucocytosis >25 x109/L

§        Neutrophils and bands >80%

§        Immature granulocytes <10%

§        Myeloblasts <1%

§        Hypercellular marrow

§        Neutrophil granulocytes increased

§        Myeloblasts <5%

§        Maturation pattern normal

§        Hepatosplenomegaly

§        Exclude reactive neutrophilia

§        Including underlying neoplasm

§        No Ph or Bcr-Abl

§        Exclude other MPD

§        Exclude MDS

§        Clinical Features

§        Splenomegaly +/- hepatomegaly

§        Bleeding from mucocutaneous surfaces in 25-30%

§        Gout and pruritus

§        Morphology

§        Neutrophilia >25

§        Immature granulocytes usually account for <5%

§        Myeloblasts almost never observed

§        Neutrophils may appear toxic, but are not dysplastic

§        Bone marrow

§        Hypercellular, M:E: 20:1 or greater

§        Fibrosis is uncommon

§        Often reported with MM, therefore need to exclude plasma cell dyscrasia

§        If MM present, need to confirm clonality of neutrophils before making a diagnosis of CNL

§        Cytogenetics

§        90% normal

§        +8, +9, del(20q), del(11q)

§        Can get a variant Bcr-Abl, P230 – should be considered CML

§        Prognosis

§        6 months – 20 years

§        Can get progressive marrow failure, MDS, AML

 

 

Myeloproliferative disease unclassifiable

§        Clinical, laboratory and morphological features of a MPD, but fail to meet the diagnostic criteria of any of the above

 


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