The BCSH do not published a single document which encompasses all MPN’s. Separate guidelines are produced for PV, ET and PMF and include best practice recommendations for investigation and clinical management. The guidelines for the investigation and management of PV were published in 2005 (McMullin et al., 2005) and updated in 2007 (McMullin et al., 2007) following the identification of a
recurrent mutations with in the JAK2 gene (Baxter et al., 2005; James et al., 2005; Kralovics et al., 2005; Levine et al., 2005; Scott et al., 2007). Diagnostic
recommendations were amended to include molecular screening for these defects.
Guidance for the investigation and management of ET were originally published in 2010 (Harrison et al., 2010) and further modified in 2014 (Harrison et al., 2014) to include recommendations for additional mutational screening following the
identification of mutations with the CALR gene (Klampfl et al., 2013a; Nangalia et al., 2013; Rotunno et al., 2013a).
Recommendations for the investigation and management of PMF were published in 2012 (Reilly et al., 2012b), with an amended version released in 2014 (Reilly et al., 2014). As in the case of ET, the updated recommendations include screening for CALR gene mutations alongside updated clinical recommendations. A summary of the BCSH diagnostic guidelines for each of these disorders are shown in Table 1-9 to 1-11.
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JAK2-positive Polycythaemia Vera
A1 High haematocrit (52 in men, 48 in women) or raised red cell mass (>25% above predicted) *
A2 Mutation in JAK2
*DIAGNOSIS REQUIRES BOTH CRITERIA TO BE PRESENT
JAK2-negative Polycythaemia Vera
A1 Raised red cell mass (>25% above
predicted) or haematocrit >60 in men, >56 in women.
A2 Absence of mutation in JAK2
A3 No cause of secondary erythrocytosis
A4 Palpable splenomegaly
A5 Presence of an acquired genetic
abnormality (excluding bcr-abl) in the haematopoietic cells
B1 Thrombocytosis (platelet count
>450 × 109/l)
B2 Neutrophil leucocytosis (neutrophil
count > 10 × 109/l in non-smokers; >12.5 × 109/l in smokers)
B3 Radiological evidence of splenomegaly
B4 Endogenous erythroid colonies or low
serum erythropoietin
*DIAGNOSIS REQUIRES A1 + A2 + A3 + EITHER ANOTHER A OR TWO B CRITERIA
A1 Sustained platelet count >450 × 109/l
A2 Presence of an acquired pathogenetic mutation (e.g. in the JAK2, CALR or MPL genes)
A3
No other myeloid malignancy, especially PV, PMF, CML or MDS
A4 No reactive cause for thrombocytosis and normal iron stores
A5 Bone marrow aspirate and trephine biopsy showing increased megakaryocyte numbers displaying a spectrum of morphology with predominant large megakaryocytes with hyperlobated nuclei and abundant cytoplasm. Reticulin is generally not increased (grades 0–2/4 or grade 0/3)
*DIAGNOSIS REQUIRES A1–A3 OR A1 + A3–A5
Table 1-10. BCSH diagnostic criteria for ET(Harrison et al., 2014).
A1 Bone marrow fibrosis ≥3 (on 0–4 scale)
A2 Pathogenetic mutation (e.g. in JAK2, CALR or MPL), or absence of both BCR-ABL1 and reactive causes of bone marrow fibrosis
B1 Palpable splenomegaly
B2 Unexplained anaemia
B3 Leuco-erythroblastosis
B4 Tear-drop red cells
B5 Constitutional symptoms (drenching night sweats, weight loss >10% over 6 months, unexplained fever (>37·5°c) or diffuse bone pains).
B6 Histological evidence of extramedullary haematopoiesis
*DIAGNOSIS REQUIRES A1 + A2 AND ANY TWO B CRITERIA Table 1-11. BCSH diagnostic criteria for PMF (Reilly et al., 2014).
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1.5.3 Differences between classification systems
The most significant difference between the two groups is the emphasis placed upon bone marrow histology in the WHO classification (Arber et al., 2016). The
assessment of morphological features in the bone marrow is a major criterion in each of the classifications shown. Within the BCSH guidelines, bone marrow histology is a major criterion in the diagnosis of PMF, however, in the diagnosis of PV and ET, it may not be clinically indicated (Harrison et al., 2014; McMullin et al., 2007; Reilly et al., 2012a).
This difference, particularly in relation to the diagnosis of ET, has caused some controversy, as it does not allow for the diagnosis of so-called Pre-PMF, where all other features would mimic those seen in ET (Gisslinger et al., 2016). A large independent cohort study had been able to identify morphological subgroup with the histological features said to indicate Pre-PMF, although longitudinal analysis did not show any evidence of increased fibrotic transformation within those patients and the adverse clinical impact of the original finding could not be confirmed (Wilkins et al., 2008).
There are small differences in the full blood count thresholds set out by each group. Within the criteria for the diagnosis of PV, the WHO includes a raised haemoglobin, whereas it is not included in the BCSH guidelines (Arber et al., 2016; McMullin et al., 2007). Differences are also present in the threshold level of haematocrit in the two sets of guidelines (Arber et al., 2016; McMullin et al., 2007). Numerical thresholds are used within all of these guidelines; however, it should be noted that there is no reference within the guidelines as to the underlying statistical basis of these values.
1.5.4 The use of thresholds in diagnostic guidelines
The use of thresholds is commonplace within diagnostic criteria and disease scoring schemes. Within the wider diagnosis of myeloid malignancy, the use of arbitrary thresholds applied to parameters such as blast percentage can make the difference between a diagnosis of myelodysplastic syndrome (MDS) and acute myeloid
leukaemia (AML), albeit, a demonstrable clinical and outcome differences between a patient presenting with 19% blasts (MDS with excess blasts) versus 21% blasts (AML) has not been established (Lichtman, 2013).
Within the diagnosis of MPNs thresholds applied to laboratory parameters are equally vague. For example, the use of a platelet count threshold of 450 x 109/L reflects the upper limit of the recognised reference range. However, by definition, a reference range only encompasses 95% of the population and as such 2.5% of individuals will have a platelet count exceeding the upper value under normal circumstances. To date there are no published studies within the field of MPNs which systematically assess the probability of diagnosing an MPN with increasing laboratory and clinical parameters to establish the most appropriate threshold to use in diagnostic guidelines.
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