EMQ: Malignant (Myeloproliferative Disease)

For each of the following clinical scenarios (1-5) choose the SINGLE diagnosis from the list below (a-h) to which the scenario best fits. Each answer may be used once, more than once or not at all.

Options:

A. Atypical CML

B. Chronic Myeloid Leukaemia (CML)

C. Chronic Myelomonocytic Leukaemia (CMML)

D. Essential Thrombocythaemia

E. Idiopathic Myelofibrosis (IMF)

F. Myelodysplastic Syndrome – Refractory Anaemia

G. Polycythaemia Rubra Vera

H. Secondary erythrocytosis

Clinical Scenarios:

1:

A 45 year old woman referred to haematology with the following investigation results:

Hb 12g/dL, WC 7 x10⁹/L, Plts 870 x10⁹/L, CRP 12

BCR-ABL negative, JAK2 V617F negative

Bone marrow biopsy revealed abnormal megakaryocytes which are clustered

Cytogenetic analysis reveals a normal karyotype.

2:

A 70 year old gentleman with splenomegaly

Hb 9.2g/dL, WCC 24 x10⁹/L, Neut 18 x10⁹/L, Mono 3 x10⁹, Platelets 110 x10⁹/L

Bone marrow aspirate report: Mild reduction in erythropoiesis and megakaryocytes. Granulopoiesis is left shifted with 13% blasts detected. Absolute increase in monocytes which account for 9% of total nucleated cells.

Cytogenetic analysis revealed a normal karyotype

3:

A 67 year old non smoker who was previously fit and well. Referred to haematology with the following investigation results:

Hb 16.4g/dL, Hct 0.59, WCC 11 x10⁹/L Plts 610 x10⁹/L and a ferritin of 9

JAK2 V617F mutation positive.

Bone marrow biopsy reported as:

"Hypercellular sample with increased numbers of large polymorphic megakaryocytes, some are located in clusters."

Cytogenetic analysis shows trisomy 8 but BCR-ABL negative.

4:

A 72 year old gentleman being investigated for increasing tiredness is found to be anaemic and to have moderate hepatosplenomegaly. Full blood results show:

Hb 7.2g/dL WCC 34.5 x10⁹/L Platelets 120 x10⁹/L

(Diff: Neutrophils 19x10⁹/L , Myelocytes 7.8x10⁹/L, blasts 1.0 x10⁹/L Monocytes 4.2 x10⁹/L, Basophils 0.3 x10⁹/L, Eosinophils 0.2 x10⁹/L, Lymphs 2 x10⁹/L)

Film: left shifted neutrophils with myelocytes and blasts seen. Hypogranular, hypolobated neutrophils present.

BCR-ABL negative, JAK2 V617F muatation negative.

5:

A 50 year old gentleman referred for investigation of tiredness and splenomegaly (10cm below costal margin). He also has a history of easy bruising. Blood film leukoerythroblastic with tear drop poikylocytes, occasional blasts and giant platelets. Bone marrow biopsy was unsuccessful.

He is JAK2 mutation negative and BCR-ABL negative

Answers:

1: Essential Thrombocythaemia

2: Chronic Myelomonocytic Leukaemia (CMML)

3: Polycythaemia Rubra Vera

4: Atypical CML

5: Idiopathic Myelofibrosis (IMF)

Explanation:

Note that new WHO diagnostic criteria for haematological malignancies are being published this year by way of an 'interim update' to the 2007/8 publication. Myeloproliferative neoplasm definitions comprise clinical and molecular findings which have seen substantial changes over the past decade and familiarity with the new guidelines is essential to properly risk-stratify and determine treatment strategies. Remember to stay on top of things this year!

1. With no secondary cause and a markedly elevated platelet count, essential thrombocythemia with one of the other genetic abnormalities in CALR or MPL are likely. However, as a young woman with no thrombosis history she is low risk for complications and can be managed with aspirin and without cytoreduction at this point.

2. CMML is defined by absence of BCR-ABL and monocytosis.

3. PRV is often iron deficient without an initial marked elevation in haematocrit: here the platelet count and JAK2 mutational status are indicative of the diagnosis and with replacement there may be a potentially hazardous marked elevation in haematocrit. Trisomy 8 is described in PRV.

4. Philadelphia chromosome negative, older patients with hepatosplenomegaly (not seen in MDS) and a blood picture resembling CML but without any underlying inflammatory cause, and often more dysplasia, less of a basophilia and more of a left shift than classical CML suggests atypical CML. It is hence a diagnosis of exclusion, most importantly, of BCR-ABL mutation.

5. Characteristic constellation of findings of myelofibrosis is described in the final patient: JAK2 V617F is found in 30-50% and a proportion of the remainder will harbour mutations of CALR.

Reference:

The new WHO definitions of myeloproliferative neoplasm are in the press as part of the 2016 revision of diagnostic criteria. The reference below is hence 18 months out of date, but is remains relevent to the clinical cases presented here until newer guidelines emerge based on the new criteria. Keep your eye out!

Geyer HL, Mesa RA. Therapy for myeloproliferative neoplasms: when, which agent and how? Blood. 2014;124(24)3529–3537